Application of Sulfonimidoyl-Substituted Allyltitanium(IV) Complexes to the Asymmetric
Synthesis of Alkenyloxiranes, 2,3-Dihydrofurans, Tetrahydrofurans, Unsaturated Proline Analogues
and Allylic Alcohols
Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-Westfälischen Technischen Hochschule Aachen zur Erlangung des
akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation
vorgelegt von
Surendra Babu Gadamsetty
aus Indien
Berichter: Universitätsprofessor Dr. H.-J. Gais
Universitätsprofessor Dr. M. Albrecht
Tag der mündlichen Prüfung: 23. Februar 2007
Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.
.
Dedicated to my Parents
Parts of this work have been published or submitted:
Asymmetric Synthesis of 2,3-Dihydrofurans and of Unsaturated Bicyclic
Tetrahydrofurans Through α-Elimination and Migratory Cyclization of Silyloxy
Alkenyl Aminosulfoxonium Salts. Generation and Intramolecular O,Si-Bond
Insertion of Chiral Disubstituted β-Silyloxy-AlkylideneCarbenes.……………………
H.-J. Gais, L. R. Reddy, G. S. Babu, G. Raabe, J. Am. Chem. Soc. 2004, 126,
4859-4864
Asymmetric Synthesis of Cycloalkenyl and Alkenyloxiranes From Allylic
Sulfoximines and Aldehydes and its Application to Solid-Phase Synthesis.
H.-J. Gais, G. S. Babu, M. Günter, P. Das, Eur. J. Org. Chem. 2004, 1464-1473
Dynamic Behavior of Chiral Sulfonimidoyl-Substituted Allyl andAlkyl Aminotitanium
Complexes: Metallotropic Shift, Reversible β-Hydride Elimination, and Ab Intio
Calculations of Allyl and Alkyl Aminosulfoxonium Ylides.
H.-J. Gais, P. Bruns, G. Raabe, R. Hainz, M. Schleusner, S. B. Gadamsetty, J.
Runsink, J. Am. Chem. Soc. 2005, 127, 6617-6631.
Functionalized Chiral Vinyl Aminosulfoxinium Salts: Asymmetric Synthesis and
Application to the Synthesis of Enantiopure Unsaturated Prolines, β,γ-Dehydro
AminoAcidsandCyclopentanoidKetoAminosulfoxiniumYlides.
S. Tiwar, H. -J. Gais, A. Lindenmaier, S. B. Gadamsetti, G. Raabe, L. R. Reddy, F.
Köhler, M. Günter, S. Koep, V. B. Iska, J. Am. Chem. Soc. 2006, 128, 7360-7373
The work here reported has been carried out at the Institut für Organische Chemie
der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-
Westfälischen Technischen Hochschule Aachen under the supervision of Prof. Dr.
H.-J. Gais between January 2001 and August 2005.
I would like to express my deep sense of gratitude to my teacher Prof. Dr. H-
J.Gais, for his inspiring guidance, and encouragement and for providing inordinate
freedom in the lab. Working with him has been a memorable experience. Many
stimulating discussions we have had have left a deep impression in my mind and I
shall always cherish these memories.
It is my pleasure to extend my heartfelt thanks to all my lab colleagues. I thank all
the non-teaching staff of the Department and particularly I wish to thank Frau C.
Vermeeren, Frau U. Ripkens for their help.
Contents I
Contents
A. THEORETICAL PART………………………………………………………………..1 1 Asymmetric Synthesis of Cycloalkeny and UAlkenyloxiranes from Allylic
Sulfoximines and Aldehydes……………………………………………………….U4 U1.1U UIntroduction U…………………………………………………………………..4
U1.1.1U UBrief introduction about relevant biologically-active molecules U .......... 4 U1.1.2U UApproaches towards the construction of Alkenyloxirane moiety U ........ 5
U1.2U UPresent workU…………………………………………………………………8 U1.2.1U UAim U .................................................................................................... 8 U1.2.2U UResults and DiscussionU ................................................................... 10
U1.2.2.1 Retro synthetic analysisU ................................................................. 10 U1.2.2.2 Asymmetric synthesis of cycloalkenyloxiranes.U .......................... 11 U1.2.2.3U USubstitution of sulfoximine-substituted homoallylic alcohols U ........ 12 U1.2.2.4 Asymmetric Synthesis of AlkenyloxiranesU .................................. 15 U1.2.2.5 Mechanistic Consideration of the Cl substitution of Sulfoximines U
................................................................................................................... 17 1.2.2.6 Recycling of the Chiral Auxillary…………………………………. 20
U1.3U UConclusion…………………………………………………………………. U21 U2U UAsymmetric Synthesis of 2,3-Dihydrofurans and of Unsaturated Bicyclic
Tetrahydrofurans…………………………………………………………………… U24 U2.1U U Introduction U ........................................................................... 24
U2.1.1 Brief introduction about relevant biologically-active molecules U ........... 24 U2.1.2U UApproaches towards the construction of dihydrofuran moietyU ........ 26
U2.2U UPresent WorkU ......................................................................... 27 U2.2.1U UAim U .................................................................................................. 27 U2.2.2 Results and DiscussionsU .................................................................. 30
2.2.2.1 Retrosynthetic analysis.............................................................. U2.2.2.2 Hydroxyalkylation of acyclic allyl sulfoximines U ............................ 31 U2.2.2.3 Hydroxy alkylation of the cyclic allyl sulfoximines U ....................... 33 U2.2.2.4 Synthesis of 2,3-dihydrofuransU ................................................... 34 U2.2.2.5 Synthesis of Bicyclic 2,3-DihydrofuransU ...................................... 35 U2.2.2.6 Mechanistic Considerations for 2,3-Dihydrofuran formation U ....... 36 U2.2.2.7 Synthesis of Unsaturated Bicyclic TetrahydrofuransU .................. 38 U2.2.2.8 Mechanistic Considerations U ........................................................ 40 U2.2.2.9 Recycling of the Chiral Auxillary ................................................. 41
U2.3U UConclusion U ............................................................................. 42 3 Asymmetric Synthesis of Acyclic, Mono-and Bicyclic γ,δ-Unsaturated
α-Amino acids by employing ClTi(NE2)3…………………………………..45 U3.1U UIntroduction U ............................................... ……………………45
U3.1.1U UBrief introduction about relavant biologically-active molecules U ........ 45 U3.1.2U UApproaches towards the construction of Proline derivatives. U .......... 48
3.2 Present Work.....................................................................................51 U3.2.2U U Results and Discussion .U .............................................................. 51
U3.2.2.1 Reterosynthetic Aproach U ............................................................ 51 U3.2.2.2 Synthesis of acyclic allylic sulfoximinesU ...................................... 52
Contents II
U3.2.2.3 Synthesis of cyclic allylic sulfoximinesU ........................................ 53 U3.2.2.4 Synthesis of the N-Bus protected α-IminoesterU .......................... 53 U3.2.2.5 Addition to α-Imino ester U ............................................................ 57 U3.2.2.6U UStereochemical consideration of the amino alkylation..................U 61 U3.2.2.7 Substitution of sulfoximine group by chlorine atom U .................... 63 U3.2.2.8 Synthesis of Proline analogoues U ................ ......... ........ 63 3.2.2.9 Cyclization of the Sulfoxonium Salts with LDA..... .................. 65
U3.3U UConclusion U ............................................................................. 67
U4. Cu-catalyzed stereoselective synthesis of Allylic Alcohols……………..U70 U4.1 Introduction……………………………………………………………………..U70
U4.1.1 Brief introduction about relevant biologically-active molecules.............U70 U4.1.2 Approaches towards the construction of allylic alcoholsU .................... 71
U4.2U UPresent WorkU ..................................................................... …73 U4.2.1 AimU ....................................................................................................... 73 U4.2.2 Results and DiscussionU .................................................................. 74
U4.2.2.1 Retero synthetic analysisU ............................................................ 74 U4.2.2.2 Hydroxy alkylation of allylic sulfoximinesU .................................... 75 U4.2.2.3 Substitution of Sulfoximine Substituted homoallylic alcohols…. U 77 U4.2.2.4 Absolute Configuration of the Allylic alcohol derivativeU ............... 78 U4.2.2.5 Mechanistic Considerations U ........................................................ 79
U4.3U UConclusion U ............................................................................. 82 UB. U UExperimental PartU ............................................................................................ 85 U5U UExperimental SectionU....................................................................................... 85
U5.1U UGeneral RemarksU ................................................................... 85 U5.2U UAnalytic U ................................................................................... 85 U5.3U U General proceduresU .............................................................. 87
U5.3.1U UGeneral procedure for the Substitution of Sulfoximine-Substituted Homoallylic Alcohols (GP1) U ............................................................................ 87 U5.3.2U UGeneral procedure for the Elimination of Alkenyl/Cycloalkenyl Chlorohydrins (GP2)U ...................................................................................... 87 U5.3.3U UGeneral Procedure for the Synthesis of Silylated Homoallylic Alcohols (GP3) U ............................................................................................... 88 U5.3.4U UGeneral Procedure for the Synthesis of Dihydrofurans (GP4) U ......... 88 U5.3.5U UGeneral Procedure for the Synthesis of Bicyclic-tetrahydrofurans (GP5)......U ....................................................................................................... 89 U5.3.6U UGeneral procedure for the synthesis of Sulfoximine substituted Amino Acids (GP6)U ........................................................................................ 89 U5.3.7U UGeneral procedure for the Synthesis of allylic alcohols (GP7) U ........ 90
5.4 Synthesis of Allylic Sulfoximine........................................................90 5.4.1 Synthesis of (S,E)-N-methyl-S-(4,2-dimethyl-2-pentenyl)-S- phenylsulfoximine and (S,Z)-N-methyl-S-(4,2-dimethyl-2-pentenyl)-S-phenylsulfoximine (E-58a and Z-58a)……………………………………………90 U5.4.2U USynthesis of (S,E)-N-methyl-S-(4,2-dimethyl-2-pentenyl)-S- ethyllsulfoximine and (S,Z)-N-methyl-S-(4,2-dimethyl-2-pentenyl)-S-ethylsulfoximine (E-109c and Z-109c). U .......................................................... 94
U5.5U U Synthesis of Syn-configurated Homoallylic Alcohols ........... 97 U5.5.1U U(1R,2R)-2-(Cyclohept-1-enyl)-2-[ (S)-N-methyl-S-phenylsulfonimidoyl]-1-phenylethanol (11c).. U ................................................. 97
Contents III
U5.5.2 Synthesis of (+)-(E)-(3R,4R,Ss)-4-(N-methyl-S- phenylsulfonimidoy)-2,6-dimethyl-oct-5-en-3-ol (2c) .U ..................................................................... 98
U5.6U U Synthesis of Alkenyl/Cycloalkenyl Chlorohydrines. U ............. 100 U5.6.1 Synthesis of (-)-(1R,2R)-2-Chloro-2-(cyclohex-1-enyl)-1-phenylethanol (21a).U 100 U5.6.2U USynthesis of (-)-(1R,2R)-1-Chloro-1-(cyclohex-1-enyl)-3-methylbutan-2-ol (21b) .U ................................................................................................... 101 5.6.3 Synthesis of (-)-(1R,2R)-2-Chloro-2-(cyclohept-1-enyl)-1-phenylethanol (21c)......................................................................................100 U5.6.4U U(1R, 2S)- and (1R,2R)-2-Chloro-5-methyl-1-phenylhex-3-en-1-ol (anti-23a and syn-23a) .U ............................................................................... 103 U5.6.5U USynthesis of (1R,2S)-and (1R,2R)-2-Chloro-4-cyclohexyl-1-phenylbut-3-en-1-ol (anti-23b and syn-23b) U ................................................. 104
U5.7 Synthesis of Cyclo/Alkenyloxiranes U ........................................ 105 U5.7.1U U(2S,3R)-2-(Cyclohex-1-enyl)-3-phenyloxirane (22a).U ..................... 105 U5.7.2U U(2S,3R)-2-(Cyclohex-1-enyl)-3-isopropyloxirane (22b).U ................. 106 U5.7.3 U U(2S,3R)-2-(Cyclohept-1-enyl)-3-phenyloxirane (22c).U .................... 107 U5.7.4 Synthesis of (3R,2R) and (3R,2S)-2-(3-Methylbut-1-enyl)-3-phenyl.oxirane (trans-24a and cis-24a).U ....................................................... 108 U5.7.5 Synthesis of (3R,2R)- and (3R,2S)-2-(2-Cyclohexylvinyl)- 3 - . phenyloxirane (trans-24b and cis-24b) U ........................................................ 110 U5.7.6 Synthesis of the Alkenyloxirane trans-24b and cis-24b from UZU-25bU 111 U5.7.7 Synthesis of the Alkenyloxiranes trans-24a and cis-24a from Z-25aU. 112
U5.7.8U USulfinamide (29a) U ............................................. 114 U5.8 Synthesis of Silylated Homoallylic Alcohols. U .......................................... 115
U5.8.1 (+)-Triethyl-[(Z)-(1R,2R)-1,2-diphenyl-3-methyl-4-[(S)-N-methyl-S- phenyl- sulfonimidoyl]-but-3-enyloxy]silane(50c). U ........................................ 115 U5.8.2U USynthesis of (+)-Triethyl-[(Z)-(1R,2R)-2-phenyl-3-methyl-4-[(S)-N-methyl-S-phenyl-sulfonimidoyl]-1-(4-methoxyphenyl)-but-3-enyloxy]silane (50d)......U ...................................................................................................... 116 U5.8.3 Synthesis of (-)-(S)-N,N-Dimethylamino-S-[(Z)-(3R,4R)-2-methyl-3-phenyl-(4-methoxyphenyl)-4-(triethylsilyl)oxy]but-enyl-phenyl-sulfoxinium tetrafluroborate (49d)U ................................................................................... 117 U5.8.4U USynthesis of (-)-Triethyl-[(Z)-(1R,2R)-2-Isopropyl-3-methyl-4-[(S)-N-methyl-S-phenyl-sulfonimidoyl]-1-phenyl-but-3-enyloxy]silane( 50a) U ........... 118 U5.8.5U USynthesis of (−)-Triethyl-[(Z)-(1R,2R)-2-Isopropyl-3-methyl-4-[(S)-N-methyl-S-phenyl-sulfonimidoyl]-1-(4-methoxyphenyl)-but-3-enyloxy] silane (50b)......U ...................................................................................................... 119 U5.8.6U USynthesis of (−)-Triethyl-[(Z)-(αR,1R)-α-(4-methoxyphenyl)-2-{[(S)-N-methyl-S-phenyl-sulfonimidoyl]-methene}-cyclohexane-methane-α-enyloxy]silane (54a). U .................................................................................... 121 U5.8.7U USynthesis of (-)-Triethyl-[(Z)-(αR,1R)-α-(4-methoxyphenyl)-2-{[(S)-N-methyl-S-phenyl-sulfonimidoyl]-methene}-cyclooctane-methane-α-enyloxy]silane (ent-54c) U ............................................................................... 122 U5.8.8U USynthese von (Z,SS,2S,3R)-N,N-Dimethylamino-S-(2-(ethoxycarbonyl-(2-methyl-propan-2-sulfonylamino)-methyl)-cyclooctylidenmethyl)-phenylsulfoxonium-tetrafluoroborat (ent-53c) U ........... 124
U5.9U U Synthesis of Monocyclic/Bicyclic 2,3-DihydrofuransU .......... 125
Contents IV
U5.9.1U USynthesis of (−)-(4R,5R)-Triethyl-(3-methyl-4,5-diphenyl-4,5-dihydro-furan-2-yl)-silane (45c) U ................................................................................. 125 U5.9.2U USynthesis of (−)-(4R,5R)-Triethyl-(4-isopropyl-3-methyl-5-phenyl-4,5-dihydro-furan-2-yl)-silane (45a) U .................................................................... 126 U5.9.3U USynthesis of (−)-(4R,5R)-Triethyl-(4-isopropyl-3-methyl-5-(4-methoxy-phenyl)-4,5-dihydro-furan-2-yl)-silane (45b) U .................................. 127 U5.9.4 U USynthesis of (−)-(4R,5R)-Triethyl-(3-(4-methoxy-phenyl)-3,3a,4,5,6,7,8,9-heptahydro-isobenzofuran-1-yl)-silane (ent-51c)U ............... 128
U5.10 Synthesis of Bicyclic TetrahydrofuransU .................................... 129 U5.10.1 Synthesis of (−)-(3R,3aR)-(3-(4-methoxy-phenyl)-1,3,3a,4,5,6-hexahydro-isobenzofuran(56a) U .................................................................... 129 U5.10.2 (−)-(3R,3aR)-3-(4-methoxy-phenyl)-3,3a,4,5,6,7-hexahydro-1H-cyclohepta[c]furan (56b).U ............................................................................. 130 U5.10.3 Synthesis of (−)-(3R,3aR)-3-(4-methoxy-phenyl)-1,3,3a,4,5,6,7,8- octahydro-1H-cycloocta[c]furan (ent-56c).U ................................................... 132
U5.11 Synthesis of Amino acid derivativesU ........................................ 133 U5.11.1 Synthesis of (+)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-(2-(N-methyl-S- phenyl- sulfonimidoyl-methylene)-cycloheptyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82c and E-83c) U .......................... 133 U5.11.2 Synthesis of (+)-(E,Ss,2R,3S)- and (−)-(E,Ss,2S,3R)-(2-(N-methyl-S-phenyl-sulfonimidoyl-methylene)-cyclooctyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82d and E-83d) U .......................... 136 U5.11.3 Synthesis of (+)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-(2-(N-methyl-S- phenyl-sulfonimidoyl-methylene)-cyclohexyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82b and E-83b).U ......................... 138 U5.11.4 Synthesis of (+)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)- (2-(N-methyl-S-phenyl-sulfonimidoyl-methylene)-cyclopentyl)-(2-methylpropane-2-sulfonylamino)-Acetic Acid Ethyl Ester (E-82a and E-83a).U ......................... 140 U5.11.5 Synthesis of(−)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-5-(N-methyl-S- phenyl-sulfonimidoyl)-3-cyclohexyl-2-(2-methylpropane-2-sulfonylamino)-pent- 4-enoic Acid Ethyl Ester (E-86b and E-87b ).U .............................................. 143 U5.11.6 Synthesis of (−)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-5-(N-methyl-S-phenyl-sulfonimidoyl)-3-isopropyl-2-(2-methylpropane-2-sulfonylamino)-pent-4-enoic Acid Ethyl Ester (E-86a and E-87a) U ................................................. 145 U5.11.7U USynthesis of (2-Chloromethyl-cyclohex-1-enyl)-(2-methyl-propane-2-sulfonylamino)-acetic acid ethyl ester (99)U ................................................... 147 U5.11.8 Synthesis of 2-(2-Methyl-propane-2-sulfonyl)-2,3,4,5,6,7-hexahydro- 1H-isoindole-1-carboxylic acid ethyl ester (100). U ......................................... 149
5.12 Synthesis of Allylic Alcohol derivatives………………………………….146 U5.12.1U USynthesis of (−)-(E)-(1S,4S)-4-Cyclohexyl-1-phenyl-oct-2en-1-ol (112)......U ....................................................................................................... 151 U5.12.2U U Synthesis of (+)-(E)-(3R,6S)-6-Ethyl-2,6-dimethyl-dec-4-en-3-ol (113)......U ....................................................................................................... 152 U5.12.3U USynthesis of (+)-(1R,2S)-2-[2-Butyl-cyclohex-(E)-ylidene]-1-nyl- phenyl-ethanol (114) U .................................................................................... 153
U6U UCrystal Structure AnalysisU ............................................................................ 155 U6.1U UCrystal structure of (+)-(E,Ss,2R,3S)-2-(N-methyl-S-phenyl-sulfonimidoyl-methylene)-cycloheptyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82c) U ...................................................................................... 155
Contents V
U6.2U Crystal structure of U(−)-(3R,3aR)-3-(4-methoxy-phenyl)-3,3a,4,5,6,7-hexahydro-1H- cyclohepta[c]furan (56b).U ......................................... 160 U6.3U Crystal structureU of (−)-(3R,3aR)-3-(4-methoxy-phenyl)- 1,3,3a,4,5,6,7,8-octahydro-1H-cycloocta[c]furan (ent-56c).U ......................................... 164
U7U UReferences U ...................................................................................................... 168
Abbreviations VI
List of Abbreviations
AAA α-Amino acid
Ac Acetyl
ACE Angiotensin-converting enzyme
Anal. Analysis
aq. Aqueous
BUS tert-Butyl-sulfonyl
Calcd. Calculated
D Doublet
Dd Doublet of doublet
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
de Diastreomericexcess
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
Dopa 3,4-dihydroxyphenylalanine
ee Enantiomericexcess
EE Ethylacetate
Et Ethyl
Eq. Equation
Gm Gram(s)
GC Gaschromatography
H Hour(s)
HRMS High-resolution mass spectrum
Hz Hertz
IR Infrared
J Coupling constant
LDA Lithium diisopropylamide
MeLi Methyllithium
M Multiplet
M Mole
mg Milligram(s)
min Minute(s)
Abbreviations VII
Ml Milli liter
mmol Milli mole
mp Melting point
n-BuLi n-Butyllithium
NMR Nuclear magnetic resonance
Ph Phenyl
ppm Parts per million
Pr Propyl
Q Quartet
RCM Ring-closing metathesis
Rt Room temperature
S Singlet
T Triplet
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin-layer chromatography TMS Trimethylsilyl UV Ultraviolet
.
THEORETICAL PART 1
A. THEORETICAL PART General Introduction Since the discovery of the sulfonimidoyl-group in (2S,5S)-methionine-sulfoximine
(Figure 1) around the 50s of last century1, the sulfoximine group has been proven
to be a versatile building block in organic synthesis.2 When Whitehead and
Bentley discovered that the sulfoximine of methionine is the agent responsible for
the toxicity of wheat flour treated with nitrogen trichloride,3 such treatment had
been widely practaised for many years. The sulfoximine has wider applications as
a chiral auxiliary4 and also as catalysts in asymmetric synthesis.5,6
O
SNH
CH3
OH
NH2
O Figure 1: (2S,5S)-Methionine-Sulfoximine.
Their uncommon versatility originates mainly from the endowment of the
sulfonymodyl group with an almost unique combination of the features, namely
chirality, carbanion stabilization, nucleofugacity, basisity, nucleophilicity and low
redox potential7 (Figure 2).
H3CS N
H
Onucleophilic und basic
asymmetric sulfur
acidic hydrogens
acidic hydrogens
Figure 2: The (S)-S-Methyl-S-phenylsulfoximin functional group.
Chiral allyltitanium complexes have emerged as valuable reagents for the
enantioselective allylation of aldehydes and imines.8,9 Particularly useful are allyl
titanium complexes that carry a hetero-atom substituent since they allow the
transfer of both an allyl moiety and a functional group, amenable to further
THEORETICAL PART 2
synthetic transformations. The most versatile use of complexes type I9c has been
shown by Hoppe et al. Other useful examples of type II has been developed by
Reggelin et al. (Figure 3).8f
R1 O
TiX3O
NR2
I II
R1 S
O
N
pTol
TiX3
Ph
CH3
*
R1 = R2 = Me, i-Pr, Bu; X = O-i-Pr, NEt2
*
*
Figure 3: Allyltitanium complexes of Hoppe et el. and Reggelin et al.
Noteworthy examples are the sulfonimidoyl-substituted allyl titanium(IV)
complexes IV and V10 (Figure 3), which have found application in the asymmetric
synthesis of a number of compounds including γ,δ-unsaturated α-amino acids,11a
bicyclic α-amino acids,11b,c γ-hydroxy β-aminoacids,11d,e homopropragylic
alcohols,11h homoallyl alcohols and unsaturated prolines. 11i
Figure 4: Applications of sulfonimidoyl substituted allyltitanium (IV) complexes.
N
EtO2CR
BusN
EtO2CR
Bus
R S
O
NCH3
Ph
Ti(NEt2)3
S
O
NCH3
PhR
III
R
SH3CN
OPh
R1
OH
SPh
NMeO
R
NHBus
EtO2C
IV
VI
VII
XXI
S
ONCH3
PhR
R1
OH
R
Nu
R1
OH
VIII
V
R S
O
NCH3
Ph
Ti(Oi-Pr)2
R1
R
Et3SiO H
XII
SPh
NMeO
R
NHBus
EtO2C
XI
XIII
2. 2 eq. ClTi(Oi-Pr)3
1. n-BuLi
2. ClTi(N
Et 2) 3
αγ
+ XI
1. n-BuLi
Aldehydeα-Iminiester
α-IminiesterAldehyde
2
THEORETICAL PART 3
CHAPTER 1
Asymmetric Synthesis of Cycloalkenyl and
Alkenyloxiranes from Allylic Sulfoximines and Aldehydes
.
THEORETICAL PART 4
1 Asymmetric Synthesis of Cycloalkenyl and Alkenyloxiranes from Allylic Sulfoximines and Aldehydes
1.1 Introduction 1.1.1 Brief introduction about relevant biologically-active
molecules
During the last decade alkenyloxiranes have been recognized as valuable
intermediates in organic synthesis.12,13 Alkenyloxiranes undergo a number of
useful transformations which include reactions with nucleophiles and Lewis acid
mediated rearrangements. Of central importance is the possibility to individually
manipulate each of the four carbon centers of an alkenyloxirane (Figure 5) by a
proper choice of reagents or reagent combinations.14
Figure 5: Alkenyloxiranes and Cycloalkenyloxiranes.
Many natural products that embody the vinyloxirane moiety often possess
remarkably high biological activity. The eicosanoid-derived algal pheromones
lamoxirene and caudoxirene (Figure 6), for example, trigger mass release of
spermatozoids from their gametangia down to threshold concentrations ranging
from 30-50 pM in seawater.15 Other eicosanoid-derived alkenyloxiranes were
identified as important intermediates in the biosynthesis of leukotrienes and other
oxylipins.16 The macrocyclic lactones (Figure 6) have attracted considerable
attention since they appear to be promising chemotherapeutic agents for the
treatment of various diseases.17
O R3R2
R1
R 1 = c C6H11, i-Pr, R2 = H, R
1+R2 = (CH2)4, (CH2)5
THEORETICAL PART 5
Figure 6: Chemotherapeutic agents.
Compounds such as (−)-carbovir, tylactone and allo-pumiliotoxin, which show
antibiotic activity, have been synthesized from alkenyloxiranes (Figure 7).18
Figure 7: Antibiotics.
1.1.2 Approaches towards the construction of the alkenyloxirane moiety Asymmetric syntheses of alkenyloxiranes have been accomplished by several
methods, including (1) epoxidation of allylic alcohols in combination with an
oxidation and olefination (Sharpless-Swern-Wittig), (2) epoxidation of dienes
(Jacobsen method), (3) chloroallylation of aldehydes in combination with 1,2-
elimination (Oehlschlager method), and (4) reactions between S-ylides and
aldehydes (Metzner method). Each of these methods will be briefly discussed
below.
OO
O
O
O
O
OCOOH
O
O
O
OO OOH
O O
OH
OH
HOOC
Macrocyclic lactones
Leukotriene Lamoxirane Caudoxirane
NH
NN
N
O
NH2HO
(-)-Carbovir
O
O
O
Tylactone
N
H3C OHOH
Allo-Pumiliotoxin
THEORETICAL PART 6
Sharpless-Swern-Wittig approach Marshall et al. have reported a method for the synthesis of alkenyloxiranes based
on an enantioselective Sharpless epoxidation of the allylic alcohol 2, followed by a
Swern oxidation in combination with a Wittig olefination (Scheme 1).12a Though the
method is well suited for the preparation of alkenyloxiranes, it is difficult to extend
the method to the generation of cycloalkenyloxiranes.
Scheme 1: Sharpless-Swern-Wittig route. Jacobsen approach An efficient asymmetric synthesis of alkenyloxiranes was reported by Jacobsen et
al. in 1990. The method is based on the oxidation of conjugated Z, E dienes by
using a Mn(salen)-complex (Scheme 2).19 The synthesis of cycloalkenyloxiranes
by this method has not been described.
Ph3P=CHCO2EtSwern Oxidation
BnOOH
BnOOO
BnOOH
BnOO
CO2Et
BnOOH
O
1. Swern Oxidation2. Ph3P=C(Me)CO2Me3. DIBAH
SharplessEpoxidierung
1 2 3
4 5
THEORETICAL PART 7
OH / H2O2
Cl BR2
O
HR1
R1
OH
Cl
R1
OBR2 = 9-BBN or BIpc2
ethanolamine
K2CO3 / MeOH92-99 %75-98 % ee
65 - 85 %76-98 % ee
cis : trans > 96 : 4
Scheme 2: Epoxidation of conjugated Z, E-dienes. Oehlschlager approach Oehlschlager et al. have reported an improved route for the synthesis of
alkenyloxiranes via the chloroallylboration of aldehydes in combination with an 1,2-
elimination (Scheme 3).20 The synthesis of cycloalkenyloxiranes by this method
has not been described.
Scheme 3: Allylboration of adehydes in combination with 1, 2-elimination.
EtO2C n-C5H9
n-C6H13 Me
EtO2COTBDMS
n-C5H9HO
CO2Et
OMn
N
O
N
Cl t-Bu
t-But-Bu
t-Bu
HH
Mn(salen) (A)
n-C6H13 OMe
OHCO
n-C5H9
CO2Et
O
EtO2CO
n-C5H9
EtO2CO
OTBDMS
81 %; 87 % ee
50 %; 92 % ee
58 %; 83 % ee
16 %; 83 % ee
58 %; 77 % ee
NaOCl / A
NaOCl / A
NaOCl / A
NaOCl / A
NaOCl / A
trans : cis = 9.0 : 1
trans : cis = 1.1 : 1
trans : cis = 7.3 : 1
trans : cis = 2.3 : 1
THEORETICAL PART 8
SR2R1
I R3
R4ArCHO
NaOH
O
ArR4
R3
O
ArR4
R3
+ + +
trans/cis : 2.2-50 : 1
R1 = Me R3 = H, Me
R2 = Me R4 = H, Ph
R3 + R4 = (CH2)464-85%, 90% ee
tBuOH, H2O
9:1
SPh
NMeOR
SPh
NMeOR
Ti(NEt2)3
SPh
NMeOR
HO R'
1. nBuLi2. ClTi(NEt2)3
R'CHO-78°C, THF
6 7 8
R = cC6H11, i-Pr R' = Ph, i-Pr 98% de
Metzner approach In 2002, Metzner et al. have reported a novel method for the synthesis of
alkenyloxiranes by the reaction of S-ylides with aldehydes. The required S-ylides
were obtained from allyl halides and chiral sulfides (Scheme 4).21The extension of
this method to the synthesis of cycloalkenyloxiranes was not successful in terms of
ee and de values.
Scheme 4: Reactions between S-ylides and aldehydes. 1.2 Present work
1.2.1 Aim As illustrated in the earlier section, chiral alkenyloxiranes are valuable
intermediates in organic synthesis. In 2000, Hainz and Bruns, former members of
our research group disclosed a method for the regio- and stereoselective
hydroxyalkylation of allylic sulfoximines (6) with aldehydes leading to the formation
of the syn-configurated β-N-methylsulfonimidoyl-substitued homoallylic alcohols
8.11f Thus, titanation of the lithiated allylic sulfoximines of type 6 with ClTi(NEt2)3
afforded the corresponding mono(2-alkenyl)tris(diethylamino) titaninum (IV)
complexes 7 which reacted with aldehydes, with moderate to high
regioselectivities and high diastereoselectivities, preferentially at the α-position to
give the corresponding syn-configured β-N-methylsulfonimidoyl-substituted
homoallylic alcohols 8 in good yields (Scheme 5).
Scheme 5: Hydroxyalkylation of acyclic allylic sulfoximines.
THEORETICAL PART 9
S
OH
R3
R2R1
OPhNMe
S
R2R1
OPhNMe
O R3R2
R1
ClCO2CH(Cl)Me
Me3OBF4 S
OH
R3
R2R1
OPhNMe2 BF4
Cl
OH
R3
R2R1
Base
12 13
14
15
16
Hainz and Bruns also extended this method to the synthesis of cyclic allylic
sulfoximines. Thus, the cyclic allylic sulfoximine 9 reacted with aldehydes at the α-
position to yield the corresponding allylic sulfoximines 11 (Scheme 6).
Scheme 6: Hydroxyalkylation of cyclic allylic sulfoximines.
A facile Cl-substitution of the sulfoximine group of S-alkylsulfoximines (12) with
chloroformate has been observed by R. Loo, a former member of our group.
Furthermore it was observed that substitution of the sulfoximine group of 13
occurred much more rapidly than to compound 12, generating compound 14.22
Additionally, it was anticipated that sulfoximine 13 upon treatment with Meerwein
salt would convert the sulfoximine group into a very good leaving group. Indeed,
upon exposure of 14, 15 to a base, intramolecular nucleophilic attack by the vicinal
hydroxyl group should furnish the alkenyloxirane 16 (Scheme 7).
Scheme 7: Synthesis of cycloalkenyl and alkenyloxiranes.
A further stimulus for the perusal of this route is its potential for an application to
solid-phase synthesis which was described by M.Günter, a former member of our
group whose synthetic strategy is shown in Scheme 8.23
SPh
NMeO SPh
NMeO
Ti(NEt2)3
SPh
NMeO
HO Ph
1. nBuLi2. ClTi(NEt2)3
PhCHO-78°C, THF
9 10 11
98% de
THEORETICAL PART 10
PSPS
PS
PhS
ON
HO Ph
PS
HO Ph
Cl
PhO
PhS
CH3
ON
PhS
ON
PS
PhS
ON
HO Ph
Me
PhS
ON
HO Ph
PhS
OHNPS Cl
Me3OBF4
ClCO2CH(Cl)MeMe
PS
BF4
PhS
ONoder
AEI-Route
oderBase
1. n-Butyllithium2. ClTi(NEt2)33. PhCHO
Scheme 8: Solid-phase synthesis of alkenyloxiranes.
Due to their immense synthetic and biological importance, alkenyloxiranes have
become the topic of intensive research activity by various research groups.19-21
Owing to the prominence of the latter compounds, we undertook a project towards
the development of a method for the synthesis of alkenyloxiranes (Scheme 9).
1.2.2 Results and Discussion 1.2.2.1 Retrosynthetic analysis As illustrated in the foregoing section, alkenyloxiranes are interesting targets and
their asymmetric synthesis has been accomplished by several methods. Although
some of these methods are very efficient for the synthesis of alkenyloxiranes, they
are not so well suited for the attainment of cycloalkenyloxiranes 16. We therefore
focused our interest in the asymmetric synthesis of both alkenyl and
cycloalkenyloxiranes from aldehydes and allylic sulfoximines (Scheme 9).24
THEORETICAL PART 11
Scheme 9: Retrosynthetic analysis.
The alkenyloxiranes (16) were realised from the corresponding chlorohydrins (14)
which in turn can be derived from 13 by substitution with chlorine atom. The
sulfoximine (13) can be derived from the allylic sulfoximine (12) whose synthesis
has been reported by our group recently.11f
1.2.2.2 Asymmetric synthesis of cycloalkenyloxiranes. The synthesis commenced with the preparation of cyclic allylic sulfoximines. The
known cyclic allylic sulfoximines 9a and 9b were prepared in a one-pot synthetic
operation without the isolation of intermediates from chiral N-methyl sulfoximine
and the corresponding cycloalkanones by the inverse Peterson-olefination and
isomerization sequence described previously.25
Scheme 10: Synthesis of cyclic allylic sulfoximine.
Treatment of the six-membered cyclic allylic sulfoximine 9a in diethyl ether at −78
°C with 1.1 eq. of n-BuLi resulted in the lithiated sulfoximine which was
subsequently transmetalated to the corresponding titanium complex with 1.2 eq. of
ClTi(NEt2)3. The allyl titanium complex was intercepted with various aldehydes
including benzaldehyde and isobutyraldehyde at −78 °C, forming the
diastereomerically-pure syn-configured, sulfoximine-substituted, homoallylic
alcohols 11a and 11b with a good yields.11f Similarly, the new diastereomerically
O R3R2
R1 Cl
OH
R3
R2R1
S
OH
R3
R2R1
OPhNMe
S
R2R1
OPhNMe
16 14 13 12
SPh
O NMe
n
9a: n = 19b: n = 2
1. n-BuLi, THF2. cycloalkanone
3. ClSiMe34. n-BuLi5. NaOMe
MeS
Ph
O NMe
THEORETICAL PART 12
pure seven-membered homoallylic alcohol 11c was obtained in 70% yield and
≥98% de from the allylic sulfoximine 9b and benzaldehyde. A 1H NMR
spectroscopic analysis of the crude reaction product showed the hydroxyalkylation
to be highly diastereoselective (≥95% de) and regioselective (Scheme 11).
Scheme 11: Hydroxyalkylation of cyclic allylic sulfoximine.
1.2.2.3 Substitution of sulfoximine-substituted homoallylic alcohols As described previously,23we envisaged that the sulfoximine group of the
homoallylic alcohols could be replaced and activated by two methods, as shown in
Scheme 12.
Scheme 12: Proposed synthesis of cycloalkenyloxiranes.
