Functionalized chiral vinyl aminosulfoxonium salts: Asymmetric synthesis and application to the synthesis of enantiopure unsaturated prolines, β,γ-dehydro amino acids, and cyclopentanoid keto aminosulfoxonium ylides

Article abstract of DOI:10.1021/ja061152i

Methylation of the enantiopure functionalized vinyl sulfoximines 5a-e and 14a-d followed by a F- ion or DBU-mediated isomerization of the vinyl aminosulfoxonium salts 7a-e and 15a-d, respectively, gave the allyl aminosulfoxonium salts 10a-e and 17a-d, res

Full text of DOI:10.1021/ja061152i

Published on Web 05/13/2006
Functionalized Chiral Vinyl Aminosulfoxonium Salts:
Asymmetric Synthesis and Application to the Synthesis of
Enantiopure Unsaturated Prolines, â,γ-Dehydro Amino Acids,
and Cyclopentanoid Keto Aminosulfoxonium Ylides
Shashi Kant Tiwari, Hans-Joachim Gais,* Andreas Lindenmaier (ne´ Schneider),
Gadamsetti Surendra Babu, Gerhard Raabe, Leleti Rajender Reddy, Franz Ko¨hler,
Markus Gu¨nter, Stefan Koep, and Vijaya Bhaskara Reddy Iska
Contribution from the Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen
Hochschule (RWTH) Aachen, Landoltweg 1, D-52056 Aachen, Germany
Received March 1, 2006; E-mail: gais@rwth-aachen.de
Abstract: Methylation of the enantiopure functionalized vinyl sulfoximines 5a-e and 14a-d followed by a
F- ion or DBU-mediated isomerization of the vinyl aminosulfoxonium salts 7a-e and 15a-d, respectively,
gave the allyl aminosulfoxonium salts 10a-e and 17a-d, respectively. A concomitant intramolecular
substitution of the aminosulfoxonium group of 10a-e and 17a-d by the amino group afforded the
unsaturated prolines 8a-e and 18a-d, respectively. The starting vinyl sulfoximines are accessible through
a highly selective and stereo-complementary aminoalkylation of the corresponding sulfonimidoyl-substituted
mono- and bis(allyl)titanium complexes with the imino ester 4. The vinyl aminosulfoxonium salts 34, 7a-d,
and E-15c experienced upon treatment with the Cl- ion a migratory substitution with formation of the δ-chloro-
â,γ-dehydro amino acids 36, E/Z-37a-d, and 38, respectively. A migratory substitution of the hydroxy-
substituted vinyl aminosulfoxonium salts 46a and 46b furnished the δ-chloro allyl alcohols E/Z-48a and
E-48b, respectively. A facile one-pot conversion of the vinyl sulfoximines 31b, 5c and 45a to the allyl chlorides
36, E/Z-37c and E/Z-48a, respectively, was achieved upon treatment with a chloroformiate. A tandem
cyclization of the vinyl aminosulfoxonium salts 7b, Al-7b and 57 with LiN(H)tBu yielded the cyclopentanoid
keto aminosulfoxonium ylides 54, Al-54, 59, 60 and 61, respectively. The structure of the tricyclic keto
aminosulfoxonium ylide Al-54 has been determined by X-ray crystal structure analysis. Ab initio calculations
and a NBO analysis of the tricyclic keto aminosulfoxonium ylide XXIII show a polar structure stabilized by
electrostatic interactions between the ylidic C atom and both the carbonyl C atom and the S atom.
Introduction
Of special interest are 3,4-disubstituted prolines because of
the occurrence of this substitution pattern in the kainoid amino
acids.9 Because of their ability to function as conformationally
restricted L-glutamic acid analogues, the kanoid amino acids
show neuroexcitatory properties and are, as such, interesting
R-Amino acids and in particular proline derivatives have
received much attention in recent years.1 Peptide mimetics
containing modified prolines are interesting probes for receptor
studies and for the development of new drugs. In particular,
3-substituted prolines are being currently considered as con-
formationally restricted arginine, norleucine, phenylalanine,
tyrosine, aspartic acid, and glutamic acid analogues2 for the
development of small molecule drugs. Therefore, the synthesis
and biological activity of mono-2-7 and bicyclic8 prolines are
being intensively studied.
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58, 1317-1334. (b) Flamant-Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki,
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7360
J. AM. CHEM. SOC. 2006, 128, 7360-7373
10.1021/ja061152i CCC: $33.50 © 2006 American Chemical Society

Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Figure 2. Migratory cyclization of cyclic amino-substituted vinyl amino-
sulfoxonium salts.
undec-7-ene (DBU) a migratory cyclization with formation of
the unsaturated bicyclic prolines XIV (Figure 2).11
Key to the facile conversion of the vinyl aminosulfoxonium
salts XII via the allyl aminosulfoxonium salt XIII to prolines
XIV is the ability of the aminosulfoxonium group to act as both
a powerful carbanion-stabilizer and an excellent nucleofuge.12-14
These features make the aminosulfoxonium group a synthetically
very interesting one, the potential of which has, however, not
been fully explored.12 In particular vinyl aminosulfoxonium salts
have received only little attention.12b For example, it was only
recently that the facile R-elimination of chiral hydroxy-
substituted vinyl aminosulfoxonium salts with formation of
substituted alkylidene carbenes has been recognized, a feature
which led to the development of enantioselective syntheses of
2,3-dihydrofurans13 and homopropargyl alcohols.14
We now describe an asymmetric synthesis of monocyclic 3,4-
unsaturated prolines of type I and 4-methylene prolines of type
III15 through a F- ion mediated migratory cyclization of the
functionalized vinyl aminosulfoxonium salts of type IX. In
addition, a complementary migratory substitution of aminosul-
foxonium salts of type IX and X by the Cl- ion is described,
which enables an asymmetric synthesis of δ-chloro-â,γ-dehydro
R-amino acids of type IV-VI. The dehydro amino acids IV-
VI are expected to be useful starting materials for the enanti-
oselective synthesis of substituted â,γ-dehydro R-amino acids16
which are of considerable interest because of their natural
occurrence and their ability to act as irreversible inhibitors of
pyridoxal phosphate-dependent enzymes. The intramolecular
substitution of chlorides of type V allows an enantioselective
synthesis of bicyclic 3,4-unsaturated proline of type II, the
regioisomers of prolines XIV.
Figure 1. Unsaturated prolines, δ-chloro-â,γ-dehydro amino acids, cy-
clopentanoid keto aminosulfoxonium ylides and chiral functionalized vinyl
aminosulfoxonium salts.
probes for a study of neurological disorder including Alzhe-
imer’s disease.10 Despite the considerable synthetic activity in
the field of proline derivatives, there is a lack of methods for
the enantioselective synthesis of mono- and bicyclic 3,4-
unsaturated prolines of type I and II, respectively and of
4-methylene prolines of type III (Figure 1).7 Proline derivatives
of this type should be interesting starting materials for the
synthesis of monocyclic 3-mono- and 3,4-disubstituted prolines,2-7
bicyclic prolines,8 and kanoid amino acids.9 We had recently
observed that the amino-substituted cyclic vinyl aminosulfoxo-
nium salts XII undergo upon treatment with diazabicyclo[5,4,0]-
(11) Koep, S.; Gais, H.-J.; Raabe, G. J. Am. Chem. Soc. 2003, 125, 13243-
13251.
(12) (a) Bordwell, F. G.; Branca, J. C.; Johnson, C. R.; Vanier, N. R. J. Org.
Chem. 1980, 45, 3884-3889. (b) Johnson, C, R.; Lockard, J. P.; Kennedy,
E. R. J. Org. Chem. 1980, 45, 264-271. (c) Barbachyn, M. R.; Johnson,
C. R. In Asymmetric Synthesis; Morrison, J. D., Scott, J. W., Eds.; Academic
Press: New York, 1984; Vol. 4, pp 227-261. (d) Okamura, K.; Ikari, K.;
Ono, M.; Sato, Y.; Kuge, S.; Ohta, H.; Machiguchi, Z. Bull. Chem. Soc.
