Asymmetric Synthesis of Unsaturated, Fused Bicyclic Proline Analogues through Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium Complexes and Migratory Cyclization of δ-Amino Alkenyl Aminosulfoxonium Salts

Article abstract of DOI:10.1021/ja030324y

Described is an asymmetric synthesis of new Δ ^3a.4-unsaturated, fused bicyclic proline analogues from cyclic bis(allylsulfoximine)titanium complexes and N-tert-butylsulfonyl imino ethyl ester. Treatment of the enantiomerically pure five-, six-,

Full text of DOI:10.1021/ja030324y

Published on Web 10/02/2003
Asymmetric Synthesis of Unsaturated, Fused Bicyclic Proline
Analogues through Amino Alkylation of Cyclic
Bis(allylsulfoximine)titanium Complexes and Migratory
Cyclization of δ-Amino Alkenyl Aminosulfoxonium Salts
Stefan Koep, Hans-Joachim Gais,* and Gerhard Raabe
Contribution from the Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen
Hochschule (RWTH) Aachen, Prof.-Pirlet-Str. 1, D-52056 Aachen, Germany
Received May 29, 2003; E-mail: Gais@RWTH-Aachen.de
Abstract: Described is an asymmetric synthesis of new ∆3a,4-unsaturated, fused bicyclic proline analogues
from cyclic bis(allylsulfoximine)titanium complexes and N-tert-butylsulfonyl imino ethyl ester. Treatment of
the enantiomerically pure five-, six-, seven-, and eight-membered cyclic bis(allylsulfoximine)titanium
complexes with the imino ester gave mixtures of the corresponding (E,syn)- and (Z,syn)-configured,
δ-sulfoximine substituted, cyclic γ,δ-unsaturated R-amino acid esters with high regio- and diastereoselec-
tivities in good yields. Activation of the N-methyl sulfoximine group of these amino acid derivatives through
methylation with Me3OBF4 afforded in nearly quantitative yields the corresponding (dimethylamino)-
sulfoxonium salts. A novel migratory cyclization of these salts with DBU gave via an isomerization to the
corresponding allylic (dimethylamino)sulfoxonium salts and an intramolecular substitution of the (dimethyl-
amino)sulfoxonium group the enantio- and diastereomerically pure, bicyclic, N-tert-butylsulfonyl protected
proline analogues having a six- and eight-membered unsaturated carbocyclic ring. Cyclization of the alkenyl
(dimethylamino)sulfoxonium salts was independent of the configuration of the double bond. N,N-
Dimethylphenylsulfinamide of g99% ee was obtained in good yield as a further reaction product. Conversion
of the sulfinamide to N,S-dimethyl-S-phenylsulfoximine of g99% ee, the starting material for the synthesis
of the allylic sulfoximines, had been accomplished previously. Finally, cleavage of the tert-butylsulfonyl
protecting group with anhydrous acid furnished the fused bicyclic proline analogue containing an unsaturated
six-membered ring in high yield.
interesting are bicyclic proline analogues4 which have not only
been studied as angiotensin,5 bradykinin,5 thyroliberin,6 and
Introduction
The synthesis and application of fused bicyclic R-amino acids
have received much attention in recent years.1-3 Many of these
amino acids display interesting pharmacological activities,1e,2
and they have served as building blocks for the synthesis of
conformationally constrained peptides.3 Frequently, such pep-
tidomimetics show besides interesting structures improved
pharmacological activities and metabolic stabilities. Particularly
glutamic acid7 analogues, but also served as building blocks
for the synthesis of peptidomimetics.3,4 Proline confers confor-
mational restrictions into peptides, which can induce the
formation of â-turns and its replacement with analogues can
provide additional information about receptor recognition and
affinity. Besides these applications, proline and its derivatives
(4) (a) Esch, P. M.; Hiemstra, H.; de Boer, R. F.; Speckamp, W. N. Tetrahedron
1992, 48, 4659. (b) Hamper, B. C.; Dukesherer, D. R.; South, M. S.
Tetrahedron Lett. 1996, 37, 3671. (c) Witulski, B.; Go¨âmann M. Chem.
Commun. 1999, 1879. (d) Bergmeier, S. C.; Fundy, S. L.; Seth, P. P.
Tetrahedron 1999, 55, 8025. (e) Valls, N.; Lo´pez-Canet, M.; Vallribera,
M.; Bonjoch, J. Chem. Eur. J. 2001, 7, 3446. (f) Tanimori, S.; Fukubayashi,
K.; Kirihata, M. Tetrahedron Lett. 2001, 42, 4013. (g) Millet, R.; Domarkas,
J.; Rombaux, P.; Rigo, B.; Houssin, R.; He´nichart, J.-P. Tetrahedron Lett.
2002, 43, 5087. (h) Zhang, J.; Xiong, C.; Wang, W.; Ying, J.; Hruby, V.
J. Org. Lett. 2002, 4, 4029. (i) Maison, W.; Adiwidjaja, G. Tetrahedron
Lett. 2002, 43, 5957. (j) Valls, N.; Vallribera, M.; Carmeli, S.; Bonjoch, J.
Org. Lett. 2003, 5, 447. (k) Jiang, B.; Xu, M. Org. Lett. 2002, 4, 4077.
(5) (a) Blankley, C. J.; Kaltenbronn, J. S.; DeJohn, D. E.; Werner, A.; Bennett,
L. R.; Bobowski, G.; Krolls, U.; Johnson, D. R.; Pearlman, W. M.; Hoefle,
M. L. J. Med. Chem. 1987, 30, 992. (b) Juvvadi, P.; Dooley, D. J.; Humblet,
C. C.; Lu, G. H.; Lunney, E. A.; Panek, R. L.; Skeean, R.; Marshall, G. R.
Int. J. Peptide Protein Res. 1992, 40, 163. (c) Dumy, P.; Keller, M.; Ryan,
D. E.; Rohwedder, B.; Wo¨hr. T, Mutter, M. J. Am. Chem. Soc. 1997, 119,
918. (d) Blanco, M.-J.; Penide, M. R.; Sardina, F. J. J. Org. Chem. 1999,
64, 8786.