It is described in the literature that the activation of 11 can be achieved through
the methylation of the N-methyl sulfoximine group with Me3OBF4 to afford the
corresponding (dimethylamino)sulfoxonium salts23. Hence based on the earlier
literature for the activation, our initial attempt towards the generation of
cycloalkenyloxiranes is proposed in Scheme 13. Sulfoximine 11a was treated with
SNMe
PhO
SNMe
PhOTi(NEt2)3
SNMe
PhO
OH
R
1. nBuLi, ether, -78 °C2. ClTi(NEt2)3, 25 °C
9a: n = 19b: n = 2
11a: n = 1, R = Ph (66%, 98% de)11b: n = 1. R = iPr (57%, 98% de)11c: n = 2, R = Ph (70%, 98% de)
*RCHO, -78°C
n n n
ClCO2CH(Cl)Me
S
OH
ROPh
NMe
Me3OBF4 S
OH
ROPh
NMe2 BF4
Cl
OH
R
O RBase
n
n
n
n
11a-c
21a-c
17a-c
22a-c
a: R = Ph, n = 1b: R = i-Pr, n = 1c: R = Ph, n = 2
THEORETICAL PART 13
S
OH
PhOPh
NMe
Me3OBF4
CH2Cl2
S
OH
PhOPh
NMe2 BF4
OH OH CHO
Ph
11a 17 18 19 20
-H
Me3OBF4 to obtain the (dimethylamino)sulfoxonium salt. To our surprise aldehyde
20 was isolated instead of obtaining the sulfoximine salt.
Scheme 13: Synthesis of aldehyde.
Formation of 20 could be explained as follows: methylation of 11a with Meerwein
salt results in the formation of the aminosulfoxonium salt 17, which suffers a
solvolysis to form the allyl cation 18. Attack by the phenyl group results in the
phenonium ion 19 which undergoes a rearrangement and a proton-loss to give
aldehyde 20 (Scheme 14).
Scheme 14: Mechanism for aldehyde formation.
Since the synthesis of 22a via the sulfoxonium salt could not be accomplished, we
tried to do the chlorine substitution of 11a-c by using 1.2 to 1.3 eq. of
ClCO2CH(Cl)Me at room temperature in DCM. Accordingly, the corresponding
chlorohydrins 21a-c, respectively, were afforded each in ≥98% de and in 85-88%
yields. In addition, sulfinamide 29a was also isolated in 94% yield (Scheme 15).
S
OH
PhOPh
NMe 1.Me3OBF4,CH2Cl2Me3OBF4CH2Cl2, 15 min.
CHOO Ph
2. DBU
20 11a 22a
THEORETICAL PART 14
NMe
CO2CH(Cl)MeSO
Ph
SNMe
PhO
OH
R
Cl
OH
R
11a: n = 1, R = Ph11b: n = 1. R = iPr11c: n = 2, R = Ph
-29a
ClCO2CH(Cl)MeCH2Cl2, 2 h, 25 °C
29a
21a: n = 1, R = Ph (88%, 98% de)21b: n =1, R = iPr (85%, 98% de)21c: n = 2, R = ph (86%, 98% de)
nn
O R
Cl
OH
RDBU, CH2Cl2, 2 h, 25 °C
21a: n = 1, R = Ph 21b: n =1, R = iPr21c: n = 2, R = ph
22a: n = 1, R = Ph(94%, 98% de)22b: n = 1, R = iPr(92%, 98% de)22c: n = 2, R = Ph(90%, 98% de)
nn
Scheme 15: Substitution with ClCO2CH(Cl)Me.
The next step in the synthesis of alkenyloxirane was the cyclisation of the
chlorhydrins to the corresponding oxiranes. In general, the formation of oxiranes
from chlorohydrins is expected to proceed with an inversion of the configuration
thus producing trans-configured oxiranes. Treatment of the chlorohydrins 21a-c
with DBU in DCM afforded the alkenyloxiranes in 90-94% yield with high selectivity
(Scheme 16). The alkenyloxiranes formed were assigned the cis-configuration by
measuring the magnitudes of the vicinal coupling constants (4.2-4.4 Hz). These
values are comparable with a literature26 report that suggests that the coupling
constants will be larger for the cis-isomer (4.0-5.0 Hz) compared to the trans-
isomer (1.5-2.0 Hz). Furthermore, the cis-configuration shows that the substitution
proceeded with retention of configuration.
Scheme 16: Asymmetric synthesis of cycloalkenyloxiranes.
THEORETICAL PART 15
R SPh
O NMe RPh
OH
SNMe
Ph O1. nBuLi, Ether, -78 °C2. ClTi(NEt2)3, 25 °C
3. PhCHO, -78 °C
6a: R = iPr 6b: R = cC6H11
8a: R = iPr(68%)8b: R = cC6H11(70%)
1.2.2.4 Asymmetric Synthesis of Alkenyloxiranes Since high selectivities were recorded in the synthesis of the cycloalkenyloxiranes
22a-c, the possibilites of an analogous synthesis of alkenyloxiranes from acyclic
allylic sulfoximines was investigated. Successive treatment of the (E)-configured
allylic sulfoximines 6a and 6b with n-BuLi and ClTi(NEt2)3 gave the corresponding
allylic titanium complexes which, upon treatment with benzaldehyde, afforded, as
described previously, the enantio- and diastereomerically pure syn-configured
sulfoximine-substituted homoallylic alcohols 8a and 8b, respectivly in good yields
(Scheme17).11f
Scheme 17: Hydroxyalkylation of acyclic allylic sulfoximine.
Substitution of the sulfoximine groups of 8a and 8b by a chlorine atom using
ClCO2CH(Cl)Me, proceeded readily to give beside 29a, the chlorohydrins 23a and
23b, respectively in 92-94% yields. 1H NMR analyses of the products showed that
there existed a mixture of anti- and syn-diastereomers in ratios of 78:22 and 74:26.
Treatment of each mixture of chlorohydrins with DBU furnished the oxiranes 24a
and 24b in high yields as a mixture of trans- and cis-isomers in ratios of 78:22 and
74:26 respectively, thus illustrating complete chirality transfer. The structures of
the trans- and cis-configured oxiranes 24a and 24b were assigned on the basis of
the magnitudes of the vicinal coupling constants from their 1H NMR spectra, which
amounted to 3J = 1.9 Hz for the trans and 3J = 4.3 Hz for the cis isomers (Scheme
18).
THEORETICAL PART 16
Scheme 18: Asymmetric synthesis of alkenyloxiranes.
An attempt was made to probe the configurational stability of the double bond in
the substituion of the sulfoximine group. Studies on the (Z)-configured double
bonds containing sulfoximine formed the corresponding syn-configured
sulfoximine-substituted homoallylic alcohols 26a and 26b. The enantio- and
diastereomerically pure homoallylic alcohols 26a and 26b were synthesized in
good yields, as described previously, from the (Z)-configured allylic sulfoximines
25a and 25b, respectively, as mentioned in Scheme 19. The treatment of
homoallylic alcohols 26a and 26b with ClCO2CH(Cl)Me and DBU afforded the
alkenyloxiranes 24a (89%) and 24b (88%), while the (E)-configured double bonds
resulted each as a mixture of trans and cis isomers in ratios of 75:25 and 80:20,
respectively. 1H NMR spectroscopy of the mixtures of trans 24a, cis 24a and trans 24b, cis 24b showed the presence of an additional 11% and 7% of the
corresponding isomers (27) with (Z)-configured double bonds. The substituion of
the sulfoximines groups of 26a and 26b had thus to a large extent been
accompanied by isomerization of the double bonds (Scheme 19).
RPh
OH
SNMe
Ph O
8a: R = iPr8b: R = cC6H11
-29a
ClCO2CH(Cl)MeCH2Cl2, 2 h, 25 °C DBU, CH2Cl2 2 h, 25 °C
RPh
OH
Cl
RPh
OH
Cl
major
minor
23a: R = iPr(94%, 56% de)23b: R = cC6H11(93%, 48% de)
+
O Ph
R
O PhR
+
24a: R = iPr(94%, 56% de)24b: R = cC6H11(93%, 48% de)
major
minor
THEORETICAL PART 17
Scheme 19: Asymmetric synthesis of alkenyloxiranes from (Z)-configured allylic
sulfoximines. 1.2.2.5 Mechanistic Consideration of the Cl substitution of Sulfoximines The reactions between the cyclic allylic sulfoximines 11a-c and ClCO2CH(Cl)Me
proceeded with almost complete retention of configuration, while those between
the acyclic allylic sulfoximines 9a and 9b and the chloroformate resulted in the
respective chlorohydrins with predominant inversion of configuration. We had
previously observed that S-alkyl-N-methyl sulfoximines are also amenable to this
latter type of Cl substitution, the mechanism of which is not yet known but the
speculative mechanism is as follows (Scheme 20).22
Scheme 20: Mechanism for chlorine substitution.
For the cyclic systems 11a-c and acyclic systems 8a,b the following mechanisms
are proposed to explain the formation of the chlorides 21a-c and 23a,b,
respectively (Scheme 21). This substitution shows some similarity to the
dealkylation of tertiary amines on treatment with chloroformates which gives the
SPh
O NMe
O Ph
R
O PhR
Ph
OH
SNMe
Ph O1. nBuLi, Ether, -78 °C2. ClTi(NEt2)3, 25 °C
3. PhCHO, -78 °C
25a: R = iPr 25b: R = cC6H11
26a: R = iPr(70%, 98% de)26b: R = cC6H11(68%, 98% de)
-29a
1. ClCO2CH(Cl)Me CH2Cl2, 2 h, 25 °C
2. DBU, CH2Cl2 2 h, 25 °C +
24a: R = iPr(89%, 50% de)24b: R = cC6H11(88%, 60% de)
major
minor
RR
O Ph
minorR
27
+
ClClCO2Me
S
NMe
PhO
R S
N
PhO
MeMeO2C
R
R ClCl S
N
PhO
MeMeO2C
R
S
NMeO2C Me
OPh
+
THEORETICAL PART 18
corresponding alkyl chlorides and urethanes.27 Based on this literature precedent,
the first step of the mechanism is speculated to involve acylation of the sulfoximine
groups of 11a-c, 8a and 8b at the N-atom to form the aminosulfoxonium salts
28a-c, 31a and 31b (Scheme 21). The allylic aminosulfoxonium groups of 28a-c,
31a and 31b would be expected to be excellent leaving groups.22 SN1 substitution
of the allylic aminosulfoxonium salts is proposed resulting in generation of the
allylic carbenium ions 30a-c, 32a and 32b, and accompanying formation of the
sulfinamide 29a. The allylic carbenium ions 30a-c, 32a and 32b would be
expected to undergo facile Cl addition to form the products. In the case of the
acyclic systems, the major products formed (anti-23a,b) are those with S-
stereochemistry, along with minor amounts of the R-isomers. Obviously, chlorine
substitution must occur preferentially at the Si face, (vs. attack at the Re face), but
why such selectivity should be observed is unclear. On the other hand, for the
cyclic systems, the only products observed are those with R-stereochemistry. This
may be explained by the fact that the cyclic allylic carbenium ions 30a-c
preferentially adopt the C(OH)-C(sp2)-conformation A, in which the hydroxy group
is gauche to the H-atom at the C(sp2)-atom (to minimize the destabilizing
interactions between the hydroxy group and the ring containing the double bond)
(Scheme 21) and the chloride ion is forced to attack from the Re face due to steric
crowding.
THEORETICAL PART 19
Scheme 21: Mechanism for Cl substitution of sulfoximines.
NMe
CO2CH(Cl)MeSO
Ph
Cl
ClS
N
PhO
OH
R
Me CO2CH(Cl)Me
ReH
RH
OH
ClCO2CH(Cl)Me
H R
HO HCl
B
SNMe
PhO
OH
R
Cl
OH
R
29a
11a-c 28a-c
-29a
30a-c
Cl
OH
R
syn-21a-c
A
anti-21a-c
RPh
OH
SNMe
Ph O ClCO2CH(Cl)Me
RPh
OH
SPh O
NMe CO2CH(Cl)Me
Cl
SiR
R
OHHH Cl
ReR
OH
RH Cl
RPh
OH
Cl
major
RPh
OH
Cl
minor
8a,b 31a,b
anti-23a,b syn-23a,b
-29a
32a,b H
THEORETICAL PART 20
S
NMeO2C Me
OPh
MeMgCl
O
NClMgOMe
Me
SMePh
O H3O
S
NMe(Cl)HCO2C Me
OPh
MeMgCl
O
NClMgOMe
Me(Cl)HC
SMePh
O H3OSMe
Ph
O
SMePh
O
O
NHOMe
Me(Cl)HC
O
NHOMe
Me
+ +THF, 78°C
+ +THF, 78°C
MeS
Ph
O NMe
29b
29a
34
(85%, 96% ee)
33
Such a mechanism could also be used to explain the (Z)/(E) isomerization that
occurred in the case of the reactions of the (Z)-configured, sulfoximine-substituted,
homoallylic alcohols described earlier. 1.2.2.6 Recycling of the Chiral Auxiliary The purpose of this work was to demonstrate that the sulfoxime moiety in the
allylic sulfoximes acts as an auxillary. Our group had previously shown that the
treatment of (S)-configured S-alkyl-N-methyl sulfoximines with ClCO2Me resulted
in the formation of the sulfinamide 29b with 98% ee (Scheme 22).11d Sulfinamide
29b was converted upon treatment with MeMgCl to sulfoxide 33 of 98% ee, the
conversion of which to the (S)-configured sulfoximine 34 of 98% ee had already
been described in the literature.28 The sulfoximine in turn is the starting material for
the synthesis of allylic sulfoximines 9a, 9b, 6a, 6b, 25a, and 25b. In order to
examine whether 29a could also be used as starting material for the synthesis of
34, the sulfonamide 29a was treated with MeMgCl which gave sulfoxide 33 with
96% ee24 (Scheme 22).
Scheme 22: Recycling of the chiral auxiliary.
THEORETICAL PART 21
1.3 Conclusion A highly selective asymmetric synthesis of cis-configured cycloalkenyloxiranes,
otherwise not easily accessible by existing methods, has been developed. The
three-step sequence consists of an allylation of an aldehyde with a cyclic allylic
sulfoximine bearing a tris(diethylamino)titanium group, a Cl substitution of the
sulfoximine group of the resulting homoallylic alcohol, and a cyclization of the
resulting chlorohydrin (Scheme 23).
Scheme 23: Synthesis of alkenyloxiranes.
The synthesis of the cyclic allylic sulfoximines is accomplished from commercially
avialable enantiomerically pure S-methyl-S-phenyl sulfoximine and the
cycloalkanone by a six-step sequence of transformations requiring the isolation
and purification of only one intermediate, N,S-dimethyl-S-phenyl sulfoximine
(Scheme 24).
Scheme 24: Synthesis of cyclic allylic sulfoximine.
A solid-phase asymmetric synthesis of cycloalkenyloxiranes by this route with the
use of the sulfoximine group as a traceless chiral linker is also feasible (Scheme
25).23 The asymmetric synthesis of alkenyloxiranes by this route is also possible,
but yields mixtures of cis and trans isomers, in which the latter dominate. The
facile Cl substitution of the sulfoximine group with retention of configuration at the
S
R2R1
OPhNMe
S
OH
R3
R2R1
OPhNMe
Cl
OH
R3
R2R1
O R3R2
R1ClCO2CH(Cl)MeAEI
SPh
O NMe
n
9a: n = 1 (76%)9b: n = 2 (77%)
1. n-BuLi, THF2. cycloalkanone
3. ClSiMe34. n-BuLi5. NaOMe
MeS
Ph
O NMe
THEORETICAL PART 22
PSPS
PS P h S
C H 3ON
P h SON
PhS
ON
HO Ph
PS
P h S N
C O2C H (C l)Me
O
P h S OH N
PS Cl
O Ph
O Ph
PS
PhS
ON
DBUCH2Cl2
ClCO2CH(Cl)M eCH2Cl2
P hOH
C l
Ph
OH
Cl
( o r)
AEI-Route
1. n-Butyllithium2. ClTi(NEt2)33. PhCHO
m i nor
m aj or
++
minor
+
major
S atom and the recycling of the sulfinamide provide the basis for a full utilization of
the sulfoximine group as a chiral auxiliary.
Scheme 25: Solid-phase synthesis.
.
THEORETICAL PART 23
CHAPTER 2
Asymmetric Synthesis of 2,3-Dihydrofurans and of Unsaturated Bicyclic Tetrahydrofurans
.
THEORETICAL PART 24
2 Asymmetric Synthesis of 2,3-Dihydrofurans and of Unsaturated Bicyclic Tetrahydrofurans
2.1 Introduction 2.1.1 Brief introduction about relevant biologically-active molecules
Five-membered oxygen-containing heterocycles have been valuable targets for
the synthetic chemists during past five decades, since they are present in a variety
of naturalproducrs, many of which possess biological activity. For example, (+)-
allomuscarine exhibits antibiotic biological activity, where its epimer (−)-
allomuscarine exihibits cholinomimetic activity. Similarly, (−)-dihydrosesamin is a
potent anticanser activity (Figure 8).29
Figure 8: Bioactive tetrahydrofurans.
Synthesis of 2,5-dihydrofurans with chiral centers and their importance for the
synthesis of natural products has been reviewed several times.27n,o The synthesis
of 2,3-dihydrofurans bearing chiral centers which are enantiomerically and
diastereomerically pure has received much less attention.27 Substituted 2,3-
dihydrofurans of type A, B (Figure 9) would make particularly interesting starting
materials for the asymmetric synthesis of tetrahydrofurans, structural motifs which
can be found in many important natural products including polyether antibiotics,
lignans and nucleosides (Figure 10).
OH3C
HO
NMe3 OH3C
HO
NMe3O
O
O OH
O O(+)-Allomuscarine (-)-Allomuscarine (-)-Dihydrosesamin
THEORETICAL PART 25
Figure 9: Applications of tetrahydrofurans.
2,3-Dihydrofurans contain a vinyl ether moiety that can undergo various chemical
transformations.28
Figure 10: Importance of the tetrahydrofuran moiety.
O
R2
R1
Me
SiEt3
O
R
SiEt3
n
O
R
SiEt3
n
O
R2
R1
Me
SiEt3
Polyether antibiotics
Nucleosides
Lignans
A
B
**
**
O
OMeMeO
HOO
OMe
OMe
O
OMe
HOO
OMe
OMe
OMeMeO
O O O OMe
OHCH2OH
H
MeH
Me
H
Et
H
Me
OCO2H
OHMe
Me
MeOMe
O OHOHOH
CO2HO
HOH
Magnone A
Magnone B
Monensin
Lonomycin
THEORETICAL PART 26
2.1.2 Approaches towards the construction of dihydrofuran moiety Pierre Bruns approach In the year 2003, Brun et al. disclosed a synthesis of (+)-phyltetralin 38, a 2,3-
dihydrofuran derivative, by using a diastereoselective, Mn-promoted, radical
addition reaction. Thus, addition of β-oxo ester 35 to the chiral N-
cinnamoyloxazolidine 36 yielded the diastereomeric 2,3-dihydrofurans 37a and
37b in 72% with 80% de. (Scheme 26).29 Though this method is novel, high
selectivity have yet to be achieved.
Scheme 26: Asymmetric synthesis of dihydrofurans.
David Evans contribution Evans et al. devised a method for the asymmetric synthesis of 2,3-dihydrofurans
via [3+2] cycloaddition (or anulation) of allenylsilanes (with bulkier substituents on
silicon) and an aldehyde or glyoxalate, catalyzed by 8-Sc[(S,S)-Ph-pybox](OTf)3.
The tert-butyldiphenylsilyl group was found to be critical to achieve optimla enantio
selectivity (92% ee) (Scheme 27).30
CO2MeO
OMeMeO
O
MeO
OMe
MeO
MeO
O N O
O
Bn
CO2MeO
MeO
OMe
MeO
MeO
O N O
O
Bn
CO2Me
OMeBn
O
N O
O
MeO
O
MeO2C CO2Me
MeO
MeO
OMeMeO
(1) Mn(OAc)3.2H2O, AcOH, 70 °C, N2, 65:35 (3/4); (2) LiBr, DBU, MeOH/THF, 0 °C, 3 h
++
(2)
(1)35
36 37a 37b
38
THEORETICAL PART 27
Scheme 27: Sc-catalyzed asymmetric synthesis of 2,3-dihydrofurans.
Davies contribution
Davies et al. disclosed an asymmetric synthesis of 2,3-dihydrofurans by a rhodium
(II) octanoate catalyzed decomposition of 2-diazo-3-siloxybutenoates containing
pentalactone as a chiral auxiliary, in the presence of vinyl ethers. Thus, the 2,3-
dihydrofurans were afforded in good yields, via the two-step reaction sequence
shown in the Scheme 28. 31
Scheme 28: Rh Catalyzed asymmetric synthesis of 2,3-dihydrofurans.
2.2 Present Work 2.2.1 Aim
As illustrated in the earlier section, chiral tetrahydrofurans can be found in many
important natural products including polyether antibiotics, lignans and nucleosides.
R1
R2O
O
OTBS
O
N2
O
O
O
R1
2RO
OOO
O Rh2(Oct)4
TBAF
R1 = MeR2 = Et
74%, 78% de
+
R
CH2•
BtuPh2Si+
EtO
O
H
O
OEtO
O
SiPh2tBu
R
80 to 91% 90 to 98% ee
N
Sc NN
OO
OTfOTfTfO
Ph Ph
CH2Cl2, -48 °C
R = Me, Et, Pr, Ph
THEORETICAL PART 28
A novel asymmetric approach to such natural products could involve using
substituted 2,3-dihydrofurans as synthetic precursors to this structural motif.27
In 2000, R. Hainz, a former member of our research group, found a method for the
region- and stereoselective hydroxyalkylation of allyl sulfoximines leading to the
synthesis of enantiopure, acyclic, homoallylic alcohols. 11f
Titanation of the lithiated (E)-configured allylic sulfoximines 39 with ClTi(OiPr)3
afforded the corresponding bis(allylsulfoximine)titanium complexes 40 which
reacted with aldehydes with high regio- and stereoselectivities at the γ-position to
give the corresponding (Z)-anti-configured, δ-N-methylsulfonimidoyl-substituted,
homoallylic alcohols 41(Scheme 29).
Scheme 29: Hydroxyalkylation of acyclic allylic sulfoximines.
Hainz also extended the method to cyclic allylic sulfoximines.11f Thus, cyclic allyl
sulfoximines reacted with aldehydes with high regio- and stereoselectivily at the γ-
position to yield the corresponding vinylic sulfoximines (Scheme 30).
Scheme 30: Hydroxyalkylation of cyclic allylic sulfoximines.
The above mentioned method was successfully applied to the asymmetric
synthesis of anti-homopropargylic alcohols by L. R. Reddy (Scheme 31). 32
SPh
NMeOR
SPh
NMe
OR
SRPh
NMe
O
Tii-PrOi-PrO
SPh
NMeORR'
OH
1. n-BuLi2. ClTi(Oi-Pr)3 R'CHO
R = cC6H11, i-Pr; R' = i-Pr, Ph 98% de
39 40 41
SPh
NMeO
SPh
NMe
O
SPh
NMe
O
Tii-PrOi-PrO
R'
SO
MeN PhOH
1. n-BuLi2. ClTi(Oi-Pr)3 R'CHO
R' = Ph, i-Pr
98% de
THEORETICAL PART 29
Scheme 31: Asymmetric synthesis of homopropargylic alcohols.
During the course of these investigations, it was observed that the β-Me-
substituted alkenyl sulfoxonium ylides 42 (R1 = Ph, R2 = i-Pr, R3 = Me) afforded the
2,3-dihydrofurans 45 rather than the expected methyl-substituted alkynes 44 (Scheme 32). The racemic acyclic siloxy alkylidene carbenes41,42of type 43 were
also reported in literature.
Scheme 32: Generation and reactivity of silyloxy-substituted alkylidene carbenes.
SPh
O
NMe
R2
OH
R1
R2
OSiEt3
R1
SPh
O
NMe
R2
OSiEt3
R1 SPh
O
NMe2
R2
OSiEt3
R1
R2
OH
R1
ClSiEt3Imidazol
CH2Cl292-99 %
1. LiN(H)t-Bu THF, -78 °C bis RT2. NaHCO3, H2O 89-95 %
Bu4NF, THF, RT
Me3OBF4BF4
OS
NMe2Ph
R1 = i-Pr, cC6H11, MeR2 = Ph, pBrC6H4, pClC6H4, pMeOC6H4, PhCH=CH, PhC≡C
92-99 %
85-98 %
R2S
R1
Et3SiO
Ph
O NMe2R3
R2
R3
R1
Et3SiO
C
R2
R1
Et3SiO H
OR2
1R Me
SiEt342
45
44
R3 = H
R1, R2 = alkyl, aryl
R3 = Me
R1 = i-Pr, R2 = Ph
43
THEORETICAL PART 30
S. Koep has recently observed that upon treatment with DBU the
(sulfonylamino)alkyl-substituted 1-alkenyl aminosulfoxonium salt 46 suffers a novel
migratory cyclization, leading to the formation of the unsaturated fused bicyclic
proline derivative 48 via the allylic aminosulfoxonium salt 47 (scheme 33).11b
Scheme 33: Migratory cyclization of sulfonylamino substituted 1-alkenyl amino- ..
sulfoxonium salts.
2.2.2 Results and Discussions 2.2.2.1 Retrosynthetic analysis Not only the activated double bond but also the vinylic silyl group of 45 should
allow useful synthetic transformations, including the replacement of the silyl moiety
by a metal atom.33-35 Up to now, the application of chiral 2,3-dihydrofurans in
natural product synthesis has been hampered by the lack of general methods for
their asymmetric synthesis.36,37 Thus, it would be a great interest to develop a
general and highly efficient asymmetric approach to access these compounds.
Thus, the dihydrofurans 45 were realized from the corresponding sulfoxonium
ylides 49. The ylide 49 can be derived from the allylic sulfoximine 50 whose
synthesis was recently reported by our group.11f As also shown in the retro
synthetic approach, the bicyclic dihydrofuranes 51 and bicyclic tetrahydrofurans 56
were realised from the ylides 53 via an analogous route (Scheme 34).
t-BuO2S(H)N
EtO2C
SPh
Me2NO
DBU
SN
EtO2C
Ph
OMe2NHt-BuO2S
DBU
BF4 BF4
46 47
NEtO2C
t-BuO2S
48
THEORETICAL PART 31
Scheme 34: Retrosynthetic analysis.
Although the primary goal of our investigations was the development of an
asymmetric synthesis of 2,3-dihydrofurans of types 45 and 51, the prospect of 1-
alkenyl aminosulfoxonium salts 49 and 53 serving as a new source for chiral
alkylidene carbenes was also of particular interest. Since carbenes of type 52
were unknown at the begining of our investigation, it was particularly interesting to
see whether 1,5-O,Si-bond insertion, with formation of the corresponding alkynes,
would occur.38-40
2.2.2.2 Hydroxyalkylation of acyclic allyl sulfoximines As depicted in the retrosynthetic approach, the initial targets in the synthesis of
acyclic sulfoximines, the vinyl sulfoximines were prepared by following the
addition-elimination-isomerization route depicted in Scheme 35.11f Thus, treatment
of the chiral sulfoximine 34 with n-BuLi at -78 °C, followed by addition of
corresponding methyl ketones and methylchloroformate, and then by DBU gave
vinylsulfoximines 57a and 57b. These were treated with DBU in acetonitrile at
O
R2
R1
Me
SiEt3
O
R
SiEt3
O
R
R2
Me
R1
Et3SiO
C
BF4
C
R
Et3SiO
O NMe2
R
Et3SiOS
Ph
BF4
R2
Me
R1
Et3SiO
SPh
O
NMe2
BF4
OMe2N
R
Et3SiOSPh
OMeN
R
Et3SiOSPh
R2
Me
R1
Et3SiO
SPh
O
NMe
51
53n
n
56n
52n
55n
45 43 49 50
54n
THEORETICAL PART 32
elevated temperatures to afford allyl sulfoximines as a mixture of (E) and (Z)
isomers. The (E/Z) ratio for compound 58a was 70:30 and 79:21 for compound
58b. These isomers were separated by preparative HPLC. Isomerization of the
unwanted (Z) isomers with DBU in acetonitrile, again gave mixtures of the (E) and
(Z) isomers.
Scheme 35: synthesis of acyclic allylic sulfoximines.
The succesive treatment of 58a and 58b with n-BuLi, ClTi(Oi-Pr)3 and 0.5 equiv of
aldehydes 59a-d, followed by subsequent silylation of the thus-formed homoallylic
alcohols with chlorotriethylsilane in the presence of imidazole, afforded the
diastereomerically pure (anti,Z)-configured silyl ethers 50a-d in good yields (Table
1). Hydroxyalkylation of the methyl substituted titanium complexes derived from
58a and 58b with the aromatic and aliphatic aldehydes 59a-d proceeded with high
regio- and stereoselectivities, similar to those of the corresponding titanium
complexes having only a disubstituted C=C double bond. 11f
Scheme 36: asymmetric synthesis of sulfoximine substituted acyclic homoallylic
alcohols.
Formation of the vinyl sulfoximines proceded in approximately 50% yields, with
recovery of unreacted allylic sulfoximines in 38-44% yield. The reason attributed
to the incomplete conversion of allyl sulfoximines is due to the formation of
bis(allyl)titanium complexes, which are capable of only transferring one allylic
sulfoximine unit with high selectivities to the aldehyde11f (Scheme 37).
MeS
Ph
O NMeS
Ph
O NMe
R
Me1. DBU, MeCN2. E/Z separation 3. DBU, MeCN
SPh
O NMeR
Me
34
1. n-BuLi, THF2. RCH2COMe3. ClCO2Me4. DBU 57a,b 58a,b
a: R = i-Pr, b: R = Ph
SPh
O NMeR
MeS
Ph
O
NMe
R2
Me
R1
Et3SiO1. n-BuLi, THF2. ClTi(Oi-Pr)3
3. RCHO (59a-d)4. ClSiEt3, ImH, DMF
58a,b 50a-d
a: R = i-Prb: R = Ph
a: R = Phb: R = pMeOC6H4c: R = pBrC6H4d: R = cC6H11
a: R1 = i-Pr, R2 = Phb: R1 = i-Pr, R2 = pMeOC6H4c: R1 = Ph, R2 = Phd: R1 = Ph, R2 = pMeOC6H4
THEORETICAL PART 33
Scheme 37: Formation of bis(allylitanium) complexes.
2.2.2.3 Hydroxy alkylation of the cyclic allyl sulfoximines The cyclic allylic sulfoximines 9a and 9b were prepared in a one-pot operation
without isolating the intermediates from sulfoximine 34 and the corresponding
cycloalkanones by the inverse Peterson-olefination and isomerization sequence.25
Thus, compound 34 was treated with n-BuLi at -78 °C and then with a
cycloalkanone to afford the corresponding β-hydroxy sulfoximine. This was without
isolation treated with chlorotrimethylsilane and then n-BuLi. Finally, treatment with
NaOMe afforded the cyclic allylic sulfoximines 9a and 9b in good yields (74-78%).
Similarly, the eight-membered cyclic allylic sulfoximine ent-9c was synthesized
from sulfoximine ent-34 and cyclooctanone in 79% yield.
Scheme 38: Asymmetric synthesis of sulfoximine-substituted cyclic homoallylic
alcohols.
The succesive treatment of the cyclic allylic sulfoximines 9a, 9b and ent-9c with n-
BuLi, ClTi(Oi-Pr)3 and 0.5 equiv of aldehyde 59b, and the subsequent silylation of
the intermediate homoallylic alcohols afforded the silyl ethers 54a, 54b and ent-
54c, respectively, each as a single diastereomer in good yields (Table 2). Similar
to the acyclic allylic sulfoximines, the conversion of 9a, 9b and ent-9c was found to
be approximately 50% with 38-40% recovery of unreacted allylic sulfoximines.11f
SPh
NMeOR
SPh
NMe
OR
SRPh
NMe
O
Tii-PrOi-PrO
Ti(Oi-Pr)4
1. 1 eq.n-BuLi
2. 1 eq. ClTi(Oi-Pr)3+
0.5 eq. 0.5 eq.
MeS
Ph
O NMe SPh
O NMe
R
Et3SiOSPh
OMeN
1. n-BuLi, THF2. ClTi(Oi-Pr)3
3. 14b4. ClSiEt3, ImH DMFn n
9a9bent-9c
54a54bent-54c
a: n = 1, b: n = 2, c: n = 3; R = pMeC6H4
1. n-BuLi, THF2. cycloalkanone
3. ClSiMe34. n-BuLi5. NaOMe
34orent-34
THEORETICAL PART 34
2.2.2.4 Synthesis of 2,3-dihydrofurans It has been found in our group that the activation of 50 can be achieved through
the methylation of the N-methyl sulfoximine group with Me3OBF4 to afford the
corresponding (dimethylamino)sulfoxonium salt 49.23,32 Hence, based on the
earlier literature for the activation, our initial attempt towards the generation of 2,3-
dihydrofurans is proposed in scheme 35. Thus, the methylation of the alkenyl
sulfoximines 50a-h with Me3OBF4 in dichloromethane afforded the
(dimethylamino)sulfoxonium salts 49a-h in almost quantitative yields. Treatment of
the salts 49a-h with 1.1 eq. of Li(NH)t-Bu in THF, first at −78 °C and then at room
temperature, afforded the silyl-substituted 2,3-dihydrofurans 45a-h in high overall
yields, based on 50a-h. The structure of the substituted 2,3-dihydrofurans were
established by spectral analysis. These results show that this 2,3-dihydrofuran
synthesis works equally well for derivatives carrying aliphatic and aromatic
substituents, including sterically demanding groups. The sulfonamide 29c was
isolated with > 98% ee in all cases in high yields (Table 1).
Scheme 39: Asymmetric synthesis of monocyclic 2,3-dihydrofurans.
Me3OBF4
SPh
O
NMe
R2
R1
Et3SiO Me
SPh
O
NMe2
R2
R1
Et3SiO Me
BF4CH2Cl2
SO
NMe2PhLiN(H)t-BuTHF
O
R1
R2 SiEt3
Me
50a−h
a: R1 = i-Pr, R2 = Phb: R1 = i-Pr, R2 = pMeOC6H4c: R1 = Ph, R2 = Phd: R1 = Ph, R2 = pMeOC6H4
49a−h
45a−h
29c−
THEORETICAL PART 35
Table 1: Asymmetric synthesis of 2,3-dihydrofurans 45a−h
compd R1 R2 R3 50
yield (%)a,b
50
dr
45
yield (%)
29c
yield (%)
a IPr CH3 Ph 77(96) ≥ 98:2 95 86
b IPr CH3 p-MeOC6H4 76(95) ≥ 98:2 90 85
c IPr CH3 p-BrC6H4 76(92) ≥ 98:2 92 85
d IPr CH3 c-C6H11 80(95) ≥ 98:2 86 87
e Ph CH3 Ph 71(94) ≥ 98:2 96 89
f Ph CH3 p-MeOC6H4 81(97) ≥ 98:2 92 85
g Ph CH3 p-BrC6H4 77(95) ≥ 98:2 94 86
h Ph CH3 c-C6H11 79(94) ≥ 98:2 92 90 a Yields are based on recovered allylic sulfoximine. b Values in parentheses are yields based on aldehyde.
2.2.2.5 Synthesis of Bicyclic 2,3-Dihydrofurans Having developed a high yield synthesis of the enantio- and diastereomerically
pure monocyclic 2,3-dihydrofurans 45a-h from the acyclic, δ-silyloxy-substituted,
alkenyl sulfoximines 50a-h, the synthesis of bicyclic 2,3-dihydrofurans of type 51
was investigated. Thus, the methylation of sulfoximines 54a, 54b, and ent-54c with
Me3OBF4 proceeded readily and gave the cyclic (dimethylaminosulfoxonium) salts
53a, 53b and ent-53c, respectively, in practically quantitative yields (Scheme 40).
Upon treatment with LiN(H)tBu, first at -78 °C and then at room temperature, salts
53a, 53b, and ent-53c cleanly delivered the enantio-and diastereomerically pure
bicyclic 2,3-dihydrofurans 51a, 51b, and ent-51c, respectively, having a six, seven,
and eight membered carbocyclic ring, in overall yields, based on 54a, 54b, and
ent-54c, respectively.
THEORETICAL PART 36
Scheme 40: Asymmetric synthesis of bicyclic 2,3-dihydrofurans.
Table 2: Asymmetric synthesis of bicyclic 2,3-dihydrofurans
compd n 54/ent-54 51/ent-51
yield (%)
29c/ent29c
Yield (%) yield (%)a,b dr
A 1 78(96) ≥ 98:2 89 86
B 2 79(95) ≥ 98:2 91 90
C 3 77(96) ≥ 98:2 90 88 a Yields are based on recovered allylic sulfoximine. b Values in parentheses are yields based on aldehyde. 2.2.2.6 Mechanistic Considerations of the 2,3-Dihydrofuran formation
The formation of 2,3-dihydrofurans 45a-h, 51a, 51b and ent-51c from the
aminosulfoxonium salts 49a-h, 53a, 53b and ent-53c, respectively may be
described mechanistically as follows (Scheme 41). On the basis of the results
obtained previously with the synthesis of ylides 42 (R3 = H),32 it is proposed that
the reaction of the aminosulfoxonium salts 49a-h, 53a, 53b and ent-53c with the
lithum amide at low temperatures affords the alkylidene carbene sulfoxonium
ylides 60a-h, 63a, 63b and ent-63c, respectively (Scheme 41).