Jpn. 1995, 68, 2313-2317. (e) Mikołajczk, M.; Drabowicz, J.; Kiełbasin´ski,
P. Chiral Sulfur Reagents; CRC Press: Boca Raton, 1997. (f) Zhou, X.-
Z.; Shea, K. J. J. Am. Chem. Soc. 2000, 122, 11515-11516. (g) Reggelin,
M.; Zur, C. Synthesis 2000, 1-64.
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6235-6238. (b) Hamper, B. C.; Dukesherer, D. R.; South, M. S.
Tetrahedron Lett. 1996, 37, 3671-3674. (c) Wagaw, S.; Rennels, R. A.;
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S. C.; Fundy, S. L.; Seth, P. P. Tetrahedron 1999, 55, 8025-8038. (e)
Donohoe, T. J.; Raoof, A.; Linney, I. D.; Helliwell, M. Org. Lett. 2001, 3,
861-864. (f) Conti, P.; Roda, G.; Negra, F. F. B. Tetrahedron: Asymmetry
2001, 12, 1363-1367. (g) Zhang, J.; Xiong, C.; Wang, W.; Ying, J.; Hruby,
V. J. Org. Lett. 2002, 4, 4029-4032. (h) Cheng, W.-C.; Liu, Y.; Wong,
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5673-5677. (i) Valls, N.; Vallribera, M.; Carmeli, S.; Bonjoch, J. Org.
Lett. 2003, 5, 447-450. (j) Harris, P. W.; Brimble, M. A.; Gluckman, P.
D. Org. Lett. 2003, 5, 1847-1850. (k) Jeanotte, G.; Lubell, W. D. J. Org.
Chem. 2004, 69, 4656-4662.
(9) (a) McGeer, E. G.; Olny, J. W.; McGeer, P. L. Kainic Acid as a Tool in
Neurobiology; Raven: New York, 1978. (b) Parsons, A. F. Tetrahedron
1996, 52, 4149-4174. (c) Moloney, M. G. Nat. Prod. Rep. 1998, 15, 205-
219. (d) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485-498. (e) Clayden,
J.; Knowles, F. E.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3397-3400.
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(15) For a preliminary communication, see: Tiwari, S. K.; Schneider, A.; Koep,
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6330. (b) Kirihata, M.; Kawahara, S.; Ichimoto, I.; Ueda, H. Agric. Biol.
Chem. 1990, 54, 753-756. (c) Havlicek, L.; Hanus, J. Collect. Czech. Chem.
Commun. 1991, 56, 1365-1399. (d) Kirihata, M.; Fukuari, M.; Izukawa,
T.; Ichimoto, I. Amino Acids 1995, 9, 317-325. (e) Woiwode, T. F.;
Wandless, T. J. J. Org. Chem. 1999, 64, 7670-7674. (f) Berkowitz, D.
B.; Chisowa, E.; McFadden, J. M. Tetrahedron 2001, 57, 6329-6343. (g)
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(10) (a) Wheal, H. V., Thomson, A. M., Eds. Excitatory Amino Acids and
Synaptic Transmission; Academic Press: London, 1995. (b) Krogsgaard-
Larsen, P., Hansen, J. J., Eds. Excitatory Amino Acids Receptors; Design
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9
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A R T I C L E S
Tiwari et al.
Scheme 1. Synthesis of Functionalized Vinyl Sulfoximines
ing (S)-configured lithiated allyl sulfoximines simply by using
ClTi(OiPr)3 and ClTi(NEt2)3 as titanation reagents.21,22
Results and Discussion
I. Unsaturated Prolines. I.a. 3,4-Dehydro Prolines. Treat-
ment of the sulfonimidoyl-substituted bis(allyl)titanium(IV)
complexes 3a-e,21 which were prepared from the corresponding
enantiomerically pure allyl sulfoximines E-2a-e through ti-
tanation following lithiation, with the N-Bus imino ester 419
afforded the corresponding functionalized vinyl sulfoximines
5a-e, respectively, with high regio- and diastereoselectivities
in good yields as described previously (Scheme 1).20 The
R-imino ester 4 was prepared from sulfonamide 6, using a
modified version of our previously reported procedure,19 which
allowed an increase of the yield by 30% to 93%.
Figure 3. Chiral sulfonimidoyl-substituted allyl titanium complexes and
chiral amino-substituted vinyl sulfoximines.
Gratifyingly, the new tert-butyl-substituted titanium complex
3d, which was obtained in a similar way from the allyl
sulfoximine E-2d, also reacted with 4 with high regio- and
diastereoselectivities (g98% de) and furnished the tert-butyl-
substituted vinyl sulfoximine 5d in 84% yield. The tert-butyl-
substituted allyl sulfoximine 2d in turn has been obtained as a
single E-isomer in 86% yield starting from (S)-sulfoximine 123
and 3,3-dimethylbutanal following the one-pot addition-
elimination-isomerization (AEI) route.21 The allyl sulfoximines
2a-c and 2e were synthesized, as described previously, by the
AEI route starting from 1 and the corresponding aldehydes.21
While 2e was formed as a single E-isomer, 2a, 2b, and 2c had
been obtained as E/Z-mixtures in ratios of 70:30, 88:12, and
92:8, respectively. The respective E- and Z-isomers were
separated by chromatography, and the Z-isomers were recycled
through treatment with DBU in MeCN to again afford a mixture
of the corresponding E/Z-isomers which were separated.
The synthesis of the 3,4-dehydro prolines 8a-e started with
the activation of the corresponding vinyl sulfoximines 5a-e
through methylation at the N atom upon treatment with Me3-
OBF4 (1.1 equiv) in CH2Cl2 at room temperature for 2 h
(Scheme 2). The thus obtained vinyl aminosulfoxonium salts
7a-e (g95% yield) were then subjected to a treatment with
KF (5-10 equiv) and a small amount of water in CH2Cl2 at
room temperature under heterogeneous conditions, which af-
forded the corresponding proline derivatives 8a-e with g98%
ee in good yields (Table 1).
As a last example of the diverse reactivity of vinyl amino-
sulfoxonium salts of type IX and XI we describe their tandem
cyclization with lithium tert-butylamide, which leads to the
formation of the novel enantio- and diastereopure tricyclic
cyclopentanoid aminosulfoxonium ylides VII and VIII, respec-
tively, the structure of which has been studied by X-ray crystal
structure analysis and ab initio calculations. Cyclopentanoid
ylides of this type could perhaps serve as starting material for
the asymmetric synthesis of highly substituted amino- and
hydroxy cyclopentanones17 through a ring-opening epoxidation
reaction with aldehydes at the C-S bond.12c,g
The enantio- and diastereopure functionalized vinyl sulfox-
imines XVI and XX, required as starting material for the
synthesis of the aminosulfoxonium salts XII and IX, respec-
tively, are prepared, as previously reported,15,18-20 through a
highly regio- and diastereoselective aminoalkylation of chiral
bis(allyl)titanium complexes of type XV and XIX, respectively,
with N-tert-butylsulfonyl imino ester (Figure 3). We now
describe a stereo-complementary γ-aminoalkylation of chiral
mono(allyl)titanium complexes of type XVII and XXI giving
the functionalized vinyl sulfoximines XVIII and XXII, respec-
tively, the C atoms of which have the opposite configuration.
Both the bis(allyl)titanium complexes and the mono(allyl)-
titanium complexes are readily accessible from the correspond-
(17) (a) Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamar´ıa, J.; Brillet, C.;
Garc´ıa-Granada, S.; Pin˜era-Nicola´s, A.; Va´zquez, J. T. J. Am. Chem. Soc.
1999, 121, 4516-4517. (b) Greck, C.; Drouillat, B.; Thomassigny, C. Eur.
J. Org. Chem. 2004, 1377-1385.
(21) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe, G.;
Runsink, J.; Nienstedt, J.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo, R.;
Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 3973-4009.
(18) Gu¨nther, M.; Gais, H.-J. J. Org. Chem. 2003, 68, 8037-8041.
(19) Schleusner, M.; Koep, S.; Gu¨nter, M.; Tiwari, S. K.; Gais, H.-J. Synthesis
2004, 967-969.