(1) (a) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon: Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(c) Barrett, G. C.; Davies, J. S. Amino Acids, Peptides, and Proteins; The
Royal Society of Chemistry: Cambridge, 2002; Vol. 33, p 1. (d) Rutjes,
F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc., Perkin Trans.
1 2000, 4197. (e) Ager, D. J.; Fotheringham, I. G. Curr. Opin. Drug
DiscoVery DeV. 2001, 4, 800.
(2) AnalgesicssFrom Chemistry and Pharmacology to Clinical Application;
Buschmann, H., Christoph, T., Friederichs, E., Maul, C., Sundermann, B.,
Eds.; Wiley-VCH: Weinheim, 2002.
(3) (a) Toniolo, C. Int. J. Peptide Protein Res. 1990, 35, 287. (b) Giannis, A.;
Kolter, T. Angew. Chem. 1993, 105, 1303; Angew. Chem., Int. Ed. Engl.
1993, 32, 1244. (c) Adang, A. E. P.; Hermkens, P. H. H.; Linders, J. T.
M.; Ottenheijm, H. C. J.; van Staveren, C. J. Recl. TraV. Chim. Pays-Bas
1994, 113, 63. (d) Gante, J. Angew. Chem. 1994, 106, 1780; Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1699. (e) Hruby, V. J.; Li, G.; Haskell-Luevano,
C.; Shenderovich, M. Biopolymers 1997, 43, 219. (f) Hanessian, S.;
Mcnaughton-Smith, G.; Lombart, H. G.; Lubell, W. D. Tetrahedron 1997,
53, 12789. (g) Conti, P.; Dallanonce, C.; De Amici, M.; De Micheli, C.;
Fruttero, R. Tetrahedron 1999, 55, 5623. (h) Gibson, S. E.; Guillo, N.;
Tozer, M. Tetrahedron 1999, 55, 585.
(6) Li, W.; Moeller, K. D. J. Am. Chem. Soc. 1996, 118, 10 106.
(7) Conti, P.; Dallanoce, C.; De Amici, M.; De Micheli, C.; Fruttero, R.
Tetrahedron 1999, 55, 5623.
9
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J. AM. CHEM. SOC. 2003, 125, 13243-13251
13243

A R T I C L E S
Koep et al.
Scheme 1. Retrosynthetic Analysis of Unsaturated Bicyclic
Scheme 2. Synthesis of Cyclic Allylic Sulfoximines
Proline Analogues
have gained considerable importance in asymmetric synthesis.8,9
All of these factors have contributed to the ever-growing interest
in the asymmetric synthesis of mono- and bicyclic proline
analogues.4,10 We have been interested in the asymmetric
synthesis of the fused bicyclic proline analogues 1 having a
Z-isomers.13 On the premise of a successful extension of this
amino alkylation to other cyclic bis(allylsulfoximine)titanium
complexes 6 (n ) 1, 3, 4) as well, an asymmetric synthesis of
1 from the monocyclic amino acids 4 was invisioned which
would involve an isomerization of the latter to the allylic
(dimethylamino)sulfoxonium salts 3 following methylation of
the sulfoximine group and a subsequent intramolecular substitu-
tion of the (dimethylamino)sulfoxonium group. Selection of
imino ester 5, whose synthesis we have described recently,13
should allow a facile deprotection of the intermediate N-sulfonyl
protected amino acid 2 with formation of 1.13,14 Although
nothing was known about allylic (dimethylamino)sulfoxonium
salts of type 3 at the outset of our investigations, observations
made15 during a study of the elimination of acyclic 1-alkenyl
(dimethylamino)sulfoxonium salts16 hinted that such a migratory
cyclization of the N-methyl derivative of 4 might perhaps be
feasible. Further support for the feasibility of a cyclization of 3
came from the demonstrated nucleofugacity of the (dimethy-
lamino)sulfoxonium group in aziridine synthesis.17
∆
3a,4-unsaturated carbocyclic ring of different size and an allylic
amine moiety (Scheme 1). Proline analogues of this type were
not known up to now.11 The only exemption being a derivative
of 1 containing a five-membered carbocyclic ring (n ) 1), which
was obtained from an â,γ-unsaturated R-amino acid by using
the Pauson-Khand cycloaddition method.4k Because of the
double bond, proline anlogues 1 should allow the stereoselective
synthesis of various derivatives which are not or only difficult
accessible thus far. In addition, access to 1-substituted and 1,3-
or 1,4-disubstiuted derivatives can perhaps be provided through
application of deprotonation methodologies12 to suitable N-
protected derivatives of 1 (vide infra). Hence, proline analogues
1 could not only serve as starting material for the synthesis of
new biologically active amino acids and peptidomimetics but
may perhaps also contribute to the development of improved
catalysts and auxiliaries.
Results and Discussion
We had recently observed that treatment of the six-membered
cyclic bis(allylsulfoximine)titanium complex ent-6 (n ) 2) with
the N-tert-butylsulfonyl imino ester 5 gave with high regio- and
diastereoselectivity the sulfoximine substituted, γ,δ-unsaturated
amino acid derivative ent-4 (n ) 2) as a mixture of E- and
Synthesis of Cyclic Allylic Sulfoximines. The known cyclic
allylic sulfoximines 9a, 9b, and ent-9d18 were prepared from
the sulfoximines 7 and ent-7 (g 99% ee),19-21 respectively and
the corresponding cycloalkanones in yields of 58-74% by using
an improved procedure described recently,22 which does not
require the isolation of any intermediate including the 1-alkenyl
sulfoximines 8a, 8b, and ent-8d (Scheme 2).
(8) For reviews, see: (a) Itsuno, M. Org. React. 1998, 52, 395. (b) Corey, E.
J.; Helal, C. J. Angew. Chem. 1998, 110, 2092; Angew. Chem., Int. Ed.
Engl. 1998, 37, 1986. (c) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.;
Enders, D. Tetrahedron 2002, 58, 2253. (d) List, B. Tetrahedron 2002,
58, 5573.