53a53bent-53c
54a54bent-54c
51a51bent-51c
R
Et3SiOSPh
OMeN
R
Et3SiOSPh
OMe2N
BF4
nn
CH2Cl2
Me3OBF4
LiN(H)t-BuTHF
− 29c
O
R
SiEt3
n
a: n = 1, b: n = 2, c: n = 3R = pMeOC6H4
THEORETICAL PART 37
Scheme 41: Mechanistic scheme for mono and bicyclic 2,3-dihydrofurans.
At higher temperatures, these alkylidene carbenoids eliminate sulfinamides 29c
and ent-29c, resulting in the formation of the δ-silyloxy alkylidene carbenes 43a-h,
52a, 52b, and ent-52c, respectively. Because of the different conformations the
alkylidene carbenes 43a-h can adopt with regard to the Csp2-Csp3 bond and the
high propensity that alkylidene carbenes normally show for C,H-bond insertion, not
only a 1,5-O,Si-bond but also a 1,5-C,H-bond insertion38 could, in principle, occur
with formation of the cyclopentene derivatives 62a-c. This was, however, not
observed within the limits of the yields obtained and the δ-silyloxy alkylidene
carbenes 43a-h, 52a, 52b and ent-52c instead delivered the 2,3-dihydrofurans
45a-h, 51a, 51b, and ent-51c, respectively, via a nonconcerted 1,5-O,Si-bond
insertion reaction followed by [1,2]–silyl migration. These postulations are in
accordance with the results of previous studies.38,41-43
SPh
O
NMe2
R2
R1
Et3SiO R3
BF4 SPh
O NMe2Me
R2
R1
Et3SiO
R2 MeR1
Et3SiO C
O
R1
R2
Me
SiEt3PhS
NMe2
O
O
R1
R2
Me
SiEt3
Me
R2
Et3SiO
R1
49a−h
45a−h
60a−h
15
62a-c
61a−h
43a−h
29c
- 29c1,5-C,H-bond insertion
1,5-O,Si-bond insertion
OR
Et3Si
R
Et3SiOS
Ph
O NMe2
C
R
Et3SiO
n n63a63bent-63c
n52a52bent-52c
64a64bent-64c
51a51bent-51c
− 29 (ent-29)
OMe2N
R
Et3SiOSPh
BF4
53a53bent-53c
n
O
R
SiEt3
n
THEORETICAL PART 38
2.2.2.7 Synthesis of Unsaturated Bicyclic Tetrahydrofurans Tetrahydrofurans 56 having the various ring size should be of particular synthetic
interest because of the many natural products containing a bicyclic
tetrahydrofuranoid skeleton or structural element (Figure 11).44-47
Figure 11: Importance of of bicyclic tetrahydrofurans.
It was rercently observed that (sulfonylamino) alkyl-substituted 1-alkenyl
aminosulfoxonium salts of type 46 suffer upon treatment with DBU a novel
migratory cyclization leading, via allylic aminosulfoxonium salts of type 47, to the
formation of unsaturated fused bicyclic proline derivatives of type 48 (Scheme
42).23
Scheme 42: Asymmetric synthesis of bicyclic proline derivatives.
This observation initiated us to study the reaction of the cyclic aminosulfoxonium
salts 53a, 53b and ent-53c with DBU in order to see whether an access to
unsaturated fused bicyclic tetrahydrofurans 56a, 56b and ent-56c respectively
(Scheme 46) could also be affected. Tetrahydrofurans 56 fused to a variety of ring
sizes should be of particular synthetic interest because of the many natural
products containing a bicyclic tetrahydrofuranoid skeleton or structural element.
The double bond present in this 56 should allow for further synthetic
transformations. An asymmetric synthesis of 56 has, to the best of knowledge not
yet been described.48 While the chances for a regioselective isomerization of 54 to
t-BuO2S(H)N
EtO2C
SPh
Me2NO
DBU
SN
EtO2C
Ph
OMe2NHt-BuO2S
DBU
BF4 BF4
46 47
NEtO2C
t-BuO2S
48
OO
O
O
O
O
H
O H
OH
OOH
H
H
O
OH O
H
HH
OH
OAc
OHH
O
H
HH
OHH
Micrandilactone A Alcyonin Massileunicellin-D
THEORETICAL PART 39
the allylic aminosulfoxonium salts 55 seemed to be good, the prospects for
cyclization of the latter and formation of 56 were considered to be less promising,
because of the poor nucleophilicity of the silyloxy group. The DBU-assisted
conversion of 47 to 48 is, perhaps, not representative because the strongly-
nucleophilic, deprotonated, sulfonylamino group attacks the C-atom in the alpha
position to the aminosulfoxonium group.
Scheme 43: Asymmetric synthesis of unsaturated fused bicyclic tetrahydrofurans.
Table 3: Asymmetric synthesis of bicyclic tetrahydrofurans.
Compd n 56/ent-56
yield (%)
29c/ent-29c
yield (%)
a 1 69 84
b 2 72 87
c 3 74 88
Treatment of 53a, 53b and ent-53c with DBU in DCM at RT lead to a highly-
regioselective migratory cyclization and gave the enantio- and diastereomerically -
pure bicyclic tetrahydrofurans 56a, 56b and ent-56c respectively, in yields of 69-
72% after aqueous workup and chromatography. Formation of 51a, 51b and ent-
51c under these conditions was not observed. The structures of the
tetrahydrofurans 56b and ent-56c, containing a seven-and eight-membered
carbocyclic ring respectively, were determined by X-ray crystal structure analysis
(Figure 8) and also establiblished by spectral analysis. Besides 56a, 56b and ent-
56c, the sulfinamides 29c and ent-29c, respectively, were isolated in good yields
(Table 3).
OMe2N
R
Et3SiOSPh
DBU
O
R
BF4
O
R
Et3SiOS
Ph
NMe2
BF4
53a53bent-53c
n n
− 16
n56a56bent-56c
55
THEORETICAL PART 40
Figure 12: Structure of the bicyclic tetrahydrofurans 56b and ent-56c derived from single crystal X-ray analysis.
2.2.2.8 Mechanistic Considerations
The formation of unsaturated fused bicyclic tetrahydrofurans 56a, 56b and ent-56c
from the aminosulfoxonium salts 53a, 53b and ent-53c, respectively may be
described mechanistically as follows (Scheme 44). Although the mechanism of the
isomerization of 53a, 53b and ent-53c is, like that of 46, not known,23 the formation
of the allylic aminosulfoxonium ylide intermediates 63a, 63b and ent-63c may play
an important role. Deprotonation of 53a, 53b and ent-53c at the γ-position is
expected to be a facile process because of the stabilization of the negative charge
of 63a, 63b and ent-63c by the aminosulfoxonium group and the double bond. For
example N,N-dimethyl-S-methylphenylsulfoxonium tetrafloroborate already has a
Pka value of 15.5, and the double bond is expected to raise the acidity of 53a, 53b and ent-53c even further.49,50 Cyclization of the allylic aminosulfoxonium salts 55a,
55b, and ent-55c should primarily lead to the silyl tetrahydrofuranium salts 65a,
65b and ent-65c, respectively.
These salts are desilylated either by DBU, the sulfonimide, or water upon aqueous
workup51 with formation of 56a, 56b and ent-56c. In considering the low reactivity
of for example silyl ethers of 3-bromomethyl-but-3-en-1-ol derivatives towards
cyclization with formation of the corresponding 3-methylene tetrahydrofurans.52
The facil cyclization of 55a, 55b and ent-55c is noteworthy. This points to a high
nucleofugacity of the allylic (dimethylamino)sulfoxonium group.
THEORETICAL PART 41
Scheme 44: Asymmetric synthesis of unsaturated fused bicyclic 2,3-dihydrofurans.
2.2.2.9 Recycling of the Chiral Auxiliary Besides the 2,3-dihydrofurans 45a-h, 51a and 51b and the tetrahydrofurans 56a
and 56b sulfinamide 29c was isolated in high yields with 98% ee. Thus, a
conversion of 29c to the sulfoximine 34, the starting material for the synthesis of
allylic sulfoximines, was desirable. To this end, sulfinamide 29c was treated with
MeMgCl, which gave, under inversion of configuration, the sulfoxide 33 which was
isolated in 93% yield with 98% ee (Scheme 45). Since the conversion of 33 to
sulfoximine 34 has already been described,53 the synthesis of 34 from 29c
represents a recycling of the chiral auxiliary.
Scheme 45: Recycling of the chiral auxiliary.
OMe2N
R
Et3SiOSPh
DBU
O
R
Et3SiOS
Ph
NMe2
O
R
BF4
R
OEt3Si
O
R
Et3SiOS
Ph
NMe2
BF4BF4
53a53bent-53c
n
nn
n
− 16
n
55a55bent-55c
56a56bent-56c
65a65bent-65c
63a63bent-63c
a: n = 1, b: n = 2, c: n = 3R = pMeOC6H4
PhS
NMe2
OMeMgClTHF Ph
SMe
O
29c 33Me
SPh
O NMe
34
THEORETICAL PART 42
2.2 Conclusion We have devised an asymmetric synthesis of highly substituted mono- and bicyclic
2-silyl-2,3-dihydrofurans from enantio- and diastereomerically pure silyloxy
alkylidene carbene (dimethylamino)sulfoxonium ylides carrying two stereogenic
centers. Key steps are the elimination of the ylides with formation of silyloxy
alkylidene carbenes and the O,Si-bond insertion of the latter.
Scheme 46: Asymmetric synthesis of 2,3-dihydrofurans.
The advantage of this synthesis is that it provides access to enantio- and
diastereomerically pure 2,3-dihydrofurans carrying various aryl and alkyl
substituents including sterically-demanding ones. The results show that 1-alkenyl
(dimethylamino)sulfoxonium salts can, with the intermediacy of alkylidene carbene
(dimethylamino) sulfoxonium ylides, serve as versatile starting materials for the
generation of chiral alkylidene carbenes.
Scheme 47: Asymmetric synthesis of bicyclic 2,3-dihydrofurans.
R2
Me
R1
Et3SiO
SPh
O
NMe
Me3OBF4CH2Cl2
BF4
R2
Me
R1
Et3SiO
SPh
O
NMe2
THF
LiN(H)t-BuR2
Me
R1
Et3SiO
C
O
R2
R1
Me
SiEt3
50 49 43 45
R1 = i-Pr, PhR2 = Ph, pMeOC6H4, pBrC6H4, cC6H11
OMeN
R
Et3SiOSPh
Me3OBF4
CH2Cl2BF4
OMe2N
R
Et3SiOSPh
THF
LiN(H)t-BuC
R
Et3SiO O
R
SiEt3
5153
nn
52
n
54
n
n = 1, 2, 3R = pMeOC6H4
THEORETICAL PART 43
Interestingly 1-alkenyl (dimethylamino) sulfoxonium salts show a synthetically
highly-useful dichotomy in their reactivity toward bases. While with strong bases
an α-elimination of the aminosulfoxonium salts occurs, weak bases induce an
isomerization to the allylic aminosulfoxonium salts whose (dimethylamino)
sulfoxonium group shows a high nucleofugacity in intramolecular substitution by a
silyloxy group leading to tetrahydrofurans.
Scheme 48: Asymmetric synthesis of bicyclic tetrahydrofurans.
OMeN
R
Et3SiOSPh
Me3OBF4
CH2Cl2BF4
OMe2N
R
Et3SiOSPh
DBU
CH2Cl2BF4
O NMe2
R
Et3SiOS
Ph O
R
56
n
55
n
54
n
53
n
n = 1, 2, 3R = pMeOC6H4
THEORETICAL PART 44
CHAPTER 3
A Method for the Asymmetric Synthesis of Acyclic, Mono- and Bicyclic γ,δ– Unsaturated α-Amino Acids by
employing ClTi(NEt2)3.
.
THEORETICAL PART 45
3 A Method for the Asymmetric Synthesis of Acyclic, Mono- and Bicyclic γ,δ – Unsaturated α-Amino Acids by employing ClTi(NEt2)3 3.1 Introduction 3.1.1 Brief introduction about relevant biologically-active molecules The synthesis of α-amino acids (AAAs) has been of immense interest to organic
chemistry for over 150 years. It is well known that AAAs are vital to life itself as the
“building blocks” for peptides, proteins and many other natural products.56 Beyond
this fundamental role, AAAs are extensively used as food additives and as
agrochemical, pharmaceutical and crop protection agents. The most important
applications of AAAs are shown in Figure 13. Amino acids have also been used as
a source of the chiral pool57 and as catalysts for asymmetric synthesis.58,59 The
importance of AAAs has prompted the development of a multitude of synthetic
methods for their preparation.
Figure 13: Applications of amino acids.
CLASSIFICATION OF α-AMINO ACIDS
AAAs are one of the five major classes of natural products and can be grouped
broadly into proteinogenic and non-proteinogenic AAAs. The proteinogenic AAAs
Amino Acids
Pharmaceuticals
Media for Fermentation
and Cell Culture
Peptides Pesticides
Food Addditives Cosmetics
Taste and Aroma Enhancers
Feed Additives
THEORETICAL PART 46
HN
O
H NH2
N
S
O COOHH
HH HN
O
H NH2
N
S
O COOHH
HH
HO
HN
O
H NH2
N
O
HHS
COOH
HN
O
H NH2
N
O
HHS
COOH
HO
HO
HO
NH2
COOH
HOOC P
H2N H
OOH
Ampicillin Amoxicillin
Ceflexin Cefadroxil
Carbidopa 67 Phosphonotricin
66
(derived by protein hydrolysis) are twenty in number, and a large number of
naturally occurring amino acids are reported in the literature. Non-proteinogenic
AAAs are simple derivatives of proteinogenic amino acids, are mainly produced by
various micro organisms and interfere with the biochemical pathways of other
organisms. According to a survey in 1985, there are about 700 natural AAAs and
the list continues to grow.60 In addition to proteinogenic and non-proteinogenic
AAAs, there is a larg number of synthetic AAAs have been reported. These AAAs
are often termed as unusal (unnatural/non-natural/non-standard) amino acids.
Unusual AAAs can be further classified depending on the degree of substitution at
the α-position.
Cα-SUBSTITUTED α-AMINO ACIDS
α-Alkylated α-amino acids play an important role in the design of therapeutically
useful products (Figure 14). Representative examples of this class are
phenylglycine and p-hydroxy phenylglycine. D-phenylglycine is used as a building
block in the synthesis of best selling drugs such as ampicillin and ceflexin.61
Similarly, D-p-hydroxy phenylglycine is used in the preparation of several
antibiotics such as amoxicillin and cefadroxil (Figure 14).
Figure 14: Therapeutically useful amino acids.
THEORETICAL PART 47
Cα N -SUBSTITUTED α-AMINO ACIDS (Constrained Imino Acids)
In this class of amino acids the nitogen atom of the amino acid group is part of a
ring. These amino acids (68-76) play an important role in inducing the
conformation of the peptide into which the amino acid is incorporated. Since the
nitogen in these amino acids is unable to act as hydrogen bond donor unless it is
located in a terminal position of a langer molecule. A few examples of this class
are shown in Figure 13. L-Azetodinecarboxylic acid 68 and its derivatives are
important amino acids both chemically and biologically.62,63 Naturally occurring
proteinogenic AAA proline (69) plays an important role in many biologically active
peptides. Recently, phenylproline 70 was used as a synthon in the synthesis of
angiotensin-converting enzyme (ACE) inhibitors.64 Several examples of peptides
which are based on the proline residue are also described in the literature.
Captopril 75 is the first orally active sulfhydryl Ala-pro derivative approved for use
in the treatment of hypertension and congestive heart failure.
Figure 15: Applications of cyclic α-amino acids.
Another interesting imino acid 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(Tic)-(71) is a critical component in quinaprilat (H) (77). Tic is commonly used as
structural replacement for phenylalanine in many biologically active peptides.
Incorporation of Tic-(71) into a peptides not only restrics the conformational
HNH
CO2HNH
H
CO2HNH
H
CO2H
Ph
NH
CO2H
N
CO2H
HS N
CO2H
CH3
Ph
CO2Et
n 71 n=1 Tic72 n=2 Sic73 n=3 Hic74 n=4 Nic
75 Captopril 76 Enalapril
68 69 70
N
HN
O
77 Quinaprilat (H)
THEORETICAL PART 48
NH
Boc2O
NBoc
Cl2Ru(PCy3)2CHMe
NBoc
CO(OMe)2, LDA
CH2Cl2
NBoc
CO2Me
NBoc
CO2Me
NBoc
CO2Me
Cyclohexane 93% 98%
THF, 0°C 83%
rac
Enzymatic kinetic resolution
+
freedom of the aromatic ring but also impose constraints in the peptide
backbone.65 These modifications provide valuble insight into the bioactive
conformations of the peptide ligands and have led to potent and selective drugs.
For example, when the phenylalanine component of the naturally-occuring farnesyl
transferase inhibitor 78, shown in Figure 14 is replaced with Tic, the peptidomimitic
structure 79 was obtained and found to be 50-fold more active than the natural
product 78.66
Figure 16: Importance of bicyclic α-amino acids.
3.1.2 Approaches towards the construction of proline derivatives
The literature on the synthesis of optically-pure AAAs is large and it is beyond the
scope of this thesis. In the following section we have opted to discuss methods for
the synthesis of 3-substituted unsaturated prolines, in order to place our work in
the proper perspective.
Helmchen approach Helmchen et al. disclosed a synthesis of proline derivatives involving ring closing
metathesis (RCM), directed alkoxycarbonylation and enzymatic kinetic resolution
of the racemate (Scheme 49).67
Scheme 49: Asymmetric synthesis of prolines via RCM.
H2N
HN
NH
HN CO2H
SH
O
O
O
S
H2N
HN
SH
O
N
HN CO2H
S
O
Cys-Val-Phe-Met Cys-Val-Tic-Met
O
78 79
THEORETICAL PART 49
Schmitt contribution Schmitt et al. disclosed an asymmetric synthesis of 3-substituted prolines by a
palladium-mediated coupling reaction of the O-triflate of 2-cyano-3-oxopyrrolidine
(Scheme 50).68 This method could generate proline derivatives but with lower de
and ee.
NTr
CO2Et
O
NTr
CO2Et
OTf
CH2Cl2 NTr
CO2Et
R
NTr
CO2Et
RTf2O, TEA, DMAP Palladium coupling
mixture of diastereomerscis/trans:15/1-4/1R=Et,3-MeO-C6H4
Scheme 50: Asymmetric synthesis of prolines via a palladium-mediated coupling reaction.
Gais approach Gais et al. disclosed the asymmetric synthesis of 3-substituted prolines by using
allyltitaniumsulfoximine chemistry.69
Scheme 51: Asymmetric synthesis of prolines using sulfoximine chemistry.
R
SPh
O NMe2S
O
EtONHOO
S
O
EtONOO
R
R
SPh
O NMeS
O
EtONHOO
SPh
O NMeR
SPh
O NMeR
T(iO iPr)2
R
SO NMe2
S
O
EtONHOO
Ph
BF4
SO
Ph NMe2
N
CO2Et
SO2
Me3OBF4CH2Cl2
BF4
21) 1.1 n-BuLi, THF
2) 2.1 ClTi(O iPr)3
5-10 KF, H2O
CH2Cl2, RT
+
R = Me, iPr, Ph, cC6H11
THEORETICAL PART 50
3.2 Present work 3.2.1 Aim As illustarted in the earlier section, proline derivatives are valuable compounds in
organic synthesis. In 2000, Hainz and Bruns, former members of our research
group, found a method for the region- and diastereoselective hydroxyalkylation of
the allylic sulfoximines (Scheme 52).
Scheme 52: Asymmetric synthesis of sulfoximine substituted homoallylic alcohols.
Schleusner extended the method to aldehyde analogues such as the α-iminoester,
as dipected in Scheme 53.70
Scheme 53: Reactivity of bis(allylsulfoximine)titanium complexes with aldehyde and α-imino ester.
SPh
NMeOR
HO R'
SPh
NMeOR
TiLx
R' SPh
O NMeR
OH
α-Hydroxy-alkylation
γ-Hydroxy-alkylation
R'CHOL = NEt2
R'CHOL = Oi-Pr
SPh
NMeOR
1. n-BuLi2. ClTiLx
SPh
NMeORR'
OH
SPh
NMe
OR
SRPh
NMe
O
Tii-PrOi-PrO
SPh
NMeOR
SPh
NMeO
R
NHBus
EtO2C
1. n-BuLi2. ClTi(Oi-Pr)3
R'CHO
N
CO2Et
Bus
THEORETICAL PART 51
The above mentioned method was succesfully applied to the asymmetric
synthesis of 3-substituted unsaturated proline derivatives by Tiwari and Schneider
(Scheme 54).69
Scheme 54: Asymmetric synthesis of proline derivatives by Tiwari and Schneider.
Based on these interesting observations, the following objectives were set forth for
the present investigation.
1) Development of γ-aminoalkylation using ClTi(NEt2)3 and α-iminoester.
2) To develop an efficient method for the synthesis of both cyclic and acyclic
allylic sulfoximines.
3) To develop a method for the asymmetric synthesis of proline derivatives
using chlorine substitution.
3.2.2 Results and Discussion . 3.2.2.1 Reterosynthetic Aproach
The reactions of allylmetal reagents with carbonyl compounds and imines have
been extensively studied during the last twenty years.71,72We have previously
reported mono-allylsulfoximinetitanium complex formation with ClTi(NEt2)3 and bis-
allyltitanium complex formation with ClTi(O-iPr)3. Though the mono-allyltitanium
complex formation with ClTi(NEt2)3 was previously known, we have explored the
use of bis-allyltitanium complexes for the synthesis of optically pure acyclic and
cyclic α-amino acids. Now, in the following section, we describe the application of
mono-allyl titanium complexes to the synthesis of monocyclic and bicyclic α-amino
R
SPh
O NMe2S
O
EtONHOO S
O
EtONOO
R
BF4
R
SPh
O NMeS
O
EtONHOO
R
Cl
S
O
EtONHOO
Me3OBF4CH2Cl2
Base
Baseaq.NaCl
THEORETICAL PART 52
acids (Scheme 55). As depicted in the retrosynthetic Scheme 55, the intial target
was the synthesis of the starting allylic sulfoximines and iminoester which has
been described by our group previously. 70
Scheme 55: Retrosynthetic scheme..
3.2.2.2 Synthesis of acyclic allylic sulfoximines As depicted in the retrosynthetic approach, the initial targets in the synthesis of the
acyclic sulfoximines, the vinyl sulfoximines, were prepared by following the
addition-elimination-isomerization route11a,39 shown in Scheme 59. Thus,
treatment of the chiral sulfoximine 3440 with n-BuLi at -78 °C, followed by the
addition of aldehydes and methylchloroformate, and subsequently by DBU gave
the corresponding vinylsulfoximines. These were again treated with DBU in
NBus
CO2Et
BF4
Cl
CO2Et
NHBus
S
CO2Et
NHBus
Ph
O NMe2
NBus
CO2Et
S
CO2Et
NHBus
Ph
O NMe
EtO2C
NHBus
R
Cl
SPh
O NMeTiN(Et2)3
N
CO2Et
Bus
SPh
O NMe
ClTi(NEt2)3
EtO2CS
NHBus
R
O
Ph
NMe2
EtO2CS
NHBus
R
O NMe
Ph
BF4
SR
Ti(OiPr)2
O NMe
Ph
MeS
Ph
O NMe
N
CO2Et
Bus
SRO NMe
Ph
2
ClTi(OiPr)3
80
81
84
82
81
85
934
7
89
86
91
92
93
THEORETICAL PART 53
acetonitrile at elevated temperatures to afford allyl sulfoximines 84a, b as mixtures
of (E) and (Z) isomers which were separated by preparative HPLC (Scheme 56).
Scheme 56: Synthesis of acyclic allylic sulfoximines..
3.2.2.3 Synthesis of cyclic allylic sulfoximines The known cyclic allylic sulfoximines 9a and 9b were prepared in a one pot
synthetic operation, without the isolation of intermediates, from the chiral N-methyl
sulfoximine 34 and the corresponding cycloalkanones by the inverse Peterson-
olefination and isomerization sequence previously described.16
Scheme 57: Synthesis of cyclic allylic sulfoximine.
3.2.2.4 Synthesis of the N-Bus-protected α-iminoester
Synthesis of tert-butylsulfonamide
The intermediate tert-butylsulfinyl chloride can be prepared from commercially-
available bis-tert-butyl disulfide as shown in scheme 58.73
S SH2O2
S SO SO2Cl2
SO
Cl
NaN3
CH3COOH 0 °C, DCM CH3CN/H2OS NH2
O
O
Scheme 58: Synthesis of tert-butylsulfonamide..
MeS
Ph
O NMeS
Ph
O NMe
R
1. DBU, MeCN2. E/Z separation 3. DBU, MeCN
SPh
O NMeR
34
1. n-BuLi, THF2. RCH2CHO3. ClCO2Me4. DBU 84a,b
a: R = i-Pr, b: R = cC6H11
SPh
O NMe
n
9a: n = 29b: n = 39c: n = 1
1. n-BuLi, THF2. cycloalkanone
3. ClSiMe34. n-BuLi5. NaOMe
MeS
Ph
O NMe
THEORETICAL PART 54
Synthesis of α-iminoester from tert-butylsulfonamide
The sulfonamide was treated with SOCl2 in refluxing toluene and followed by the
addition of ethyl glyoxylate to give the N-Bus α-Imino ester (Scheme 59).73
S NH2
O
OS NO
OS O
O
EtO2C H N
EtO2Ctoluene, reflux
1.5 eq SOCl2
toluene, reflux
1.6 eqBus
Scheme 59: Synthesis of the α-imino ester...
3.2.2.5 Addition to α-Imino Ester Having now synthesized the starting materials by using literature procedures we
now set out to reach the goals presented earlier in this chapter. For the study of
the addition of mono-allyl titanium complexes to the α-imno ester, we selected
both cyclic and acyclic allylic sulfoximines. Titanation of lithiated-9a-d with 1.4-1.5
eq. of ClTi(NEt2)3 at -78 °C for one hour, was followed by the dropwise addition of
the α–imino ester. After stirring the reaction mixture for 15 h at room temperature,
a diastereomeric mixture of (E)-82a-d and (E)-83a-d was formed. The dr was
determined by 1H NMR spectroscopy of the crude reaction mixture. The crude
reaction mixture was recrystallised to afford (E)-82a-d and (E)-83a-d (69-87%, 2-
14% depending upon the ring size). The 1H NMR spectrum of (E)-82c showed a
multiplet at 4.22 for 11-H, and the signal of the 2-H protons as a doublet of
doublets at 4.04. For (E)-83c we observed signals for the corresponding protons at
3.90 and 3.71, respectively. This indicates the formation of (E)-82c, as the major
diastereomer, the structure of which was further established by X-ray crystal
analysis (Figure16).
THEORETICAL PART 55
Scheme 60: Asymmetric synthesis of sulfoximine substituted α-amino acid
derivatives.
Table 4: Asymmetric synthesis of γ,δ-unsaturated α-amino acids
n Allylic sulfoximine
AminoalkylationProduct
E82ad/Ea- 83a-d
E-82a-d Yield de
E-83a-d Yield de
1 9a E-82a / E-83a 5.7-6 : 1 70 ≥98 14 ≥982 9b E-82b / E-83b 9.7-10 : 1 69 ≥98 8 ≥983 9c E-82c / E-83c 23-24 : 1 82 ≥98 4 ≥984 9d E-82d / E-83d 45-46 :1 87 ≥98 2 ≥98
aDetermined by 1H NMR spectroscopy of the crude reaction mixture
We have observed the exclusive formation of the (E)-isomer in case of entries 3
and 4 (Table 4). The configuration of the double bond of each set of isomers was
determined by NOE experiments that revealed strong NOE effects between the
olefinic proton and the allylic proton at the stereogenic center for the (E)-isomer,
and also a strong NOE between the phenyl and the methylene protons of the
alaiphatic ring (Figure 15).
Figure 15: NOEs of compound E-82c and E- 83c (500 MHz, CDCl3)..
CO2Et
HNBusS
O NCH3
HH
H
H
CO2Et
HNBusS
O NCH3
HH
H
H
E-82c E-83c
SPh
O NMe
SPh
O NMe
CO2Et
HNSO2t-Bu
THF
EtO2C
NSO2t-Bu
S Ti(NEt2)3Ph
O NMe
nn
+
n
1. 1.1 eq. n-BuLi2. 1.5 eq. ClTi(NEt2)3
E-82 E-83
a: n = 1 b: n = 2 c: n = 3 d: n = 4
9 80
81
SPh
O NMe
CO2Et
HNSO2t-Bu
n
THEORETICAL PART 56
The spectroscopic data of the minor diastereomer E-83c showed complete
agreement with the data previously reported by our group.23 We have observed
high diastereoselectivity in the case of 7- and 8-membered rings. Having
confirmed, the formation of (E)-82c as the major diastereomer, we wished to
examine the effect of ring size on diastereoselectivity. Following the same
experimental procedure, we performed futher reactions using substrates with
various ring sizes. High diastereoselectivity and yield were observed in the case of
the 7- and 8-membered systems (Table 4, entries 3, 4). This shows that ring size
affects the distereoselectivity of the amino alkylation reaction. The configuration of
(E)-82c was determined by X-ray crystal analysis which was carried out by Prof.
Dr. G. Raabe (Figure 16).
Figure 16: Structure of Compound E-82c as determined by single crystal X-ray
analysis.
Having successfully completed the study of cyclic systems we turned our attention
towards the acyclic systems in order to demonstrate the efficiency of our
approach. As examples, 84a and 84b were chosen to prove the feasibility of regio-
and stereoselective addition of acyclic mono-allyl titanium complexes 85a and 85b
to α-imino ester. Thus, the treatment of 85a and 85b, which were prepared from
allylic sulfoximine 84a and 84b in the usual manner with 1.2 equiv of N-Bus α-
imino ester 81 in the presence of ClTi(NEt2)3 resulted in a 95-96% conversion of
84a and 84b. Diastereomeric mixtures of the acyclic amino acid derivatives (E)-
86a-b and (E)-87a-b were obtained in a ratio of 6:1 and 1.9:1, respectively (Table
5). Spectroscopic data for the minor diastereomer matched that previously
reported by our group.70
THEORETICAL PART 57
Scheme 61: Asymmetric synthesis of sulfoximine substituted α-amino acid.derivatives..
Table 5: Asymmetric synthesis of γ,δ-unsaturated α-amino acids
n Allylic sulfoximine
Aminoalkylation Product
E-86a-b/Ea- 87a-b
E-86a-b Yield de
E-87a-b Yield de
1 84a E-86a / E-87a 1.8-1.9 : 1 56 ≥98 10 ≥982 84b E-86b / E-87b 5.8-6 : 1 58 ≥98 32 ≥98
aDetermined by 1H NMR spectroscopy of the crude reaction mixture.
3.2.2.6 Stereochemical consideration of the amino alkylation The stereochemical outcome of reactions involving mono(alkenyl)aminotitanium
complexes was already rationalised in the case of reactions with aldehydes.11 A
stereochemical rationalisation of the aminoalkylation of cyclic allylic sulfoximines
using ClTi(OiPr)3 was proposed by Schleusner and Koep.70 In this case
compounds 83 and 94 were obtained.23,70
For the rationalization of the regio- and stereoselectivities of the reactions of the
mono (alkenyl) aminotitanium complexes 9a-d with imines, we make the following
assumptions.
(1) Complex 88 is an equilibrium mixture of C-Ti complexes 88A and epi-
88A and the N-Ti comlexe 88B (Figure 17).
(2) The reactions of 88A, epi-88A, and 88B with the iminoester are
governed by the Curtin-Hammett principle.70 As a conseqvence, the
product composition is not in direct proportion to the relative
concentration of 88A and epi-88A of the substrate, but is controlled
mainly by the difference in standard free energies of the respective
R1 SPh
O NMe
THF
EtO2C
NSO2t-Bu
SPh
O NMe
R1
EtO2C
NHt-BuO2S
R1 SPh
O NMe
Ti(NEt2)3
SPh
O NMe
R1
EtO2C
NHt-BuO2S
1. n-BuLi, -78°C2. ClTi(NEt2)3
+
major (86) minor (87)
8485
3
a : R1 = iPrb : R1 = cC6H1
THEORETICAL PART 58
transition states. Thus, 88A leads to TS-89 and TS-90, whereas epi-
88A leads to TS-91 and TS-92 (Figure 17).
(3) The reactions of the titanium complexes with the iminoester proceed
through cyclic six-membered transition states.
Figure 17: Stereochemical consideration of the aminoalkylation of cyclic allyl(titanium) complexes.
SNMe
Ph
O
Ti(NEt2)3
S
O
NMe
Ph
Ti(NEt2)3
S
O
NMe
Ph
Ti(NEt2)388A
EtO2C
NSO2t-Bu
EtO2C
NSO2t-Bu
EtO2C
NSO2t-Bu
PG
SiSS O Si ReSi
Ti
N
LL
S
MeN
O
Ph
E
PGL
Ti
NS
NMe
PhH
H
EL
L
L
PG
Re S Si R
LN
Ti
ESMeN
Ph
O
L
L
TS89 S
TSATS91
CO2Et
HNPG
S
Ph
O NMe
S
CO2Et
HNPG
S
Ph
O NMe
E
NPGTiL3
S
Ph NMe
O
CA
S
PG
S
R Si Re
E
TiN
PG
S
MeN
OPh
L
LL
L
N
Ti
ELL
SMeN
O
Ph
SiSRe
TS90TS92
n
nn
(SS,RCα,Si,Re)
(E,SS,2S,3R)
(SS,SCα,Si,Re)
(SS,SCα,Re,Si)
(E,SS,2R,3S)
(SS,RCα,Re,Si)
n
n
n
n n
epi-88A
E-82a-dE-83a-d
88B
n
n
THEORETICAL PART 59
On the basis of the above-mentioned assumptions the following proposals are
made to explain the regio- and diastereo-selectivities.
(1) In TS-89 and TS-91, the iminoester and the sulfoximine group are co-
ordinated through their N-atoms to the Ti-atom, and the tert-Bus and the
ester group both occupy pseudoaxial positions.
(2) The major and decisive differences between the Si and Re chairlike
transition state models TS-91 and TS-92 and the analogous Re and Si
transition state models TS-89 and TS-90, which would lead to the formation
of the distereomers of (E/Z)-82 having the opposite configurations at both
stereogenic C-atoms are the positions of the sulfoximine group being
pseudo-equatorial in the case of the former and pseudo-axial in the case of
the latter.
(3) In comparing TS-89 and TS-91, the difference between both is the position
of the phenyl group of the sulfoximine moiety. In TS-89 the phenyl group is
in the sterically-non-hindering exo position, where as in TS-91, it is in the
sterically hindering endo-position. Thus making TS-89 lower in energy. In
TS-91 the sulfoximine group is expected to cause 1,2 interaction with the
methylene groups of the unsaturated ring, whereas it is not possible in TS-
89.
It is proposed that for larger rings (n = 3 and 4) the 1,2 interactions are expected to
be very high which could give very high diastereoselectivity leading to the
formation of compound 82. The complex 88B should react with imino ester via
transition state TS-A to give the diastereomer CA. Formation of this isomer has,
however, not been observed. This can be ascribed to an unfavorable steric
interaction of the phenyl group with the Bus group of the imino ester.
Similar transition state models (not depicted in Figure 18) and arguments can be
applied to the reactions of the acyclic, mono(allylisulfoximine)titanium complexes
with the imino ester.
THEORETICAL PART 60
Figure 18: Stereochemical consideration of the aminoalkylation of (allyl)titanium complexes.
Ti
N
E
PG
LL
S
MeN
O
Ph
TiN
E
PG
S
MeN
OPh
L
LL
Si
Re
R
S
Si
Re
S S
CO2Et
HNPG
S
Ph
O NMe
CO2Et
HNPG
SPh
O NMe
n
n
n
n(SS,SCα,Re,Si) (E,SS,2R,3S)
(SS,RCα,Re,Si) (Z,SS,2R,3S)
E = CO2Et, PG = SO2t-Bu, L = NEt2
(Re,Si)-Process
L
TS- 89
TS- 90
E-82a-d
Z-93 a-d
PG
N
TiESMeN
Ph
OL
L Si Re
N
TiEL
L
L
SMeNO
Ph
S
PGS
R
ReSi
S
CO2Et
HN PG
S Ph
O NMe
CO2Et
HNPGS
Ph
O NMe
n
n
n
n(SS,RCα,Si,Re) (E,SS,2S,3R)
(Z,SS,2S,3R)(SS,SCα,Si,Re)
(Si,Re)-Process
L
TS-91
TS-92 Z-94 a-d
E-83a-d
THEORETICAL PART 61
3.2.2.7 Substitution of the sulfoximine group by a chlorine atom Chlorine substitution of vinylic sulfoximines 95a-d has been observed by Tiwari
and Schindier.69 This substitution was performed by first activating the
sulfoximines 87a-d through methylation at the N-atom by treatment with Me3OBF4
(1.1eq.) in CH2Cl2 at room temperature for 2 h.
The aminosulfoxonium salts 95a-d (95%) thus obtained from this reaction were
than treated with saturated brine solution (in excess) in ethyl acetate at room
temperature for 3 h-3 d (Table 6) to afford the corresponding chlorine substituted
α-amino acid derivatives 97a-d. The chlorides were obtained in high yields as a
mixture of (E/Z) isomers which were separable by column chromatography.