(22) Gais, H.-J.; Bruns, P. R.; Raabe, G.; Hainz, R.; Schleusner, M.; Runsink,
J.; Babu, G. S. J. Am. Chem. Soc. 2005, 127, 6617-6631.
(20) Schleusner, M.; Gais, H.-J.; Koep, S.; Raabe, G. J. Am. Chem. Soc. 2002,
124, 7789-7800.
(23) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909-912.
9
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Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Scheme 2. Synthesis of 3,4-Dehydro Prolines
Scheme 3. Rationalization of the Formation of the 3,4-Dehydro
Prolines
Table 1. Synthesis of 3,4-Dehydro Prolines
entry
derivative
R
t (h)
8, yield (%)
9, yield (%)
1
2
3
4
5
a
b
c
d
e
Me
iPr
cC6H11
tBu
Ph
3
1
2
1
51
89
86
92
66
83
96
90
96
84
0.75
The conversion of 5a-e to 8a-e, respectively, has also been
carried out with similar results without isolation of 7a-e. It is
noteworthy that the yields were particularly good in the case
of the proline derivatives 8b-d which carry a sterically
demanding substituent at the â-position (entries 2, 3, and 4).
The moderate yield of the methyl-substituted proline derivative
8a (entry 1) seems to be due to a competing fluoride ion-
mediated deprotonation of the aminosulfoxonium salt 7a at the
N atom, leading to a generation of 4 and the corresponding allyl
aminosulfoxonium salt (vide infra), which both in turn react
with formation of the corresponding vinyl aziridine ester
derivative.24 In addition to the proline derivatives 8a-e the
sulfinamide 9 with g98% ee was isolated in each case in high
yield. Conversion of sulfinamide 9 to (S)-sulfoximine 123 of
g98% ee, the starting material for the synthesis of E-2a-e,
had already been described.13
would experience a regioselective F--catalyzed isomerization
to the allyl aminosulfoxonium salts 17a-c, leaving the stereo-
genic center at the γ-position intact, via the intermediate
formation of the allyl aminosulfoxonium ylides 16a-c. Depro-
tonation at the methyl group should be preferred over a
deprotonation at the γ-position because of statistical reasons
and the higher kinetic acidity of methyl hydrogen atoms.
Cyclization of 17a-c should afford the proline derivatives 18a-
c. Prerequisite to the successful realization of such a synthesis
of 18a-c would be a highly stereoselective reaction of the
methyl-substituted titanium complexes 13a-c with 4. Aside of
this objective it was of interest to see whether the methyl group
of complexes 13a-c would have any influence on the stereo-
selectivity of the reaction with 4.
The enantiomerically pure allyl sulfoximines 12a, 12b,13 12c,
12d, and 12e26 were obtained from (S)-sulfoximine 123 and the
corresponding methyl ketones by the one-pot AEI-route in 68%,
75%, 72%, 61%, and 73% yield, respectively, including a
separation and recycling of the Z-isomer.27 The reaction
sequence includes a deprotonation of sulfoximine 1 with n-BuLi
followed by the addition of the lithiated sulfoximine to the
ketone with formation of the corresponding lithium alcoholate
(not shown in Scheme 4). Silylation of the lithium alcoholates
with ClSiMe3 and elimination of the corresponding silyl ethers
with n-BuLi in THF at room temperature gave the corresponding
vinyl sulfoximines (not shown in Scheme 4) as mixtures of
isomers.21 The crude vinyl sulfoximines were subjected to a
NaOMe-catalyzed isomerization in THF to afford mixtures of
the allyl sulfoximines E-12a-e and Z-12a-e, which were
separated by preparative HPLC.27 The configuration of the
Because of the high solubility of the vinyl aminosulfoxonium
salts 7a-e in CH2Cl2, it is assumed that in the three-phase
system composed of solid KF, water, and CH2Cl2 an anion
exchange between 7a-e and KF occurs with formation of the
ion pairs 7a-e containing the F- ion as counterion (Scheme
3).25 The F- ion which ought to be a reasonably strong base in
CH2Cl2 then could cause a deprotonation of the aminosulfoxo-
nium salts 7a-e at the γ-position with formation of the
corresponding allyl aminosulfoxonium ylides Z-10a-e.11,13
A
protonation of the ylides at the R-position would give the
thermodynamically more stable allyl aminosulfoxonium salts
Z-11a-e. Because of the high nucleofugacity of the allylic
aminosulfoxonium group,11,13 salts Z-11a-e could undergo a
cyclization following a deprotonation of the sulfonamide group
by the F- ion with formation of the corresponding prolines 8a-e
and sulfinamide 9. There is evidence (vide infra) suggesting
that the reaction of 7a-e with the F- ion could also give to a
minor extent the isomeric allyl aminosulfoxonium ylides
E-10a-e and subsequently the allyl aminosulfoxonium salts
E-11a-e. Salts E-11a-e, which cannot cyclize, may be,
however, in equilibrium with Z-11a-e.
I.b. 4-Methylene Prolines. Having accomplished a synthesis
of unsaturated prolines of type I, a perhaps facile synthesis of
4-methylene prolines of type III (cf. Figure 1) was envisioned
starting from the functionalized â-methyl vinyl sulfoximines
14 (Scheme 4). It was speculated that the methyl-substituted
vinyl aminosulfoxonium salts E-15a-c (Scheme 5, vide infra)
(26) Scommoda, M.; Gais, H.-J.; Bosshammer, S.; Raabe, G. J. Org. Chem.
1996, 61, 4379-4390.
(27) Gais, H.-J.; Mu¨ller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe, G. J.
Am. Chem. Soc. 1995, 117, 2453-2466.
(24) Iska, V. B. R.; Tiwar, S. K.; Gais, H.-J.; Babu, G. S.; Adrien, A.
Unpublished results.
(25) Clark, J. H. Chem. ReV. 1980, 80, 429-452.
9
J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006 7363

A R T I C L E S
Tiwari et al.
Scheme 4. Synthesis of Functionalized â-Methyl Vinyl Sulfoximines
Scheme 5. Synthesis of 4-Methylene Prolines with KF
Table 2. Synthesis of Functionalized â-Methyl Vinyl Sulfoximines
Table 3. Synthesis of 4-Methylene Prolines with KF
entry
derivative
R
E-14, yield (%)
Z-14, yield (%)
entry
derivative
R
18, yield (%)
9, yield (%)
1
2
3
4
5
a
b
c
d
e
Me
iPr
33
64
45
14a
58
38
10
16
36
-
1
2
3
4
a
a
b
c
Mea
63
54
77
72
98
97
94
84
Meb
cC6H11
(CH2)2OSitBuMe2
Ph
iPr
cC6H11
a Starting from E-14a°. b Starting from Z-14a.
a The allyl sulfoximine 12d was recovered in 12% yield.
highly E-selective. The configurations of the double bonds of
E-14a-e and Z-14a-e were assigned by 1H NOE experiments.
A final proof for the configuration of all stereogenic elements
of E-14b was provided by an X-ray crystal structure analysis
(Figure 4). The configuration of Z-14a was secured by conver-
sion of both E-14a and Z-14a to proline 18a (vide infra).
1
double bonds of E-12a-e and Z-12a-e was assigned by H
NOE experiments. Isomerization of the minor isomers Z-12a-e
with NaOMe in THF again delivered a mixture of E-12a-e
and Z-12a-e which were separated. Lithiation of the enantio-
merically pure E-configured allyl sulfoximines E-12a-e with
n-BuLi (1.1 equiv) at -78 °C in THF followed by a titanation
with ClTi(iOPr)3 (2.1 equiv) gave the corresponding bis(allyl)-
titanium(IV) complexes 13a-e which were, however, not
isolated. Gratifyingly, the reaction of complexes 13a-e with
419 (1.1 equiv) also proceeded with high regio- and diastereo-
selectivities and afforded the corresponding functionalized
â-methyl-vinyl sulfoximines E-14a-e and Z-14a-e in good
yields (Table 2).