Similarly, the new eight-membered cyclic sulfoximine 9c23
was obtained from 7 and cyclooctanone without isolation of 8c
(9) For selected recent examples, see: (a) Laabs, S.; Munch, W.; Bats, J. W.;
Nubbemeyer, U. Tetrahedron 2002, 58, 1317. (b) Amedijkouh, M.; Ahlberg,
P. Tetrahedron: Asymmetry 2002, 13, 2229. (c) Bogevig, A.; Juhl, K.;
Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem. 2002,
114, 1868; Angew. Chem., Int. Ed. Engl. 2002, 41, 1790. (d) Corey, E. J.;
Shibata, T.; Lee, T. W.; J. Am. Chem. Soc. 2002, 124, 3808. (e) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124,
827.
(10) (a) Genin, M. J.; Baures, P. W.; Johnson, R. L. Tetrahedron Lett. 1994,
35, 4967. (b) Pyne, S. G.; Javidan, A.; Skeleton, B. W.; White, A. H.
Tetrahedron 1995, 51, 5157. (c) Mazzini, C.; Sambri, L.; Regeling, H.;
Twanenburg, B.; Chittenden, G. J. F. J. Chem. Soc., Perkin Trans. 1 1997,
3351. (d) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 3, 759. (e)
Shireman, B. T.; Miller, M. J.; Jonas, M.; Wiest, O. J. Org. Chem. 2001,
66, 6046.
(13) Schleusner, M.; Gais, H.-J.; Koep, S.; Raabe, G. J. Am. Chem. Soc. 2002,
124, 7789.
(14) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62, 8604.
(15) Reddy, L. R.; Gais, H.-J., unpublished results.
(16) Reddy, L. R.; Gais, H.-J.; Woo, C.-W.; Raabe, G. J. Am. Chem. Soc. 2002,
124, 10427.
(17) Johnson, C. R.; Lockard, J. P.; Kennedy, E. R. J. Org. Chem. 1980, 45,
264.
(18) Gais, H.-J.; Mu¨ller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe, G. J.
Am. Chem. Soc. 1995, 117, 2453.
(19) Fusco, R.; Tericoni, F. Chem. Ind. (Milan) 1965, 47, 61.
(20) Johnson, C. R.; Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973,
95, 7424.
(21) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(22) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe, G.;
Runsink, J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo,
R.; Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 24, 3973.
(23) Reddy, L. R.; Gais, H.-J.; Babu, S., unpublished results.
(11) For saturated analogues of 1, see: ref 4a, 4d and 5a.
(12) (a) Wirth, T. In Organic Synthesis Highlights IV; Schmalz, H.-G., Ed.;
Wiley-VCH: Weinheim, 2000; p 26. (b) Whisler, M. C.; Beak, P. J. Org.
Chem. 2003, 68, 1207.
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Unsaturated, Fused Bicyclic Proline Analogues
A R T I C L E S
Scheme 3. Amino Alkylation of Cyclic Bis(allylsulfoximine)-
titanium Complexes
Figure 1. Structure of Z-4c in the crystal.
CR-atom and Câ-atom (vide infra). Thus, it is proposed that
R-amino acid derivatives E-4a-c and Z-4a-c all have the same
configuration at the CR-atom and Câ-atom.
Table 1. Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium
Complexes 6 With Imino Ester 5.
Stereochemical Consideration of the Amino Alkylation.
On the basis of the synthesis, structure, dynamics, and reactivity
of acyclic bis(allylsulfoximine))titanium complexes22 and the
similar stereochemical course of the reaction of both the
acyclic13 and the cyclic titanium complexes with 5, the following
is proposed for the conversion of 9a-c into E-4a-c and Z-4a-c
and of ent-9d into ent-E-4d and ent-Z-4d. First, titanation of
the lithio derivative of 9 with ClTi(Oi-Pr)3 leads to a mixture
of the diastereomeric complexes (R,R)-6 and (S,S)-6 and
equimolar amounts of Ti(Oi-Pr)4 (Scheme 4). Second, these
complexes are configurationally labile in regard to the CR-atoms
and their reaction with 5 is slower than their equilibration, a
situation which can be described by the Curtin-Hammett
principle.24 Third, transfer of the allylic moieties of 6 to 5 occurs
stepwise with the intermediate formation of the mixed mono-
(allylsulfoximine)titanium complexes R,E-10 and R,Z-10, which
are also configurationally labile in regard to the CR-atom and
are thus in equilibrium with their stereoisomers S,E-10 and S,Z-
10, respectively. Fourth, asymmetric induction in the stereose-
lective generation of the CR-atom and Câ-atom of E/Z-4 is
provided by the sulfoximine group and not by the CR-atom
because of the configurational lability of the latter.
To rationalize the E/Z-stereoselectivities of the reaction of 6
with 5 in dependence of the ring size, the two Si,Re chairlike
six-membered cyclic transition state models TS-1 and TS-2 are
proposed for the transfer of the first allylic moiety. Similar
transition state models have been put forward previously to
rationalize the stereochemistry of the reaction of similar acyclic
bis(allylsulfoximine)titanium complexes with 5.13 In TS-1 and
TS-2 the imino ester and the sulfoximine group are coordinated
through their N-atoms to the Ti-atom, and the tert-butylsulfonyl
and the ester group both occupy pseudoaxial positions. The
major and decisive differences between the Si,Re transition state
models TS-1 and TS-2 and the analogous Re,Si transition state
models TS-3 and TS-4, which would lead to the formation of
the diastereomers of E/Z-4 having the opposite configurations
at both stereogenic C-atoms, are the positions of the S-phenyl
groups. In TS-1 and TS-2 the phenyl groups are placed in
sterically less encumbered positions than in TS-3 and TS-4 thus
making the former transitions states lower in energy. In
E
Z
allylic
sulfoximine
amino acid
derivative
a
E:Z
yield (%) dea(%) yield (%) dea(%)
6a
E-4a/Z-4a
1.3-1.4:1
43
56
25
7
g98
g98
g98
g98
25
13
72
78
g98
g98
g98
g98
ent-6d ent-E-4d/ent-Z-4d 4.6-5.3:1
6b
6c
E-4b/Z-4b
E-4c/Z-4c
1:2.7-2.8
1:11-13
a Determined by H NMR spectroscopy of the crude reaction mixture.