Scheme 61: Synthesis of substituted α-amino acid derivatives.
It is noteworthy that the (E/Z) ratios are depended on bulkiness of the R group.
The tert-butyl substituted sulfoximine salt 95c gave exclusively (Z)-isomer in 82%,
besides sulfinamide was isolated in medium to high yield (Table 6, entry 3). In
contrast, the methyl-substituted sulfoximines (Table, entry 4) gave a mixture of the
(E/Z)-isomers, the (E)-isomer predominanting. Conversion of sulfonamide 29c to
(S)-N,S-dimethyl-S-phenyl sulfoximine of 98% ee has already been described.
S
NH
R
EtO
O
O
NMe
Ph
Bus
CH2Cl2
Me3OBF4 (1.1 eqv.)
EtOAc
SNH
R
EtO
O
O
NMe2
Ph
Bus
BF4
NH
R
EtO
O
Bus Cl NH
R
EtO
O
Bus
Cl
S
NH
R
EtO
O
O
NMe2
Ph
Bus
S
NH
R
EtO
O
O
NMe2
Ph
Bus
S
O
NMe2Ph
BF4
BF4
a: R = iPrb: R = cC6H11c: R = tBud: R = Me
RT, 2 h
Brine solution
+
+ +
87 95
E-96Z-96
Z-97 E-97 29c
THEORETICAL PART 62
Table6: Synthesis of substituted α -amino acid derivatives
Entry R Time Yield (29c) (%)
0BE/Z Yield ( 97) (%)
1 iPr 3 h 93 4/1 94 2 cC6H11 2.5 d 89 6/4 80 3 tBu 3 d 82 Only Z 76 4 2BMe 2.5 d 82 88/12 81
It is assumed that the vinyl aminosulfoxonium salts 95a-d suffer a Cl catalyzed
isomerisation with the formation of the corresponding allyl aminosulfoxonium salts
96a-d. Due to the high nucleofugacity of the allylic amino sulfoxinium group, salts
96a-d undergo a facile nucleophilic substitution with the Cl ion which is present in
the organic phase and leads to the formation of chlorine substituted α-amino acids
(Scheme 62).
Scheme 62: Postulated reaction pathway of the Cl substitution
After a successful demonstration of unexpected brine-assisted substitution of the
sulfoxonium group in various acyclic systems, we were intrested to test the
feasibility of this novel substitution in cyclic systems. Therefore, as a last example
we treated the vinylic sulfoxmine (E)-82b under the conditions described earlier, to
R
SO NMe2
S
O
EtONHOO
Ph
BF4S
Ph
O NMe2S
O
EtONHOO
R HR
SO NMe2
S
O
EtONHOO
Ph BF4
R
ClS
O
EtONHOO
R
Cl
S
O
EtONHOO
BF4
Cl
Cl
SO
NMe2Ph
DBU
R
BusN
O
OEt
+
++
95a-d Z-96a-d E-96a-d
THEORETICAL PART 63
afford the chlorine substituted cyclic amino acid derivative 99 in 70 % yield and
sulfonamide 29c in 72% yield (Scheme 62). The structure of chloride 99 was
confirmed by comparison of its spectral data with that reported for similar
compounds in the literature.
CO2Et
HNS
Ph
O NMeSO2t-Bu
BF4
CO2Et
HNS
Ph
O NMe2
SO2t-Bu
CO2Et
HNSO2t-BuCl
PhS
NMe2
O
+1.4 eq. Me3OBF4
CH2Cl2, 1.5 h, RT
aq. NH4Cl or NaCl
EtOAc, 24 h, RT
82b 99 29c98
Scheme 63: Synthesis of bicyclic proline derivatives.
3.2.2.8 Synthesis of proline analogoues As described in the introduction section, proline derivatives have gained much
attention in recent years. Particularly interesting are prolines that carry
substituents at the 3- and 4-positions. This substitution pattern offers not only new
possibilities for the attainment of conformationally-restricted peptide mimetics, but
can also be found as the core structure of the kainod amino acids.74,75
Figure 16: Natural products containing 3-substituted prolines.
Treatment of (Z)-97a-c with 1.2 eq. of DBU for 30 min in CH2Cl2 afforded the 3-
substituted, unsaturated proline analogues 101a-c in quantitative yields (Scheme
64). The spectroscopic data of the unsaturated proline analogues thus obtained
show complete agreement with the data reported in the literature.70
Subsequently, our attention turned towards the synthesis of bicyclic proline
derivative of type 100. Thus, the chlorine-substituted cyclic amino acid 99 also
cyclised in similar fashion to that described above, and afforded in quantitative
HNHO2C
HO2C
HNHCo2
HO2COH
HNHCo2
HO2CCO2H
Domoic Acid Kainic Acid Isodomic Acid
THEORETICAL PART 64
yield 100. It is assumed that the reaction pathway follows the base- catalysed,
intramolecular, nucleophilic substitution reaction to lead to the proline derivatives.
Scheme 64: Synthesis of proline derivatives.
It should be noted that the proline derivative 101c was deprotected by treatment
with CF3SO3H in DCM (0.05-0.1 M)76 to afford the proline ester 107 in good yield
(Scheme 65).
Scheme 65: Deprotection of the unsaturated proline 101c.
CO2Et
HNSO2t-BuCl N CO2Et
SO2
1.4 eq. DBU
CH2Cl2, 1.5 h, RT
99 100
R
ClNH
EtO
O
Bus
N
OEt
O
R
Bus
DBU (1.2 equiv.),CH2Cl2 (10 mL)
RT, 30 min.; quant.
Z-97a-c 101a-c
a) R = tBu; b) R = cC6H11; c) R = iPr
iPr
BusN
O
OEt
1) 3.1 CF3SO3H CH2Cl2, 0 °C, 2 h
2) sat. NaHCO3, H2O
iPr
NH O
OEt
101c 10780%
THEORETICAL PART 65
3.2.2.9 Cyclization of the Aminosulfoxonium Salts with LDA
In 1980, Johnson et al. reported the formation of sulfur ylides starting from S-
aminosulfoxonium salts.77,78 According to the results of Günter and Köhler, the
compounds 102 and 103, upon treatment with LiNHt-Bu, gave the corresponding
keto alkylsulfoxonium ylides 104 and 105, respectively (Scheme 66).
Scheme 66: Günter route for the synthesis of keto aminosulfoxonium ylide.
Similarly, we observed the formation of amino sulfoxonium ylides by deprotonation
of the salt by using more than two equivalents of LDA. Thus, treatment of the salt
of (E)-83b with 3.1 eq. of LDA at -78 °C in 30 min gave the keto aminosulfoxonium
ylide 106. Unfortunately, this compound could not be isolated in pure form due to
its unstability. The 13C NMR spectrum of the crude product shows the appearance
of a new signal at δ = 185 ppm attributed to carbonyl carbon of the ester group.
SPh
O
NMe2
OSiEt3EtO
O
LiNHt-Bu
O
OSiEt3S
Cl3CPh
OMe2NBF4
LiCCl3, THFSPh
O
NMe
OSiEt3EtO
O
Me3OBF4
102 104
SO NMe2
S
O
EtONOO BF4
SO NMe2
S
O
EtONOO
LiLi
BF4
-LiOEt
NS
O
OO
S
Li
OMe2N
3 eq. LiNHt-BuTHF
S O
NH S
O
O
O NMe2
IntramolekulareMichael Addition
103
105
THEORETICAL PART 66
We have also observed in 1H NMR of the crude product a new signal at 5.5 ppm,
which is indicative of the allylic proton. These results suggest that the reaction
occurred via the mechanism proposed in Scheme 67.
Scheme 67: Possible mechanism for the formation of the keto aminosulfoxonium
ylide.
SPh
O NMe
N
CO2Et
Bus
O
NBus
SPh
O NMe2
O
NBus
SPh
O NMe2
S
CO2Et
NHBus
Ph
O NMe
O
NHBus
SPh
O NMe2
SPh
O NMe2
OOEt
N Bus
DCM
Me3OBF4
BF4
S
CO2Et
NBus
Ph
O NMe2
S
CO2Et
NHBus
Ph
O NMe21. n-BuLi2. ClTi(O-iPr)3
2 LDA
OEt-
LDA
E-83b
106
THEORETICAL PART 67
3.2 Conclusion
In summary, we have achieved a highly-efficient asymmetric aminoalkylation of
cyclic and acyclic allyl sulfoximines with the α-imino ester using ClTi(NEt2)3, which
led to the unexpected formation of diastereomers ( Scheme 68).
R1 SPh
O NMe
THF
EtO2C
NSO2t-Bu
R1 SPh
O NMe
Ti(NEt2)3
SPh
O NMe
R1
EtO2C
NHt-BuO2S
1. n-BuLi, -78°C2. ClTi(NEt2)3
+
3
R2 R2
R2
SPh
O NMe
R1
EtO2C
NHt-BuO2S
R2
Scheme 68: Asymmetric synthesis of sulfoximine substituted cyclic and acyclic
α-amino acid derivatives.
Further to our study, we have observed the substitution of the sulfoxonium group
by Cl ion during the normal work up with saturated brine solution (Scheme 69).
S
NH
R
EtO
O
O
NMe
Ph
Bus1) Me3OBF4,DCM
a: R = iPrb: R = cC6H11c: R = tBud: R = Me
RT, 2 h
87
2) Brine solution EtOAc
NH
R
EtO
O
Bus Cl
(E/Z)-97
S
O
NMe2Ph
29c
+
Scheme 69: Synthesis of substituted α-amino acid derivatives.
CO2Et
HNS
Ph
O NMeSO2t-Bu
BF4
CO2Et
HNS
Ph
O NMe2
SO2t-Bu
CO2Et
HNSO2t-BuCl
PhS
NMe2
O
+1.4 eq. Me3OBF4
CH2Cl2, 1.5 h, RT
aq. NH4Cl or NaCl
EtOAc, 24 h, RT
82b 99 29c98
THEORETICAL PART 68
The base-catalyzed cyclization of acyclic and cyclic α-amino acids has
demonstrated the capacity of the newly developed strategy to allow formation of
unsaturated acyclic cyclic and bicyclic α-amino acids ( Scheme 70).
R1
R2
CO2Et
HNSO2t-BuCl N CO2Et
R1 R2
Bus
1.4 eq. DBU
CH2Cl2, 1.5 h, RT
R1+R2 = (CH2)4
R2 = tBu, cC6H11, iPr; R1 = H Scheme 70: Synthesis of proline derivatives.
THEORETICAL PART 69
CHAPTER 4
Cu-catalyzed stereoselective synthesis of Allylic Alcohols
.
THEORETICAL PART 70
4. Cu-catalyzed stereoselective synthesis of Allylic Alcohols
4.1 Introduction 4.1.1 Brief introduction about relevant biologically-active molecules During the last decade, allylic alcohols have been recognized as valuable
intermediates in organic synthesis. The allylic alcohols of type 108a-c would be of
particular interest due to the presence of additional chiral center at the δ-position
(Figure 19).78-80
Figure 19: Allylic alcohols.
Allylic alcohols of this type are found as structural elements of many natural
products, which often possess remarkably high biological activity.81,82 In addition
these are synthetically useful chiral building blocks. Amphidinium R (Figure 20))
belongs to the family of amphidinolides, which were isolated from dinoflagellate
Amphidinium sp. found off the coast of Okinawa/japan in 1986.83, They exihibited
significant toxicity against murine lymphoma L1210 and human epidermoid
carcinoma KB cells.84An example of a antifungal macrolide is the antibiotic
roxaticin.85 Besides being interesting synthetic targets per se, allylic alcohols with
additional chiral center at the δ-position of defined conifiguration also represent
exceedingly valuable key intermediates for the preparation of more complex
compounds like fluviricin B1.86
OH
R3
R2R1R4 Bu
a:R1 = cC6H11, R2 = H, R3 = Ph, R4 = Hb:R1 = Et, R2 = H, R3 = i-Pr, R4 = Mec: R1+R2 = (CH2)4, R3 = Ph, R4 = H
108a-c
THEORETICAL PART 71
Figure 20: Importance of allylic alcohols.
Siphonarienolone is a member of the siphonarienes, a class of polypropionates
produced by mollusks of the genus Siphonaria. It was isolated and tentatively
identified in 1988 by Norte et al.87 Compounds bearing a chiral quaternary carbon
center are ubiquitous in nature. Their construction poses a difficult challenge to the
synthetic chemists.88
In the following section we discuss various approaches reported in the literature
for the synthesis of allylic alcohol derivatives.
4.1.2 Approaches towards the construction of allylic alcohols Marshall approach Marshall et al. have reported a method for the synthesis of 1,4-bifunctional
compounds based on the Cu-catalyzed SN2′ reaction of alkenyloxiranes (Scheme
71). 89
O O
H
HH
OHH
O
O
OH OH OH OH OH
OH
HO
Constanolacton A (+)-Roxaticin
HN
OH
O
O
O
O
O
Fluviricin B1
O
O OH OH
OH
Amphidinolld R
OH O
Siphonarienolone
THEORETICAL PART 72
Scheme 71: Asymmetric synthesis of allylic alcohols by Marshal.
Trost approach In 1997, Trost et al. have reported a novel method involving a palladium catalyzed
reaction of alkenyloxiranes with prenucleophiles.90 The required alkenyloxirane
was obtained by Sharpless-Swern-Wittig route.
Scheme 72: Asymmetric Synthesis allylic alcohols by Trost.
Tanaka approach An efficient asymmetric synthesis of 1,4-bifunctional compounds has been
reported by Tanaka et al. in 2004.91 This method involves alkenylation of a α-
hydroxyaldehyde followed by regio- and diastereoselective Pd-catalyzed allylic
substitution as shown in Scheme 73. The substitution however, usually proceeds
not with high enantioselectivity.
OH
BnO
O
BnO
O
A
OHBnO
OH
A
OHBnO
OH
B
BnOOH
OH
B
BnOOH
OH
+
A:B = 84:16
Me2CuCl, THF-20 °C-0 °C
+
A:B = 94:6
Me2CuCl, THF-20 °C-0 °C
O
EWG'
EWGR
H
O P
O
O
Et EWG'
OH EWGPd(0)
Ligand
Ligand
a: R = H, EWG = EWG' = PhSO2 62%b: R = H, EWG = PhSO2 EWG' = CH3CO 55%c: R = Me, EWG = PhSO2EWG' = CN 52%
THEORETICAL PART 73
Scheme 73: Asymmetric synthesis of allylic alcohols by Tanaka.
4.2 Present Work 4.2.1 Aim From the above discussion it is clear that only very few methods are available for
the asymmetric synthesis of allyl alcohols. Most of the known methods start with
alkenyloxirane, which are not easy to access (Scheme 74). The documented
difficulties with the known routes for the synthesis of allyl alcohols encouraged us
to search for alternative methods.
Scheme 74: Sharpless-Swern-Wittig route.
CHOMe
OTBS
MeBu
OTBS
OH
Li Bu
(CF3CO)2O
MeBu
OTBS
OH
MeBu
OTBS
OC(O)CF3
MeBu
OTBS
OHMe
BuOTBS
CH(CO2Me)2
MeBu
OTBS
Pd*L
ether, -65 °C
79%
Py, 0 °C
86%
+
Pd(Ph3)4 (10 mol%)NaCH(CO2Me)2THF, rt.
7% 90%, 97:3 dr
anti:syn75:25
Ph3P=CHCO2EtSwern Oxidation
BnOOH
BnOOO
BnOOH
BnOO
CO2Et
BnOOH
O
1. Swern Oxidation2. Ph3P=C(Me)CO2Me3. DIBAH
SharplessEpoxidierung
THEORETICAL PART 74
N. Giesen, a former member of our group, had studied the asymmetric synthesis
of allylic alcohols of type 108d,f from sulfoximine substituted homoallylic alcohols
of type 892 (Scheme 75). It was thus of interest to see whether this method could
be extended to the synthesis of various cyclic alcohols of type 108a,b.
Scheme 75: Substitution of sulfoximine-substituted homoallylic alcohols
4.2.2 Results and Discussion 4.2.2.1 Retero synthetic analysis As illustrated in the foregoing section, allylic alcohols are interesting targets and
their asymmetric synthesis has been accomplished by several methods. Although
some of these methods are very efficient, they all lack of generality and are not
well suited for the synthesis of allylic alcohols of type 108b,c. We were therefore
interested in the asymmetric synthesis of both acyclic and cyclic allylic alcohols of
type 108a-c from aldehydes and allylic sulfoximines (Scheme 76).93
Scheme 76: Retrosynthetic analysis.
S
OH
R3
R2R1
OPhNMe
S
R2R1
OPhNMe
OH
R3
R2R1
Bu
MeS
Ph
O NMe
108a-c
S
OH
R2R1
OPhNMe
S
OH
R3OPh
NMe
OH
R2R1
Bu
OH
R3Bu
n-BuCu
n-BuCu
n n
n = 1,2R3 = i-Pr, Ph
8d,f 108d,f
11a,b 107a,b
R1 = i-Pr, EtR2 = i-Pr, Et
THEORETICAL PART 75
The synthesis of the allylic alcohols 108a-c were envisioned from the
corresponding sulfoximine substituted homoallylic alcohols 13 which in turn can be
derived from 12 via the α-hydroxyalkylation whose synthesis is reported by our
group recently.93 The allylic sulfoximine 12 can be derived from the sulfoximine
34 by addition, elimination and isomerisation route (AEI).11
4.2.2.2 Hydroxyalkylation of allylic sulfoximines The acyclic allylic sulfoximines 110a-c were selected for the synthesis of the 1,4-
bifunctional compounds of type 108a-c. Sulfoximines 110a and 110b were
prepared from sulfoximine 34 and the corresponding aldehydes following the
addition-elimination-isomerization route depicted in Scheme 77. Similarly the new
allylic sulfoximine 110c was synthesized from sulfoximine 34 and 2-methyl-
butyraldehyde. The intermediate 1-alkenyl sulfoximine 109c was not isolated but
treated with DBU in MeCN at elevated temparature to give mixtures of the (E) and
(Z)- configured allylic sulfoximines (E)-110c and (Z)-110c in ratio of 70:30. The
(E/Z)–isomers were readily separated by preparative HPLC. Isomerization of the
unwanted (Z)-isomer with DBU in MeCN again gave a mixture of the (E)- and (Z)-
isomers which were separated. The N-methyl-S-phenyl sulfoximines 110a-c were
selected because of the ease of the preparation of 34 in enantiomerically pure
form.11
Scheme 77: Asymmetric synthesis of allylic sulfoximines.
SPh
O NMeR1
R22. E/Z separation 3. DBU, MeCN
1. DBU, MeCNSPh
O NMeR1
R2MeS
Ph
O NMe
34
1. n-BuLi, THF2. R1CH(R2)CHO3. ClCO2Me4. DBU 109a-c 110a-c
a: R1 = cC6H11, R2=Hb: R1 = Ph, R2= Mec: R1 = Et, R2= Me
THEORETICAL PART 76
Successive lithiation and titanation of the 110a with 1.1 equiv. of nBuLi and 1.2 eq.
of ClTi(NEt2)3 at –78 °C in THF afforded the corresponding allylic titanium
complex, which upon treatment with benzaldehyde at –78 °C gave, as described
previously,11 the diastereomerically pure syn-configured sulfoximine-substituted
homoallylic alcohol 111a in good yield (Table 7). Similarly, the new
diastereomerically pure homoallylic alcohols 111b and 111c were obtained in
good yields from the allylic sulfoximines 110b and 110c, respectively and
isobutyraldehyde. (Table7) NMR spectroscopic analysis of the crude reaction
products showed the hydroxyalkylation to be, as in all previously described cases,
highly diastereoselective (≥ 98% de) and regioselective (≥ 98:2).
Scheme 78: Asymmetric synthesis of sulfoximine substituted homoallylic alcohols.
Table7: Synthesis of sulfonimidoyl-substituted homoallylic alcohols
Entry Starting
material
Aldehyde Product dr (%)a Yield (%)
1 E-110a PhCHO E-111a ≥98 : 2 70
2 E-110b i-PrCHO E-111b ≥98 : 2 -b-
3 E-110c i-PrCHO E-111c ≥98 : 2 75 aFrom 1H NMR spectroscopic analysis. b not isolated..
SPh
O NMeR1
R2
R1 R3
OH
SNMe
OPhR2
110a-c 111a-c
a: R1 = cC6H11, R2 = Hb: R1 = Ph, R2 = Mec: R1 = Et, R2 = Me
a: R = Phb: R = i-Pr
a: R1 = cC6H11, R2 = H, R3 = Phb: R1 = Ph, R2 = Me R3 = i-Prc: R1 = Et , R2 = Me , R3 = i-Pr
1. n-BuLi, THF2. ClTi(NEt2)3
3. RCHO (a,b)
THEORETICAL PART 77
4.2.2.3 Substitution of sulfoximine substituted homoallylic alcohols The substitution recently developed in our group by N. Giesen90 for the synthesis
of allylic alcohols is depicted in Scheme 79.
Scheme 79: Asymmetric synthesis of allylic alcohols compounds.
To a solution of CuI (3.2 mmol) in THF (5 mL) and Me2S (3 mL) was added nBuLi
(3.2 mmol) at -78 °C. After stirring the mixture for 45 min at this temperature, the
allylic sulfoximine 111a (1 mmol) in THF (2 mL) was added. The solution was
stirred for 18 h at -78 °C. Aqueous workup of the reaction mixture and purification
of crude product by chromatography gave the allylic alcohol 112 in 75% yield and
≥98% de. Similarly, the diastereomercally pure allylic alcohol 113 was obtained in
67% yield from allylic sulfoximine 111c. In this reaction, 10% of unreacted 111c was recovered.
The structure of 112 and 113 were established based on their spectral data. The
de-values were determined by NMR spectroscopy of crude reaction products.
Scheme 80: Asymmetric synthesis of allylic alcohols.
Ph
OH
SNMe
OPh
Ph
OH
SNMe
OPh
Et
Ph
OH
Bu
EtPh
OH
Me Bu
CuI(3.2 eq.)/n-BuLi (3.2 eq.)
THF, -78 °C 5 °C18 h 75% yield
CuI(3.2 eq.)/n-BuLi (3.2 eq.)
THF, -78 °C 5 °C18 h
111a
111c
112
11367% yield
S
OH
R2R1
ONMe
R3Ph
OH
R2R1Bu R3
THF, -78 °CCuI/n-BuLi
a: R1 = i-Pr, R2 = i-Pr, R3 = Hb: R1 = cC6H11 , R2 = i-Pr, R3 = Hc: R1 = cC6H11 , R2 = i-Pr, R3 = Me
70-80%, >98% de
THEORETICAL PART 78
After having a successful demonstration of Cu assisted substitution of sulfoximine
substituted homoallylic alcohols in various acyclic systems, we studied the
feasibility of this novel substitution also in cyclic systems. Therefore as a last
example sulfoximine 11a was treated with n-BuCu (3.2 eq.) to afford allylic alcohol
derivative 114. Thus, to a solution of CuI (3.2 mmol) in THF (5 mL) and Me2S (3
mL) was added n-BuLi (3.2 mmol) at -78 °C. After stirring for 45 min at this
temperature, the allylic sulfoximine 11a (1 mmol) in THF (2 mL) was added. The
solution was stirred for 18 h at -78 °C. Aqueous workup of the reaction mixture and
purification of crude product by chromatography gave the allylic alcohol 114 in
70% yield and ≥98% de. In addtion 10% of unreacted 11a was recovered.
The structure of 114 was established based on their spectral data. The de-value
was determined by NMR spectroscopy of the crude reaction product.
Scheme 81: Asymmetric synthesis of allylic alcohols.
4.2.2.4 Absolute Configuration of the Allylic alcohol derivative The absolute configuration of the alcohol 118 had been determined by convertion
to the corresponding urethane derivative and X-ray crystal structure analysis by N.
Giesen (Scheme 82).92
Scheme 82: Synthesis of urethane derivative by N. Giesen.
Ph
OH
SNMe
OPhPh
OH
BuCuI(3.2 eq.)/n-BuLi (3.2 eq.)
THF, -78 °C 5 °C18 h
70% yield
11a 114
Bu
OH NCO
Bu
O
O
NH
Petrolether
118
THEORETICAL PART 79
Attempts to convert alcohol 114 to urethane 115 were unsuccessful. Treatment of
114 with phenylisocyanate in n-hexane led to a decomposition of the starting
material.92
Scheme 83: Urethane derivative synthesis.
After having these unsuccesesful results we turned our attention towards a
chemical correlation method which was described by our group previously.93,94
Thus the ozonolysis of (+)-114 gave the decomposition of the starting material.
Scheme 84: Ozonolysis of compounds 116 and 114 4.2.2.5 Mechanistic Considerations
The creation of central chirality by the γ-substitution of an allylic substrate with an
organocopper or an organocuprate reagent constitutes an important process in
organic synthesis. 95-100 The mechanistic scheme put forward by Rudler et al.,101
Goering et al.,102 and Bäckvall et al.103 for the reaction of primary biased allylic
substrates with cupper organyls is based on homoleptic cuprates B (Y = R) and
heteroleptic cuprates B (Y = Hal) and features the following steps (Scheme 84):
(1) reaction of substrate A with cuprate B with formation of the π-complex C, (2)
convertion of C through an oxidative addition-substitution to σ-allycomplex D, and
(3) reductive elimination of D to give the substitution product F. In the case of γ-D
Ph
OH
Bu NCO
Petrolether
Ph
O
Bu
O
NH
114 115
Ph
OH
BuO
Bu1. O3, CH2Cl2, MeOH -60 °C2. O3 O2
3. Me2S, -60 °C-rt
BuO
Bu1. O3, CH2Cl2, MeOH -60 °C2. O3 O2
3. Me2S, -60 °C-rt116 117
114
THEORETICAL PART 80
(Y = R2), reductive elimination is though to be relatively slow because of the two C-
bonded organic ligands, thus allowing for an equilibration via π-allyl complex E (Y
= R2), to isomeric α-D (Y = R2), followed by the reductive elimination of the latter to
α-F. Reductive elimination of α-D is anticipated to be faster than that of γ-D
perhaps because of steric reasons. In the case of γ-D (Y = Hal), reductive
elimination is assumed to be faster than its isomerization to α-D (Y = Hal) because
of the electronegative halide and thus γ-F would be formed preferentially.
Scheme 85: Mechanistic scheme for the allylic substitution.
The selectivity of the reactions of the acyclic and cyclic allylic sulfoximines
(Scheme 86 and 87) with n-BuCu can be summarized as follows.
High regioselectivity was observed in case of 111a,c and 11a resulting in the
formation of the corresponding γ-subsitution product. The formation of the α-
substitution product was not observed. According to the absolute configuration of
the newly formed stereogenic center it was clear that the substitution involved a
Re-face addition to the double bond.
According to the crystal structure the hydroxy allylic sulfoximine (E)-8 has a rigid
cyclic six membered ring through H-bonding as shown in Scheme 86. The α-H and
β-H are anti-periplanar to each other. The butenyl and R2 groups occupy pseudo
equatorial positions and β-H and γ-H are antpriplanar to each other.
MR1 X R1 X
CuY R2
A B C
-MX
R1
R1R1
CuR2Y
CuR2YCu
R2Y
-CuY-CuY
R1
R2R1
R2
M Cu(Y)R2
X = Hal, OR (R = H, COR', SO2R', PO(OR')2, SR, SeR, SOR, SO2R, SO(NR')R".Y = R2, Hal.
α-D E γ-D
α-F γ-F
THEORETICAL PART 81
It is clear from our results that at least 2 equivalents of the Cu-reagent are
necessary to achieve the substitution. The first equivalent could deprotonate the
OH group. The proposed structure for the deprotonated intermediate (E)-8 is
shown in Scheme 86. Here the Cu atom is co-ordinated with the oxygen atom of
the sulfoximine group. The high regioselectivity (γ-position) observed in the
substitution reaction supports a favorable chair like transition state which was
depicted in Scheme 87.
Scheme 86: Deprotonation of E-8 with 1 eq. of n-BuCu.
The high selectivity of the reaction with the second equivalent of the n-BuCu may
be attributed to the intramolecular syn-nucliophilic attack of n-BuCu at the γ-carbon
atom (Scheme 87). It is proposed that the second equivalent of the n-BuCu is co-
ordinated to the lone pair of the sulfoximine N-atom before the nucleophile attack.
This co-ordination might be responsible for the attack on the Re-face of the double
bond which leads to the product.
Scheme 87: Mechanistic scheme for the formation of allylic alcohols..ifor the
forma
SO
N
OH
H
H
H
R1R2
Ph
Me SPh
O
OCu
H
H
H
R1R2
N
Me
E-8
1 equiv. n-BuCu
deprot. E-8
12
R1 = Et, i-Pr, cC6H11
R2 = i-Pr, Ph
SPh
O
OCu
H
H
H
R1R2
N
MeCuBu
HOR1
R2
Bu
1
2
deprot E-8 107
R1 = Et, i-Pr, cC6H11
R2 = i-Pr, Ph
THEORETICAL PART 82
4.3 Conclusion
In summary, we have achieved a highly efficient asymmetric synthesis of allyl
alcohols based on Cu-mediated SN2′ reaction of sulfoximine substituted
homoallylic alcohols (Scheme 88). We have also demonstrated that this method
allows the construction of a quaternary carbon center.
SPh
O NMeR1
R2
R1 R3
OH
SNMe
OPhR2
2. E/Z separation 3. DBU, MeCN
1. DBU, MeCNSPh
O NMeR1
R2
R1 R3
OH
R2 Bu
MeS
Ph
O NMe
34
1. n-BuLi, THF2. R1CH(R2)CHO3. ClCO2Me4. DBU 109a-c 110a-c
a: R = Phb: R = i-Pr
1. n-BuLi, THF2. ClTi(NEt2)3
3. RCHO (a,b)
109a: R1 = cC6H11, R2=H109b: R1 = Ph, R2= Me109c: R1 = Et, R2= Me
111a-c
a: R1 = cC6H11, R2 = H, R3 = Phb: R1 = Ph, R2 = Me R3 = i-Prc: R1 = Et 1, R2 = Me , R3 = i-Pr
112a-c
a: R1 = cC6H11, R2 = H, R3 = Phb: R1 = Ph, R2 = Me R3 = i-Prc: R1 = Et 1, R2 = Me , R3 = i-Pr
CuI(3.2 eq.)/n-BuLi (3.2 eq.)THF, -78 °C 5 °C18 h
70-75%, >98% de
67-75%, >98% de
Scheme 88: Asymmetric synthesis of allylic alcohols.
THEORETICAL PART 83
we have also successfully demonstrated that the Cu assisted substitution also
works in the case of cyclic sulfoximie substituted homoallylic alcohol of type 11a.
Scheme 89: Asymmetric synthesis of allylic alcohols.
Ph
OH
SNMe
OPhPh
OH
BuCuI(3.2 eq.)/n-BuLi (3.2 eq.)
THF, -78 °C 5 °C18 h
70% yield
11a 114
84
CHAPTER 5 Experimental Part
.
EXPERIMENTAL PART 85
B. 1BExperimental Part 5 Experimental Section 5.1 General Remarks All reactions were carried out in absolute solvents under argon with syringe
Schlenk techniques in oven-dried glassware. THF and ether were distilled under
argon from potassium/benzophenone and sodium/benzophenone, respectively.
Reagents and solvents were transferred under argon via syringe or cannula. Thin-
layer chromatography was performed on silica gel 60 (Merck F254), coated on
aluminium plates and visualized by UV or permanganate treatment. Flash
chromatography was performed on silica gel 60 particle size 0.040-0.063 mm
(Merck). Solutions of crude reactions mixture were filtered through Celite (Fluka
535). ClTi(Oi-Pr)3, ClTi(NEt2)3 of ≥96% purity (1H NMR) were prepared according
to the literature.104 Enantiomerically pure (S)- and (R)-S-methyl-S-
phenylsulfoximine, which are also commercially available, were synthesized as
described previously. CuI was purchased by Aldrich. All other chemicals were
obtained from commercial sources used without further purification.
5.2 Analytic U
1H NMR Spectroscopy Varian Mercury 300 (300 MHz)
Varian Inova 400 (400 MHz)
Varian Unity 500 (500 MHz)
Internal Standard: Tetramethysilan
The following abbreviations are used to designate the multiplicity of the peaks in
the 1H NMR spectra:
s = Singlet
d = Doublet
t = Triplet
q = Quartet
quin = Quintet
sext = Sextet
sept = Septet
EXPERIMENTAL PART 86
oct = Octett
m = Multiplet
br = broad
%100//
..
..•=
nInI
gesges
beobbeobNOE
Ibeob. = Signalintensität (Integral) des beobachteten Kerns
Iges. = Betrag der Signalintensität (negatives Integral) des gesättigten
Kerns
nbeob., nges. = Anzahl der jeweils chemisch äquivalenten Kerne
U
13C NMR Spectroscopy: Varian Mercury 300 (75 MHz)
Varian Inova 400 (100 MHz)
Varian Unity 500 (125 MHz)
Internal Standard: Tetramethysilan
Peaks in the 13C NMR spectra are donated as „u“ for carbons with zero or two
attached protons or d for carbons with one or three attached protons, as
determined from APT pulse sequence.
UInfrared Spectroiscopy IR spectra were taken with a Perkin-Elmer PE 1759 FT, Perkin Elmer FTIR 1760 S, and only peaks of > 600 cm are listed.
w = weak (Absorption 20 – 40 %)
m = medium (Absorption 40 – 70 %)
s = strong (Absorption > 70 %)
UMass Spectrometry Varian Mat 212 S und Finnigan MAT 312
EI. 70 eV; chemical Ionisation (CI) 100 eV; Directe chemical Ionisation (DCI) 70
eV.
HRMS: Varian MAT 95 (EI, 70 eV).
EXPERIMENTAL PART 87
UElemental Analysis Heraeus CHN-O-RAPID and Elemental Vario El.
UOptical Rotatoary Power Optical rotations were measured on a Perkin Elmer Model 241 Polarimeter at 25
°C.
UMelting Point Melting points were determined using a Büchi apparatus SMP-20 and are
uncorrected.
5.3 General procedures
5.3.1 General Procedure for the Substitution of Sulfoximine-Substituted Homoallylic Alcohols (GP1)
ClCO2CH(Cl)Me (1.3 mmol) was added at room temperature to a solution of the
sulfoximine-substituted homoallylic alcohol (1 mmol) in CH2Cl2 (10 mL). The
progress of the reaction was monitored by TLC ( EtOAc/n-hexane, 1:9). After the
mixture had been stirred at room temperature for 1.5 h, it was concentrated in
vacuo. Purification by flash chromatography (EtOAc/n-hexane, 1:9) gave the
alkenyl/cycloalkenyl chlorohydrine and sulfinamide as colorless oils.
5.3.2 General Procedure for the Elimination of Alkenyl/Cycloalkenyl
Chlorohydrins (Gp2) DBU (1 mmol) was added at room temperature to a solution of chlorohydrine (1
mmol) in CH2Cl2 (10 mL). The progress of the reaction was monitored by TLC
(EtOAc/hexane, 1:9). After the mixture had been stirred at room temperature for
1.5 h, CH2Cl2 was carefully evaporated under reduced pressure (highly volatile
compound!). Conventional workup followed by purification by flash
chromatography (EtOAc/n-hexane, 1:9) gave the alkenyl/cycloalkenyloxirane as a
colorless oil.
EXPERIMENTAL PART 88
5.3.3 General Procedure for the Synthesis of Silylated Homoallylic Alcohols (GP3)
To a solution of the allylic sulfoximine (2 mmol) in THF (20 mL) was added at −78 oC n-BuLi (2.1 mmol, 0.69 mL of 1.6 M in hexane) and the reaction mixture was
stirred at −78 oC for 1 h. Then neat ClTi(Oi-Pr)3 (2.1 mmol) was added and the
resulting mixture was stirred first at −78 oC for 30 min and then at 0 oC for 2 h.
Subsequently the mixture was cooled to –100 oC and the aldehyde (1.0 mmol)
was added. After stirring the mixture at –78 oC for 2 h, saturated aqueous
(NH4)2CO3 (10 mL) was added and the mixture was stirred at room temperature
for 30 min. Then the mixture was extracted with ethyl acetate and the combined
organic phases were dried (MgSO4) and concentrated in vacuo. The residue was
dissolved in DMF (10 mL) and imidazole (273 mg, 4 mmol) and ClSiEt3 (4 mmol)
dropwise were added successively. After stirring the reaction mixture for 20 h at
room temperature, half-saturated aqueous NaHCO3 was added and the resulting
mixture was extracted with ether. The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The crude product was purified by column
chromatography (silica gel, ethyl acetate/hexane, 1:3 then 1:1) to give the silyl
ether and allylic sulfoximine.