Methylation of the vinyl sulfoximines E/Z-14a-c through
treatment with Me3OBF4 (1.1 equiv) in CH2Cl2 afforded the
corresponding aminosulfoxonium salts E/Z-15a-c, respectively,
in high yields (g95%) (Scheme 5). Isomerization of E/Z-15a-c
and cyclization of 17a-c both proceeded readily upon treatment
of the former salts with KF (5-10 equiv) and a small amount
of water in CH2Cl2 under heterogeneous conditions and
furnished the corresponding cis-configured 3-substituted 4-me-
thylene prolines 18a-c, respectively, with g98% ee and g98%
de in medium to good yields (Table 3).
The E- and Z-isomers of 14a-e were each formed with
g98% de. Because of the further synthetic studies, the E- and
Z-isomers of 14a-e were separated by preparative HPLC. Thus,
both the methyl-substituted titanium complexes 13a-e and the
unsubstituted titanium complexes 3a-e exhibit in the reaction
with 4 similar high syn diastereoselectivities. However, the
methyl group of 13a-e causes the reaction to be of low E/Z-
selectivity in regard to the double bond. Such a difference in
the E/Z-selectivity between 13a-e and 3a-e was not observed
in their reactions with aldehydes.28 Interestingly, the reaction
of the phenyl-substituted titanium complex 13e with 4 was
Both isomers Z-15a and E-15a afforded the proline derivative
18a. Thus, a separation of the E- and Z-isomers is not required
for the synthesis of 18a and presumably also not for that of
18b and 18c. The conversion of E/Z-14a-c to 18a-c, respec-
tively, has been carried out with the same results without
isolation of E/Z-15a-c. In addition to the proline derivatives
18a-c sulfinamide 9 with g98% ee was isolated in each case
in high yield.
The facile cyclization of the allyl aminosulfoxonium salts
17a-c with formation of 18a-c, respectively, prompted us to
study the cyclization of a derivative of 17, the double bond of
(28) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.; Raabe, G. Eur. J. Org. Chem.
2003, 1500-1526.
9
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Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Figure 4. Structure of the functionalized â-methyl vinyl sulfoximine E-14b in the crystal.
Scheme 6. Synthesis of 4-Ethylidene Prolines
which carries an additional substituent. It was hoped to obtain
information whether the cyclization involves a SN or SN′
reaction. The corresponding allyl sulfoximine 19 was prepared
as an E/Z-mixture starting from sulfoximine 1 and diethyl ketone
by the AEI-route (Scheme 6). Chromatographic separation of
the isomers and recycling of the Z-isomer Z-19 afforded the
enantiomerically pure E-isomer in 53% yield.
The aminoalkylation of E-19 with 4 following lithiation and
titanation of the sulfoximine gave with high regio- and diaste-
reoselectivity the Z-configured functionalized â-ethyl vinyl
sulfoximine 20 in 60% yield. Activation of sulfoximine 20
through methylation with Me3OBF4 furnished the vinyl ami-
nosulfoxonium salt 21 which upon treatment with KF and a
small amount of water in CH2Cl2 afforded a mixture of prolines
Z-23 and E-23 in a ratio of 94:6 in 46% yield based on 20 and
the R-methylated proline 24, the configuration of which was
not determined, in 5% yield based on 20.
kainoid amino acids, from the aminosulfoxonium salt Z-15d
could not be accomplished by using KF/H2O for the migratory
cyclization of because of a concomitant desilylation. However,
treatment of the vinyl aminosulfoxonium salt Z-15d with DBU
in CH2Cl2 caused a facile migratory cyclization and gave the
proline derivative 18d in 78% yield besides sulfonamide 9
(81%). Similarly, reaction of the vinyl aminosulfoxonium salt
E-15b with DBU afforded proline 18b in 83% yield and 9 in
94% yield (cf. Scheme 5). The vinyl salts E-15b and Z-15d are
most likely converted by DBU via the allyl ylides 16b and 16d,
respectively, to the allyl aminosulfoxonium salts 17b and 17d,
respectively, which suffer a DBU-assisted cyclication with
formation of the corresponding prolines.
I.c. Deprotection of the Unsaturated Prolines. The final
step of the synthesis of the unsaturated prolines of type I and
The configuration of Z-23 was revealed by X-ray structure
analysis (Figure 5). Besides prolines Z/E-23 sulfinamide 9 was
isolated in 84% yield. This result shows that the intermediate
allyl aminosulfoxonium salts Z-22 and E-22 preferentially
cyclize through a SN reaction. Noteworthy is the high Z-
selectivity of the cyclization. This may be ascribed to (1) an
unselective formation of the allyl aminosulfoxonium salts Z-22
and E-22, (2) a fast F--catalyzed equilibration of Z-22 and E-22,
and (3) a cyclization of Z-22 being faster than that of E-22
because of less 1,3-allylic strain in the transition state, leading
to Z-23. Alternatively, the preferential formation of Z-23 could
be rationalized by proposing a highly selective isomerization
of 21 to Z-22 being configurationally stable.
The synthesis of the substituted proline derivative 18d
(Scheme 7), a potential starting material for the synthesis of
Figure 5. Structure of the 4-ethylidene proline Z-23 in the crystal.
9
J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006 7365

A R T I C L E S
Tiwari et al.
Scheme 7. Synthesis of a Functionalized 4-Methylene Proline with DBU
Scheme 8. Deprotection of Unsaturated N-Bus Prolines
Table 4. Synthesis of Functionalized Cyclic Vinyl Sulfoximines
E-31
yield (%)
E-29
yield (%)
entry
derivative
n
E-31:E-29
de (%)
de (%)
1
2
3
4
a
b
c
1
2
3
4
6:1
10:1
24:1
46:1
70
69
82
87
g98
g98
g98
g98
14
8
4
g98
g98
g98
g98
d
2
contrast it was found that the mono(allyl)titanium complexes
30a-d, which are also readily available from 27a-d through
lithiation and titanation with ClTi(NEt2)3, react with aldehydes
with high regio- and diastereoselectivities at the R-position to
furnish the corresponding allyl sulfoximines.21,22,30 It was thus
of interest to study the reactions of 30a-d with 4 to see whether
the mono(allyl)titanium complexes show a similar reactivity
toward the imino ester.
III is the deprotection of the N atom of 8 and 18. Because of
the deliberate selection of the Bus group, this transformation
should be possible by applying a water-free acid.29 Indeed,
treatment of the proline derivatives 8b and 18b with CF3SO3H
in CH2Cl2 (0.05-0.1 M) afforded the proline esters 25 in 80%
yield and 26 in 76% yield, respectively (Scheme 8).
Care had to be taken in the case of the isolation of 25 and 26
from the acidic reaction mixture. Workup was carried out by
the addition of water and extraction with CH2Cl2 following the
adjustment of the pH of the mixture to a value of 6.8 by the
addition of 0.1 M NaOH. The adjustment of the pH to a value
of 9 prior to the extraction of 26 surprisingly caused a partial
epimerization at C2 and the formation of a mixture of 26 and
its trans diastereomer. A partial epimerization of 26 was also
observed upon treatment of the ester with NaOMe, NEt3, and
DBU. Interestingly, an epimerization of the protected proline
ester 18b was not observed with the later bases.
II. Stereo-Complementary Aminoalkylation of Sulfonimi-
doyl-Substituted Mono(allyl)titanium Complexes. We had
previously shown that the bis(allyl)titanium complexes 28a-
d, which are derived from the corresponding cyclic allyl
sulfoximines 27a-d through lithiation and titanation with ClTi-
(OiPr)3, react with the R-imino ester 4 with high regio- and
diastereoselectivities at the γ-position to give E-syn- and Z-syn-
configured functionalized vinyl sulfoximines E-29a-d and
Z-29a-d, respectively, both with very high diastereoselectivities
in ratios of 1.4:1, 5:1, 1:3, and 1:12, respectively (Scheme 9).20
Similarly the titanium complexes 28a-d react with aldehydes
with high regio- and diastereoselectivities at the γ-position to
afford the corresponding anti-configured homoallyl alcohols
having, however, a Z-configured vinylic sulfoximine.21 In
Surprisingly, the mono(allyl)titanium complexes 30a-d
reacted with 4 also at the γ-position and gave the corresponding
functionalized cyclic vinyl sulfoximines 31a-d and 29a-d in
ratios ranging from 6:1 to 46:1 (Table 4), both with very high
diastereoselctivities. The ratio of the two diastereomers is
strongly dependent on the ring size of the allyl sulfoximine,
being the highest for the eight-membered cyclic derivative 30d
(entry 4). It is interesting to note that the major diastereomers,
31a-d, derived from the mono(allyl)titanium complexes 30a-d
and the major diastereomers obtained from the bis(allyl)titanium
complexes, 28a-d, have the opposite configuration at the two
stereogenic C atoms. Thus, both enantiomers of a given target
molecule derived from 29 and 31 after substitution of the
sulfoximine group (vide infra) are accessible from one enanti-
omer of the corresponding allyl sulfoximine, 27, merely by
choice of the titanation reagent ClTi(NEt2)3 and ClTi(OiPr)3.