1
in 79% overall yield, based on 7. The S-phenyl derivatives 9a-c
and ent-9d were selected for the synthesis of 1 because of the
extreme ease of the attainment of 7 and ent-7 in enantiomerically
pure form.21
Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium
Complexes. We were pleased to see that the successive
treatment of the allylic sulfoximines 9a-c with n-BuLi, 2.1
equiv of ClTi(Oi-Pr)3 and imino ester 513 gave mixtures of the
E- and Z-configured R-amino acid derivatives E-4a-c and
Z-4a-c, respectively, in good yields (Scheme 3, Table 1).
Similarly, a mixture of ent-E-4d and ent-Z-4d was prepared as
described previously from the allylic sulfoximine ent-9d and
5.13 Crystallization and chromatography of the mixtures of the
E- and Z-diastereomers allowed for the isolation of the pure
amino acid derivatives. The diastereoselectivities of the forma-
tion of both the Z- and E-isomers were in all cases high (g98%
de) as indicated by NMR spectroscopy of the crude reaction
mixtures and independent of the ring size of the allylic
sulfoximine. Interestingly, the E/Z ratios changed from 1.3 to
1.4:1 for the five-membered cyclic 1-alkenyl sulfoximine 4a to
1:11-13 for the eight-membered cyclic 1-alkenyl sulfoximine
4c. Assignment of the configurations of the double bond of the
isomers was made by NOE experiments, which revealed for
the E-isomers strong NOE effects between the olefinic proton
and the allylic proton at the stereogenic center whereas for the
Z-isomers strong NOE effects between the olefinic proton and
an allylic proton of the methylene group were observed.
The absolute configuration of ent-E-4d had already been
established by X-ray crystal structure analysis.13 A X-ray crystal
structure analysis of Z-4c showed it to have the absolute
configuration depicted in Figure 1. Thus, both compounds have
the same relative configurations at the S-atom, CR-atom and
Câ-atom. In addition, chemical correlation showed that isomers
ent-E-4d and ent-Z-4d both have the same configuration at the
(24) (a) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111. (b) Seeman, J. I. Chem.
ReV. 1983, 83, 83.
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13245

A R T I C L E S
Koep et al.
Scheme 4. Stereochemical Rationalization of the Amino Alkylation
an activation of the bis(allyl)titanium complex by Ti(Oi-Pr)4
and for the second step that of the mono(allyl)titanium complex
by ClTi(Oi-Pr)3.13 We have proposed that the role played by
these Lewis acids may be that of a coordination to the N-atom
of the sulfoximine group25 of the mono- and bis(allyl)titanium
complexes, thereby creating a free coordination site at the Ti-
atoms for the coordination of 5.13 Because we assumed that the
cyclic complexes 6 and 10 would require a similar activation
by the Lewis acids, 2 equiv of ClTi(Oi-Pr)3 were used from
the start in the synthesis of 4.
Migratory Cyclization of 4-(Dimethylamino) 1-Alkenyl
Sulfoxonium Salts. Treatment of the 1-alkenyl sulfoximines
16
ent-E-4d, ent-Z-4d, and Z-4c with Me3OBF4 in CH2Cl2 at
ambient temperature for 1.5 h afforded the 1-alkenyl (dimethy-
lamino)sulfoxonium salts ent-E-11a, ent-Z-11a, and Z-11b,
respectively, in essentially quantitative yields (Scheme 5). The
methylation reagent has to be free of HBF4 because of an
otherwise occurring protonation of the starting sulfoximine,
which prevents its complete conversion. As hoped for, treatment
of the E-configured sulfoxonium salt ent-E-11a with 1.1 equiv
of DBU at ambient temperature gave the protected bicyclic
R-amino acid ent-2a in 80% yield (Table 2). The relative
configuration of ent-2a was determined through a combination
of 1H NMR spectroscopy and NOE experiments which revealed
a strong NOE effect between 1-H and 7a-H and between 7a-H
and 6-Haxial (Figure 2). According to the magnitudes of the
vicinal coupling constants and the NOE’s the cyclohexene ring
of ent-2a adopts a half-chair conformation and the sulfonyl
group a N-S conformation where the tert-butyl group is placed
in the anti position to the ester group. Because of the formation
of mixtures of E- and Z-isomers in the reaction of the titanium
complexes 6a-c and ent-6d with 5, it was of particular
importance to see whether the Z-isomer ent-Z-4d could also be
converted to ent-2a. To this end the Z-configured salt ent-Z-
11a was treated with DBU under the same conditions, which
also furnished ent-2a in 76% yield.
The formation of ent-2a from both the Z-isomer ent-Z-4d
and the E-isomer ent-E-4d also proves that both have the same
configuration at the CR-atom and Câ-atom. Finally, the cy-
clization of the eight-membered cyclic sulfoxonium salt Z-11b
was studied. Gratifyingly, treatment of Z-11b with DBU
afforded the bicyclic amino acid 2b in 81% yield. The bicyclic
amino acids were obtained as single diastereomers. No epimer-
ization at the C1-atom with formation of the more stable trans
isomers had taken place during treatment with the base.
Cyclization of salt ent-E-11a could also be achieved upon
treatment with 1.1 equiv of freshly prepared LiN(H)t-Bu first
at -78 °C and then at ambient temperature, which gave ent-2a
in 77% yield.
In the cyclizations described above, the sulfinamides 12 and
ent-12,16 respectively, were isolated in 74-76% yield as a
further reaction product. GC analysis showed them to be of
g99% ee. We had already shown that treatment of 12 with
MeMgCl in THF at -78 °C afforded (S)-methyl phenylsulfoxide
of g99% ee in 93% yield.23 This sulfoxide can easily be
converted to sulfoximine 7 of g99% ee.19,20,26
comparing TS-1 and TS-2, the major difference between both
is the position of the sulfoximine group, being pseudoequatorial
in the first and pseudoaxial in the second. The sulfoximine group
is expected to cause in TS-1 a destabilizing 1,2-interaction with
the methylene groups of the unsaturated ring and in TS-2 a
destabilizing 1,3-interaction with the tert-butylsulfonyl group.