5.3.4 General Procedure for the Synthesis of Dihydrofurans (GP4) Sulfoximin (1 mmol) and Me3OBF4 (1.3 mmol) were placed under argon in a
Schlenk flask. The flask was consecutively evacuated and refilled with dry argon
(3 times). Then CH2Cl2 (30 mL) was added and the reaction mixture was stirred at
room temperature for 1 h. Subsequently water (25 mL) was added and the
reaction mixture was stirred at room temperature for 15 min. Then the mixture was
extracted with CH2Cl2 and the combined organic phases were dried (MgSO4) and
concentrated in vacuo and the residue was dried in high vacuum (10-3 mbar) for 3
h. The thus obtained salt was dissolved in THF (50 mL) and freshly prepared
LiN(H)tBu (1.1 mmol, 1.1 ml of 1 M in THF) was added at −78 °C. After stirring the
mixture at room temperature for 15 h, saturated aqueous NaHCO3 (25 mL) was
added and stirring was continued for 10 min. Then the mixture was extracted with
EXPERIMENTAL PART 89
ether and the combined organic phase were dried (MgSO4) and concentrated in
vacuo. Purification of the residue by column chromatography (silica gel, ethyl
acetate/hexane, 1:20) gave the dihydrofuran as a colorless oil and sulfinamide (ethyl acetate/hexane, 1:1)
5.3.5 General Procedure for the Synthesis of Bicyclic Tetrahydrofurans (GP5)
Sulfoximine (1 mmol) and Me3OBF4 (1.3 mmol) were placed under argon in a
Schlenk flask. The flask was consecutively evacuated and refilled with dry argon
(3 times). Then CH2Cl2 (30 mL) was added and the reaction mixture was stirred at
room temperature for 1 h. Subsequently water (25 mL) was added and the
reaction mixture was stirred at room temperature for 15 min. Then the mixture was
extracted with CH2Cl2 and the combined organic phases were dried (MgSO4) and
concentrated in vacuo and the residue was dried in high vacuum (10-3 mbar) for 3
h. The thus obtained salt was dissolved in CH2Cl2 (50 mL) and DBU (1.5 mmol)
was added at room temparature. After stirring the mixture at room temperature for
8-10 h, water (15 mL) was added and stirring was continued for 10 min. Then the
mixture was extracted with DCM and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification of the residue by column
chromatography (flashsilica gel, ethyl acetate/hexane, 1:20) gave the
tetrahydrofuran as colorless crystals and sulfinamide (ethyl acetate/hexane, 1:1).
5.3.6 General Procedure for the Synthesis of Sulfoximine Substituted Amino Acids (GP6)
n-BuLi (1.37 mL of 1.6 M solution in n-hexane, 2.2 mmol) was added dropwise at –
78 °C to a solution of the allylic sulfoximine (2.0 mmol) in THF (20 mL). After the
mixture was stirred at –78 °C for 40 min, neat ClTi(NEt2)3 (2.8 mmol) was added,
and stirring at this temperature was continued for 45 min. The cooling bath was
removed and the mixture was allowed to stir for 60 min, then recooled to –78 °C,
and allowed to stir at this temparature for 60 min. Then the α-imino ester (2.4
mmol) was added dropwise and the mixture was stirred at –78 °C for 5 h. Then it
was allowed to warm to ambient temperature within 15 h. Saturated aqueous
(NH4)CO3 (150 ml) was added, and the mixture was stirred at ambient temperature
EXPERIMENTAL PART 90
for 30 min. Then the mixture was extracted with ethyl acetate (150 ml) and the
combined organic phases were dried (MgSO4) and concentrated in vacuo. The
residual yellow oil was dissolved in CH2Cl2 and n-pentane was added until the
solution became slightly turbid. The solution was kept overnight at 2 °C to give the
major diastereomer of the amino acid derivative of ≥98% de (1H NMR) as fine
white crystals. Preparative HPLC (EtOAc/n-hexane, 4:1) of the mother liquor
afforded the minor diastereomer as a colorless solid of ≥98% de (1H NMR).
5.3.7 General Procedure for the Synthesis of Allylic Alcohols (GP7) To a solution of CuI (3.2 mmol) in THF (5 mL) and Me2S (3 mL) was added nBuLi
(3.2 mmol) at -78 °C. After stirring for 45 min at this temperature, and the allylic
sulfoximine (1 mmol) in THF (2 mL) was added. The solution was stirred for 18 h
at -78 °C, and then a 10:1 mixture of saturated aqueous NH4Cl and concentrated
NH3 was added. The resulting mixture was stirred for 30 min. at room temperature,
and extracted with Et2O (4 x 20 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Purification of the residue by chromatography
(9% EtOAc/n-hexane) gave the allylic alcohol. In addition 10% of allylic sulfoximine
was isolated.
EXPERIMENTAL PART 91
5.4 Synthesis of Allylic Sulfoximine 5.4.1 Synthesis of (S,E)-N-methyl-S-(4,2-dimethyl-2-pentenyl)-S-
phenylsulfoximine and (S,Z)-N-methyl-S-(4,2-dimethyl-2-pentenyl)-S-phenylsulfoximine (E-58a and Z-58a).
To a solution of 34 (12.0 g, 0.07mol) in THF (200 ml) at –780C was added n-BuLi
(48.5 mL, 1.60 M solution in hexane, 0.08 mol). After stirring the mixture for 30min,
4-methyl-2-pentanone (10 mL, 0.08 mol) was added. The mixture was stirred for 2
h and then CICOOMe (6 mL, 0.08 mmol) was added. After warming the resulting
mixture to room temperature, it was stirred for 1h. It was then cooled to –78 °C and
DBU (13.5 mL, 0.09 mol) was added, which led to the deposition of a colorless
precipitate. After allowing the mixture to warm to room temperature over a period
of 12 h, it was treated with half-saturated aqueous NH4Cl solution and extracted
with EtOAc. The combined organic phases were dried (MgSO4) and the solvent
was removed in vacuo. The residue was dissolved in acetonitrile (200 mL) and
DBU (13.5 mL, 0.09 mol) was added. After heating the mixture to 80-90 °C for 8 d,
it was allowed to cool to room temperature, treated with half-saturated aqueous
NH4Cl, and extracted with EtOAc. The combined organic phases were dried
(MgSO4) and the solvent was removed in vacuo. Purification of the residue by
chromatography (EtOAc/hexane, 1:1) gave a mixture of E-58a and Z-58b (15.3 g,
86%) in a ratio of 60:40 as a colorless oil. The (E) and (Z) isomers were separated
by HPLC (EtOAc/n-hexane, 4:1).
SPh
O NMe
H
NOE
NOE
E-58a E-58a: 1H NMR (400 MHz, CDCl3): δ 0.68 (dd, 3 H, J =6.6, J =2.2 Hz, CH3), 0.80 (dd, 3 H,
J =6.6, J =2.2 Hz, CH3), 1.76 (s, 3 H, CH3), 2.24 (m, 1 H, CH(CH3)3), 2.72 (s, 3 H,
EXPERIMENTAL PART 92
NCH3), 3.79 (d, 2 H, CH2), 4.68 (d, J =9.3 Hz, 1 H, CH=C), 7.55 (m, 3 H, Ph),
7.80 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 16.66 (CH3, d), 22.15, 22.18 (CH3, d), 27.33
(CH(CH3)3, d), 29.75 (NCH3, d), 66.11 (CH2, u), 121.34 (C=CH, u), 128.74,
129.51, 129.75, 132. 40 (o-, m-, p-C, d), 136.38 (i-C, u), 143.50 (C=CH).
1H{1H}-NOE-Experiment (400 MHz, CDCl3) of E-58a
[%] H-2 H-3 H-5 H-6H-2 0.7 5.2H-3 0.8 7.5 0.01H-4 5.0H-5 2.2 1.2H-6 1.5 0.1 1.2H-7 1.1
-
Emitted Frequency
Obs
erve
d Fr
eque
ncy
IR (capillary): ν 3061 (s), 2959 (vs), 2926 (s), 2870 (s), 2802 (s), 1463 (m), 1446
(m), 1404 (m), 1388 (m), 1246 (vs), 1157 (vs), 1106 (s), 1081 (s), 896 (s), 858 (s)
cm−1.
CI-MS m/z (relative intensity, %): 252 [M++1] (100), 251 [M+] (2), 212 (2), 208 (6),
194 (2), 158 (2), 157 (3), 156 (28), 154 (4), 140 (3), 126 (3), 99 (2), 98 (6), 97 (3),
85 (2).
Elemental Analysis: Anal. Calcd for C14H21NOS (251.39): C, 66.89; H, 8.42; N, 5.57
Found : C, 66.74; H, 8.63; N, 5.55.
Optical rotation: [α]D = +80.5 (c 1.01, MeOH)
EXPERIMENTAL PART 93
SPh
O NMeMe
H
NOE
Z-58a Z-58a:
1H NMR (400 MHz, CDCl3): δ 0.60 (d, 3 H, J =6.6 Hz, CH3), 0.72 (d, 3 H, J =6.6
Hz, CH3), 1.78 (d, J =1.4 Hz, 3 H, CH3), 2.10 (m, 1 H, CH(CH3)3), 2.69 (s, 3 H,
NCH3), 3.97 (quart, J =11.00 Hz, 2 H, CH2), 5.23 (dd, J =9.8, J =0.8 Hz, 1 H,
CH=C), 7.60 (m, 3 H, Ph), 7.87 (m, 2 H, Ph). 13C NMR (100 MHz, CDCl3): δ 22.31 (CH3, d), 22.52 (CH3, d), 23.90 (CH3, d),
29.60 (CH(CH3)3, d), 27.69 (NCH3, d), 59.31 (CH2, u), 120.52 (C=CH, u), 128.95,
129.48, 132.56 (o-, m-, p-C, d), 137.34 (i-C, u), 142.12 (C=CH, d).
1H{1H}-NOE-Experiment (500 MHz, CDCl3) of Z-58a
[%] H-3 H-5 H-10 NCH3
H-1 2.0 0.4H-2 0.8H-3 5.0H-4 0.4 3.0H-5 3.7
H-11NCH3 -
Emitted Frequency
Obs
erve
d Fr
eque
ncy
IR (capillary): ν 3061 (s), 2957 (vs), 2869 (s), 2803 (s), 1465 (m), 1445 (m), 1410
(m), 1382 (m), 1249 (vs), 1156 (vs), 1140 (vs), 1105 (s), 1181 (s), 906 (s), 863 (s)
cm−1.
CI-MS m/z (relative intensity, %): 252 [M++1] (100), 250 [M+] (2), 212 (3), 208 (4),
194 (3), 167 (2), 157 (3), 156 (33), 154 (14), 140 (3), 126 (3), 99 (4), 98 (10), 97
(5), 85 (7), 85 (6), 83 (4), 81 (4), 71 (4).
EXPERIMENTAL PART 94
Elemental Analysis: Anal. Calcd for C14H21NOS (251.39): C, 66.89; H, 8.42; N, 5.57
Found : C, 66.61; H, 8.30; N, 5.60.
Optical rotation: [α]D = +82.4 (c 1.01, MeOH)
5.4.2 Synthesis of (S,E)-N-methyl-S-(3-methyl-2-pentenyl)-S- phenylsulfoximine and (S,Z)-N-methyl-S-(3-methyl-2-pentenyl)-S-phenylsulfoximine (E-109c and Z-109c).
To a solution of 34 (12.0 g, 0.07mol) in THF (200 ml) at –78 °C was added nBuLi
(48.5 mL, 1.60 M solution in hexane, 0.08 mol). After stirring the mixture for 30
min, 2-methylbutyraldehyde (8.6 mL, 0.08 mol) was added. The mixture was
stirred for 2 h and then CICOOMe (6 mL, 0.08 mmol) was added. After warming
the resulting mixture to room temperature, it was stirred for 1h. It was then cooled
to –78 °C and DBU (13.5 mL, 0.09 mol) was added, which led to the deposition of
a colorless precipitate. After allowing the mixture to warm to room temperature
over a period of 12 h, it was treated with half-saturated aqueous NH4Cl solution
and extracted with EtOAc. The combined organic phases were dried (MgSO4) and
the solvent was removed in vacuo. The residue was dissolved in acetonitrile (200
mL) and DBU (13.5 mL, 0.09 mol) was added. After heating the mixture to 70-80 °C for 5 d, it was allowed to cool to room temperature, treated with half-saturated
aqueous NH4Cl, and extracted with EtOAc. The combined organic phases were
dried (MgSO4) and the solvent was removed in vacuo. Purification of the residue
by chromatography (EtOAc/hexane, 1:1) gave a mixture of E-110c and Z-110c
(14.3 g, 85%) in a ratio of 70:30 as colorless oil. The E and Z isomers were was
separated by HPLC (EtOAc/n-hexane, 4:1).
EXPERIMENTAL PART 95
SPh
O NMeH
NOE
NOE
E-110c
E-110c:
1H NMR (400 MHz, CDCl3): δ 0.90 (t, J =6.6, 3 H, CH3), 1.20 (br s, 3 H, CH3), 1.98
(q, J = 7.4 Hz 2 H, CH2CH3), 2.72 (s, 3 H, NCH3), 3.88 (m, 2 H, SCH2), 5.20 (m, 1
H, CH=C), 7.55 (m, 3 H, Ph), 7.80 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 12.25 (CH3, d), 15.83 (CH3, d), 29.65 (NCH3, d),
32.38 (CH2, u), 55.80 (SCH2),109.34 (C=CH, u), 128.82, 129.69,132.53 (o-, m-, p-
C, d), 136.57 (C=CH, u), 147.23 (i-C, u).
IR (capillary): ν 3060 (s), 2929 (w), 2876 (w), 2802 (m), 1446 (w), 1467 (s), 1246
(w), 1151 (w), 1106 (s), 1081 (w), 942 (s), 856 (s), 737 (w) cm−1.
CI-MS m/z (relative intensity, %): 238 [M++1] (63), 237 [M+] (2), 184 (3), 156
(100), 125 (11), 83 (9), 81 (4).
Elemental Analysis: Anal. Calcd for C13H19NOS (237.39): C, 65.78; H, 8.07; N, 5.90
Found : C, 65.78; H, 8.29; N, 5.93
Optical rotation : [α]D = +70.5 (c 1.01, CH2Cl2)
EXPERIMENTAL PART 96
SPh
O NMeH
Me
NOE
Z-110c
Z-110c: 1H NMR (400 MHz, C6D6): δ 0.56 (t, J =7.4, 3 H, CH3), 1.45 (br s, 3 H, CH3), 1.55
(q, J = 7.4 Hz 2 H, CH2CH3), 2.85 (s, 3 H, NCH3), 3.78 (d, J = 7.9 2 H, SCH2), 5.25
(m, 1 H, CH=C), 7.15 (m, 3 H, Ph), 7.80 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 12.07 (CH3, d), 22.89 (CH3, d), 29.63 (NCH3, d),
24.67 (CH2, u), 55.65 (SCH2),110.48 (C=CH, u), 129.08,129.78,132.78 (o-, m-, p-
C, d), 136.94 (C=CH, u), 147.26 (i-C, u).
IR (capillary): ν 3058 (s), 2935 (m), 2802 (m), 2729 (s), 1446 (w), 1403 (s), 1410
(m), 1248 (w), 1152 (w), 1140 (vs), 1105 (s), 997 (s), 969 (s), 894 (m), 856 (m),
772 (w) cm−1.
EI-MS m/z (relative intensity, %): 238 [M++1] (63), 237 [M+] (2), 184 (3), 156
(100), 125 (11), 83 (9), 81 (4), 71 (4).
Elemental Analysis: Anal Calcd for C13H19NOS (237.39): C, 65.78; H, 8.07; N, 5.90
Found : C, 65.24 ; H,8.03 ; N, 6.24.
Optical rotation: [α]D = +76.4 (c 1.01, CH2Cl2)
EXPERIMENTAL PART 97
5.5 Synthesis of Syn-configurated Homoallylic Alcohols
5.5.1 (1R,2R)-2-(Cyclohept-1-enyl)-2-[ (S)-N-methyl-S-phenylsulfonimidoyl]-1-phenylethanol (11c)..
SNMe
PhO
OH
Ph
11c
n-BuLi (3.12 mL, 5.0 mmol, 1.6 M solution in hexane) was added at -78 °C to a
solution of the cyclic allylic sulfoximine 1b (1.20 g, 4.56 mmol) in Et2O (50 mL).
After the mixture was stirred for 10 min at -78 °C, neat ClTi(NEt2)3 (1.76 mL, 5.7
mmol) was added. The resulting mixture was stirred for 10 min at -78 °C, warmed
to room temperature, and stirred for 2 h. After the mixture was cooled to -78 °C,
benzaldehyde (689 mg, 8.2 mmol) was added dropwise. After the mixture was
stirred for 2 h at -78 °C, it was poured into aqueous (NH4)2CO3 solution and
extracted with EtOAc. The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Recrystallization from diethyl ether afforded 11c (1.17 g,
70%, 98% de) as colorless crystals.
1H NMR (400 MHz, CDCl3): δ 0.90-1.06 (m, 4H, cC7H11), 1.30-1.74 (m, 6 H,
cC7H11), 2.70 (s, 3 H, NCH3), 3.75 (m, 1 H, CHS), 5.46 (br. d, J = 9.7 Hz, 1 H,
CHOH), 7.48-7.72 (m, 5 H, Ph), 7.78-7.84 (m, 3H, Ph).
13C NMR (100 MHz, CDCl3): δ 21.1 (cC7H11, u), 24.3 (cC7H11, u), 28.2 (cC7H11, u),
28.5 (cC7H11, u), 28.6 (d), 28.7 (cC7H11, u), 71.9 (CHS, d), 72.4 (CHOH, d), 125.9
(d), 126.0 (d), 126.4 (d), 126.6 (d), 126.7 (d), 127.5 (d), 127.8 (d), 131.9 (d), 135.3
(u), 139.2 (u). CI-MS m/z (relative intensity, %): 370 (M+ +1) (10), 264 (44), 231 (10), 215 (43),
156 (100), 140 (13), 107 (19).
EXPERIMENTAL PART 98
IR (capillary): ν 3631 (s), 3460 (s, br), 3183 (w), 3056 (m), 3025 (s), 2962 (m),
2802 (w), 2802 (w), 2696 (S), 2475 (s), 2373 (s), 2344 (s), 2282 (s), 2160 (s),
2064 (s), 1985 (s), 1964 (s), 1918 (s), 1890 (s), 1809 (s), 1737 (s), 1702 (s), 1687
(s), 1605 (s), 1582 (s), 1545 (s), 1496 (s), 1170 (m), 896 (s), 856 (w), 822 (s), 777
(w), 764 (m) cm−1.
Elemental Analysis: Anal. Calcd for C22H27 NO2: C, 71.51; H, 7.36; N, 3.79
Found : C, 71.64; H, 7.77; N, 3.65.
Optical rotation: [α]D –21.4 (c 1, CH2Cl2).
M.p: 115-116 °C
5.5.2 Synthesis of (+)-(E)-(3R,4R,Ss)-4-(N-methyl-S- phenylsulfonimidoy)-2,6-dimethyl-oct-5-en-3-ol (2c) .
S
OH
ONMePh
2c n-BuLi (3.12 mL, 5.0 mmol, 1.6 M solution in hexane) was added at -78 °C to a
solution of the allylic sulfoximine 110c (1.20 g, 3.88 mmol) in THF (50 mL). After
the mixture was stirred for 10 min at -78 °C, neat ClTi(NEt2)3 (1.76 mL, 5.7 mmol)
was added. The resulting mixture was stirred for 10 min at -78 °C, warmed to room
temperature, and stirred for 2 h. After the mixture had again been cooled to -78 °C,
isobutyraldehyde (689 mg, 8.2 mmol) was added dropwise. After the mixture was
stirred for 2 h at -78 °C, it was poured into aqueous (NH4)2CO3 solution and
extracted with EtOAc. The combined organic phases were dried (MgSO4) and
concentrated in vacuo. Recrystallization from diethyl ether afforded 2c (1.11 g,
71%, 98% de) as colorless oil.
EXPERIMENTAL PART 99
1H NMR (400 MHz, CDCl3): δ 0.75 (d, J = 6.9 Hz, 6 H, CH(CH3)2), 0.85 (t, J = 7.5
Hz, 3 H CH2CH3), 1.05 (d, J = 6.4 Hz, 3 H CH3), 1.70 (m, 1 H, CH(CH3)2, 1.90 (m,
2 H, CH2CH3), 2.66 (s, 3 H, NCH3), 3.90 (dd, J = 9.4 Hz, J = 1.7 Hz, 1 H, CHS),
4.36 (dd, J = 9.1, J = 1.9 Hz, 1 H, CHOH), 5.0 (m, 1 H, =CH), 6.9 (br s, OH) 7.48-
7.72 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 12.3, 13.8 (CH(CH3)2, d), 15.5 (CH2CH3, d), 20.0
(CH3, d), 29.6 (NMe, d), 30.9 (CH(CH3)2, d), 32.4 (CH2CH3, u), 68.0 (CHS, d), 72.4
( CHOH, d), 112.1 (CH=C, d), 128.7 (d), 128.8 (d), 129.0 (d), 147.0 (i-C, u), 136.4 (
C=CH, u). CI-MS m/z (relative intensity, %): 311 (M+ +2) (9), 310 (M+ +2) (6), 157 (9), 156
(100), 155 (35), 137 (53).
IR (capillary): ν 3661 (s), 3260 (m), 3061 (s), 3025 (s), 2931 (w), 2805 (m), 2725
(s), 2381 (s), 2344 (s), 1817 (s),1809 (s), 1724 (s), 1664 (s), 1605 (s), 1582 (s),
1545 (s), 1447 (w), 1308 (s), 1282 (s), 1108 (m), 938 (s), 861 (w), 856 (w), 754 (w)
cm-1.
HRMS (EI, 70 eV):
calcd for C17H27NO2S-C4H8O: 237.118000
Found : 237.118737.
Optical rotation: [α]D = +241.4 (c 1.22, CH2Cl2).
EXPERIMENTAL PART 100
5.6 Synthesis of Alkenyl/Cycloalkenyl Chlorohydrines. 5.6.1 Synthesis of (-)-(1R,2R)-2-Chloro-2-(cyclohex-1-enyl)-1-phenylethanol
(21a).
Cl
OH
Ph
21a Following GP3, reaction of 11a (550 mg, 1.55 mmol) with ClCO2CH(Cl)Me (0.2
mL, 1.86 mmol) afforded chlorohydrine 21a (322 mg, 88%, ≥98% de) and
sulfinamide 29a (380 mg, 94%):
1H NMR (400 MHz, CDCl3): δ 1.34-1.54 (m, 4H, cC6H9), 1.75-2.00 ( m, 2H, cC6H9),
2.05-2.15 (m, 2H, cC6H9 ), 2.66 (br. s, 1H, OH), 4.51 (d, J = 8.5 Hz, 1H, 2-H), 4.79
(d, J = 8.5 Hz, 1H, 1-H), 5.52 (m, 1H, =CH), 7.27-7.35 (m, 5H, Ph).
13C NMR (100 MHz, CDCl3): δ 21.8 (cC6H9, u), 22.2 (cC6H9, u), 24.5 (cC6H9, u),
25.0 (cC6H9, u), 75.3 (C-2, d), 76.2 (C-1, d), 126.6 (o-Ph, d), 128.0 (m-Ph, d),
128.1 (p-Ph, d), 129.0 (=CH, d), 133.7 (i-Ph, u), 139.3 (=C, u). CI-MS m/z (relative intensity, %): 236( M+) (11), 218(66), 201(9), 183(43), 159(17),
141(100), 128(18), 115(31), 91(35).
IR (capillary): ν 3450 (m, br), 3062 (m), 3031 (m), 2709 (s), 2667 (s), 1951 (s),
1884 (s),1767 (s), 1632 (s), 1600 (s), 1496 (m), 1372 (s), 1349 (m), 1324 (m),
1249 (m), 1190 (m), 1142 (m), 1085 (m), 1028 (m), 969 (w), 912 (s), 891 (s), 845
(s) cm-1.
Elemental Analysis: Anal. Calcd for C14H17ClO (236.74): C, 71.03; H, 7.24
Found : C, 71.16; H, 6.86.
EXPERIMENTAL PART 101
Optical rotation: [ α]D = -10.8 (c 0.45, CH2Cl2)
5.6.2 Synthesis of (-)-(1R,2R)-1-Chloro-1-(cyclohex-1-enyl)-3-methylbutan-2-ol (21b) .
Cl
OH21b
Following GP3, reaction of 11b (520 mg, 1.62 mmol) with ClCO2CH(Cl)Me (0.21
mL, 1.94 mmol) afforded chlorohydrine 21b (294 mg, 85%, ≥98% de) and
sulfinamide 29a (393 mg, 93%).
1H NMR (400 MHz, CDCl3): δ 0.85 (d, J = 6.8 Hz, 3 H, CH3), 0.95 ( d, J = 6.8, 3 H,
CH3), 1.40-1.70 (m, 4 H, cC6H9),1.75-1.90(m, 4 H, cC6H9), 1.95-2.05 (m, 1 H,
CH(CH3)2), 2.10-2.20 (br. s, 1 H, OH), 3.55 (dd, J = 8.2 , J = 3.3 Hz, 1 H, 2-H),
4.35 (d, J = 8.2 Hz, 1 H, 1-H), 5.75 (m, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ 15.2 (CH3, d), 20.9 (CH3, d), 24.4 (cC6H9, u), 22.7 (
cC6H9, u), 24.1 (cC6H9, u) 25.5 (cC6H9, u) 30.3 (CH(CH3)3, d),74.3 (C-2, d), 76.9 (
C-1, d), 128.5 (=CH, d), 135.3 (=C, u).
CI-MS m/z (relative intensity, %): 201 [M+ -1] (2), 180(4), 185(9), 167(35), 150(33),
149(100), 135(14), 123(22), 107(14), 95(19), 79 (11), 69 (19).
IR (capillary): ν 3470 (m, br), 3043 (m), 2660 (s), 1730 (s), 1659 (s), 1465 (m),
1368 (m), 1302 (s), 1270 (s), 1235 (m), 1173 (m), 1138 (m), 1061 (m), 971 (s), 920
(m), 891 (s), 848 (s), 817 (s) cm-1.
HRMS (EI, 70 eV):
calcd for C11H19ClO: 202.112505
Found : 202.112443.
EXPERIMENTAL PART 102
Optical rotation: [ α]D = -14.2 (c 0.30, CH2Cl2)
5.6.3 Synthesis of (-)-(1R,2R)-2-Chloro-2-(cyclohept-1-enyl)-1-phenylethanol (21c) .
Cl
OH
Ph
21c
Following GP3, reaction of 11c (525 mg, 1.42 mmol) with ClCO2CH(Cl)Me (0.18
mL, 1.70 mmol) afforded chlorohydrine 21c (306 mg, 86%, ≥98% de) as a
colorless oil and sulfinamide 29a (341 mg, 92%)
1H NMR (400 MHz, CDCl3): δ 1.30-1.45 (m, 3 H, cC7H11), 1.50-1.60 ( m, 2 H,
cC7H11), 1.8-2.0 (m, 3 H, cC7H11 ), 2.1-2.2 (m, 1 H, cC7H11), 2.30 (m, 1 H, cC7H11),
2.81 (br. s, 1 H, OH), 4.58 (d, J = 8.9 Hz, 1 H, 2-H), 4.79 (d, J = 8.9 Hz, 1 H, 1-H),
5.65 (m, 1 H, 4-H), 7.22-7.40 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 26.2 (cC7H11, u), 26.8 (cC7H11, u), 28.2 (cC7H11, u),
29.1 (cC7H11, u), 32.2 (cC7H11, u), 76.4 (C-2, d), 77.2 (C-1, d), 127.0 (o-Ph, d),
128.30 (m-Ph, d), 128.4 (p-Ph, d), 134.4 (=CH, d), 139.5 (i-Ph, u), 139.26 (=C, u).
CI-MS m/z (relative intensity, %): 250 (M+) (1.5), 232 (11), 155 (8), 144 (9),
141(30), 129(11), 108(33), 107(100), 105(29), 91 (17), 79 (33), 77 (22).
IR (capillary): ν 3444 (s, br), 3020 (m), 2927 (w), 2853 (m), 1954 (s), 1882 (s),
1703 (w), 1601 (s), 1493 (s), 1383 (s), 1318 (s), 1275 (s), 1147 (s), 1053 (m), 965
(s), 915 (s), 852 (s) cm−1.
HRMS (EI, 70 eV): calcd for C15H19ClO: 250.112421
Found : 250.112443.
Optical rotation: [ α]D = -18.8 (c 1, CH2Cl2)
EXPERIMENTAL PART 103
5.6.4 (1R, 2S)- and (1R,2R)-2-Chloro-5-methyl-1-phenylhex-3-en-1-ol (anti-23a and syn-23a) .
Ph
OH
ClPh
OH
Cl+
anti-23a syn-23a
Treatment of 8a (650 mg, 1.89 mmol) with ClCO2CH(Cl)Me (0.26 mL, 2.46 mmol)
as described in GP1 afforded a mixture of chlorohydrins anti-23a and syn-23a
(377 mg, 89%) in a ratio of 78:22 together with sulfinamide 29a (465 mg, 94%).
Compound syn-23a: 1H NMR (400 MHz, CDCl3): δ 0.80 (d, J = 6.7 Hz, 3 H, 6-H),
0.86 ( d, 2 J = 6.7 Hz, 3 H, 7-H), 2.22-2.30 (m, 1 H, 5-H ), 2.32-2.40 (br. s, 1 H,
OH), 4.52 (dd, J = 7.3, J = 8.2 Hz, 1 H, 2-H), 4.69 (d, J = 7.3 Hz, 1 H, 1-H), 5.36-
5.46 (m, 2 H, 3-H, 4-H), 7.28-7.36 (m, 5 H, Ph).
Compound syn-23a: 13C NMR (100 MHz, CDCl3): δ 21.6 (C-6 or C-7, d), 21.7 (C-
6 or C-7, d), 30.6 (C-5, d), 70.0 (C-2, d), 77.6 (C-1, d), 123.6 (C-4, d), 139.2 (i-Ph,
u), 142.9 (C-3, d). Compound syn-23a + anti-23a : CI-MS m/z (relative intensity, %): 207 (23), 190
(14), 189(100), 173(10), 107(13).
IR (capillary) ν 3425 (m, br), 3085 (s), 3062 (m), 3031 (m), 2929 (w), 2870 (w),
2386 (s), 2286 (s), 1951 (s), 1882 (s), 1807 (s), 1663 (m), 1601 (s), 1546 (s), 1494
(m), 1454 (w), 1385 (m), 1366 (m), 1328 (m), 1232 (s), 1189 (m), 1054 (w), 1028
(w), 917 (s), 854 (m), 763 (w) cm-1.
Compound anti-23a: 1H NMR (400 MHz, CDCl3): δ 0.90 (d, J = 6.7 Hz, 3H, 6-H),
0.93 ( d, J = 6.7 Hz, 3H, 7-H), 2.22-2.30 (m, 1H, 5-H ), 2.32-2.40 (br. s, 1H, OH),
4.50 (m, 1H, 2-H), 4.90 (d, J = 4.7 Hz, 1H, 1-H), 5.46-5.54 (m, 2H, 3-H, 4-H), 7.25-
7.35 (m, 5H, Ph).
EXPERIMENTAL PART 104
Compound anti-23a: 13C NMR (100 MHz, CDCl3): δ 21.8 (C-6, C-7, d), 31.1 (C-5,
d), 68.1 (C-2, d), 77.1 (C-1, d), 122.4 (C-4, d), 139.3 (i-Ph, u), 143.6 (C-3, d).
5.6.5 Synthesis of (1R,2S)-and (1R,2R)-2-Chloro-4-cyclohexyl-1-phenylbut-3-en-1-ol (anti-23b and syn-23b)
Ph
OH
Cl
Ph
OH
Cl
+
anti-23b syn-23b Following GP3, reaction of 8b (400 mg, 1.04 mmol) with ClCO2CH(Cl)Me (0.26
mL, 2.46 mmol) afforded a mixture of chlorohydrins anti-23b and syn-23b (249
mg, 90%) in ratio of 74:26 together with sulfinamide 29a (255 mg, 93%):
Compound syn-23b:1H NMR (400 MHz, CDCl3): δ 0.85-1.35 (m, 5 H, cC6H11),
1.48-1.72 (m, 5 H, cC6H11), 1.80-1.86 (m, 1 H, 5-H), 2.55-2.59 (br. s, 1 H, OH),
4.50-4.55 (m, 1 H, 2-H), 4.68 (d, J = 7.6 Hz, 1 H, 1-H), 5.38-5.54 (m, 2 H, 3-H, 4-
H), 7.28-7.36 (m, 5 H, Ph).
Compound syn-23b: 13C NMR (100 MHz, CDCl3): δ 25.6 (cC6H11, u), 25.7
(cC6H11, u), 25.9 (cC6H11, u), 32.1 (cC6H11, u), 32.2 (cC6H11, u), 40.1 (C-5, d), 68.1
(C-2, d), 70.3 (C-1, d), 123.9 (C-4, d), 139.1 (i-Ph, u), 141.9 (C-3, d).
Compound syn-23b + anti-23b : CI-MS m/z (relative intensity, %): 264 (M+) (38),
263 (14), 262 (100), 183(8), 126(14).
IR (capillary): ν 3188 (m, br), 3028 (m), 2924 (w), 2853 (w), 2800 (m), 1656 (m),
1448 (w), 1384 (m), 1330 (m), 1235 (w), 1203 (m), 1177 (m), 1146 (w), 1107 (m),
1081 (w), 1049 (w), 997 (m), 913 (m), 865 (w), 851 (w), 784 (w), 742 (w), 702 (w)
cm−1.
EXPERIMENTAL PART 105
Elemental Analysis: Anal. Calcd for C13H17ClO: C, 72.58; H, 7.99
Found: C, 72.59; H, 8.21.
Compound anti-23b: 1H NMR (400 MHz, CDCl3): δ 0.85-1.35 (m, 5H, cC6H11),
1.48-1.72 (m, 5H, cC6H11), 1.90-1.98 (m, 1H, 5-H ), 2.84 (br. s, 1 H, OH), 4.50-
4.55 (m, 1 H, 2-H), 4.90 (d, J = 4.6 Hz, 1 H, 1-H), 5.38-5.54 (m, 2H, 3-H, 4-H),
7.28-7.36 (m, 5H, Ph).
13C NMR (100 MHz, CDCl3): δ 25.7 (cC6H11, u), 25.7 (cC6H11, u), 25.9 (cC6H11, u),
32.1 (cC6H11, u), 32.2 (cC6H11, u), 39.9 (C-5, d), 68.1 (C-2, d), 70.3 (C-1, d), 122.7
( C-4, d), 139.1 (i-Ph, u), 142.6 (C-3, d).
5.7 Synthesis of Cyclo/Alkenyloxiranes 5.7.1 (2S,3R)-2-(Cyclohex-1-enyl)-3-phenyloxirane (22a).
O Ph
22a
Following GP4, reaction of 21a (430 mg, 1.82 mmol) with DBU (0.29 mL, 2.00
mmol) afforded oxirane 22a (342 mg, 94%, ≥98% de) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.20-1.34 (m, 4 H, cC6H9), 1.40-1.50 (m, 2 H,
cC6H9), 1.65-2.00 (m, 2 H, cC6H9), 3.62 (m, 1 H, 2-H), 4.12 (d, J = 4.4 Hz, 1 H, 1-
H), 5.71 (m, 1 H, cC6H9), 7.20-7.25 (m, 5 H, Ph).
EXPERIMENTAL PART 106
13C NMR (100 MHz, CDCl3): δ 22.1 (cC6H9, u), 22.3 (cC6H9, u), 22.5 (cC6H9, u),
25.4 (cC6H9, u), 58.3 (C-2, d), 61.1 (C-1, d), 126.7 (o-Ph, d), 127.3(m-Ph, d),
127.5(p-Ph, d), 125.4 (=CH, d), 130.2 (=C, u), 135.4 (i-Ph, u).
CI-MS m/z (relative intensity, %): 201 [M+ + 1] (9), 200 (M+) (63) 199 (100), 171
(72), 157(36), 143 (19), 129 (91), 105 (78), 91 (71).
IR (capillary): ν 3087 (m), 3061 (m), 3031 (m), 2859 (w), 2835 (w), 2673 (s), 1951
(s), 1885 (s), 1723 (m), 1671 (m), 1605 (m), 1585 (s), 1451 (w), 1410 (m), 1337
(m), 1315 (m), 1270 (m), 1251 (m), 1195 (m), 1137 (m), 1001 (m), 967 (m), 921
(w), 830 (m), 801 (m), 751 (w) cm−1.
HRMS (EI, 70 eV):
calcd for C14H16O: 200.120047
Found: 200.120115
Optical rotation: [ α]D = -14.6 (c 0.30, CH2Cl2)
5.7.2 (2S,3R)-2-(Cyclohex-1-enyl)-3-isopropyloxirane (22b).
O
22b Following GP4, reaction of 21b (420 mg, 2.08 mmol) with DBU (0.34 mL, 2.29
mmol) afforded oxirane 22b (318 mg, 92%, ≥98% de) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 0.85 (d, J = 6.6 Hz, 3 H, CH3), 1.05 (d, J = 6.6 Hz, 3
H, CH3), 1.38-1.47 (m, 1 H, CH(CH3)2), 1.50-1.70 (m, 4 H, cC6H9), 1.90-2.08 ( m,
4 H, cC6H9), 2.68 (dd, J = 4.1, J = 9.0 Hz, 1 H, 1-H), 3.29 (m, 1 H, 2-H), 5.61 (m, 1
H, =CH).