The configuration of the seven-membered sulfoximine 31c
was determined by X-ray crystal structure analysis (Figure 6).31
The observation of a stereo-complementary aminoalkylation
of the cyclic titanium complexes 28a-d and 30a-d with 4 led
us to investigate whether the acyclic titanium complexes 32a
and 32d (Scheme 10) also show a reactivity toward 4 being
(30) Gais, H.-J.; Babu, G. S.; Gu¨nter, M.; Das, P. Eur. J. Org. Chem. 2004,
1464-1473.
(31) Only crystals of minor quality could be obtained from compound 31c.
Although the diffraction data collected at 150 K were sufficient for a
solution of the structure, they did not allow a complete anisotropic
refinement of the structure. Thus, the molecule shown in Figure 5 is the
result of an isotropic refinement and merely a proof of the three-dimensional
connection of the atoms in space.
(29) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604-8608.
9
7366 J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006

Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Figure 6. Structure of the functionalized cyclic vinyl sulfoximine 31c in the crystal.
Scheme 9. Stereo-Complementary Aminoalkylation of Cyclic Sulfonimidoyl-Substituted Allyl Titanium Complexes
Scheme 10. Aminoalkylation of Acyclic Sulfonimidoyl-Substituted Mono(allyl)titanium Complexes
Table 5. Synthesis of Functionalized Acyclic Vinyl Sulfoximines
Scheme 11. Reactivity Model for the Aminoalkylation of the
Acyclic Allyl Titanium Complexes 30a-d with the R-Imino Ester 4
33
5
derivative
33:5
yield (%)
de (%)
yield (%)
de (%)
a
b
6:1
2:1
56
58
g98
g98
10
32
g98
g98
stereo-complementary to that of the corresponding bis(allyl)-
titanium complexes 3a and 3d. Treatment of 32a and 32b with
4 afforded the corresponding functionalized acyclic vinyl
sulfoximines 33a,b and 5a,b (Table 5), both with very high
diastereoselectivities.
A NMR spectroscopic investigation of the structure of the
acyclic mono(allyl)titanium complexes 32a and 32b had re-
vealed a low configurational stability of the CR atom and a
fast CR,N-shift of the titanium atom leading to the formation
of an equilibrium mixture of complexes 32A-C in ratios of
84:13:3 and 86:12:2, respectively (Scheme 11).21,22 The forma-
tion of the syn-configured diastereomers 33 and 5 in the reaction
of 32 with 4 can thus be rationalized, on the assumption of the
operation of the Curtin-Hammett principle,32 by proposing a
stereo- and regioselective reaction of the (SCR)-configured
complex 32A with 4 through a six-membered cyclic transition
state of type TS-E-33 giving 33 and of the (RCR)-configured
(32) Seeman, J. L. Chem. ReV. 1983, 83, 83-134.
9
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A R T I C L E S
Tiwari et al.
Scheme 12. Reactivity Model for the Aminoalkylation of the Cyclic
Allyl Titanium Complexes 32a,b with the R-Imino Ester 4
Scheme 13. Synthesis of a Cyclic δ-Chloro-â,γ-Dehydro Amino
Acid
Scheme 14. Synthesis of Acyclic δ-Chloro-â,γ-Dehydro Amino
Acids
complex 32C with 4 through TS-E-5 leading to 5. The
preferential formation of the E,RCR,SCâ-configured vinyl sul-
foximine E-33 points to a higher reactivity of the (SCR)-
configured complex 32A.
The similarity in the reactivity between the acyclic complexes
32a,b and the cyclic complexes 30a-d toward 4 gives strong
support to the notion of the existence of a similar fast
equilibrium between the complexes A-C also in the case of
30 (Scheme 12). Here the (SCR)-configured complex 30A is
proposed to react through a six-membered cyclic transition state
of type TS-31 to afford E-31 and the (RCR)-configured complex
30C with 4 through TS-E-29 with formation of E-29. The
preferential formation of the E,RCR,SCâ-configured vinyl sul-
foximine E-33 points to a higher reactivity of the (SCR)-
configured complex 30A.
III. δ-Chloro-â,γ-Dehydro Amino Acids, δ-Chloro Allyl
Alcohols and Bicyclic Prolines. III.a. δ-Chloro-â,γ-Dehydro
Amino Acids. The synthesis of the 3,4-unsaturated proline
derivatives 8a-e from the acyclic vinyl aminosulfoxonium salts
7a-e, respectively, led us to investigate the possibility of a
similar synthesis of the bicyclic prolines of type II from the
cyclic vinyl aminosulfoxonium salts XVIII (cf. Figures 1 and
3) by using KF as base. We had already observed that the
migratory cyclization of the diastereomeric vinyl aminosulfoxo-
nium salt XII with DBU gives the regioisomeric bicyclic
prolines of type XIV (cf. Figure 2). Thus, it would synthetically
be attractive to open an access to both regioisomers from the
same starting material.
Activation of the cyclic vinyl sulfoximine 31b through
methylation with Me3OBF4 delivered the aminosulfoxonium salt
34 (Scheme 13). Surprisingly, an inadvertent treatment of salt
34 with NH4Cl instead of KF in THF/water resulted in both a
facile isomerization to the allyl aminosulfoxonium salt 35 and
its concomitant substitution by the Cl- ion and gave the allyl
chloride 36 in 64% yield and sulfinamide 9 in 92% yield.
The unexpected facile migratory substitution of the vinyl
aminosulfoxonium salt 34 by the Cl- ion prompted a study of
the acyclic vinyl aminosulfoxonium salts 7a-d (Scheme 14)
and E-15c (Scheme 15) to see whether this is a reactivity typical
for vinyl and allyl aminosulfoxonium salts.
of the allyl chlorides E-37a-d and Z-37a-d, respectively,
which were separated by chromatography, in good yields (Table
6). Surprisingly, the tert-butyl-substituted salt 7d afforded only
the Z-configured chloride Z-37d. Similarly, treatment of the
methyl-substituted vinyl aminosulfoxonium salt E-15c with
NaCl or NH4Cl in water and ethyl acetate gave the allyl chloride
38 in 63% yield.
The vinyl aminosulfoxonium salts 34, 7a-d, and E-15c
perhaps suffer a Cl- ion-mediated isomerization to the allyl
aminosulfoxonium salts 35, E/Z-11a-d, and 17c, respectively,
which then experience an allylic substitution by the Cl- ion
with formation of the corresponding allyl chlorides and sulfi-
namide 9. The vinyl aminosulfoxonium salts most likely form
ion pairs in CH2Cl2 and EtOAc containing the Cl- ion as the
counterion. The Cl- ion acts as a base in a way similar to that
of the F- ion to form the corresponding allyl aminosulfoxonium
ylides, the protonation of which gives the thermodynamically
more stable allyl aminosulfoxonium salts (cf. Scheme 3). In
the case of unsaturated sulfones and sulfoximines the allyl
isomer is strongly favored over the vinyl isomer in the
equilibrium.13,21,26,33 Because of the similarities in the structure
of the sulfonimidoyl group and the aminosulfoxonium group
which is, however, much more carbanion-stabilizing, it is to
Treatment of the vinyl aminosulfoxonium salts 7a-d either
with NaCl or NH4Cl and water in CH2Cl2 furnished a mixture
(33) Lee, P. S.; Du, W.; Boger, D. L.; Jorgensen, W. L. J. Org. Chem. 2004,
69, 5448-5453.