It is proposed that in the case of small rings (n ) 1, 2) the
1,2-interaction is less destabilizing than the 1,3-interaction, while
in the case of larger rings (n ) 3, 4) it is vice versa. Hence, in
the reaction of 5 with 6, n ) 1 and 2, the (R,R)-configured
complex is more reactive giving via TS-1 preferentially E-4,
whereas with 6, n ) 3 and 4, it is the (S,S)-configured complex
which has the higher reactivity yielding via TS-2 preferentially
Z-4. Similar transition state models (not depicted in Scheme 4)
and arguments can be applied to the reaction of the mono-
(allylsulfoximine)titanium complexes E-10 and Z-10 with 5.
We had previously observed that the reaction of acyclic
complexes of type 6 with 5 requires for the first step to occur
It is assumed that the DBU induced formation of ent-2a and
2b starts with a regioselective isomerization of the 1-alkenyl
(25) For reviews on sulfoximines, see: (a) Pyne, S. G. Sulfur Reports 1999,
21, 281. (b) Reggelin, M.; Zur, C. Synthesis 2000, 1, 1.
(26) Bach, T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 1033.
9
13246 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Unsaturated, Fused Bicyclic Proline Analogues
A R T I C L E S
Table 2. Synthesis of Unsaturated Bicyclic Proline Analogues.
Scheme 5. Cyclization of 4-Amino 1-Alkenyl Sulfoximines
sulfoxonium
salt
proline
analog
yield
(%)
dea
(%)
sulfinamide
yield
(%)
ee
(%)
b
b
ent-E-11a
ent-Z-11a
Z-11b
ent-2a
ent-2a
2b
80
76
81
g98
g98
g98
ent-12
ent-12
12
76
b
74
g99
a Determined by 1H NMR spectroscopy of the reaction mixture. bNot
determined.
Figure 2. NOE’s of ent-2a.
pKa of 33, that of the corresponding (dimethylamino)sulfoxo-
nium salt is 14.4,27a and the acidity of the allylic sulfoxonium
salts ent-3a and 3b are expected to be even higher because of
the additional double bond. As the final step of the cyclization,
we propose an intramolecular substitution of the allylic sul-
foxonium group of ent-3a and 3b following deprotonation with
DBU at the N-atom. The nucleofugacity of the (dimethylamino)-
sulfoxonium group attached to an alkyl group toward N-
nucleophiles has already been demonstrated in the synthesis of
aziridines from 1-alkenyl (dimethylamino)sulfoxonium salts and
primary amines17 and the (dimethylamino)sulfoxonium group
located in an allylic position should have even a higher
reactivity.28
Somewhat surprising was the formation of ent-2a in the
reaction of salt ent-E-11a with 1.1 equiv of the strong base LiN-
(H)t-Bu. On the basis of the reaction of the δ-silyloxy alkenyl
sulfoxonium salt 14 with LiN(H)t-Bu, formation of the isomer
13 would have been expected (Scheme 6). Salt 14 reacts with
the lithium amide under deprotonation at the R-position to give
the ylide 15 which suffers an elimination of sulfinamide 12 with
formation of the alkylidene carbene 16.16 The later undergoes
cyclization and 1,2-silyl migration to give the 2,3-dihydrofuran
derivative 17. The lack of an analogous formation of 13 from
salt ent-E-11a via alkylidene carbene formation and cyclization
of the latter may perhaps be due to the unique properties of the
sulfonamide group of ent-E-11a. It is not only acidic but also
positioned in close spatial proximity to both the olefinic and
the two allylic H-atoms of ent-E-11a. The six-membered ring
of sulfoximine ent-E-4d, the starting material for the synthesis
of salt ent-E-11a, adopts in the crystal and in solution a
conformation in which the allylic substituent is placed in a
pseudoaxial position.13 Thus, it is assumed that salt ent-E-11a
adopts preferentially a similar conformation in solution. Depro-
tonation of salt ent-E-11a with LiN(H)t-Bu can take place either
at the N-atom or at the double bond. Deprotonation of ent-E-
11a at the double bond would give ylide 18,16 which could suffer
an intramolecular proton transfer from the N-atom to the C-atom
(dimethylamino)sulfoxonim salts ent-E-11a, ent-Z-11a and
Z-11b, respectively, leading to the novel allylic (dimethylami-
no)sulfoxonium salts ent-3a and 3b, respectively. Isomerization
of the sulfoximines ent-8d and 8c to the allylic sulfoximines
ent-9d and 9c, respectively, already is a facile process (cf.
Scheme 2) and that of the sulfoxonium salts ent-E-11a, ent-Z-
11a, and Z-11b should be even more facile because of the much
stronger acidifying effect of the (dimethylamino)sulfoxonium
group.27a,b For example, while sulfoximine 7 has an estimated
(27) (a) Bordwell, F. G.; Branca, J. C.; Johnson, C. R.; Vanier, N. R. J. Org.
Chem. 1980, 45, 3884. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(c) Kravtsov, D. N.; Peregudov, A. S.; Petrov, E. S.; Terekhova, M. I.;
Shatenstein, A. I. Bull. Acad. Sci. USSR 1981, 30, 993.
(28) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry: Reactions,
Mechanisms, and Structure; Wiley: New York, 2001.
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13247

A R T I C L E S
Koep et al.
Scheme 6. Reaction of 1-Alkenyl Aminosulfoxonium Salts With
LiN(H)t-Bu
Figure 3. Calculation of model compounds.
Scheme 7. Deprotection of ent-2a
sulfoxonium salts suggest pKa-values of the former two sul-
foxonium salts in the range of 10-20. Because, for example,
N-methyl-phenylsulfonamide has a pKa-value of 17.527c the
crucial proton-transfer reactions depicted in Scheme 6 would
be conceivable. Thus, it is proposed that the isomerization of
the double bond of salt ent-E-11a through an intramolecular
1,3-H-shift mediated by the sulfonamido group is faster than
the R-elimination.