EXPERIMENTAL PART 107
13C NMR (100 MHz, CDCl3): δ 18.8 (CH3, d), 20.1 (CH3, d) 22.5 (cC6H9, u), 22.6 (
cC6H9, u), 24.5 (cC6H9, u), 25.7 (CH(CH3)3, d), 26.4 (cC6H9, u), 58.8 (C-1, d), 64.6
( C-2, d), 122.7 (=CH, d), 131.0 (=C, u).
CI-MS m/z (relative intensity, %): 166 (M+) (45) 150 (11), 149 (100), 113(11), 71
(18), 70 (14), 57 (26), 55 (11).
IR (capillary): ν 2932 (w), 2669 (s), 1729 (s), 1673 (s), 1462 (m), 1387 (s), 1364
(s), 1340 (s), 1252 (s), 1162 (s), 1136 (s), 1075 (s), 958 (m), 922 (m), 828 (s), 801
(s), 752 (s) cm-1.
HRMS (EI, 70 eV):
calcd for C11H18O: 166.135698
Found: 166.135765.
Optical rotation: [ α]D = -43.4 (c 0.35, CH2Cl2)
5.7.3 (2S,3R)-2-(Cyclohept-1-enyl)-3-phenyloxirane (22c)
O Ph
22c Following GP4, reaction of 21c (450 mg, 1.80 mmol) with DBU (0.29 mL, 1.98
mmol) afforded oxirane 22c (347 mg, 90%, ≥98% de) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.22-1.34 (m, 4 H, cC6H9), 1.42-1.55 ( m, 4 H,
cC6H9), 1.60-2.00 (m, 2 H, cC6H9), 3.67 (m, 1 H, 2-H), 4.13 (d, J = 4.2 Hz, 1 H, 1-
H), 5.88-5.93 (m, 1 H, cC7H11), 7.22-7.28 (m, 5 H, Ph).
EXPERIMENTAL PART 108
13C NMR (100 MHz, CDCl3): δ 25.7 (cC7H11, u), 26.7 (cC7H11, u), 28.0 (cC7H11, u),
29.7 (cC7H11, u), 32.1 (cC7H11, u), 58.6 (C-2, d), 62.2 (C-1, d), 126.9 (o-Ph, d),
127.4 (m-Ph, d), 127.5 (p-Ph, d), 129.8 (=CH, d), 135.2 (=C, u), 135.6 (i-Ph, u).
CI-MS m/z (relative intensity, %): 215 [M+ + 1] (100), 214 (M+) (27) 197 (34), 105
(27).
IR (capillary): ν 3030 (m), 2696 (s), 1946 (s), 1880 (m), 1730 (s), 1671 (s), 1605
(s), 1540 (s), 1495 (s), 1450 (w), 1407 (s), 1377 (s), 1274 (s), 1221 (s), 1193 (s),
1075 (s), 1027 (s), 966 (s), 899 (m), 860 (m), 770 (s), 748 (w) cm−1.
Elemental Analysis: Anal. Calcd for C15H18O (214.): C, 84.07; H, 8.47
Found : C, 84.28; H, 8.27.
Optical rotation: [ α]D = -7.1 (c 1.80, CH2Cl2)
5.7.4 Synthesis of (3R,2R) and (3R,2S)-2-(3-Methylbut-1-enyl)-3-phenyl.oxirane (trans-24a and cis-24a)
O Ph O Ph+
trans-24a cis-24a
Treatment of mixture of anti-23a and syn-23a (640 mg, 2.85 mmol) with DBU
(0.43 mL, 2.85 mmol) as described in GP2 afforded a mixture of the oxirane trans-
24a and cis-24a (504 mg, 94%) in a ratio of 78:22.
Compound cis-24a: 1H NMR (400 MHz, CDCl3): δ 0.88 (d, J = 7.4 Hz, 3 H, 6-H),
0.91 (d, J = 6.9 Hz, 3 H, 7-H), 2.21 (octd, J = 6.6 Hz, J = 1.1 Hz, 1 H, 5-H), 3.64
EXPERIMENTAL PART 109
(dd, J = 4.1 Hz, J = 8.5 Hz, 1 H, 2-H), 4.20 (d, J = 4.4 Hz, 1 H, 1-H), 4.97 (ddd, J =
8.5, J = 15.4, J = 1.1 Hz, 1 H, 3-H), 5.94 (dd, J = 6.9, J = 15.4 Hz, 1 H, 4-H), 7.25-
7.37 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 21.9 (C-6, C-7, d), 30.9 (C-5, d), 58.9, 59.8 (C-1, C-
2, d), 120.2 (C-4, d), 126.3,127.1, 127.9 (o-, m-, p-Ph, d), 135.29 (i-Ph, u), 146.5
(C-3, d).
Compounds cis-24a + trans-24a : CI-MS m/z (relative intensity, %): 188 [M+] (6),
171 (16), 106 (10), 105 (100), 77 (34), 51 (12).
IR (capillary): ν 3063 (s), 3031 (m), 2963 (w), 2872 (m), 1963 (s), 1884 (s), 1692
(m), 1623 (s), 1598 (s), 1580 (s), 1495 (m), 1465 (m), 1386 (m), 1315 (s), 1179 (s),
1136 (s), 1106 (w), 1068 (w), 1009 (m), 969 (m), 894 (m), 842 (s), 760 (w) cm−1.
Elemental Analysis: Anal. Calcd for C13H16O: C, 82.93; H, 8.51
Found: C, 82.94; H, 8.69.
Compound trans-24a: 1H NMR (400 MHz, CDCl3): δ 1.01 (d, J = 6.6 Hz, 3H, 6-H),
1.03 ( d, J = 6.6 Hz, 3H, 7-H), 2.32-2.41 (octd, J = 6.9 Hz, J = 1.4 Hz, 1H, 5-H),
3.33 (dd, J = 1.9, J = 8.0 Hz, 1H, 2-H), 3.76 (d, J = 2.2 Hz, 1H, 1-H), 5.26-5.30
(ddd, J = 8.0, J = 15.7, J = 1.4 Hz, 1H, 3-H), 5.94-5.98 (dd, J = 6.6, J = 15.4 Hz,
1H, 4-H), 7.25-7.37 (m, 5H, Ph).
13C NMR (100 MHz, CDCl3): δ 22.1 (C-6, C-7, d), 30.9 (C-5, d), 60.2, 63.3 (C-1, C-
2, d), 124.0 (C-4, d), 125.5, 127.1, 127.9 (o-, m-, p-Ph, d), 137.40 (i-Ph, u), 144.2
(C-3, d).
EXPERIMENTAL PART 110
5.7.5 Synthesis of (3R,2R)- and (3R,2S)-2-(2-Cyclohexylvinyl)- 3 - ..
.phenyloxirane (trans-24b and cis-24b) O Ph
O Ph
+
trans-24b cis-24b Treatment of a mixture of anti-23b and syn-23b (450 mg, 1.7 mmol) with DBU
(0.28 mL, 1.87 mmol) as described in GP2 afforded a mixture of oxiranes trans-
24b and cis-24b (361 mg, 93%) in a ratio of 74:26.
Compound cis-24b: 1H NMR (400 MHz, CDCl3): δ 0.90-1.30 (m, 5 H, cC6H11),
1.60-1.80 (m, 5 H, cC6H11), 3.64 (dd, J = 4.4 Hz, J = 8.8 Hz, 1 H, 2-H), 4.20 (d, J =
4.4 Hz, 1 H, 1-H), 1.95-2.05 (m, 1 H, 5-H), 4.97 (ddd, J = 8.5, J = 15.4, J = 1.1 Hz,
1 H, 3-H), 5.89 (dd, J = 6.6, J = 15.3 Hz, 1 H, 4-H), 7.25-7.37 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 26.2 (cC6H11, u), 26.5 (cC6H11, u), 29.7 (cC6H11, u),
32.7 (cC6H11, u), 32.8 (cC6H11, u), 41.1 (C-5, d), 60.6, 63.7 (C-1, C-2, d), 120.9 (C-
4, d), 145.5 (C-3, d), 125.8, 128.7, 128.3 (o-, m-, p-C, d), 135.7 (i-Ph, u).
Compounds cis-24b + trans-24b : CI-MS m/z (relative intensity, %): 228 [M+] (5),
145 (100), 144 (12), 146 (26), 127 (8), 117 (36), 105 (10), 91 (29), 77 (13), 55 (18).
IR (capillary) ν 3087 (s), 3063 (s), 2666 (s), 1948 (s), 1881 (s), 1807 (s), 1762 (s),
1691 (s), 1663 (s), 1604 (m), 1542 (s), 1497 (m), 1449 (w), 1421 (s), 1374 (m),
1349 (s), 1255 (s), 1197 (s), 1152 (s), 1072 (s), 1027 (s), 966 (w), 916 (s), 878 (w),
849 (m), 753 (w), 740 (m) cm-1.
HRMS (EI, 70 eV)
Calcd for C16H20O: 228.151504
Found: 228.151415.
EXPERIMENTAL PART 111
Compound trans-5e: 1H NMR (400 MHz, CDCl3): δ 0.90-1.30 (m, 5 H, cC6H11),
1.55-1.80 (m, 5 H, cC6H11), 3.32 (dd, J = 1.9, J = 8.0 Hz, 1 H, 2-H), 3.76 (d, J = 1.9
Hz, 1 H, 1-H), 1.95-2.05 (m, 1 H, 5-H), 5.28 (ddd, J = 8.0, J = 15.6, J = 1.4 Hz, 1
H, 3-H), 5.90 (dd, J = 6.6, J = 15.3 Hz, 1 H, 4-H), 7.25-7.37 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 26.3 (cC6H11, u), 26.4 (cC6H11, u), 30.1 (cC6H11, u),
32.8 (cC6H11, u), 32.9 (cC6H11, u), 40.8 (C-5, d), 59.4, 60.3 (C-1, C-2, d), 120.9 (C-
4, d), 143.3 (C-3, d), 126.7, 127.8, 127.7 (o-, m-, p-Ph, d), 137.6 (i-Ph, u).
5.7.6 Synthesis of the Alkenyloxirane trans-24b and cis-24b from Z-25b Reaction of Z-25b (400 mg, 1.04 mmol) with ClCO2CH(Cl)Me (1.32 mL, 1.25 ml)
according to GP3 procedure afforded a mixture of chlorohydrines anti-23b and
syn-23b together with sulfinamide (253 mg, 93%). Treatment of the mixture of
chlorohydrines with DBU (0.15 mL, 1 mmol) according to GP2 afforded a mixture
of trans-24b and cis-24b (203 mg, 89 %) in ratio of 75:25, also containing 11% of
the correspondig Z isomers.
trans- 24b: 1H NMR (400 MHz, CDCl3): δ 1.05-1.30 (m, 5 H, cC6H11), 1.60-1.80
(m, 5 H, cC6H11), 3.33 (dd, J = 1.9 Hz, J = 8.0 Hz, 1 H, 2-H), 3.76 (d, J = 1.9 Hz, 1
H, 1-H), 1.95-2.05 (m, 1 H, 5-H), 5.28 (ddd, J = 8.0, J = 15.7, J = 1.4 Hz, 1 H, 3-H),
5.89 (dd, J = 6.6, J = 15.3 Hz, 1 H, 4-H), 7.25-7.37 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 26.2 (u, cC6H11), 26.3 (u, cC6H11), 26.5 (u, cC6H11),
32.8 (u, cC6H11), 32.9 (u, cC6H11), 40.7 (d, C-5), 59.3, 60.5 (d, C-1, C-2), 120.9 (d,
C-4), 143.2 (d, C-3), 126.7, 127.8, 127.7 (d, o-, m-, p-Ph), 137.6 (u, i-Ph).
CI-MS m/z (relative intensity, %): 228 [M+] (5), 146 (26), 145 (100), 144 (12), 127
(8), 117 (36), 105 (10), 91 (29), 81 (10), 77 (13), 67 (10), 55 (18).
IR (capillary): ν 3061 (s), 3030 (m), 2666 (s), 1949 (s), 1881 (s), 1807 (s), 1726
(s), 1663 (s), 1495 (m), 1449 (m), 1371 (s), 1348 (s), 1260 (s), 1196 (s), 1071 (s),
1027 (s), 967 (w), 916 (s), 879 (m), 843 (s), 753 (m) cm−1.
EXPERIMENTAL PART 112
HRMS (EI, 70 eV) Calcd for C16H20O: 228.151504
Found: 228.151415.
cis-24b: 1H NMR (400 MHz, CDCl3): δ 1.05-1.30 (m, 5 H, cC6H11), 1.60-1.80 (m, 5
H, cC6H11), 3.65 (dd, J = 4.4, J = 8.8 Hz, 1 H, 2-H), 4.21 (d, J = 1.4 Hz, 1 H, 1-H),
1.95-2.05 (m, 1 H, 5-H), 4.97 (ddd, J = 8.5, J = 15.4 Hz, J = 1.1 Hz, 1 H, 3-H), 5.89
(dd, J = 6.6 Hz, J = 15.3 Hz, 1 H, 4-H), 7.25-7.37 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 26.1 (u, cC6H11), 26.2 (u, cC6H11), 26.4 (u, cC6H11),
32.8 (u, cC6H11), 33.6 (u, cC6H11), 41.1 (d, C-5), 60.3, 63.7 (d, C-1, C-2), 120.9 (d,
C-4), 145.5 (d, C-3), 125.6, 128.65, 128.2 (d, o-, m-, p-Ph), 135.7 (u, i-Ph).
CI-MS m/z (relative intensity, %): 228 [M+] (5), 146 (26), 145 (100), 144 (12), 127
(8), 117 (36), 105 (10), 91 (29), 81 (10), 77 (13), 67 (10), 55 (18).
IR (capillary): ν 3061 (s), 3030 (m), 2666 (s), 1949 (s), 1881 (s), 1807 (s), 1726
(s), 1663 (s), 1495 (m), 1449 (m), 1371 (s), 1348 (s), 1260 (s), 1196 (s), 1071 (s),
1027 (s), 967 (w), 916 (s), 879 (m), 843 (s), 753 (m) cm−1.
HRMS (EI, 70 eV)
Calcd for C16H20O: 228.151504
Found: : 228.151415.
5.7.7 Synthesis of the Alkenyloxiranes trans-24a and cis-24a from Z-25a
Reaction of Z-25a (344 mg, 1.00 mmol) with ClCO2CH(Cl)Me (0.13 mL, 1.2 mmol)
according to GP3 procedure afforded a mixture chlorohydrines syn-23a and anti-
23a together with sulfinamid (243 mg, 93%). Treatment of the mixture of
EXPERIMENTAL PART 113
chlorohydrins with DBU (0.15 mL, 1 mmol) according to GP2 afforded a mixture of
the oxiranes trans-5e and cis-5e (166 mg, 88%) in ratio of 80:20, also containing
7% of the corresponding (Z) isomers.
trans-24a:1H NMR (400 MHz, CDCl3): δ 1.01 (d, J = 6.6 Hz, 3 H, 6-H), 1.05 ( d, J =
6.6 Hz, 3 H, 7-H), 2.30-2.45 (octd, J = 8.1 , J = 1.5 Hz, 1 H, 5-H), 3.34 (dd, J = 2.0,
J = 7.9 Hz, 1 H, 2-H), 3.77 (d, J = 2.0 Hz, 1 H, 1-H), 5.23-5.30 (ddd, J = 7.9, J =
15.6, J = 1.2 Hz, 1 H, 3-H), 5.94-5.99 (dd, J = 6.7, J = 15.6 Hz, 1 H, 4-H), 7.25-
7.39 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 21.9 (d, C-6, C-7), 30.9 (d, C-5), 60.2, 63.2 (d, C-1,
C-2), 124.0 (d, C-4), 125.5, 126.5, 127.5 (d, o-, m-, p-Ph), 137.40 (u. i-Ph), 146.5
(d, C-3).
CI-MS m/z (relative intensity, %): 188 [M+] (6), 171 (16), 106 (10), 105 (100), 77
(34), 51 (12).
IR (capillary): ν 3063 (s), 3031 (m), 2963 (w), 2872 (m), 1963 (s), 1884 (s), 1692
(m), 1623 (s), 1598 (s), 1580 (s), 1495 (m), 1465 (m), 1386 (m), 1315 (s), 1179 (s),
1136 (s), 1106 (w), 1068 (w), 1009 (m), 969 (m), 894 (m), 842 (s), 760 (w) cm−1.
cis-24a: 1H NMR (400 MHz, CDCl3): δ 0.88 (d, J = 2.2 Hz, 3H, 6-H), 0.90 (d, J =
1.0 Hz, 3H, 7-H), 2.20-2.27 (octd, J = 1.50 Hz, J = 6.7 Hz, 1H, 5-H), 3.63-3.66 (dd,
J = 4.7 Hz, J = 8.6 Hz, 1H, 2-H), 4.23 (d, J = 4.2 Hz, 1 H, 1-H), 4.95-5.0 (ddd, J =
8.8, J = 15.7, J = 1.2 Hz, 1H, 3-H), 5.94-5.98 (dd, J = 6.7, J = 15.6 Hz, 1H, 4-H),
7.25-7.37 (m, 5H, Ph).
13C NMR (100 MHz, CDCl3): δ 20.0 (d, C-6, C-7), 31.2 (d, C-5), 59.0, 59.9 (d, C-1,
C-2), 120.4 (d, C-4), 128.0,128.4, 129.0 (d, o-, m-, p-Ph), 135.20 (u, i-Ph), 145.8
(d, C-3).
CI-MS m/z (relative intensity, %): 188 [M+] (6), 171 (16), 106 (10), 105 (100), 77
(34), 51 (12).
EXPERIMENTAL PART 114
IR (capillary): ν 3063 (s), 3031 (m), 2963 (w), 2872 (m), 1963 (s), 1884 (s), 1692
(m), 1623 (s), 1598 (s), 1580 (s), 1495 (m), 1465 (m), 1386 (m), 1315 (s), 1179 (s),
1136 (s), 1106 (w), 1068 (w), 1009 (m), 969 (m), 894 (m), 842 (s), 760 (w) cm−1.
5.7.8 (−)-(S)-N-Phenylsulfinyl-N-methyl-chlrocarboxylicacidethylester (29a)
NMe
CO2CH(Cl)MeSO
Ph
29a
1H NMR (400 MHz, CDCl3): δ 1.90 (d, J = 6.0 Hz, 3 H), 2.70 (d, J = 5.5 Hz, 3 H, N-
CH3), 6.55-6.60 (m, 1H), 7.25-7.37 (m, 5H, Ph).
13C NMR (100 MHz, CDCl3): δ 25.2 (NCH3, d), 25.3 (d), 83.5 (d) 124.9 (d), 129.2
(d), 131.95 (d), 141.71 (u).
CI-MS m/z (relative intensity, %): 261 [M+] (2), 201 (3), 199 (40), 142 (22), 126
(10), 125 (100), 105 (12), 97 (21), 94 (25), 78 (12), 74 (10), 59 (11), 51 (16), 45
(18).
IR (capillary): ν 3063 (m), 2940 (m), 1906 (w), 1949 (s), 1728 (s), 1726 (s), 1663
(s), 1495 (m), 1449 (m), 1371 (s), 1348 (s), 1260 (s), 1196 (s), 1071 (s), 1027 (s),
967 (w), 916 (s), 879 (m), 843 (s), 753 (m) cm−1.
HRMS (EI, 70 eV)
calcd. For C10H12SClNO3 : 261.022674
Found : 261.022644
Optical rotation: [ α]D = -69.4 (c 1, CH2Cl2)
EXPERIMENTAL PART 115
5.8 Synthesis of Silylated Homoallylic Alcohols.
5.8.1 (+)-Triethyl-[(Z)-(1R,2R)-1,2-diphenyl-3-methyl-4-[(S)-N-methyl-S- phenyl- sulfonimidoyl]-but-3-enyloxy]silane( 50c).
S
Ph
O
NMe
Ph
Me
Ph
Et3SiO
50c Following GP3, reaction of sulfoximine 58b (2.85 g, 10 mmol) with benzaldehyde
(530 mg, 5 mmol) afforded ether 50c (2.37, 94%) as a viscous liquid and
sulfoximine 58b (1.25 g, 44%).
1H NMR (400 MHz, CDCl3): δ 0.42 (m, 6 H, Si(CH2CH3)3), 0.84 (m, 9 H,
Si(CH2CH3)3), 2.05 (d, J = 1.1 Hz, 3 H, CH3), 2.79 (s, 3 H, NCH3), 5.16 (d, J
=9.6,Hz, 1 H, CHPh), 5.57 (d, J = 9.9 Hz, 1 H, SiOCH), 6.08 (d, J = 1.4 Hz, 1 H, S-
CH=C), 7.05 (m, 5 H, Ph), 7.15 (m, 3 H, Ph), 7.25 (m, 2 H, Ph), 7.48 (m, 3 H, Ph),
7.94 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 4.85 (Si(CH2CH3)3, u), 6.76 (Si(CH2CH3)3, d),
21.04 (CH3, d), 29.45 (NCH3, d), 52.62 (CHPh, d), 75.93 (SiOCH, d), 126.34,
127.31, 127.44, 127.53, 127.62, 127.75, 128.19, 128.73, 128.98 (o-, m-, p-C, d),
131.89 (CH=C, d), 138.01 (C=CH, u), 141.18, 142.61, 155.72 (i-C, u).
IR (capillary): ν 3063 (s), 3030 (s), 2954 (vs), 2910 (vs), 2877 (vs), 2805 (s), 1613
(m), 1493 (m), 1457 (m), 1414 (m), 1238 (vs), 1153 (s), 1082 (vs), 1013 (vs), 972
(s), 841 (vs) cm−1.
CI-MS m/z (relative intensity, %): 506 [M++1] (100), 505 [M+] (3), 504 (2), 477 (2),
476 (2), 351 (2), 350 (4), 330 (2), 329 (7), 222 (2), 221 (8), 220 (2), 219 (7), 218
(2), 156 (10).
EXPERIMENTAL PART 116
Elemental Analysis: Anal. Calcd for C30H39NO2SSi (505.79) : C, 71.24; H, 7.77; N, 2.77
Found : C, 71.09; H, 7.68; N, 2.77
Optical rotation : [α]D = +66.1 (c 0.91, MeOH).
5.8.2 Synthesis of (+)-Triethyl-[(Z)-(1R,2R)-2-phenyl-3-methyl-4-[(S)-N-
methyl-S-phenyl-sulfonimidoyl]-1-(4-methoxyphenyl)-but-3-enyloxy]silane (50d).
S
Ph
O
NMe
C6H4OMep
Me
Ph
Et3SiO
50d
Following GP3, reaction of sulfoximine 58b (2.85 g, 10 mmol) with 4-
methoxybenzaldehyde (680 mg, 5 mmol) afforded ether 50d (2.60, 97%) as a
viscous liquid and sulfoximine 58b (1.14 g, 4.0 mmol, 40%):
1H NMR (400 MHz, CDCl3): δ 0.41 (m, 6 H, Si(CH2CH3)3), 0.85 (m, 9 H,
Si(CH2CH3)3), 2.03 (d, J = 1.4 Hz, 3 H, CH3), 2.80 (s, 3 H, NCH3), 3.71 (s, 3 H,
OCH3), 5.13 (d, J =9.9, Hz, 1 H, CHPh), 5.55 (d, J = 9.9 Hz, 1 H, SiOCH), 6.07 (d,
J = 1.1 Hz, 1 H, S-CH=C), 6.70 (m, 2 H, Ph), 7.04 (m, 5 H, Ph), 7.20 (m, 2 H, Ph),
7.49 (m, 3 H, Ph), 7.94 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 4.87 (Si(CH2CH3)3, u), 6.80 (Si(CH2CH3)3, d), 20.88
(CH3, d), 29.46 (NCH3, d), 52.27 (CHPh, d), 54.94 (OCH3, d), 75.32 (SiOCH, d),
EXPERIMENTAL PART 117
112.98, 126.28, 127.31, 127.75, 128.18, 128.54, 128.72, 128.97 (o-, m-, p-C, d),
131.88 (CH=C, d), 138.16 (C=CH, u), 134.82, 141.22, 155.94, 158.60 (i-C, u).
IR (capillary): ν 3060 (s), 3029 (s), 2955 (vs), 2910 (vs), 2876 (s), 2836 (s), 1738
(m), 1611 (m), 1512 (m), 1445 (m), 1245 (vs), 1175 (s), 1153 (s), 1078 (s), 1048
(s), 1007 (s), 853 (s), 835 (s) cm−1.
CI-MS m/z (relative intensity, %): 536 [M++1] (100), 535 [M+] (2), 534 (2), 506 (2),
546 (2), 406 (4), 405 (9), 404 (35), 382 (2), 381 (7), 380 (8), 359 (8), 252 (3), 251
(12), 249 (7), 156 (10).
Elemental Analysis:
Anal. Calcd for C31H41NO3SSi (535.81) : C, 69.49; H, 7.71; N, 2.61
Found : C, 69.27; H, 7.76; N, 2.74
Optical rotation : [α]D = +57.5 (c 1.01, MeOH).
5.8.3 Synthesis of (-)-(S)-N,N-Dimethylamino-S-[(Z)-(3R,4R)-2-methyl-3-phenyl-(4-methoxyphenyl)-4-(triethylsilyl)oxy]but-enyl-phenyl-sulfoxinium tetrafluroborate (49d)
BF4
C6H4OMep
Me
Ph
Et3SiO
SPh
O
NMe2
49d 1H NMR (400 MHz, CDCl3): δ 0.42 (m, 6 H, Si(CH2CH3)3), 0.86 (m, 9 H,
Si(CH2CH3)3), 2.37 (s, 3 H, CH3), 3.15 (s, 6 H, N(CH3)2), 3.74 (s, 3 H, OCH3),
5.25 (d, J = 9.3 Hz, 1 H, CHPh), 5.37 (d, J = 9.6 Hz, 1 H, SiOCH), 6.78 (m, 2 H,
Ph), 6.98 (m, 1 H, S-CH=C), 7.04 (m, 5 H, Ph), 7.20 (m, 2 H, Ph), 7.78 (m, 3 H,
Ph), 8.19 (m, 2 H, Ph).
EXPERIMENTAL PART 118
13C NMR (100 MHz, CDCl3): δ 4.80 (Si(CH2CH3)3, u), 6.77 (Si(CH2CH3)3, d), 22.28
(CH3, d), 37.38 (N(CH3)2, d), 53.48 (CHPh, d), 55.05 (OCH3, d), 75.65 (SiOCH, d),
113.34, 127.45, 128.04, 128.32, 128.39, 128.62, 128.86, 129.53 (o-, m-, p-C, d),
115.03 (CH=C, d), 130.72 (C=CH, u), 133.57, 135.94, 159.09, 174.53 (i-C, u).
5.8.4 Synthesis of (-)-Triethyl-[(Z)-(1R,2R)-2-Isopropyl-3-methyl-4-[(S)-N-
methyl-S-phenyl-sulfonimidoyl]-1-phenyl-but-3-enyloxy]silane( 50a)
S
Ph
O
NMe
Ph
Me
i-Pr
Et3SiO
50a
Following GP3, reaction of sulfoximine 58a (2.51 g, 10 mmol) with benzaldehyde
(0.53 g, 5 mmol) afforded ether 50a (2.26, 96%) as a viscous liquid and
sulfoximine 58a (0.95 g, 3.8 mmol, 38%).
1H NMR (400 MHz, CDCl3): δ 0.50 (m, 9 H, Si(CH2CH3)3, CH3), 0.85 (m, 9 H,
Si(CH2CH3)3), 0.95 (d, J = 6.4 Hz, 3 H, CH3), 1.94 (m, 1 H, CH(CH3)3), 2.00 (d, J =
1.1 Hz, 3 H, CH3), 2.30 (s, 3 H, NCH3), 3.87 (dd, J = 9.6, J = 4.4 Hz, 1 H, CHiPr),
5.05 (d, J = 4.4 Hz, 1 H, SiOCH), 5.89 (d, J = 1.4 Hz, 1 H, S-CH=C), 7.30 (m, 5 H,
Ph), 7.50 (m, 3 H, Ph), 7.75 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 4.92 (Si(CH2CH3)3, u), 6.82 (Si(CH2CH3)3, d), 20.76
(CH3, d), 21.19 (CH3, d), 22.83 (CH3, d), 26.88 (CH(CH3)3, d), 29.00 (NCH3, d),
51.76 (CHiPr, d), 75.61 (SiOCH, d), 126.80, 126.96, 127.67, 128.16, 128.40,
128.68 (o-, m-, p-C, d), 131.79 (CH=C, d), 141.39 (C=CH, u), 143.34, 156.89 (i-C,
u).
IR (capillary): ν 3061 (s), 3028 (s), 2958 (vs), 2910 (vs), 2876 (vs), 2801 (s), 1609
(m), 1448 (m), 1415 (m), 1376 (m), 1243 (vs), 1149 (s), 1069 (vs), 1007 (s), 981
(s), 858 (vs) cm−1.
EXPERIMENTAL PART 119
CI-MS m/z (relative intensity, %): 472 [M++1] (100), 470 (6), 444 (2), 443 (4), 442
(3), 317 (2), 316 (6), 295 (2), 221 (3), 222 (2), 221 (3), 187 (1), 184 (2), 156 (7).
Elemental Analysis:
Anal. Calcd for C27H41NO2SSi (471.77) : C, 68.74; H, 8.76; N, 2.97
Found : C, 68.64; H, 8.43; N, 2.73.
Optical rotation : [α]D = −130.1 (c 0.88, MeOH).
5.8.5 Synthesis of (−)-Triethyl-[(Z)-(1R,2R)-2-Isopropyl-3-methyl-4-[(S)-N-methyl-S-phenyl-sulfonimidoyl]-1-(4-methoxyphenyl)-but-3-enyloxy] silane (50b)
S
Ph
O
NMe
C6H4OMep
Me
i-Pr
Et3SiO
50b
Following GP3, reaction of sulfoximine 58a (2.51 g, 10 mmol) with 4-
methoxybenzaldehyde (680 mg, 5 mmol) afforded ether 50b (2.37, 95%) as a
viscous liquid and sulfoximine 58a (950 mg, 3.8 mmol, 38%).
1H NMR (400 MHz, CDCl3): δ 0.49 (m, 9 H, Si(CH2CH3)3, CH3), 0.85 (m, 9 H,
Si(CH2CH3)3), 0.92 (d, J = 6.4 Hz, 3 H, CH3), 1.89 (m, 1 H, CH(CH3)3), 1.96 (d, J =
1.3 Hz, 3 H, CH3), 2.42 (s, 3 H, NCH3), 3.80 (s, 3 H, OCH3), 3.85 (dd, J = 9.7, J
= 5.0 Hz, 1 H, CHiPr), 4.99 (d, J = 4.9 Hz, 1 H, SiOCH), 5.92 (d, J = 1.3 Hz, 1 H,
S-CH=C), 6.87 (m, 2 H, Ph), 7.26 (m, 2 H, Ph), 7.46 (m, 3 H, Ph), 7.80 (m, 2 H,
Ph).
EXPERIMENTAL PART 120
13C NMR (100 MHz, CDCl3): δ 4.93 (Si(CH2CH3)3, u), 6.85 (Si(CH2CH3)3, d), 20.77
(CH3, d), 21.21 (CH3, d), 22.69 (CH3, d), 26.99 (CH(CH3)3, d), 29.03 (NCH3, d),
51.92 (CHiPr, d), 55.08 (OCH3, d), 75.24 (SiOCH, d), 113.05, 127.97, 128.11,
128.40, 128.64, (o-, m-, p-C, d), 131.79 (CH=C, d), 141.44 (C=CH, u), 135.69,
157.17, 158.56 (i-C, u).
IR (capillary): ν 3063 (s), 2956 (vs), 2910 (vs), 2876 (vs), 1611 (m), 1512 (m),
1462 (m), 1246 (vs), 1174 (s), 1150 (s), 1107 (s), 1079 (s), 1036 (s), 1008 (s), 979
(s), 855 (s) cm−1.
CI-MS m/z (relative intensity, %): 502 [M++1] (100), 501 [M+] (2), 500 (3), 473 (2),
472 (4), 427 (2), 426 (4), 372 (4), 371 (13), 370 (51), 347 (8), 346 (12), 342 (7),
341 (10), 326 (4), 325 (6), 294 (4), 252 (2), 251 (9), 156 (11).
Elemental Analysis:
Anal. Calcd for C28H43NO3SSi (501.80) : C, 67.02; H, 8.64; N, 2.79
Found : C, 66.98; H, 8.89; N, 2.83.
Optical rotation : [α]D = −137.3 (c 0.88, MeOH).
EXPERIMENTAL PART 121
5.8.6 Synthesis of (−)-Triethyl-[(Z)-(αR,1R)-α-(4-methoxyphenyl)-2-{[(S)-N-methyl-S-phenyl-sulfonimidoyl]-methene}-cyclohexane-methane-α-enyloxy]silane (54a).
OMeN
C6H4MeOp
Et3SiOSPh
54a
Following GP3, reaction of sulfoximine 9a (2.49 g, 10 mmol) with 4-
methoxybenzaldehyde (680 mg, 5 mmol) afforded ether 54a (2.40, 96%) as a
viscous liquid and sulfoximine 9a (970 mg, 3.9 mmol, 39%).
1H NMR (400 MHz, CDCl3): δ 0.38 (m, 6 H, Si(CH2CH3)3), 0.83 (m, 9 H,
Si(CH2CH3)3), 1.15 (m, 1 H, Cy), 1.35 (m, 3 H, Cy), 1.60 (m, 1 H, Cy), 1.95 (m, 1
H, Cy), 2.15 (m, 1 H, Cy), 2.40 (m, 1 H, Cy), 2.75 (s, 3 H, NCH3), 3.81 (s, 3 H,
OCH3), 3.88 (m, 1 H, Cy), 4.80 (d, J =9.6 Hz, 1 H, SiOCH), 6.28 (d, J = 1.0 Hz, 1
H, S-CH=C), 6.85 (m, 2 H, Ph), 7.32 (m, 2 H, Ph), 7.50 (m, 3 H, Ph), 7.96 (m, 2 H,
Ph).
13C NMR (100 MHz, CDCl3): δ 4.81 (Si(CH2CH3)3, u), 6.75 (Si(CH2CH3)3, d),
20.69, 27.54, 29.32, 33.64 (Cy, u), 29.12 (NCH3, d), 44.55 (Cy-CH, d), 55.08
(OCH3, d), 77.37 (SiOCH, d), 113.20, 125.29, 128.20, 128.25, 128.60, (o-, m-, p-
C, d), 131.58 (CH=C, d), 136.03 (C=CH, u), 141.71, 158.81, 161.45, (i-C, u).
IR (capillary): ν 2952 (vs), 2911 (vs), 2875 (vs), 2838 (vs), 2803 (vs), 1739 (s),
1700 (m), 1601 (m), 1579 (m), 1512 (s), 1461 (m), 1446 (m), 1242 (vs), 1160 (s),
1102 (s), 1080 (s), 1045 (s), 1016 (s), 838 (vs) cm−1.
CI-MS m/z (relative intensity, %): 500 [M++1] (29), 470 (2), 387 (2), 386 (6), 369
(2), 368 (8), 344 (3), 252 (6), 251 (6), 250 (38), 231 (2), 212 (2), 175 (2), 157 (2),
156 (25), 138 (7), 137 (100), 135 (2), 125 (3).
EXPERIMENTAL PART 122
Elemental Analysis:
Anal. Calcd for C28H41NO3SSi (499.78) : C, 67.29; H, 8.27; N, 2.80
Found : C, 67.14; H, 8.13; N, 2.91.
Optical rotation : [α]D = –238.5 (c 1.02, MeOH).
5.8.7 Synthesis of (-)-Triethyl-[(Z)-(αR,1R)-α-(4-methoxyphenyl)-2-{[(S)-N-methyl-S-phenyl-sulfonimidoyl]-methene}-cyclooctane-methane-α-enyloxy]silane (ent-54c)
OMeN
C6H4MeOp
Et3SiOSPh
ent-54c
Following GP3, reaction of sulfoximine ent-9c (2.77 g, 10 mmol) with 4-methoxy-
benzaldehyde (0.68 g, 5 mmol) afforded ether ent-54c (2.53, 96%) as a viscous
liquid and sulfoximine ent-9c (1.05 g, 38%).
1H NMR (400 MHz, CDCl3): δ 0.20 (m, 1 H, Cy), 0.52 (m, 7 H, Si(CH2CH3)3,Cy),
0.85 (m, 10 H, Si(CH2CH3)3, Cy), 1.05 (m, 2 H, Cy), 1.20 (m, 2 H, Cy), 1.35 (m, 2
H, Cy), 1.64 (m, 2 H, Cy), 1.90 (m, 1 H, Cy), 2.73 (s, 3 H, NCH3), 3.37 (m, 1 H,
CH(Cy)), 3.79 (s, 3 H, OCH3), 5.02 (d, J =5.9 Hz, 1 H, SiOCH), 6.35 (s, 1 H, S-
CH=C), 6.79 (m, 2 H, Ph), 7.20 (m, 2 H, Ph), 7.56 (m, 3 H, Ph), 7.93 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 4.84 (Si(CH2CH3)3, u), 6.91 (Si(CH2CH3)3, d),
19.42, 24.81, 24.87, 28.12, 33.08, 34.13 (Cy, u), 29.20 (NCH3, d), 48.85 (Cy-CH,
d), 55.12 (OCH3, d), 76.45 (SiOCH, d), 112.84, 128.45, 128.63, 129.03, 129.26 (o-
, m-, p-C, d), 132.20 (CH=C, d), 134.87 (C=CH, u), 140.31, 158.75, 165.83 (i-C,
u).