9
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Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Scheme 15. Synthesis of an Acyclic δ-Chloro γ-Methylene Amino Acid
Table 6. Synthesis of Acyclic δ-Chloro-â,γ-Dehydro Amino Acids
Scheme 17. One-Pot Synthesis of an Acyclic
δ-Chloro-â,γ-Dehydro Amino Acid
derivative
R
t (d)
37, yield (%)
E:Z
9, yield (%)
a
b
c
Me
iPr
cC6H11
tBu
2.5
3
2.5
3
82
93
89
82
88:12
80:20
66:34
1:100
81
94
80
76
d
Scheme 16. One-Pot Synthesis of a Cyclic δ-Chloro-â,γ-Dehydro
Amino Acid
be expected that the aminosulfoxonium group also favors the
allyl isomer. The difference in reactivity of the allyl aminosul-
foxonium salts toward the Cl- and the F- ions, i.e., intermo-
lecular substitution versus cyclization (vide supra), can be related
to the differences in nucleophilicity and basisicity of the two
anions. In the case of the migratory substitution of salts 34,
7a-d, and E-15c with NH4Cl in the presence of water it could
also be NH3 which causes the isomerization.
Most interestingly, the allyl chloride 36 can also be obtained
starting from the vinyl sulfoximine 31b in a one-pot sequence
by using a chloroformiate for the activation and migratory
substitution (Scheme 16). Thus, treatment of 31b with ClCO2-
CH(Cl)Me gave chloride 36 in 86% yield. In addition sulfina-
mide 4130,34 with >98% ee was isolated in 93% yield.
Conversion of sulfinamide 41 to (S)-sulfoximine 123 of g98%
ee had already been described.34
The acyclic allyl chlorides of type 37 can also be obtained
by the one-pot sequence starting from the vinyl sulfoximine 5
and using the chloroformiate (Scheme 17). Thus, treatment of
5c with ClCO2CH(Cl)Me gave the allyl chloride 37c as a E/Z-
mixture in a ratio of 30:70 in 92% yield. In addition sulfinamide
4130,34 with >98% ee was isolated in 93% yield. Most likely
sulfoximines 31b and 5c react with the chloroformiate with
formation of the aminosulfoxonium salts 39 and 42, respectively,
which suffer a Cl- ion-mediated isomerization to give the
corresponding allyl aminosulfoxonium salts 40 and E/Z-43,
respectively. Their substitution by the Cl- ion yields chlorides
36 and E/Z-37c, respectively. Support for this mechanistic
rationalization comes from a previous investigation in which
we showed that allyl sulfoximines are readily converted to the
corresponding chlorides and sulfinamide 41 upon reaction with
the chloroformiate.30,34 Interestingly, the E/Z-selectivities of the
formation of chlorides E/Z-37c from the aminosulfoxonium salt
7c and 42 are almost opposite.
III.b. Cyclization of δ-Chloro-â,γ-Dehydro Amino Acids.
Treatment of chlorides 36, Z-37b-d, and 38 with DBU gave
the corresponding proline derivatives 44, 8b-d, and 18c,
respectively, in practically quantitative yields except 18c which
was obtained in only 66% yield (Scheme 18).
III.c. δ-Chloro Allyl Alcohols. Because of the ready avail-
ability of the hydroxy-substituted vinyl sulfoximines 45a and
45b (Scheme 19) from the corresponding bis(allyl)titanium
complexes XIV (cf. Figure 2) and aldehydes, it was of interest
to see whether the corresponding vinyl aminosulfoxonium salts
46a and 46b would also undergo a migratory substitution.
Treatment of the vinyl aminosulfoxonium salt 46a, which was
obtained from sulfoximine 45a through methylation,13 first with
DBU and then with saturated aqueous NH4Cl in CH2Cl2 gave
after a short reaction time a mixture of the allyl chlorides E-48a
and Z-48a in a ratio of 92:8 in high yield (Table 7). A similar
experiment with salt 46b, which was prepared through methy-
lation of 45b,13 afforded the allyl chloride E-48b as a single
isomer in almost quantitative yield. The treatment of 45a and
45b with DBU most likely caused a facile isomerization to the
(34) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.; Raabe, G. Eur. J. Org. Chem.
2003, 1500-1526.
9
J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006 7369

A R T I C L E S
Tiwari et al.
Scheme 20. One-Pot Synthesis of a δ-Chloro Allyl Alcohol
Scheme 18. Cyclization of δ-Chloro-â,γ-Dehydro Amino Acids
Scheme 19. Synthesis of δ-Chloro Allyl Alcohols
IV. Cyclopentanoid Aminosulfoxonium Ylides. IV.a. Syn-
thesis of Amino-Substituted Tricyclic Ylides. The facile
isomerization of vinyl aminosulfoxonium salts of type 7 to the
corresponding allyl aminosulfoxonium salts by the Cl- and F-
ions led us to explore the possibility of generation and isolation
of the intermediate allyl aminosulfoxonium ylides of type 10
(cf. Scheme 3) by using a strong base. Previously, we had
studied the structure of ylides of type 10 by ab initio calcula-
tion,22 and their isolation would also permit further structural
investigations. Therefore, the vinyl aminosulfoxonium salt 7b
was treated with LiN(H)t-Bu (2-3 equiv) in THF at low
temperatures. Surprisingly, the tricyclic keto aminosulfoxonium
ylide 54 was isolated in 39% yield as a single diastereomer
besides the proline derivative 8b in 32% yield (Scheme 21). A
similar reaction of the N-allyl vinyl aminosulfoxonium salt Al-
7b afforded only the keto ylide Al-54 in 49% yield as a single
diastereomer. Formation of the tricyclic ylides can perhaps be
rationalized as follows. We had previously observed that vinyl
aminosulfoxonium salts of type 46 (cf. Scheme 18) are
deprotonated by strong bases at the R-position to the amino-
sulfoxonium group with formation of the corresponding vinyl
aminosulfoxonium ylides.13,14 These ylides are stable at low
temperatures but decompose at higher temperatures with forma-
tion of the corresponding alkylidene carbenes. Thus, it seems
reasonable to assume that 7b and Al-7b are deprotonated by
the lithium amide to give the vinyl ylides 51 and Al-51,
respectively. Subsequently the ylides suffer a cyclization through
attack of the ylidic C atom at the ethoxycarbonyl group with
formation of the cyclopentenone derivatives 52 and Al-52,
respectively, the double bond and the phenyl group of which
are both activated by the aminosulfoxonium group.12b,g There-
fore, the phenylsulfoxonium derivatives 52 and Al-52 react with
the lithium amide through ortho lithiation of the phenyl group
to generate the lithiophenyl derivatives 53 and Al-53, respec-
tively, which undergo a highly stereoselective intramolecular
enone addition of the phenyl group35 with formation of ylides
Table 7. Synthesis of δ-Chloro Allyl Alcohols
48
R1
R2
yield (%)
E:Z
aa
ab
bc
Ph
Ph
iPr
iPr
iPr
Me
89
81
98
92:8
90:10
g100:1
a From 46a. b One-pot synthesis from 45a and ClCO2CH(Cl)Me. c From
46b.
allyl aminosulfoxonium salts E/Z-47a and E/Z-47b, which
suffered a similarly facile substitution by the Cl- ion.
Allyl chlorides of type 48 can also be obtained by the one-
pot sequence starting from the corresponding vinyl sulfoximine
45 and using the chloroformiate (Scheme 20). For example,
treatment of 45a with ClCO2CH(Cl)Me gave a mixture of the
allyl chlorides E-48a and Z-48a in a ratio of 90:10 in 81% yield.
In addition sulfinamide 4130,34 was isolated in 93% yield. Most
likely sulfoximine 45a reacts with the chloroformiate with
formation of the aminosulfoxonium salt 49a which suffers a
Cl- ion-mediated isomerization to give the corresponding allyl
isomer E/Z-50a, the substitution of which by the Cl- ion gives
chlorides E/Z-48a.