To exclude the notion that the alkylidene carbene pathway
is in fact operating in the reaction of salt ent-E-11a with LiN-
(H)t-Bu and that 13 escapes isolation only because of a base-
catalyzed isomerzation to ent-2a orienting calculations for the
model compounds 22 and 23 have been carried out at both the
B3LYP/6-31+G* and the MP2/6-31+G* level. These calcula-
tions revealed that the enamine 22 is about 2.5-3.1 kcal/mol
more stable than the allylic amine 23 (Figure 3).29 Thus, a
primary formation of 13 in the reaction of ent-E-11a with the
base and its subsequent isomerization to ent-2a with tBuNH2
can be ruled out with a high probability.
Deprotection of N-tert-Butylsulfonyl Amino Acid. The
N-tert-butylsulfonyl imino ester 513 was selected for the
synthesis of the amino acid derivatives 1 and not the corre-
sponding N-tolylsulfonyl derivative30 because of the much easier
deprotection of N-tert-butylsulfonylamines14 as compared to
N-tolylsulfonylamines.14,31 This feature of the tert-butylsulfonyl
group had already been successfully exploited in the deprotec-
tion of acyclic N-tert-butylsulfonyl amino acids of type 4.13 As
anticipated treatment of the amino acid derivative ent-2a with
3.3 equiv of CF3SO3H in CH2Cl2 (0.1 M) at -30 °C for 45
min led to its ready deprotection and afforded the R-amino acid
ester ent-1 in 83% yield (Scheme 7).
Conclusion
We have described a highly selective asymmetric synthesis
of new unsaturated fused bicyclic proline analogues, the key
steps of which are a highly regio- and diastereoselective amino
alkylation of cyclic bis(allylsulfoximine)titanium complexes with
tert-butylsulfonyl imino ester and a novel migratory cyclization
of δ-amino alkenyl sulfoxonium salts. Fortunately, the cycliza-
tion is independent of the configuration of the exocyclic double
with formation of the betaine 19. A subsequent second intramo-
lecular proton transfer in 19 from the allylic position to the
N-atom would yield the allylic ylide 20 which then could
undergo a third proton transfer from the N-atom to the C-atom
with formation of the betaine 21. Finally, betaine 21 should
cyclize with formation of ent-2a and ent-12. The alternative
deprotonation of salt ent-E-11a at the N-atom would directly
give betaine 19.
(29) A detailed computational study is currently carried out in our laboratories
and a full account of the research will be published elsewhere.
(30) Tschaen, D. H.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984, 49, 5058.
(31) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis;
Wiley: New York, 1991.
Although the pKa-values of 2-alkenyl and 1-alkenyl (di-
methylamino)sulfoxonium salts have not been determined yet,
estimations27b based on the acidity of alkyl (dimethylamino)-
9
13248 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Unsaturated, Fused Bicyclic Proline Analogues
A R T I C L E S
mL of 1.6 M solution in n-hexane, 2.2 mmol) was added dropwise to
a solution of the allylic sulfoximine (2.0 mmol) in THF (20 mL) at
-78 °C. After the mixture had been stirred at -78 °C for 30 min, neat
ClTi(Oi-Pr)3 (4.0 mmol) was added dropwise, and stirring at this
temperature was continued for 30 min. The cooling bath was removed
and the mixture was allowed to stir for 15 min at ambient temperature
for homologization. After cooling the mixture to -78 °C, the imino
ester (2.2 mmol) was added dropwise and the mixture was stirred for
5 h. Then the mixture was allowed to warm to ambient temperature
within 16 h. Saturated aqueous (NH4)2CO3 (150 mL) was added, and
the mixture was stirred at ambient temperature for 30 min. Then the
mixture was extracted with EtOAc (150 mL) and the combined organic
phases were dried (MgSO4) and concentrated in vacuo. The remaining
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 g98%
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 g98% de (1H NMR).
bond. Although the synthesis has been completed only for the
six- and eight-membered fused proline analogues, we are
confident that the five- and the seven-membered analogues can
also be obtained. The allylic (dimethylamino)sulfoxonium group
seems to be endowed with a high nucleofugacity. The nucle-
ofuge, the (dimethylamino)sulfoxonium group, can be isolated
as N,N-dimethylphenylsulfinamide of g 99% ee and converted
in two steps to the sulfoximine used as the starting material for
the synthesis of the cyclic allylic sulfoximines. The value of
the N-tert-butylsulfonyl imino ester is again demonstrated by
the ready cleavage of the N-tert-butylsulfonyl protected bicyclic
amino acid to give the parent amino acid derivative.
Experimental Section
General. The allylic sulfoximines 9a-d of g99% ee were synthe-
sized from sulfoximines 7 and ent-7, respectively,18,23 by using the
procedure described previously.22 Sulfoximines 7 and ent-7,19-21 imino
ester 5,13 the amino acid derivatives ent-E-4d and ent-Z-4d,13 and ClTi-
General Procedure for the Synthesis of the Aminosulfoxonium
Salts ent-E-11a, ent-Z-11a and Z-11b (GP2). The sulfoximine (1
mmol) and Me3OBF4 (1.1 mmol) were placed at ambient temperature
in a Schlenk flask, which was then consecutively evacuated and refilled
with dry argon three times. Then CH2Cl2 (30 mL) was added and the
mixture was stirred at ambient temperature for 90 min. Subsequently
water (20 mL) was added and stirring at ambient temperature was
continued for 10 min. The mixture was extracted with CH2Cl2 and the
combined organic phases were dried (MgSO4) and concentrated in
vacuo to give the salt admixed with approximately 5% (1H NMR) of
the starting material. The salt was used without further purification for
the cyclization step.
(Oi-Pr)3 of g96% purity (1H NMR) were prepared according to the
32
literature. All reactions were carried out in absolute solvents under an
argon atmosphere with syringe and Schlenk techniques in oven-dried
glassware. THF and Et2O were distilled under argon from lead/sodium/
benzophenone, and CH2Cl2 was distilled from CaH2. Me3OBF4, which
was prepared according to the literature,33 was thoroughly washed with
several portions of absolute CH2Cl2 and absolute Et2O in order to
remove HBF4, dried by passing a stream of argon through the filter
cake, and stored at 2 °C under argon. Reagents were obtained from
commercial sources and used without further purification unless
otherwise stated. Column chromatography: silica gel 60, 0.063-0.200
mm. HPLC was performed with LiChrosorb Si 60, 250 × 25 mm, 7
µm. Melting points are uncorrected. Optical rotations were measured
at approximately 22 °C. Specific rotations are in grad‚mL/dm‚g, and c
General Procedure for the Synthesis of the Bicyclic Proline
Analogues ent-2a and 2b (GP3). To a solution of the freshly prepared
(dimethylamino)sulfoxonium salt (1.0 mmol) in THF (20 mL) was
added DBU (165 µL, 1.1 mmol) dropwise at ambient temperature. After
the mixture had been stirred at ambient temperature for 8 h, saturated
aqueous NH4Cl (30 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. The
remaining yellow oil was purified by flash chromatography (Et2O/n-
hexane, 1:1) to afford the protected R-amino acid and the sulfinamide.