EXPERIMENTAL PART 123
IR (capillary): ν 3671 (s), 3602 (s), 3003 (w), 2800 (m), 2732 (s), 2687 (s), 2546
(s), 2475 (s), 2066 (s), 1894 (s), 1815 (s), 1772 (s), 1726 (s), 1416 (m), 1369 (m),
1300 (w), 970 (w), 820 (w) cm−1.
CI-MS m/z (relative intensity, %): 528 [M++1] (100), 527 [M+] (2), 498 (4), 397 (6),
396 (22), 391 (4), 375 (4), 367 (10), 351 (7), 251 (14), 243 (8), 156 (42), 137 (16),
133 ( 6).
HRMS (EI, 70 ev):
Calcd for C30H45NO3Si : 527.288946
Found : 527.289127.
Optical rotation : [α]D = –119.5 (c 1.01, CH2Cl2).
EXPERIMENTAL PART 124
5.8.8 Synthese von (Z,SS,2S,3R)-N,N-Dimethylamino-S-(2-(ethoxycarbonyl-
(2-methyl-propan-2-sulfonylamino)-methyl)-cyclooctylidenmethyl)-phenylsulfoxonium-tetrafluoroborat (ent-53c)
BF4
OMe2N
R
Et3SiOSPh
ent-53c
1H NMR (400 MHz, CDCl3): δ 0.45 (m, 6 H, Si(CH2CH3)3), 0.65 (m, 1 H, Cy), 0.85-
0.95 (m, 9 H, Si(CH2CH3)3), 1.0−1.11 (m, 3 H, Cy), 1.30-1.75 (m, 4 H, Cy), 1.97−
2.02 (m, 2 H, Cy), 2.26-2.32 (m, 1 H, Cy), 2.60 (m, 1 H, Cy), 3.05 (s, 6 H,
N(CH3)2), 3.64−3.69 (m, 1 H, CH(Cy)), 3.85 (s, 3 H, OCH3), 4.54 (d, J = 7.1 Hz, 1
H, SiOCH), 6.95 (m 2 H, Ph), 7.10 (s, 1 H, S-CH=C), 7.25 (m, 2 H, Ph), 7.78 (m,
3 H, Ph), 8.22 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 4.72 (Si(CH2CH3)3, u), 6.77 (Si(CH2CH3)3, d),
24.09, 24.21, 24.58, 26.99, 33.48, 33.80 (Cy, u), 37.16 (N(CH3)2, d), 49.40 (Cy-
CH, d), 55.29 (OCH3, d), 77.84 (SiOCH, d), 113.58, 128.44, 128.92, 131.24 (o-, m-
, p-C, d), 116.58 (CH=C, d), 134.61 (C=CH, u), 136.46, 159.44, 184.36 (i-C, u).
EXPERIMENTAL PART 125
5.9 Synthesis of Monocyclic/Bicyclic 2,3-Dihydrofurans
5.9.1 Synthesis of (−)-(4R,5R)-Triethyl-(3-methyl-4,5-diphenyl-4,5-dihydro-furan-2-yl)-silane (45c)
O
Me
SiEt3
45c Following GP4, reaction of sulfoximine 50c (2.02 g, 4 mmol) with Me3OBF4 (765
mg, 5.2 mmol) and LiN(H)tBu (4.4 mmol, 4.4 mL of 1 M in THF) afforded
dihydrofuran 45c (1.34 g, 96%) and sulfinamide 29b (600 mg, 89%).
1H NMR (400 MHz, CDCl3): δ 0.85 (m, 6 H, Si(CH2CH3)3), 1.10 (m, 9 H,
Si(CH2CH3)3), 1.53 (s, 3 H, CH3), 3.78 (dd, J =6.9, J =1.1 Hz, 1 H, CHPh), 5.25
(d, J =6.9 Hz, 1 H, COCH), 7.28 (m, 10 H, Ph).
13C NMR (100 MHz, CDCl3): δ 3.69 (Si(CH2CH3)3, u), 7.90 (Si(CH2CH3)3, d), 11.13
(CH3, d), 65.37 (CHPh, d), 90.65 (COCH, d), 124.43, 143.63 (C=C, u), 125.31,
126.96, 127.44, 128.12, 128.60, 128.96 (o-, m-, p-C, d), 144.29, 152.64 (i-C, u).
IR (capillary): ν 3061 (s), 3027 (s), 2954 (vs), 2911 (vs), 2875 (vs), 1634 (m), 1601
(m), 1493 (m), 1453 (s), 1415 (m), 1261 (m), 1237 (s), 1074 (vs), 1006 (s), 973 (s),
928 (s) cm−1.
CI-MS m/z (relative intensity, %): 351 [M++1] (100), 350 [M+] (13), 349 (6), 321 (2),
274 (3), 273 (), 219 (2), 115 (2).
Elemental Analysis:
Anal. Calcd for C23H30OSi (350.57): C, 78.80; H, 8.63
Found : C, 78.82; H, 8.65.
EXPERIMENTAL PART 126
Optical rotation: [α]D = −210.0 (c 1.25, CH2Cl2).
5.9.2 Synthesis of (−)-(4R,5R)-Triethyl-(4-isopropyl-3-methyl-5-phenyl-4,5-dihydro-furan-2-yl)-silane (45a)
O
Me
SiEt3
45a
Following GP4, reaction of sulfoximine 50a (940 mg, 2 mmol) with Me3OBF4 (382
mg, 2.6 mmol) and LiN(H)tBu (2.2 mmol, 2.2 mL of 1 M in THF) afforded
dihydrofuran 45a (600 mg, 95%) and sulfinamide 29c (290 mg, 86%).
1H NMR (400 MHz, CDCl3): δ 0.75 (m, 6 H, Si(CH2CH3)3), 0.85 (d, J = 6.9 Hz, 3 H,
CH3), 1.00 (m, 12 H, Si(CH2CH3)3, CH3), 1.65 (d, J = 1.0 Hz, 3 H, CH3), 1.94 (m, 1
H, CH(CH3)3), 2.62 (m, 1 H, CHiPr), 5.09 (d, J = 4.7 Hz, 1 H, SiOCH), 7.32 (m, 5
H, Ph).
13C NMR (100 MHz, CDCl3): δ 3.28 (Si(CH2CH3)3, u), 7.41 (Si(CH2CH3)3, d), 10.91
(CH3, d), 16.57 (CH3, d), 20.68 (CH3, d), 28.02 (CH(CH3)3, d), 64.08 (CHiPr, d),
82.03 (COCH, d), 125.08, 126.81, 128.25 (o-, m-, p-C, d), 122.42, 145.76 (C=C,
u), 151.33 (i-C, u).
IR (capillary): ν 3062 (s), 3028 (s), 2957 (vs), 2955 (vs), 2876 (vs), 1635 (m), 1458
(m), 1415 (m), 1384 (m), 1238 (s), 1083 (s), 1007 (s), 962 (s) cm−1.
CI-MS m/z (relative intensity, %): 317 [M++1] (100), 316 [M+](14), 315 (4), 287 (3),
273 (3), 239 (3), 186 (2), 185 (7), 145 (2), 115 (2).
EXPERIMENTAL PART 127
Elemental Analysis:
Anal. Calcd for C20H32OSi (316.55): C, 75.88; H, 10.19
Found : C, 75.79; H, 10.28.
Optical rotation: [α]D = −61.9 (c 1.43, MeOH).
5.9.3 Synthesis of (−)-(4R,5R)-Triethyl-(4-isopropyl-3-methyl-5-(4-methoxy-phenyl)-4,5-dihydro-furan-2-yl)-silane (45b)
O
MeO
SiEt3
45b Following GP4, reaction of sulfoximine 50b (1.00 g, 2 mmol) with Me3OBF4 (382
mg, 2.6 mmol) and LiN(H)tBu (2.2 mmol, 2.2 mL of 1 M in THF) afforded
dihydrofuran 45b (620 mg, 90%) and sulfinamide 29c (280 mg , 85%).
1H NMR (400 MHz, CDCl3): δ 0.75 (m, 6 H, Si(CH2CH3)3), 0.90 (d, J =6.9 Hz, 3 H,
CH3), 1.02 (m, 12 H, Si(CH2CH3)3, CH3), 1.65 (d, J =1.1 Hz, 3 H, CH3), 1.97 (m, 1
H, CH(CH3)2), 2.62 (m, 1 H, CHiPr), 3.77 (s, 3 H, OCH3), 5.04 (d, J =4.7 Hz, 1
H, COCH), 6.87 (m, 2 H, Ph), 7.20 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 3.26 (Si(CH2CH3)3, u), 7.41 (Si(CH2CH3)3, d), 10.91
(CH3, d), 16.53 (d, CH3), 20.58 (d, CH3), 27.93 (d, CH(CH3)2, 55.11 (OCH3, d),
63.86 (CHiPr, d), 81.68 (COCH, d), 113.46, 126.15 (o-, m-C, d), 122.28, 137.77
(C=C, u), 150.98, 158.33 (i-C, u).
IR (capillary): ν 2954 (vs), 2875 (vs), 2835 (s), 1612 (m), 1512 (m), 1461 (m),
1416 (s), 1383 (m), 1300 (m), 1247 (vs), 1174 (s), 1083 (s), 1037 (s), 1009 (s),
961 (s), 819 (s) cm−1.
EXPERIMENTAL PART 128
CI-MS m/z (relative intensity, %): 347 [M++1] (100), 346 [M+](26), 345 (6), 317 (3),
304 (2), 303 (6), 240 (2), 239 (10), 217 (2), 215 (3), 176 (2), 115 (3).
Elemental Analysis:
Anal. Calcd for C21H34O2Si (346.58): C, 72.78; H, 9.89
Found :C, 72.75; H, 9.75.
Optical rotation: [α]D = –84.5 (c 1.01, MeOH).
5.9.4 Synthesis of (−)-(4R,5R)-Triethyl-(3-(4-methoxy-phenyl)-3,3a,4,5,6,7,8,9-heptahydro-isobenzofuran-1-yl)-silane (ent-51c)
O
SiEt3
H3CO
ent-51c Following GP4, reaction of sulfoximine ent-54c (2.10 g, 4 mmol) with Me3OBF4
(765 mg, 5.2 mmol) and LiN(H)tBu (4.4 mmol, 4.4 mL of 1 M in THF) afforded
dihydrofuran ent-51c (1.34 g, 90%) and sulfinamide 29c (590 mg, 88%).
1H NMR (400 MHz, CDCl3): δ 0.75 (m, 6 H, Si(CH2CH3)3), 1.00 (m, 9 H,
Si(CH2CH3)3), 1.5−1.79 (m, 9 H, Cy), 1.8-1.85 (m, -1 H, Cy), 2.0−2.06 (m, 1 H,
Cy), 2.48-2.52 (m, 1 H, Cy), 2.81−2.85 (m, 1 H, Cy), 3.78 (s, 3 H, OCH3), 4.83 (d,
J =9.3 Hz, 1 H, COCH), 6.87 (m, 2 H, Ph), 7.27 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 3.19 (Si(CH2CH3)3, u), 7.50 (Si(CH2CH3)3, d),
24.60, 24.66, 25.94, 26.84, 28.97, 29.58 (Cy, u), 55.14 (OCH3, d), 56.41 ((CH)Cy,
d), 87.88 (COCH, d), 113.52, 126.78 (o-, m-C, d), 129.85, 135.95 (C=C, u),
152.11, 158.69 (i-C, u).
IR (capillary): ν 2729 (s), 2692 (s), 2545 (s), 2278 (s), 2067 (s), 1878 (s), 1762 (s),
1680 (s), 1614 (w), 1585 (m), 1416 (m), 1374 (s), 1301 (m), 1174 (w), 1072 (w),
1017 (w), 959 (m), 828 (w) cm−1.
EXPERIMENTAL PART 129
CI-MS m/z (relative intensity, %) 373 [M++1] (100), 372 [M+] (26), 371 (8), 265
(7), 241 (22), 253 (2), 251 (5), 245 (2), 230 (2), 229 (8), 133 (2), 221 (2), 75 (3).
Elemental Analysis:
Anal. Calcd for C23H36O2Si (372.62): C, 74.14; H, 9.74
Found : C, 74.22; H, 9.33
HRMS (EI, 70 ev):
Calcd for C23H36SiO2: 372.248474
Found : 372.248459
Optical rotation: [α]D = −60.5 (c 4.5, CH2Cl2).
5.10 Synthesis of Bicyclic Tetrahydrofurans
5.10.1 Synthesis of (−)-(3R,3aR)-(3-(4-methoxy-phenyl)-1,3,3a,4,5,6-hexahydro-isobenzofuran(56a)
O
H3CO56a
Following GP5, reaction of sulfoximine 54a (2.00 g, 4 mmol) with Me3OBF4 (765
mg, 5.2 mmol) and DBU (6 mmol, 912 mg) afforded tetrahydrofuran 16a (640 mg,
69%) and sulfinamide 29c (560 mg, 84%).
1H NMR (400 MHz, CDCl3): δ 1.10-1.25 (m, 1 H, Cy), 1.40-1.50 (m, 1 H, Cy),
1.85−1.90 (m, 2 H, Cy), 2.05−2.10 (m, 2 H, Cy), 2.32 (m, 1 H, Cy), 3.85 (s, 3 H,
OCH3), 4.20 (d, J = 9.9 Hz, 1 H, OCH), 4.33 (m, 1 H, OCH2), 4.66 (m, 1 H,
OCH2), 5.56 (m, 1 H, CH=C), 6.87 (m, 2 H, Ph), 7.30 (m, 2 H, Ph).
EXPERIMENTAL PART 130
13C NMR (100 MHz, CDCl3): δ 21.59, 24.32, 24.65, (Cy, u), 48.00 ((CH)Cy, d),
55.27 (OCH3, d), 69.99 (OCH2, u), 86.68 (OCH, d), 113.76, 127.44 (o-, m-C, d),
117.29 (CH=C, d), 133.18 (C=C, u), 140.96, 159.24 (i-C, u)
IR (capillary): ν 2998 (m), 2489 (s), 2287 (s), 2023 (s), 1884 (s), 1764 (s), 1612
(w), 1586 (m), 1460 (w), 1369 (s), 1303 (m), 1175 (w), 1135 (s), 1096 (m), 954
(m), 625 (m), 863 (s), 830 (w) cm−1.
EI-MS m/z (relative intensity, %): 231 [M++1] (4), 230 [M+] (35), 138 (9), 137
(100), 135 (17), 94 (40), 91 (8), 79 (68), 77 (18).
HRMS (EI, 70 ev):
Calcd for C15H18O2: 230.130623
Found : 230.130680
Optical rotation: [α]25D = −21.6 (c 0.20, CH2Cl2).
5.10.2 (−)-(3R,3aR)-3-(4-methoxy-phenyl)-3,3a,4,5,6,7-hexahydro-1H-cyclohepta[c]furan (56b).
O
H3CO56b
Following GP5, reaction of sulfoximine 54b (2.05 g, 4 mmol) with Me3OBF4 (765
mg, 5.2 mmol) and DBU (6 mmol, 912 mg) afforded tetrahydrofuran 16b (702 mg,
72%) and sulfinamide 29c (676 mg, 87%).
1H NMR (400 MHz, CDCl3): δ 1.20−1.45 (m, 3 H, Cy), 1.65−2.05 (m, 2 H, Cy),
2.22−2.28 (m, 3 H, Cy), 2.48−2.53 (m, 1 H, Cy), 3.81 (s, 3 H, OCH3), 4.30 (d, J =
9.2 Hz, 1 H, OCH), 4.33 (m, 1 H, OCH2), 4.58 (m, 1 H, OCH2) 5.67 (m, 1 H,
CH=C), 6.85 (m, 2 H, Ph), 7.33 (m, 2 H, Ph).
EXPERIMENTAL PART 131
13C NMR (100 MHz, CDCl3): δ 27.60, 28.88, 29.04, 29.95 (Cy, u), 52.78 ((CH)Cy,
d), 55.26 (OCH3, d), 71.93 (OCH2, u), 88.17 (OCH, d), 113.74, 128.03 (o-, m-C,
d), 119.74 (CH=C, d), 132.94 (C=C, u), 145.83, 159.36 (i-C, u).
IR (capillary): ν 3008 (m), 2838 (w), 2605 (s), 2543 (s), 2373 (s), 2345 (s), 2049
(s), 1849 (s), 1737 (s), 1615 (w), 1586 (m), 1460 (w), 1383 (w), 1305 (w), 1179
(w), 1109 (m), 1080 (m), 969 (m), 927 (m), 889 (s), 869 (s), 837 (w) cm−1.
EI-MS m/z (relative intensity, %): 245 [M++1] (7), 244 [M+] (45), 138 (7), 137
(100), 136 (9), 135 (18), 109 (8), 108 (29), 93 (47), 91 (12), 80 (11), 79 (28), 77
(15).
Elemental Analysis:
Anal. Calcd for C16H20O2 (244.146): C, 78.65; H, 8.25
Found : C, 78.67; H, 7.74.
HRMS (EI, 70 ev):
Calcd for C16H20O2: 244.146457
Found: 244.146330
Optical rotation: [α]D = −34 (c 0.20, CH2Cl2).
Mp: 84−86 °C.
EXPERIMENTAL PART 132
5.10.3 Synthesis of (−)-(3R,3aR)-3-(4-methoxy-phenyl)-1,3,3a,4,5,6,7,8-
octahydro-1H-cycloocta[c]furan (ent-56c).
O
H3COent-56c
Following GP5, reaction of sulfoximine 54c (2.10 g, 4 mmol) with Me3OBF4 (765
mg, 5.2 mmol) and DBU (6 mmol, 912 mg) afforded tetrahydrofuran ent-56c (760
mg, 74%) and sulfinamide 29b (590 mg, 88%).
1H NMR (400 MHz, CDCl3): δ 0.75−1.00 (m, 1 H, Cy), 1.30−1.9 (m, 7 H, Cy), 2.12
(m, 2 H, Cy), 2.73 (m, 1 H, Cy), 3.80 (s, 3 H, OCH3), 4.44 (m, 2 H, OCH2), 4.54
(d, J = 4.7 Hz, 1 H, OCH), 5.49 (m, 1 H, CH=C), 6.86 (m, 2 H, Ph), 7.24 (m, 2 H,
Ph).
13C NMR (100 MHz, CDCl3): δ 25.08, 25.68, 26.22, 28.07, 35.48 (Cy, u), 49.98
((CH)Cy, d), 55.27 (OCH3, d), 71.61 (OCH2, u), 88.34 (OCH, d), 113.76, 127.34
(o-, m-C, d), 118.23 (CH=C, d), 134.96 (C=C, u), 143.56, 159.04 (i-C, u).
IR (capillary): ν 3002 (m), 2686 (s), 2547 (s), 2060 (s), 1885 (s), 1722 (s), 1670
(s), 1611 (w), 1459 (w), 1371 (s), 1301 (m), 1176 (w), 898 (s), 832 (w) cm−1.
EI-MS m/z (relative intensity, %): 259 [M++1] (10), 258 [M+] (62), 137 (100), 136
(18), 135 (29), 122 (30), 121 (12), 107 (30), 94 (27), 93 (43), 91 (12), 81 (13), 77
(16), 68 (10), 67 (12).
Elemental Analysis:
Anal. Calcd for C17H22O2 (258.36): C, 79.03; H, 8.60
Found : C, 78.68; H, 9.14.
EXPERIMENTAL PART 133
Optical rotation: [α]D = –104.8 (c 0.25, CH2Cl2).
Mp: 55-57 °C.
5.11 Synthesis of Amino acid derivatives 5.11.1 Synthesis of (+)-(E,Ss,2R,3S)-and (−)-(E,Ss,2S,3R)-(2-(N-methyl-S-
phenyl-sulfonimidoyl-methylene)-cycloheptyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82c and E-83c)
S
O
HN
O
O
NMe
S O
O
E-82c
12
4
10
S
O
HN
O
O
NMe
S O
O
E-83c
Following GP6, reaction of sulfoximine 9c (1.50 g, 5.7 mmol) with imino ester 81
(1.52 g, 6.8 mmol) gave a crude mixture of the alkenyl sulfoximines E-82c and E-
83c in ratio of 23-24:1 in approximately 98% chemical yield (1H NMR).
Recrystallization from CH2Cl2 afforded E-82c (1.98 g, 72%) as colorless crystals.
The mother liquor was concentrated in vacuo and the residue was purified by
preparative HPLC (ethyl acetate/n-hexane, 4:1) to afford an additional 10% of E-
82c (276 mg) and E-83c (110 mg, 4%).
E-82c:
1H NMR (400 MHz, CDCl3): δ 0.66-0.70 (m, 1 H, Cy), 0.93-1.01 (m, 1 H, Cy), 1.23-
1.25 (m, 1 H, Cy), 1.30 (t, J = 7.1 Hz, 3 H, 12-H), 1.36 (s, 9 H, 18-H), 1.50-1.75 (m,
3 H, Cy), 1.96-2.00 (m, 3 H, Cy), 2.60-2.61 (m, 1 H, 3-H), 2.65 (s, 3 H, NCH3),
3.34-3.38 (m, 1 H, Cy), 4.04-4.07 (m, 1 H, 2-H), 4.20-4.28 (m, 2 H, 11-H), 4.99 (d,
J = 10.7 Hz, 1 H, NH ), 6.32 (s, 1 H, 10-H), 7.53-7.61 (m, 3 H, Ph), 7.90 (m, 2 H,
Ph).
EXPERIMENTAL PART 134
13C NMR (100 MHz, CDCl3): δ 14.01 (C-12, d), 24.19 (C-18, d), 25.48 (Cy, u),
27.71 (Cy, u), 28.01 (Cy, u), 28.59 (Cy, u), 29.91 (Cy, u), 29.12 (NMe, d), 52.40
(C-3, d), 60.28 (C-17, u), 61.93 (C-2, d), 62.02 (C-11, u), 128.83 (C-14, d), 129.07
(C-15, d), 129.88 (C-10, d), 132.33 (C-16, d), 140.23 (C-13, u), 158.82 (C-9, u),
170.55 (C-1, u).
IR (KBr): ν 3442 (m), 3095 (s), 3061 (m), 2986 (w), 2861 (w), 2806 (s), 2682 (s),
2074 (s), 1780 (s), 1606 (m), 1396 (s), 1370 (m), 1078 (w), 1019 (m), 980 (s), 857
(w) cm−1.
EI-MS m/z (relative intensity, %): 485 [M++1] (1), 484 [M+] (2), 284 (28), 214 (30),
208 (36), 184 (16), 181 (9), 134 (13), 124 (18), 101 (11), 57 (22).
EXPERIMENTAL PART 135
1H{1H}-NOE-Experiment (500 MHz, CDCl3) of E-82c:
[%] H-2 H-5ax H-5eq H-6ax H-7eq H-7eq H-8eq H-8ax H-10 H-14 NH NCH3
H-2 - 5.7 2.4 2.3
H-3 3.8 4.8 2.0 9.4 2.8
H-4ax 2.8 5.0 14.6 2.1
H-4eq 1.9 3.7 3.7 0.7
H-5ax 41.1 - 31.6 3.4 2.4
H-6eq 5.2 37.8 - 4.2
H-7ax 38.3 39.8 3.6 2.4
H-8eq 4.9 - 4.0 4.3 0.5
H-9ax 1.3 4.6 - 30.5 0.8
H-9eq 5.0 45.3 -
H-10 2.5 0.5 12.7 - 0.9 1.6 0.9
H-14 2.2 3.1 - 1.1
H-16
NH 1.1 2.3 2.5 0.8 -
NCH3 0.8 -
H-17
Obs
erve
d Fr
eque
ncy
Emitted Frequency
Elemental Analysis:
Anal. Calcd for C23H36N2O5S2 (484.67): C, 57.00; H, 7.49; N, 5.78
Found : C, 56.63; H, 7.57; N, 5.51.
Optical rotation: [α]D = +58.4 (c 0.50, CH2Cl2).
M.p: 111-113 °C
The analytical data of E-83c were in agreement with those previously reported.23
EXPERIMENTAL PART 136
5.11.2 Synthesis of (+)-(E,Ss,2R,3S)- and (−)-(E,Ss,2S,3R)-(2-(N-methyl-S-
phenyl-sulfonimidoyl-methylene)-cyclooctyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82d and E-83d)
S
O
HN
O
O
NMe
S O
O
E-82d
12
4
11
S
O
HN
O
O
NMe
S O
O
E-83d
Following GP6, reaction of sulfoximine 9d (1.50 g, 5.4 mmol) with imino ester 81
(1.44 g, 6.5 mmol) gave a crude mixture of the alkenyl sulfoximines E-82d and E-
83d in ratio of 48-48.5:1 in approximately 98% chemical yield (1H NMR).
Recrystallization from CH2Cl2 afforded E-82d (2.20 g, 82%) as colorless solid. The
mother liquor was concentrated in vacuo, and the residue was purified by
preparative HPLC (ethyl acetate/n-hexane, 4:1) to afford an additional 5% of E-
82d (135 mg) and E-83d (53 mg, 2%).
E-82d:
1H NMR (400 MHz, CDCl3): δ 0.90-0.94 (m, 1 H, Cy), 1.07-1.11 (m, 1 H, Cy), 1.24
(t, J = 7.1 Hz, 3 H, 13-H), 1.36 (s, 9 H, 19-H), 1.45-2.00 (m, 8 H, Cy), 2.46-2.58 (m,
3 H, Cy), 2.63 (s, 3 H, NCH3), 3.98-4.01 (m, 1 H, 2-H), 4.02-4.14 (m, 2 H, 12-H),
4.96 (d, J = 10.7 Hz, 1 H, NH ), 6.33 (s, 1 H, 11-H), 7.60 (m, 3 H, Ph), 7.90 (m, 2
H, Ph).
13C NMR (100 MHz, CDCl3): δ 13.96 (C-13, d), 24.16 (C-19, d), 25.12 (Cy, d),
25.80 (Cy, u), 26.17 (Cy, u), 26.86 (Cy, u), 28.51 (Cy, u), 29.03 (Cy, u), 29.64
EXPERIMENTAL PART 137
(NMe, d), 51.42 (C-3, d), 60.20 (C-18, u), 61.76 (C-2, u), 61.93 (C-12, u), 128.53
(C-11, d), 128.64 (C-15, d), 128.95 (C-16, d), 132.22 (C-17, d), 140.05 (C-14, u),
160.41 (C-10, u), 170.68 (C-1, u).
1H{1H}-NOE-Experiment (500 MHz, C5D5NCl3) of E-82d:
[%] H-2 H-3 H-4ax H-7ax H-7eq H-8eq H-9ax H-9eq H-11 H-15 NH NCH3
H-2 - 6.2 3.3 5.7 2.4 1.8
H-3 2.4 - 9.1 3.7 2.6
H-4ax 3.0 - 7.8 14.6 1.7
H-4eq 2.9 3.7 50.9 0.6
H-7ax 8.6 - 31.6 5.7 2.4
H-7eq 45.9 - 2.9
H-8ax 42.8 3.6 2.4
H-8eq 7.0 2.7 - 4.0 4.3
H-9ax 1.3 14.9 2.5 4.6 - 30.5 0.8
H-9eq 5.0 39 - 4.2
H-11 2.9 0.5 12.7 - 1.6 0.9
H-15 2.2 1.4 - 1.1
H-16 9.4
NH 1.4 2.3 5.0 2.5 -
NCH3 0.6 -
H-17 1.1
Obs
erve
d Fr
eque
ncy
Emitted Frequency
, IR (KBr): ν 3441 (m), 3276 (m), 3058 (m), 2802 (m), 2690 (s), 2345 (s), 1785 (s),
1610 (m), 1372 (m), 1181 (m), 1022 (m), 955 (m), 917 (m), 805 (s) cm−1.
EI-MS m/z (relative intensity, %): 498 [M+] (1), 425 (9), 362 (20), 299 (21), 298
(100), 277 (12), 276 (30), 250 (15), 229 (18), 200 (23), 170 (40), 169 (65), 155
(24), 149 (18), 140 (10), 124 (41), 120 (11), 91 (13).
EXPERIMENTAL PART 138
Elemental Analysis:
Anal. Calcd for C24H38N2O5S2 (498.70): C, 57.80; H, 7.68; N, 5.62
Found : C, 57.46; H, 8.08; N, 5.23.
Optical rotation: [α]D = +76.1 (c 1.20, CH2Cl2).
M.p: 78-80 °C
The analytical data of E-82d were in agreement with those previously reported.23
5.11.3 Synthesis of (+)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-(2-(N-methyl-S- phenyl-sulfonimidoyl-methylene)-cyclohexyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82b and E-83b).
S
O
HN
O
O
NMe
S O
O
12
37
912
1014
16
E-82b
S
O
HN
O
O
NMe
S O
O
12
3
4
9
11
12
14
16
E-83b
Following GP6, reaction of sulfoximine 9b (1.05 g, 4.2 mmol) with imino ester 81
(1.12 g, 5.1 mmol) gave a crude mixture of the alkenyl sulfoximines E-82b and E-
83b in ratio of 9.7-10:1 in approximately 95% chemical yield (1H NMR).
Recrystallization from ether afforded E-82b (1.17 g, 59%) as colorless solid. The
mother liquor was concentrated in vacuo, and the residue was purified by
preparative HPLC (ethyl acetate/n-hexane, 4:1) to afford an additional 10% of E-
82b (198 mg) and E-83b (158 mg, 8%).
EXPERIMENTAL PART 139
E-82b: 1H NMR (400 MHz, CDCl3): δ 0.67-0.71 (m, 1 H, Cy), 1.30 (t, J = 7.1 Hz, 3 H, 11-
H), 1.35 (s, 9 H, 17-H), 1.40-1.50 (m, 2 H, Cy), 1.55-1.65 (m, 2 H, Cy), 2.12-2.32
(m, 3 H, Cy), 2.61 (s, 3 H, NCH3), 3.14 (m, 1 H, Cy), 4.08-4.12 (m, 2 H, 10-H),
4.16-4.28 (m, 1 H), 4.77 (d, J = 7.4 Hz, 1 H, N-H ), 6.28 (s, 1 H, 9-H), 7.50-7.58
(m, 3 H, Ph), 7.88 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 14.15 (C-11, d), 20.38 (Cy, u), 24.35 (C-17, d),
26.32 (Cy, u), 26.45 (Cy, u), 28.74 (Cy, u), 29.31 (NMe, d), 50.04 (C-3, d),57.26
(C-2, d), 60.28 (C-16, u), 62.14 (C-10, u), 127.57 (C-9, d), 128.85 (C-13, d),
129.13 (C-14, d), 132.33 (C-15, d), 140.81 (C-12, u), 157.42 (C-8, u), 171.75 (C-1,
u).
1H{1H}-NOE-Experiment (500 MHz, CDCl3) of E-82b:
[%] H-2 H-3 H-6 H-6' H-9 12H-2 - 1.7 1.1H-3 1.5 - 9.6H-4 4.2H-5H-6'H-7 4.5 0.6 - 1.1
H-12 1.6NMe 0.9 1.8 0.5 0.7
Obs
erve
d Fr
eque
ncy
Emitted Frequency
IR (KBr): ν 3438 (w), 3057 (w), 2993 (m), 2938 (w), 2860 (m), 2797 (m), 2759 (s),
2727 (s), 1796 (s), 1560 (s), 1525 (s), 1152 (w), 1017 (w), 928 (w), 834 (m), 805
(s) cm−1.
EXPERIMENTAL PART 140
EI-MS m/z (relative intensity, %): 471 [M+ +1] (7), 470 [M+] (27), 271 (11), 270
(60), 249 (16), 217 (9), 200 (26), 195 (15), 194 (100), 167 (17), 166 (44), 155 (41),
124 (49), 122 (18), 121 (13), 120 (21), 102 (22), 93 (11), 77 (11), 57 (44) .
Elemental Analysis:
Anal. Calcd for C22H34N2O5S2 (470.65): C, 56.14; H, 7.28; N, 5.95
Found : C, 55.65; H, 7.62; N, 5.78.
Optical rotation: [α]D = +28.4 (c 0.25, CH2Cl2).
M.p: 148-150 °C
The analytical data of E-83b were in agreement with those previously reported.23
5.11.4 Synthesis of (+)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)- (2-(N-methyl-S-phenyl-sulfonimidoyl-methylene)-cyclopentyl)-(2-methylpropane-2-sulfonylamino)-Acetic Acid Ethyl Ester (E-82a and E-83a).
S
O
HN
O
O
NMe
S O
O
12
3
7
912
15
E-82a
S
O
HN
O
O
NMe
S O
O
12
36
7
8
912
15
E-83a
Following GP6, reaction of sulfoximine 9a (1.02 g, 4.3 mmol) with imino ester 81
(1.14 g, 5.2 mmol) gave a crude mixture of the alkenyl sulfoximines E-82a and E-
83a in ratio of 5.7-6:1 in approximately 95% chemical yield (1H NMR).
Recrystallization from ether afforded E-82a (1.15 g, 58%) as colorless solid. The
mother liquor was concentrated in vacuo, and the residue was purified by
EXPERIMENTAL PART 141
preparative HPLC (ethyl acetate/n-hexane, 4:1) to afford an additional 12% of E-
82a (237 mg) and E-83a (276 mg, 14%).
E-82a: 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J = 7.1 Hz, 3 H, 10-H), 1.36 (s, 9 H, 16-H),
1.60-1.95 (m, 5 H, Cy), 2.62 (m, 1 H, Cy), 2.69 (s, 3 H, NCH3), 2.99 (m, 1 H, 3-H),
4.12-4.34 (m, 3 H, 9-H, 2-H), 4.88 (d, J = 7.4 Hz, 1 H, N-H ), 6.36 (s, 1 H, 8-H),
7.50-7.58 (m, 3 H, Ph), 7.92 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 14.0 (C-10, d), 24.10 (Cy, u), 24.20 (C-16, d),
27.40 (Cy, u), 30.30 (Cy, u), 29.20 (NMe, d), 50.60 (C-3, d),58.50 (C-2, d), 60.40
(C-15, u), 62.00 (C-9, u), 127.57 (C-8, d), 128.70 (C-12, d), 129.60 (C-13, d),
132.40 (C-14, d), 140.00 (C-11, u), 160.50 (C-7, u), 171.30 (C-1, u).
1H{1H}-NOE-Experiment (500 MHz, CDCl3) of E-82a:
[%] H-2 H-3 H-6 H-6' H-8 NHH-2 - 3.5 2.8 1.9H-3 3.2 - 3.1 4.1H-4 0.7 2.2 3.1H-5 1.1 2.5 2.9H-6' 16.5 -H-8 2.8 3.8 - 1.7
H-12 2.5 0.7 0.9 1.7 4.0NH 0.9 2.9 0.8 -
Obs
erve
d Fr
eque
ncy
Emitted Frequency
IR (KBr): ν 3438 (w), 3057 (w), 2993 (m), 2938 (w), 2860 (m), 2797 (m), 2759 (s),
2727 (s), 1796 (s), 1560 (s), 1525 (s), 1152 (w), 1017 (w), 928 (w), 834 (m), 805
(s) cm−1.
EXPERIMENTAL PART 142
EI-MS m/z (relative intensity, %) 456 [M+] (13), 455 (9), 234 (12), 182 (25), 165
(17), 156 (16), 155 (41), 124 (49), 122 (18), 121 (13), 120 (21), 102 (22), 93 (11),
77 (11), 57 (44).
Elemental Analysis:
Anal. Calcd for C21H32N2O5S2: C, 55.24; H, 7.06; N, 6.13
Found : C, 55.07; H, 7.32; N, 5.89.
Optical rotation: [α]D = +14.2 (c 2.9, CH2Cl2).
M.p: 148-150 °C
The analytical data of E-82a were in agreement with those previously reported.23
EXPERIMENTAL PART 143
5.11.5 Synthesis of(−)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-5-(N-methyl-S- phenyl-sulfonimidoyl)-3-cyclohexyl-2-(2-methylpropane-2-sulfonylamino)-pent- 4-enoic Acid Ethyl Ester (E-86b and E-87b ).
SPh
O NMe
EtO2C
NHO2S
E-86b
SPh
O NMe
EtO2C
NHO2S
E-87b
Following GP6, reaction of sulfoximine 84b (1.50 g, 5.4 mmol) with imino ester 81 (1.44 gm, 6.5 mmol) gave a crude mixture of the alkenyl sulfoximines E-86b and
E-87b in ratio of 5.8-6:1 in approximately 95% chemical yield (1H NMR).
Purification of this mixture by preparative HPLC (ethyl acetate/n-hexane, 4:1) gave
E-86b (1.496 g, 56%) as colorless oil, and E-87b (269 mg, 10%) as colorless
solid.