9
7370 J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006

Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Scheme 21. Synthesis of Amino-Substituted Tricyclic Ylides
54 and Al-54, respectively.36 It has been shown that the ortho
lithiation of phenylsulfoximines with lithium amides is a facile
process37-41 and that of the phenylaminosulfoxonium salts
52 and Al-52 should be even more facile because of the
powerful carbanion-stabilizing effect of the aminosulfoxonium
group.12a,b,g,14
The formation of the proline derivative 8b in the reaction of
7b with the base can be ascribed to a competing deprotonation
of the vinyl aminosulfoxonium salt at the Cγ atom with
formation of the allyl ylide Z-10b which cyclizes following a
proton transfer from the N-sulfonyl group to the CR atom of
the ylide. While the N-protected ylide Al-Z-10b may have also
been formed, it cannot cyclize.
The novel tricyclic ylides 54 and Al-54 should make
interesting starting materials for the synthesis of highly substi-
tuted cyclopentanone derivatives, as for example, through a ring-
opening reaction of the aminosulfoxonium ylide moiety with
aldehydes at the CR-S bond.12c,g
IV.b. Experimental and Calculated Structures of Tricyclic
Keto Aminosulfoxonium Ylides. Besides the determination of
the relative configuration of Al-54, the knowledge of the
bonding parameters of the keto aminosulfoxonium ylide struc-
tural element was also of interest. Although aminosulfoxonium
ylides are valuable reagents in stereoselective synthesis, we are
unaware of any crystal structure analysis of such an ylide.42
Figure 7. Structure of the keto aminosulfoxonium ylide Al-54 in the crystal.
Thus, X-ray crystal structure analysis of ylide Al-54 (Figure 7)
was carried out.
Compared with the average value of 1.208(7) Å obtained from
155 solid-state structures of cyclopentanones43 the carbonyl bond
of Al-54 (1.227(3) Å) (Table 8) appears to be somewhat
elongated, indicating a weak enolic character of this bond.
However, an ab initio structure optimization of the model ylide
XXIII (Figure 8) at the MP2 level employing the 6-31+G*
basis set and the Gaussian 03 suite of quantum-chemical
routines44 resulted in a CO bond length of 1.236 Å, which is
only slightly longer than that of cyclopentanone (1.227 Å)
obtained at the same level of theory. This indicates that the
experimental average value for the cyclopentanones43 is probably
too small. At an experimental value of 1.409(3) Å the C1-C2
bond is quite short. The calculated value for the model ylide
XXIII is 1.447 Å. According to both the X-ray structure
determination and calculation, the carbonyl carbon atom C2 is
planar. Moreover, at a sum of bond angles of 352.4(2)° carbon
(35) Piers, E.; Harrison, C. L.; Zetina-Rocha, C. Org. Lett. 2001, 3, 3245-
3247.
(36) Acyclic keto aminosulfoxonium ylides had previously been obtained through
acylation of (dimethylamino)sulfoxonium methylides: (a) Johnson, C. R.;
Haake, M.; Schroeck, C. W. J. Am. Chem. Soc. 1970, 92, 6594-6598. (b)
Johnson, C. R.; Rogers, P. E. J. Org. Chem. 1973, 38, 1798-1903. (c)
Fisher, M. J.; Overman, L. E. J. Org. Chem. 1988, 53, 2630-2634.
(37) Reggelin, M. Ph.D. Thesis, Universita¨t Kiel, 1989.
(38) Mu¨ller, J. Ph.D. Thesis, Universita¨t Basel, 1993.
(39) Mu¨ller, J. F. K.; Neuburger, M.; Zehnder, M. HelV. Chim. Acta 1997, 80,
2182-2190.
(40) (a) Bosshammer, S. Ph.D. Thesis, RWTH Aachen, 1998. (b) Wessels, M.
Ph.D. Thesis, RWTH Aachen, 2002.
(41) (a) Levacher, V.; Eriksen, B. L.; Begtrup, M.; Dupas, G.; Que´guiner, G.;
Duflos, J.; Bourguignon, J. Tetrahedron Lett. 1999, 40, 1665-1668. (b)
Gaillard, S.; Papamicae¨l, C.; Dupas, G.; Marsais, F.; Levacher, V.
Tetrahedron 2005, 61, 8138-8147.
(43) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.;
Taylor, R. J. Chem. Soc., Perkin Trans. II 1987, S1.
(44) Frisch, M. J.; et al. Gaussian 03, Revision C.02; Gaussian, Inc., Wallingford
CT, 2004.
(42) A search in the Cambridge crystallographic data files revealed no entry
for an acyclic or cyclic aminosulfoxonium ylide of type Al-54.
9
J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006 7371

A R T I C L E S
Tiwari et al.
as a single bond between a sp2.22 hybrid at the S atom and a
sp2.53 hybrid at C1. There are no significant interactions between
the lone pair at C1 and the empty orbitals at the S atom. (iv)
The natural atomic charges at S, C1, and C2 are +2.23, -0.76,
and +0.67 e, respectively. Electrostatic interactions, therefore,
contribute significantly to the shortening of the bonds between
C1 and C2 on the one and between C1 and S on the other hand
relative to the values of the corresponding typical single bonds.
(v) According to the NBO analysis the S-O bond is not a
double bond as depicted in the structural formulas. This bond
is a single bond between a sp2.64 hybrid at the S atom and a
sp2.87 hybrid at the O atom.47 There are three lone pairs at the
O atom, two of the orbitals of which are essentially p orbitals
while the third one has about 74% s and 26% p character. The
natural atomic charge at the O atom is -1.0 e. (vi) The lengths
of the S-N bond is 1.696 Å and, therefore, only slightly shorter
than a typical S-N single bond (1.722 Å in Ph-S-NH2 at the
same level of theory). The natural atomic charge of the N atom
is -0.80 e, and its lone pair has about 87% p and 13% s
character. The charge distribution can be expressed in a first
approximation through the conventional polarized structure
XXIIIA.48 Stabilization of ylides Al-54 and XXIII is thus
mainly provided by electrostatic interactions.
Table 8. Bond Lengths (Å) and Dihedral Angles (deg) of the Keto
Ylides Al-54 (experimental) and XXIII (calculated)
bond
Al-54
XXIII
angle
Al-54
XXIII
S-O
1.442(1) 1.478 C1-S-N-Me -174.1(2) -179.7
S-N
1.645(2) 1.696 C1-S-N-Me
1.661(2) 1.650 N-S-C1-C2
1.758(2) 1.781 N-S-C1-C5
49.6(2)
46.3
C1-S
C7-S
100.9(2)
106.8
-111.7(2) -107.2
-22.5(2)
124.9(1)
C1-C2 1.409(3) 1.447 O-S-C1-C2
C1-C5 1.531(3) 1.510 O-S-C1-C5
C2-C3 1.559(3) 1.541
-18.7
127.3
C2-O
1.227(3) 1.236
Figure 8. Calculated structure of the keto aminosulfoxonium ylide XXIII.
atom C1 is distinctly pyramidalized. The perpendicular distance
of C1 from the plane defined by S1, C2, and C5 is 0.245(2) Å.
Within its standard deviation this value coincides with the one
from the ab initio calculation (351.9°).
Ylide Al-54 and the model ylide XXIII adopt a C1-S
conformation in which the lone pair at C1 and the S-N bond
are approximately in a syn/planar position. According to an ab
initio calculation of (dimethylamino)phenylsulfoxonium meth-
ylide this conformation allows for a stabilizing nC-σ*SN
hyperconjugative interaction (vide supra).22 Furthermore the
methylene ylide adopts, according to the calculations, S-N and
C-S conformations in which the lone pairs at the C atom and
N atom are in an almost orthogonal position. Thereby, a
destabilizing interaction between both lone pairs is avoided that
results when they are in a planar position.22 Ylide Al-54 and
the model ylide XXIII adopt similar S-N and C-S conforma-
tions.