(-)-(E,SS,2S,3R)- and (-)-(Z,SS,2S,3R)-(2-(N-Methyl-S-phenyl-
sulfonimidoyl-methylene)-cyclopentyl)-(2-methylpropane-2-sulfony-
lamino)-Acetic Acid Ethyl Ester (E-4a and Z-4a). Following GP1,
the reaction of sulfoximine 9a (1.02 g, 4.3 mmol) with the imino ester
5 (1.05 g, 4.8 mmol) gave a mixture of the crude alkenyl sulfoximines
E-4a and Z-4a in a ratio of 1.3-1.4:1 in approximately 95% chemical
yield (1H NMR). Recrystallization from CH2Cl2/n-pentane afforded E-4a
(851 mg, 43%) of g98% de as colorless crystals. Preparative HPLC
(EtOAc/n-hexane, 4:1) of the mother liquor provided Z-4a (492 mg,
25%) of g98% de as a colorless solid.
E-4a. mp 130 °C; [R]D -48.2 (c 0.33, CDCl3); 1H NMR (400 MHz,
CDCl3) δ 1.21 (t, J ) 7.2 Hz, 3H), 1.29 (s, 9H), 1.54-1.86 (m, 4H),
2.04-2.18 (m, 1H), 2.67 (s, 3H), 2.97-3.05 (m, 1H), 3.06-3.16 (m,
1H), 4.00 (dq, J ) 7.2, J ) 10.7 Hz, 1H), 4.12-4.23 (m, 2H), 4.62 (d,
J ) 9.9 Hz, 1H), 6.47 (s, 1H), 7.49-7.59 (m, 3H), 7.91-7.96 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 14.06 (d), 23.87 (u), 24.09 (d),
26.85 (u), 29.22 (d), 30.34 (u), 50.20 (d), 57.80 (d), 60.26 (u), 61.91
(u), 125.35 (d), 128.82 (d), 129.01 (d), 132.17 (d), 139.38 (u), 159.45
(u), 171.10 (u); IR (KBr) ν 3447 (w), 3116 (m), 2995 (m), 2943 (m),
2880 (s), 2802 (m), 2771 (w), 1733 (s), 1615 (w), 1471 (s), 1448 (m),
1368 (w), 1315 (s), 1244 (s), 1229 (s), 1126 (s), 1097 (s), 1069 (s),
1021 (s) cm-1; MS (EI) m/z 456 (M+, 26), 256 (26), 235 (21), 234
(16), 203 (30), 187 (38), 186 (99), 182 (15), 180 (30), 165 (12), 157
(12), 156 (45), 155 (19), 125 (57), 110 (17), 109 (22), 108 (55), 107
1
is in g/100 mL. H NMR spectra were recorded at 300, 400, and 500
MHz. Chemical shifts (δ) in 1H NMR and 13C NMR spectra are reported
in ppm relative to Me4Si (δ 0.00 ppm). 13C NMR spectra were recorded
at 75, 100, and 125 MHz. Peaks in the 13C NMR spectra are denoted
as “u” for carbons with zero or two attached protons or “d” for carbons
with one or three attached protons, as determined from APT puls
sequence. Assignments in the 1H NMR spectra were made by
GMQCOSY, GNOE, or GTOCSY experiments, and those in the 13C
NMR spectra were made by DEPT, HETCOR, or GHSQC experiments.
IR spectra: only peaks of ν > 1000 cm-1 are listed, s ) strong, m )
medium, and w ) weak. MS: EI, 70 eV; CI, 100 eV, only peaks of
m/z > 80 and an intensity >10%, except decisive ones, are listed.
Elemental analyses were carried out in the Microanalytical Laboratory
of the Institut fu¨r Organische Chemie, RWTH Aachen.
X-ray Analyses. The crystal structure was solved using direct
methods as implemented in the XTAL3.7 package of crystallographic
routines.34,35 The crystal of Z-4d contained severely disordered solvent
molecules. The disorder could not be resolved. Therefore carbon atoms
have been assigned to each of the five highest electron density peaks
from the solvent molecules. The absolute configuration of Z-4d as
depicted in Figure 1 was determined by the method of Flack.36 The
molecular structure was visualized with the program SCHAKAL.37
General Procedure for the Synthesis of Sulfoximine Substituted
R-Amino Acid Derivatives E-4a-c and Z-4a-c (GP1). n-BuLi (1.37
(32) Reetz, M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.;
Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421.
(33) (a) Meerwein, H. Org. Synth. 1966, 46, 120. (b) Curphey, T. J. Org. Synth.
1971, 51, 142.
(34) XTAL 3.7 System, Hall, S. R.; du Boulay, D. J.; Olthof-Hazekamp, R.,
Eds.; Universities of Western Australia and Maryland, Lamb: Perth, 2000.
(35) CCDC 208638 contains the supplementary crystallographic data for this
paper.
(36) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
(37) Keller, E. SCHAKAL 92; Universita¨t Freiburg, Germany, 1992.
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13249

A R T I C L E S
Koep et al.
(17), 106 (17), 102 (56), 81 (11), 80 (16); Anal. Calcd for
C21H32N2O5S2: C, 55.24; H, 7.06; N, 6.13. Found: C, 54.91; H, 6.95;
N, 6.10.
amino)-Acetic Acid Ethyl Ester (Z-4c and E-4c). Following GP1,
the reaction of sulfoximine 9c (1.278 g, 4.6 mmol) with the imino ester
5 (1.120 g, 5.1 mmol) gave a mixture of the crude alkenyl sulfoximines
Z-4c and E-4c in a ratio of 11-13:1 in approximately 95% chemical
yield (1H NMR). Recrystallization from CH2Cl2/n-pentane afforded Z-4c
(1.797 g, 78%) of g 98% de as colorless crystals. Preparative HPLC
(EtOAc/n-hexane, 4:1) of the mother liquor provided E-4c (163 mg,
7%) of g 98% de as a colorless oil.