E-86b:
1H NMR (400 MHz, CDCl3): δ 0.65-1.24 (m, 5 H, Cy), 1.28 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 1.34 (s, 9 H, C(CH3)3), 1.40-1.70 (m, 6 H, Cy), 2.32 (dt, J = 6.6, J =
10.9 Hz, 1 H, 3-H), 2.74 (s, 3 H, NCH3), 4.12-4.24 (m, 2 H, OCH2CH3), 4.29 (dd, J
= 6.8, J = 10.2 Hz, 1 H, 3-H), 4.88 (d, J = 10.1 Hz, 1 H, N-H ), 6.39 (d, J = 14.8 Hz,
1 H, 5-H), 7.50-7.60 (m, 3 H, Ph), 7.88 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 14.1 (OCH2CH3, d), 24.1 (C(CH3)3), d), 25.7 (Cy, u),
25.9 (Cy, u), 29.3 (NMe, d), 29.4 (Cy, u), 31.2 (Cy, u), 37.6 (Cy, d), 52.8 (C-3, d),
56.9 (C-2, d), 60.0 (C(CH3)3, u), 61.8 (OCH2CH3, u), 128.4 (o-ph, d), 129.1 (m-ph,
d), 132.4 (p-ph, d), 133.9 (C-5, d), 139.2 (i-ph, u), 142.6 (C-4, d), 170.5 (C-1, u).
EXPERIMENTAL PART 144
IR (KBr): ν 3246 (m), 3055 (m), 2929 (w), 2854 (w), 2800 (s), 2755 (s), 2659 (s),
1740 (w), 1630 (s), 1581 (s), 1544 (s), 1450 (w), 1395 (s), 1370 (s), 1246 (w),
1197 (s), 1145 (w), 1083 (w), 983 (s) cm−1.
EI-MS m/z (relative intensity, %) 498 [M+] (7), 278 (8), 277 (30), 276 (100), 231
(10), 222 (18), 156 (28), 152 (11), 151 (27), 150 (55), 125 (72).
HRMS (EI, 70 ev):
Calcd for C24H38N2O5S2: 498.222252
Found : 498.222218
Optical rotation: [α]D = −3.4 (c 2.01, CDCl3).
The analytical data of E-87b were in agreement with those previously reported.70
EXPERIMENTAL PART 145
5.11.6 Synthesis of (−)-(E,Ss,2R,3S)-and(−)-(E,Ss,2S,3R)-5-(N-methyl-S-
phenyl-sulfonimidoyl)-3-isopropyl-2-(2-methylpropane-2-sulfonylamino)-pent-4-enoic Acid Ethyl Ester (E-86a and E-87a)
SPh
O NMe
EtO2C
NHO2S
E-86a
SPh
O NMe
EtO2C
NHO2S
E-87a
Following GP6, reaction of sulfoximine 84a (1.02 g, 4.3 mmol ) with imino ester 81
(1.14 gm, 5.2 mmol) gave a crude mixture of the alkenyl sulfoximines E-86a and
E-87a in ratio of 1.8-1.9 : 1 in approximately 95% chemical yield (1H NMR).
Purification of this mixture by preparative HPLC (ethyl acetate/n-hexane, 4:1) gave
E-86a (1.142 g, 58%) as colorless oil, and E-87a (630 mg, 32%) as colorless solid.
E-86a:
1H NMR (400 MHz, CDCl3): δ 0.78 (d, J = 6.9 Hz, 3 H, CH(CH3)2), 0.90 (d, J = 6.7
Hz, 3 H, CH(CH3)2), 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.34 (s, 9 H, C(CH3)3),
1.40-1.70 (m, 6 H, Cy), 2.32 (dt, J = 6.6, J = 10.9 Hz, 1 H, 3-H), 2.74 (s, 3 H,
NCH3), 4.12-4.24 (m, 2 H, OCH2CH3), 4.29 (dd, J = 6.8, J = 10.2 Hz, 1 H, 3-H),
4.88 (d, J = 10.1 Hz, 1 H, N-H ), 6.39 (d, J = 14.8 Hz, 1 H, 5-H), 7.50-7.60 (m, 3 H,
Ph), 7.88 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): δ 14.1 (OCH2CH3, d), 19.0 (CH(CH3)2, d), 20.9
(CH(CH3)2, d), 24.1 (C(CH3)3, u), 28.2 (CH(CH3)2, d), 29.4 (NMe, d), 54.1 (C-3, d),
57.8 (C-2, d), 60.2 (C(CH3)3, u), 62.0 (OCH2CH3, u), 128.6 (o-ph, d), 129.9 (m-ph,
d), 133.7 (p-ph, d), 134.5 (C-5, d), 139.3 (i-ph, u), 142.3 (C-4, d), 170.5 (C-1, u).
EXPERIMENTAL PART 146
IR (KBr): ν 3127 (m), 3056 (w), 2978 (w), 2955 (w), 2908 (w), 2796 (s), 2719 (s),
1747 (w), 1629 (s), 1581 (s), 1476 (w), 1450 (w), 1396 (s), 1370 (m), 1222 (w),
1179 (w), 1145 (w), 1083 (w), 983 (s) cm−1.
EI-MS m/z (relative intensity, %) 460 [M+ +2] (7), 459 [M+ +1] (100), 457 (10), 237
(8), 236 (29).
Elemental Analysis:
Anal. Calcd for C21H34N2O5S2 (458.64): C, 54.99; H, 7.47; N, 6.11
Found : C, 54.79; H, 7.67; N, 5.94.
Optical rotation: [α]D = −12.7 (c 1.25, CDCl3).
The analytical data of E-87a were in agreement with those previously reported.70
EXPERIMENTAL PART 147
5.11.7 Synthesis of (+)- (2-Chloromethyl-cyclohex-1-enyl)-(2-methyl-propane-2-sulfonylamino)-acetic acid ethyl ester (99)
Sulfoximine E-86c (300 mg, 0.64 mmol) and Me3OBF4 (133 mg, 0.89 mmol) were
placed under argon in a Schlenk flask. The flask was consecutively evacuated and
refilled with dry argon (3 times). Then CH2Cl2 (25 mL) was added and the reaction
mixture was stirred at room temperature for 90 min. Subsequently water (15 mL)
was added and the reaction mixture was stirred at room temperature for 10 min.
Then the mixture was extracted with CH2Cl2 and the combined organic phases
were dried (MgSO4) and concentrated in vacuo and the residue was dried in high
vacuum for 2 h. The thus obtained salt was dissolved in EtOAc (15 mL) and
saturated aqueous NH4Cl (20 mL) was added at room temperature, and stirring at
this temperature was continued for 72 h. The progress of the reaction was
monitored by using TLC (ethyl acetate). Then the mixture was extracted with ethyl
acetate and the combined organic phases were dried (MgSO4) and concentrated
in vacuo. Purification of the residue by flash chromatography (ethyl
acetate/hexane, 9:1) gave chloride 99 (144 mg, 64%) and sulfinamide (99 mg,
92%) as colorless oils.
C
O
O
ClNH
SO2
312
8
910
12
99
EXPERIMENTAL PART 148
1H NMR (400 MHz, CDCl3): δ 1.29 (t, J = 7.1 Hz, 3 H, H-11), 1.37 (s, 9 H, H-13),
1.45-2.38 (m, 8 H, Cy), 4.14-4.32 (m, 4 H, H-8, H-10), 4.99 ( d, J = 7.4 Hz, 1 H,
NH), 5.16 ( d, J = 7.4 Hz, 1 H, H-2).
13C NMR (100 MHz, CDCl3): δ 14.09 (C-11, d), 22.19 (Cy, u), 22.58 (Cy, u), 24.10
(C-13, d), 24.64 (Cy, u), 28.22 (Cy, u), 44.04 (C-8, u), 56.73 (C-1, d), 59.96 (C-
12, u), 62.49 (C-10, u), 131.72 (C-2, u), 133.62 (C-3, u), 170.81 (C-9, u).
IR (KBr): ν 3127 (m), 3056 (w), 2978 (w), 2955 (w), 2796 (s), 2719 (s), 1747 (w),
1629 (s), 1581 (s), 1476 (w), 1396 (s), 1370 (m), 1222 (w), 1179 (w), 1145 (w),
1083 (w), 983 (s) cm−1 .
EI-MS m/z (relative intensity, %): 278 [M+ -CO2Et] (37), 195 (25), 179 (16), 160
(29), 158 (100), 122 (38), 57 (49).
HRMS (EI, 70 ev):
Calcd for C15H25NO4S-HCl: 315.150425
Found : 315.150431.
Optical rotation: [α]D = +30.4 (c 1.25, CHCl3).
EXPERIMENTAL PART 149
5.11.8 Synthesis of 2-(2-Methyl-propane-2-sulfonyl)-2,3,4,5,6,7-hexahydro- 1H-isoindole-1-carboxylic acid ethyl ester (100).
N
C
O
O
SO2
1
23
9
10 11
12
13
100
To a solution of chloride 99 (150 mg, 0.43 mmol) in CH2Cl2 (10 ml) was added
DBU (0.82 mL, 0.55 mmol) dropwise at ambient temperature. After the mixture
was stirred at ambient temperature for 0.5 h, saturated aqueous NH4Cl (20 ml)
was added and stirring was continued for 5 min. Then the mixture was extracted
with CH2Cl2 and the combined organic phases were dried (MgSO4) and
concentrated in vacuo. Purification of the residue by flash chromatography ( ethyl
acetate/hexane, 9:1) gave the protected α-amino acid 100 (125 mg, 93%) as a
colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.28 (t, J = 7.1 Hz, 3 H, H-12), 1.42 (s, 9 H, H-14),
1.60-2.10 (m, 8 H, Cy), 4.14-4.26 (m, 3 H, H-3’, H-11), 4.36 (br d, J = 13.1 Hz, 1
H, H-3), 5.11 (br s, 1 H, H-1).
13C NMR (100 MHz, CDCl3): δ 14.24 (C-12, d), 22.13 (Cy, u), 22.43 (Cy, u), 22.9
(Cy, u), 24.22 (C-14, d), 29.65 (Cy, u), 59.33 (C-3, u), 61.09 (C-11, u), 61.47 (C-
13, u), 70.95 (C-1, d), 128.79 (C-9, u), 133.73 (C-4, u), 170.91 (C-10, u).
IR (CHCl3): ν 2979 (m), 2936 (w), 2874 (m), 1480 (m), 1456 (m), 1393 (s), 1376
(w), 1321 (s), 1231 (w), 1193 (s), 1130 (s), 1054 (s), 1023 (m), 946 (w), 810 (w),
756 (s) cm−1.
EI-MS m/z (relative intensity, %) 316 [M++1] (100), 196 (34), 194 (6).
EXPERIMENTAL PART 150
HRMS (EI, 70 ev):
Calcd for C15H25NO4: 315.150425
Found: : 315.150431
Elemental Analysis:
Anal. Calcd for C15H25NO4S (315,15): C, 57.12; H, 8.22; N, 4.44
Found : C, 56.83; H, 8.63; N, 4.10.
Optical rotation: [α]D = +21.4 (c 1.2, CH2Cl2).
EXPERIMENTAL PART 151
5.12 Synthesis of Allylic Alcohol derivatives
5.12.1 Synthesis of (−)-(E)-(1S,4S)-4-Cyclohexyl-1-phenyl-oct-2en-1-ol (112)
OH
Ph
112
Following GP7, treatment of sulfoximine 14c (384 mg, 1 mmol) with BuCu (3.2
mmol CuI, 3.2 mmol n-BuLi) afforded the allylic alcohol 112 (215 mg, 75%).
1H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 6.9 HZ, 3 H, C4H9), 1.00-1.50 (m, 10 H,
Cy, C4H9), 1.95 (br s, 1 H, OH), 1.65-1.89 (m, 8 H, Cy, C4H9), 5.18 (d, J = 5.1 Hz,
1 H, CHOH), 5.50-5.62 (m, 2 H, =CH), 7.26-7.38 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 14.1 (CH3, d), 22.8 (u), 26.70 (u), 29.86 (u), 29.9
(u), 31.3 (u), 31.6 (u), 42.0 (CyCHCH2, d), 48.3 (Cy, d), 75.1 (CHOH, d), 126.2,
127.8, 128.0 (o-, m-,p-C, d), 132.9 (=CH, d), 135.8 (=CH, d), 143.5 (i-C, u).
IR (KBr): ν 3786 (s), 3060 (s), 2922 (w), 2852 (w), 2663 (s), 2345 (s), 1951 (s),
1892 (s), 1602 (s), 1494 (m), 1408 (s), 1316 (s), 1270 (m), 1102 (s), 973 (w), 889
(s), 851 (s), 743 (w) cm−1.
CI-MS m/z (relative intensity, %): 286 [M+] (3), 271 (3), 270 (20), 269 (100).
Elemental Analysis: Anal. Calcd for C20H30O (286.23): C, 83.86; H, 10.56
Found : C, 83.63; H, 10.46.
EXPERIMENTAL PART 152
Optical rotation: [α]D = +15.5 (c 0.51, CH2Cl2).
5.12.2 Synthesis of (+)-(E)-(3R,6S)-6-Ethyl-2,6-dimethyl-dec-4-en-3-ol (113)
OH113
Following GP7, treatment of sulfoximine 111c (309 mg, 1 mmol) with BuCu (3.2
mmol CuI, 3.2 mmol n-BuLi) afforded the allylic alcohol 113 (143 mg, 67%).
1H NMR (400 MHz, CDCl3): δ 0.78 (t, J = 7.4 Hz, 3 H, C4H9), 0.85-0.95 (m, 12 H,
Me, CH(CH3)2, C4H9), 1.2-1.4 (m, 8 H, C4H9), 1.65 (br s, 1 H, OH), 1.75 (m, 1 H,
CH(CH3)2), 3.80 (t, J = 5.1 Hz, 1 H, CHOH), 5.35 (dd, J = 7.4, J = 15.9, 1 H, =CH),
.35 (dd, J = 1.4 Hz, J = 15.9 Hz, 1 H, =CH ).
13C NMR (100 MHz, CDCl3): δ 8.44 (C4H9, d), 14.15 (CH3, d), 18.24, 18.32
(CH(CH3)2, d) 22.64 (d), 26.30 (d), 33.20, 40.50 (CH2, d), 33.95 (CH(CH3)2, d),
38.70 (EtMeUCUBuCH, u), 78.80 (CHOH, d), 141.69 (=CH, d), 128.30 (=CH, d).
IR (KBr): ν 3254 (w), 3060 (s), 2965 (w), 2804 (w), 2663 (s), 2345 (s), 1951 (s),
1892 (s), 1663 (s), 1450 (m), 1237 (s), 1108 (s), 939 (s), 862 (w), 741 (w) cm−1.
CI-MS m/z (relative intensity, %): 212 [M+] (1), 195 (18), 170 (12), 169 (100), 151
(19), 125 (10), 113 (13), 111 (10), 109 (16), 100 (13), 99 (17), 97 (13), 85 (40), 71
(72).
EXPERIMENTAL PART 153
HRMS (EI, 70 ev):
Calcd for C23H36SiO2: 212.214057
Found : 212.214015.
Optical rotation: [α]D = +15.5 (c 0.51, CH2Cl2).
5.12.3 Synthesis of (+)-(1R,2S)-2-[2-Butyl-cyclohex-(E)-ylidene]-1-nyl- phenyl-ethanol (114)
OH
Ph
114 Following GP7, treatment of sulfoximine 11c (355 mg, 1 mmol) with BuCu (3.2
mmol CuI, 3.2 mmol n-BuLi) afforded the allylic alcohol 114 (182 mg, 69%).
1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 6.9 Hz, 3 H, C4H9), 1.2-1.8 (m, Cy,
C4H9), 2.2-2.4 (m, 2 H, Cy), 5.36 (d, J = 8.6 Hz, 1 H, CHOH), 5.57 (d, J = 8.6 Hz, 1
H, =CH), 7.20-7.40 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): δ 14.10 (CH3, d), 28.8 (C4H9, u), 23.60 (C4H9, u),
27.46 (C4H9,u), 28.39 (Cy, u), 29.84 (Cy, u), 31.46 (Cy, u), 33.5 (Cy, u), 44.40 (Cy,
d), 69.8 (CHOH, d), 123.6 (=CH, d), 127.10, 128.40, 128.75 (o-, m-,p-C, d), 144.50
(Cy, u), 146.2 (i-C, u).
IR (KBr): ν 3690 (s), 3651 (s), 3083 (s), 2997 (s), 2858 (w), 2669 (s), 2370 (s),
1957 (s), 1811 (s), 1637 (s), 1601 (s), 1494 (m), 1436 (m), 1234 (s), 1137 (m),
1316 (s), 920 (w), 864 (s), 770 (w) cm−1.
EXPERIMENTAL PART 154
CI-MS m/z (relative intensity, %): 258 [M+] (2), 257 (M+ -1) (2), 242 (21), 241 (100).
Elemental Analysis: Anal. Calcd for C20H30O (286.23): C, 83.67; H, 10.14
Found : C, 83.90; H, 10.32.
Optical rotation: [α]D = +10.5 (c 0.55, CH2Cl2).
CRYSTAL STRUCTURE ANALYSIS 155
6 Crystal Structure Analysis
6.1 Crystal structure of (+)-(E,Ss,2R,3S)-2-(N-methyl-S-phenyl-sulfonimidoyl-methylene)-cycloheptyl)-(2-methylpropane-2- sulfonylamino)-Acetic Acid Ethyl Ester (E-82c)
Experimental Details Crystal data:
Chemical formula : C23H36N2O5S2
formula weight : 484.68
Crystal system : monoclinic
Space group (No.) : P 21 (4)
Z : 2
a (Å) : 8.986(4)
b (Å) : 10.080(2)
c (Å) : 14.350(3)
α (°) : 90.0
β (°) : 102.97(3)
γ (°) : 90.0
cell volume : 1266.6(7)Å3
Density calc. : 1.271g/cm3
Radiation : CuKα (1.54179Å)
Range for lattice parameters : Ε<Θ <Ε
CRYSTAL STRUCTURE ANALYSIS 156
Absorption coefficient : 2.194mm-1
Temperature : 150K
Crystal source : recrystallized from
Crystal colour : colourless
Crystal shape : irregular
Crystal size : ca. 0.3x0.3x0.3mm
Data Collection
Diffractometer type : Enraf-Nonius CAD4
Collection method : ω/2Θ - scans
Absorption correction : none
No. of reflections measured : 2679
No. of independent reflections : 2293
No. of observed reflections : 2128
Θ max (Ε) : 72.94
hmin 6 hmax : -11 6 11
kmin 6 kmax : - 4 6 4
lmin 6 lmax : -17 6 17
Criterion for observed : I > 2σ (I )
Rint : 0.050(37)
Standard reflections : -1 -1 4; -1 -2 3; 2 -2 -4
Variation : 1197(36) 4363(86) 1575(60)
Refinement:
On : F
Treatment of hydrogens : Positions calculated. The Us have
been
fixed to 1.5ΗU oft the relevant heavy
Atom prior to final refinement. No H
parameters refined.
R : 0.109
Rw : 0.135
Weighting sheme : w=1/[σ(F)2]
No. of parameters refined : 130
CRYSTAL STRUCTURE ANALYSIS 157
No. of reflections in refmnt. : 2126
Residual electron density : -1.21/0.94e/Å3
r*[1] : not refined
XABS[2] :
Goodness of fit : 5.77
Solution : XTAL3.7[3]
Definitions :
Ueq = 1/3ΣiΣjUijai*aj*ai aj
The anisotropic displacement factor in the structure factor expression is:
t = exp[-2π2(ΣiΣjUijhihjai*aj* )]
Atomcoordination: Atom x/a y/b z/c Ueq/Å2
S2 0.6965(3) 0.4287(6) 0.1531(2) 0.0316(7)
S6 1.1467(2) 0.3774(6) 0.6606(1) 0.0190(5)
O1 1.0349(7) 0.258(1) 0.3798(4) 0.024(2)
O2 1.0432(8) 0.461(1) 0.3187(5) 0.036(2)
O3 0.7939(8) 0.501(1) 0.1070(5) 0.035(2)
O4 0.699(1) 0.285(2) 0.1484(7) 0.062(3)
O5 1.1842(8) 0.243(1) 0.6507(5) 0.028(2)
N1 1.263(1) 0.490(2) 0.6590(6) 0.028(2)
N2 0.7249(9) 0.476(2) 0.2684(5) 0.024(2)
C1 0.802(1) 0.373(2) 0.3408(6) 0.026(2)
C2 0.773(1) 0.430(2) 0.4370(6) 0.023(2)
C3 0.873(1) 0.356(2) 0.5213(6) 0.019(2)
C4 0.836(1) 0.223(2) 0.5490(7) 0.023(2)
C5 0.723(1) 0.225(2) 0.6163(7) 0.026(2)
C6 0.562(1) 0.270(2) 0.5707(8) 0.031(3)
C7 0.553(1) 0.412(2) 0.5268(7) 0.031(2)
C8 0.600(1) 0.411(2) 0.4317(6) 0.024(2)
C9 0.9968(9) 0.435(2) 0.5675(5) 0.015(2)
CRYSTAL STRUCTURE ANALYSIS 158
C10 1.0786(9) 0.382(2) 0.7689(5) 0.017(2)
C11 1.077(1) 0.511(2) 0.8112(7) 0.030(3)
C12 1.022(1) 0.519(2) 0.8945(9) 0.046(4)
C13 0.971(1) 0.403(2) 0.9323(7) 0.038(3)
C14 0.980(1) 0.275(2) 0.8899(9) 0.043(3)
C15 1.034(1) 0.266(2) 0.8079(8) 0.035(3)
C16 1.400(1) 0.490(2) 0.7373(7) 0.025(2)
C17 0.975(1) 0.383(2) 0.3432(6) 0.025(2)
C18 1.201(1) 0.247(2) 0.3937(7) 0.029(3)
C19 1.242(1) 0.197(2) 0.3069(8) 0.035(3)
C20 0.502(1) 0.487(2) 0.1058(8) 0.035(3)
C21 0.397(2) 0.403(3) 0.144(1) 0.066(4)
C22 0.473(1) 0.465(3) -0.0031(9) 0.048(4)
C23 0.492(2) 0.637(3) 0.133(1) 0.065(5)
H4a 0.9245(-) 0.1691(-) 0.5798(-) 0.029(-)
H4b 0.7854(-) 0.1681(-) 0.4933(-) 0.029(-)
H5a 0.7645(-) 0.2846(-) 0.6678(-) 0.029(-)
H5b 0.7195(-) 0.1373(-) 0.6464(-) 0.029(-)
H6a 0.4975(-) 0.2615(-) 0.6137(-) 0.037(-)
H6b 0.5223(-) 0.2063(-) 0.5175(-) 0.037(-)
H7a 0.6178(-) 0.4681(-) 0.5699(-) 0.042(-)
H7b 0.4494(-) 0.4439(-) 0.5174(-) 0.042(-)
H8a 0.5425(-) 0.4751(-) 0.3905(-) 0.030(-)
H8b 0.5737(-) 0.3239(-) 0.4025(-) 0.030(-)
H18a 1.2439(-) 0.3389(-) 0.4015(-) 0.027(-)
H18b 1.2457(-) 0.2020(-) 0.4512(-) 0.027(-)
H19a 1.3362(-) 0.2160(-) 0.2961(-) 0.015(-)
H19b 1.1633(-) 0.2003(-) 0.2512(-) 0.015(-)
H19c 1.2503(-) 0.0895(-) 0.3164(-) 0.015(-)
H15 1.0328(-) 0.1835(-) 0.7782(-) 0.027(-)
H14 0.9461(-) 0.1971(-) 0.9174(-) 0.066(-)
H13 0.9330(-) 0.4067(-) 0.9911(-) 0.080(-)
H12 1.0163(-) 0.5999(-) 0.9270(-) 0.071(-)
H11 1.1122(-) 0.5838(-) 0.7828(-) 0.017(-)
CRYSTAL STRUCTURE ANALYSIS 159
H9 0.9990(-) 0.5243(-) 0.5472(-) 0.016(-)
H1 0.7664(-) 0.2783(-) 0.3297(-) 0.028(-)
H21a 0.4121(-) 0.4163(-) 0.2122(-) 0.106(-)
H21b 0.4213(-) 0.3108(-) 0.1350(-) 0.106(-)
H21c 0.2963(-) 0.4197(-) 0.1142(-) 0.106(-)
H22a 0.5488(-) 0.5187(-) -0.0292(-) 0.144(-)
H22b 0.3791(-) 0.4815(-) -0.0364(-) 0.144(-)
H22c 0.5041(-) 0.3725(-) -0.0156(-) 0.144(-)
H23a 0.5666(-) 0.6894(-) 0.1093(-) 0.088(-)
H23b 0.5242(-) 0.6477(-) 0.2041(-) 0.088(-)
H23c 0.3965(-) 0.6732(-) 0.1134(-) 0.088(-)
H16a 1.4165(-) 0.5758(-) 0.7638(-) 0.088(-)
H16b 1.4896(-) 0.4644(-) 0.7143(-) 0.088(-)
H16c 1.3911(-) 0.4282(-) 0.7867(-) 0.088(-)
H2 0.7964(-) 0.5219(-) 0.4444(-) 0.028(-)
H02 0.7911(-) 0.5783(-) 0.2759(-) 0.024(-)
CRYSTAL STRUCTURE ANALYSIS 160
6.2 Crystal structure of (−)-(3R,3aR)-3-(4-methoxy-phenyl)-3,3a,4,5,6,7-hexahydro-1H- cyclohepta[c]furan (56b).
Experimental Details
Crystal data :
Chemical formula : C16H20O2
formula weight : 244.33
Crystal system : monoclinic
Space group (No.) : P 21 (4)
Z : 2
a (Å) : 7.441(2)
b (Å) : 5.405(2)
c (Å) : 16.108(6)
α (°) : 90.0
β (°) : 91.71(2)
γ (°) : 90.0
cell volume : 647.6(4)Å3
Density calc. : 1.253g/cm3
Radiation : CuKα (1.54179Å)
Range for lattice parameters : 20.61<Θ <37.35°
Absorption coefficient : 0.636mm-1
Temperature : 150K
Crystal source : recrystallized from
Crystal colour : colourless
Crystal shape : irregular
Crystal size : 1.10x0.20x0.14mm
CRYSTAL STRUCTURE ANALYSIS 161
Data Collection
Diffractometer type : CAD4
Collection method : ω / 2Θ
Absorption correction : none
No. of reflections measured : 9336
No. of independent reflections : 2547
No. of observed reflections : 2519
Θ max (°) : 73.16
hmin → hmax : -9 → 9a)
kmin → kmax : -6 → 6a)
lmin → lmax : -19 → 19a)
Criterion for observed : I > 2σ (I )
Rint : 0.07(4)
Standard reflections : 3 2 1; 2 1 5; 2 1 6
Variation : 10746(210) 6264(91) 905(19)
Refinement:
On : F
Treatment of hydrogens : Positions except H16c located.
All located positions refinied isotropically
R : 0.063
Rw : 0.065
Weighting sheme : w=1/[18.0σ (F)2]
No. of parameters refined : 238
No. of reflections in refmnt. : 2517
Residual electron density : -0.57/+0.33e/Å3
r*[1] : not refined
XABS[2] : -0.18(44)b)
Goodness of fit : 1.002
Solution : XTAL3.7[3]
Remarks :
a)Friedel pairs collected
b)From separate calculation
CRYSTAL STRUCTURE ANALYSIS 162
Definitions:
Ueq = 1/3ΣiΣjUijai*aj*ai aj
The anisotropic displacement factor in the structure factor expression is:
t = exp[-2π2(ΣiΣjUijhihjai*aj* )]
Atomcoordination:
Atom x/a y/b z/c Ueq / A2
O1 0.2266(2) 0.05022(-) 1.09124(9) * 0.0239(8)
O2 0.2369(2) -0.1942(4) 0.7088(1) * 0.031(1)
C1 0.3024(3) -0.2129(6) 0.6261(2) * 0.033(1)
C2 0.4951(3) -0.1233(5) 0.6315(1) * 0.025(1)
C3 0.6162(3) -0.1607(6) 0.5740(1) * 0.031(1)
C4 0.8112(3) -0.0820(6) 0.5785(2) * 0.034(1)
C5 0.8493(3) 0.1825(6) 0.6052(2) * 0.033(1)
C6 0.8150(3) 0.2430(6) 0.6955(1) * 0.032(1)
C7 0.6171(3) 0.2498(6) 0.7179(2) * 0.030(1)
C8 0.5198(3) 0.0011(5) 0.7150(1) * 0.023(1)
C9 0.3254(3) 0.0223(5) 0.7439(1) * 0.025(1)
C10 0.2996(2) 0.0312(5) 0.8356(1) * 0.022(1)
C11 0.2054(3) 0.2265(5) 0.8703(1) * 0.024(1)
C12 0.1784(3) 0.2412(5) 0.9551(1) * 0.022(1)
C13 0.2455(3) 0.0569(5) 1.0073(1) * 0.020(1)
C14 0.3417(3) -0.1403(5) 0.9736(1) * 0.022(1)
C15 0.3680(3) -0.1521(5) 0.8893(1) * 0.022(1)
C16 0.1287(3) 0.2494(6) 1.1273(1) * 0.026(1)
H14 0.404(3) -0.261(7) 1.011(1) 0.033(7)
H4a 0.878(3) -0.205(6) 0.616(2) 0.032(7)
H11 0.160(3) 0.353(6) 0.830(2) 0.035(7)
H3a 0.581(3) -0.269(7) 0.521(2) 0.037(7)
H15 0.444(3) -0.298(6) 0.867(1) 0.033(7)
H8 0.582(3) -0.117(5) 0.757(1) 0.008(5)
CRYSTAL STRUCTURE ANALYSIS 163
H16a 0.003(3) 0.245(6) 1.101(1) 0.025(6)
H6a 0.880(4) 0.136(6) 0.735(2) 0.036(8)
H1a 0.277(4) -0.373(8) 0.604(2) 0.06(1)
H5b 0.979(3) 0.214(7) 0.591(2) 0.039(7)
H16b 0.132(3) 0.211(5) 1.185(1) 0.021(6)
H7a 0.610(4) 0.326(8) 0.781(2) 0.06(1)
H4b 0.857(4) -0.088(9) 0.519(2) 0.06(1)
H5a 0.770(3) 0.297(6) 0.569(2) 0.032(7)
H9 0.279(3) 0.166(5) 0.710(1) 0.011(5)
H1b 0.227(4) -0.113(7) 0.582(2) 0.045(9)
H12 0.104(3) 0.376(7) 0.981(2) 0.034(7)
H7b 0.552(4) 0.359(8) 0.677(2) 0.07(1)
H6b3 0.874(4) 0.397(8) 0.711(2) 0.041(8)
H16c 0.1870(-) 0.4025(-) 1.1172(-) 0.180(-)
CRYSTAL STRUCTURE ANALYSIS 164
6.3 Crystal structure of (−)-(3R,3aR)-3-(4-methoxy-phenyl)- 1,3,3a,4,5,6,7,8-octahydro-1H-cycloocta[c]furan (ent-56c).
Experimental Details
Crystal data :
Chemical formula : C17H22O2
formula weight : 258.36
Crystal system : orthorhombic
Space group (No.) : P 21 21 21 (19)
Z : 4
a (Å) : 6.4237(3)
b (Å) : 11.7880(6)
c (Å) : 18.2871(19)
α (°) : 90.0
β (°) : 90.0
γ (°) : 90.0
cell volume : 1384.75(17)Å3
Density calc. : 1.239g/cm3
Radiation : CuKα (1.54179Å)
Range for lattice parameters : 16.04<Θ <45.60°
Absorption coefficient : 0.621mm-1
Temperature : 150K
Crystal source : recrystallized from
Crystal colour : coluorless
Crystal shape : irregular
Crystal size : 0.80x0.30x0.10mm
Data Collection
Diffractometer type : CAD4
CRYSTAL STRUCTURE ANALYSIS 165
Collection method : ω / 2Θ
Absorption correction : none
No. of reflections measured : 3242
No. of independent reflections : 2735
No. of observed reflections : 2637
Θ max (°) : 72.57
hmin → hmax : -7 → 7a)
kmin → kmax : -14 → 14a)
lmin → lmax : -22 → 22a)
Criterion for observed : I > 2σ (I )
Rint : 0.02(3)
Standard reflections : -2 3 2; -2 3 1; 2 -1 -4
Variation : 5683(99) 2694(54) 1380(48)
Refinement :
On : F
Treatment of hydrogens : Positions located and refinied isotropically
R : 0.043
Rw : 0.051
Weighting sheme : w=1/[7.8σ (F)2]
No. of parameters refined : 260
No. of reflections in refmnt. : 2630
Residual electron density : -0.39/+0.23e/Å3
r*[1] : not refined
XABS[2] : -0.15(37)b)
Goodness of fit : 1.005
Solution : XTAL3.7[3]
Remarks :
a)Friedel pairs collected
b)From separate calculation
CRYSTAL STRUCTURE ANALYSIS 166
Definitions:
Ueq = 1/3ΣiΣjUijai*aj*ai aj
The anisotropic displacement factor in the structure factor expression is:
t = exp[-2π2(ΣiΣjUijhihjai*aj* )]
Atomcoordination:
Atom x/a y/b z/c Ueq/A2
O1 0.8828(2) 0.2516(1) 0.41435(8) * 0.0305(7)
O2 0.2432(2) 0.6342(1) 0.32818(8) * 0.0343(7)
C1 0.1594(3) 0.7411(2) 0.3499(1) * 0.0277(9)
C2 0.3281(3) 0.7965(1) 0.3935(1) * 0.0236(8)
C3 0.3059(3) 0.8640(2) 0.4509(1) * 0.0284(9)
C4 0.4840(3) 0.9217(2) 0.4884(1) * 0.0301(9)
C5 0.5355(3) 1.0376(2) 0.4537(1) * 0.030(1)
C6 0.5609(3) 1.0369(2) 0.3710(1) * 0.0271(9)
C7 0.7205(3) 0.9516(2) 0.3403(1) * 0.0279(9)
C8 0.6298(3) 0.8431(1) 0.3070(1) * 0.0237(8)
C9 0.5307(2) 0.7572(1) 0.3595(1) * 0.0202(8)
C10 0.4649(3) 0.6483(1) 0.3171(1) * 0.0243(9)
C11 0.5742(3) 0.5414(1) 0.3413(1) * 0.0214(8)
C12 0.7692(3) 0.5145(1) 0.3124(1) * 0.0233(8)
C13 0.8777(3) 0.4186(1) 0.3354(1) * 0.0240(8)
C14 0.7898(3) 0.3477(1) 0.3872(1) * 0.0240(8)
C15 0.5948(3) 0.3735(1) 0.4165(1) * 0.0269(9)
C16 0.4899(3) 0.4695(2) 0.3938(1) * 0.0267(9)
C17 1.0593(3) 0.2096(2) 0.3757(1) * 0.039(1)
H10 0.494(3) 0.661(1) 0.261(1) 0.017(5)
H8a 0.533(3) 0.861(2) 0.267(1) 0.021(5)
H7a 0.817(4) 0.932(2) 0.381(1) 0.038(6)
H12 0.824(4) 0.565(2) 0.272(1) 0.037(6)
H5a 0.438(4) 1.091(2) 0.467(1) 0.045(7)
H9 0.628(4) 0.739(2) 0.397(1) 0.027(6)
CRYSTAL STRUCTURE ANALYSIS 167
H17a 1.033(4) 0.201(2) 0.324(1) 0.034(6)
H4a 0.601(4) 0.876(2) 0.484(1) 0.040(7)
H7b 0.793(4) 0.989(2) 0.297(1) 0.031(6)
H6a 0.589(3) 1.117(2) 0.357(1) 0.025(5)
H15 0.540(3) 0.323(2) 0.451(1) 0.028(5)
H6b 0.436(3) 1.020(2) 0.346(1) 0.026(5)
H3 0.154(5) 0.884(2) 0.472(2) 0.058(8)
H1b 0.131(3) 0.788(2) 0.303(1) 0.030(5)
H4b 0.449(4) 0.934(2) 0.543(1) 0.035(6)
H13 1.015(4) 0.399(2) 0.310(1) 0.047(7)
H5b 0.663(4) 1.071(2) 0.476(1) 0.033(6)
H1a 0.032(4) 0.727(2) 0.380(1) 0.045(7)
H17b 1.086(4) 0.137(2) 0.398(1) 0.044(7)
H8b 0.737(4) 0.800(2) 0.276(1) 0.047(7)
H16 0.368(4) 0.486(2) 0.417(1) 0.043(7)
H17c 1.179(5) 0.264(2) 0.384(2) 0.060(8)
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Resume Surendra Babu Gadamsetty Date of birth: 14.12.1977 Place of Birth: Guvvadi Nationality: Indian Marital status: Single
04/1993-04/1996 B.Sc., Chemistry; First Class with Distinction Sri Venkateswara University, Tirupati, India 08/1996-09/1998 M.Sc., Organic Chemistry; First Class witDistinction Sri Venkateswara University, Tirupati, India
02/1999- 08/2000 Project, Indian Institute of Technology-Bombay (I.I.T-B), India. Title: “Asymmetric Synthesis of β-amino acids through application of chiral sulfoxide”
01/2001-08/2005 Ph.D, Institut für Organische Chemie der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-Westfälischen Technischen Hochschule Aachen in the research group of Prof. Dr. H.-J. Gais Title: “Apllication of Sulfonimidoyl–Substituted Allyltitanium (IV) Complexes to the Asymmetric Synthesis of Alkenyloxiranes, 2,3-Dihydrofurans, Tetrahydrofurans, Unsaturated Proline Analogous and Allyclic Alcohols”
23.02.2007 Ph.D examination