IV.c. Synthesis of Hydroxy-Substituted Mono- and Tri-
cyclic Ylides. Having observed a facile tandem cyclization of
the amino-substituted salts 7b and Al-7b, it was of interest to
see whether a hydroxy-substituted vinyl aminosulfoxonium salt
of type 57 is also able to undergo such a series of transforma-
tions, giving the tricyclic ylide 59 (Scheme 22). The required
functionalized vinyl aminosulfoxonium salt 56 was synthesized
by a highly selective reaction of the bis(allyl)titanium complex
3b with ethyl glyoxylate, which gave the substitute vinyl
sulfoximine 55 as a single diastereomer in 36% yield. Protection
of the hydroxy group of 55 afforded the silyl ether 56 in 92%
yield. The treatment of the vinyl aminosulfoxonium salt 57,
which was obtained through methylation of the vinyl sulfox-
A natural bond orbital (NBO) analysis45 of the bonding in
the model ylide XXIII revealed the following interesting
features. (i) There is no double bond between the carbonyl C
atom C2 and the neighboring tri-coordinate carbon atom C1.
The atoms are bonded by a single bond between a sp1.89 hybrid
at the carbonyl C and a sp1.73 hybrid at the neighboring carbon
atom C1. The latter atom carries a lone pair with about 98% p
character and an occupancy of 1.59 which strongly interacts
with an only weakly occupied p orbital (occupancy 0.67) at the
carbonyl C atom resulting in a stabilization energy43b,46 of ∆E2
) -157 kcal/mol. At stabilization energies of -13 and -33
kcal/mol the interactions of the lone pair at C1 with the σSO
*
and σSN* bonds, respectively, are of minor importance. (ii) The
CO bond is also a single bond between a sp2.02 hybrid at the C
atom and a sp1.40 hybrid at the O atom. The O atom carries
three lone pairs, one with about 58% s- and 42% p character
and two essentially pure p orbitals. One of these p lone pairs
gives a strong second-order stabilization energy (∆E2 ) -365
kcal/mol) with the above-mentioned weakly occupied p orbital
at the carbonyl C atom. (iii) Although it is significantly shorter
than a typical S-C single bond (1.811 Å in Me-S-NH2, MP2/
6-31+G*), the C1-S linkage is not a double bond. It is formed
(45) (a) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88, 899.
(b) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO
3.0 Program Manual, Theoretical Chemistry Institute and Department of
Chemistry: University of Wisconsin, Madison, Wisconsin 53706, U.S.A.
(46) ∆E2 ) -qdo do|F |ac 2/(ꢀac-ꢀdo), where F is the Fock operator of the
molecule, qdo the occupation number of the donor orbital. ꢀac and ꢀdo are
the NBO orbital energies of the acceptor and the donor orbital, respectively.
(47) (a) Chesnut, D. B.; Quin, L. D. J. Comput. Chem. 2004, 25, 734-738. (b)
Glendening, E. D.; Shrout, A. L. J. Phys. Chem. A 2005, 109, 4966-4972.
(c) Mu¨ller, J. F. K.; Batra, R. J. Organomet. Chem. 1999, 584, 27-32. (d)
Kumar, P. S.; Bharatam, P. V. Tetrahedron 2005, 61, 5633-5639.
(48) For a discussion of the importance of polarized structures of this type in
the case of enolate ions, see: Wiberg, K. B.; Ochterski, J.; Streitwieser,
A. J. Am. Chem. Soc. 1996, 118, 8291-8299.
9
7372 J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006

Asymmetric Synthesis of Proline Derivatives
A R T I C L E S
Scheme 22. Synthesis of Hydroxy-Substituted Cyclic Ylides
aminosulfoxonium salts. Particularly illustrative is the one-pot
activation and migratory substitution of the amino- and hydroxy-
substituted vinyl sulfoximines with formation of the correspond-
ing allyl chlorides upon treatment with a chloroformiate. The
facile conversion of the hydroxy-substituted vinyl aminosul-
foxonium salts to the corresponding allyl chlorides gives further
proof for the generality of the migratory substitution of vinyl
aminosulfoxonium salts. The proline derivatives and δ-chloro-
â,γ-dehydro amino acids should make interesting building
blocks for the enantioselective synthesis of nonnatural amino
acids.
A further example for the high reactivity of the functionalized
vinyl aminosulfoxonium salts is provided by the stereoselective
conversion of the ethoxycarbonyl-substituted aminophenylsul-
foxonium salts 7b, Al-7b, and 57 to the corresponding highly
substituted tricyclic keto aminosulfoxonium ylides 54, Al-54,
and 59, respectively, upon treatment with a strong base.
Although the yields of the ylides are only moderate at present,
their tricyclic structure and the four-step reaction sequence
leading to their formation are remarkable, and an optimization
of the reaction conditions may perhaps lead to higher yields.
The structure of the keto aminosulfoxonium ylide Al-54 in the
crystal shows some remarkable features including a CO bond
which is only slightly longer than that of cyclopentanones. Ab
initio calculations of the model ylide showed a good correlation
between theoretical and experimental bonding parameters. An
NBO analysis of the model keto aminosulfoxonium ylide XXIII
revealed within the framework of the model interesting structural
features including the absence of CO, CS, CC, and SO double
bonds in the keto aminosulfoxonium unit and pointed to the
importance of a polar structure of type XXIIIA.
The key step in the synthesis of the functionalized cyclic and
acyclic vinyl sulfoximines is the highly regio- and stereoselective
aminoalkylation of the sulfonimidoyl-substituted bis(allyl)-
titanium complexes with the N-Bus imino ester. A similar
aminoalkylation of the mono(allyl)titanium complexes, which
are accessible from the same lithiated allyl sulfoximine used in
the synthesis of the bis(allyl)titanium complexes, permits in the
case of cyclic allyl sulfoximines a highly selective stereo-
complementary synthesis of the corresponding functionalized
cyclic vinyl sulfoximines of opposite configurations at the C
atoms.
imine 55 in practically quantitative yield, with the lithium amide
furnished the tricyclic keto ylide 59 in 30% yield as a single
diastereomer. It is assumed that the formation of 59 from 57
takes a similar course as that of 54 from 7b except for the
additional requirement of a Z/E-isomerization of the vinyl ylide
derived from salt 57. Support for this notion came from reactions
of 57, samples of which were inadvertently admixed with CH2-
Cl2 or CHCl3, with the lithium amide. Here the monocyclic
ylides 60 and 61, respectively, were isolated each in 22% yield,
respectively, as single diastereomers. Formation of the ylides
can be explained by the stereoselective addition of LiCCl3 and
49
LiCHCl2 to the cyclopentenone derivative 58, being derived
from 57 through deprotonation and cyclization. The isolation
of 60 and 61 gives support to the postulated formation of the
cyclopentenone derivatives 52, Al-52, and 58 as intermediates
in the formation of the tricyclic ylides.
Acknowledgment. Financial support of this work by the
Gru¨nenthal GmbH, Aachen, and the Deutsche Forschungsge-
meinschaft (Collaborative Research Center “Asymmetric Syn-
thesis with Chemical and Biological Methods” SFB 380) is
gratefully acknowledged. We thank Dr. Jan Runsink for NOE
experiments, Dr. Christian W. Lehmann, MPI Mu¨lheim, for the
data set of Al-54, Cornelia Vermeeren for the HPLC separations,
and Dominique J. Hahne for experimental assistance.
Conclusion
Chiral amino-substituted vinyl aminosulfoxonium salts are
versatile starting materials for the asymmetric synthesis of
unsaturated mono- and bicyclic prolines and δ-chloro-â,γ-
dehydro amino acids. The strong carbanion-stabilizing effect
and the high nucleofugacity of the aminosulfoxonium group are
the key factors responsible for the facile migratory intra- and
intermolecular substitution reactions of the vinyl and allyl
Supporting Information Available: General, experimental
procedures and characterization for all new compounds de-
scribed in this work, crystallographic data for the reported
structures (CIF format), and complete ref 44. This material is
available free of charge via the Internet at http://pubs.acs.org.
(49) (a) Koebrich, G.; Flory, K.; Fischer, R. H. Chem. Ber. 1966, 99, 1793-
1804. (b) Koebrich, G.; Merkle, H. R. Chem. Ber. 1966, 99, 1782-1792.
(c) Brantley, S. E.; Molinsky, T. F. Org. Lett. 1999, 1, 2165-2167.
JA061152I
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J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006 7373