Z-4a. mp 52 °C; [R]D -150.2 (c 0.37, CDCl3); 1H NMR (400 MHz,
CDCl3) δ 1.27 (t, J ) 7.2 Hz, 3H), 1.32 (s, 9H), 1.39-1.49 (m, 1H),
1.55-1.67 (m, 1H), 1.70-1.84 (m, 2H), 2.22-2.34 (m, 1H), 2.53-
2.66 (m, 4H), 3.65 (m, 1H), 4.22 (m, 2H), 4.74 (dd, J ) 4.4, J ) 9.9
Hz, 1H), 5.36 (d, J ) 9.9 Hz, 1H), 6.26 (s, 1H), 7.42-7.54 (m, 3H),
7.83-7.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.54 (d), 22.36
(u), 24.63 (d), 28.03 (u), 29.53 (d), 36.13 (u), 44.46 (d), 60.43 (d),
60.68 (u), 62.25 (u), 124.76 (d), 128.91 (d), 129.38 (d), 132.68 (d),
140.43 (u), 161.83 (u), 171.46 (u); IR (KBr) ν 3289 (w), 3061 (w),
2976 (s), 2936 (m), 2874 (m), 2803 (w), 1737 (s), 1631 (m), 1478
(m), 1446 (m), 1368 (m), 1309 (s), 1239 (s), 1148 (s), 1129 (s), 1106
(s), 1081 (m), 1024 (m) cm-1; MS (EI) m/z 456 (M+, 5), 383 (11), 336
(17), 335 (83), 320 (12), 235 (18), 181 (15), 180 (100), 156 (25), 155
(13), 152 (11), 125 (38), 109 (13), 108 (37), 107 (12), 106 (18), 102
(11); Anal. Calcd for C21H32N2O5S2: C, 55.24; H, 7.06; N, 6.13.
Found: C, 55.24; H, 7.29; N, 6.10.
Z-4c. mp 157 °C; [R]D -121.0 (c 0.85, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 0.45-0.60 (m, 2H), 1.14-1.47 (m, 4H), 1.02-1.13, (m, 1H),
1.38 (s, 9H), 1.38 (t, J ) 7.1 Hz, 3H), 1.49-1.59 (m, 1H), 1.72-1.87
(m, 1H), 1.87-1.98 (m, 1H), 2.23-2.35 (m, 1H), 2.36-2.46 (m, 1H),
2.63 (s, 3H), 3.54-3.63 (m, 1H), 4.21-4.31 (dq, J ) 7.1, J ) 10.7
Hz, 1H), 4.31-4.42 (dq, J ) 7.2, J ) 11.0 Hz, 1H), 4.48 (dd, J ) 4.7,
J ) 9.6 Hz, 1H), 5.25 (d, J ) 9.6 Hz, 1H), 6.43 (s, 1H), 7.50-7.62
(m, 3H), 7.90-7.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.60
(d), 23.64 (u), 24.54 (d), 24.82 (u), 27.68 (u), 25.23 (u), 29.39 (d),
33.36 (u), 34.06 (u), 43.39 (d), 60.84 (u), 62.27 (u), 62.58 (d), 129.32
(d), 129.49 (d), 130.05 (d), 132.74 (d), 140.20 (u), 162.79 (u), 171.24
(u); IR (KBr) ν 3676 (w), 3655 (w), 3593 (w), 3447 (w), 3306 (w),
3062 (w), 2928 (s), 2869 (s), 2800 (m), 1735 (s), 1604 (m), 1448 (s),
1385 (m), 1369 (m), 1317 (s), 1228 (s), 1129 (s), 1080 (s), 1025 (m)
cm-1; MS (EI) m/z 498 (M+, 2), 377 (11), 223 (24), 222 (100), 194
(17), 156 (21), 150 (24), 125 (22), 102 (10); Anal. Calcd for
C24H38N2O5S2: C, 57.80; H, 7.68; N, 5.62. Found: C, 57.82; H, 7.99;
N, 5.36.
(-)-(Z,SS,2S,3R)- and (-)-(E,SS,2S,3R)-(2-(N-Methyl-S-phenyl-
sulfonimidoyl-methylene)-cycloheptyl)-(2-methylpropane-2-sulfony-
lamino)-Acetic Acid Ethyl Ester (Z-4b and E-4b). Following GP1,
the reaction of sulfoximine 9b (960 mg, 3.6 mmol) with the imino
ester 5 (887 mg, 4.0 mmol) gave a crude mixture of the alkenyl
sulfoximines Z-4b and E-4b in a ratio of 2.7-2.8:1 in approximately
98% chemical yield (1H NMR). Recrystallization from CH2Cl2/n-
pentane afforded Z-4b (1.279 g, 72%) of g 98% de as colorless crystals.
Preparative HPLC (EtOAc/n-hexane, 4:1) of the mother liquor provided
E-4b (446 mg, 25%) of g98% de as a colorless solid.
1
E-4c. [R]D -70.3 (c 0.19, CH2Cl2); H NMR (400 MHz, CDCl3) δ
0.74-0.89 (m, 2H), 0.92-1.05 (m, 1H), 1.08-1.57 (m, 3H), 1.14 (t,
J ) 7.1 Hz, 3H), 1.22 (s, 9H), 1.57-1.71 (m, 2H), 1.74-1.91 (m,
2H), 2.17-2.28 (m, 1H), 2.34-2.44 (m, 1H), 2.59-2.70 (m, 1H), 2.60
(s, 3H), 3.77-3.93 (m, 3H), 4.33 (d, J ) 10.4 Hz, 1H), 6.24 (m, 1H),
7.44-7.54 (m, 3H), 7.82-7.87 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 14.42 (d), 24.47 (d), 25.59 (u), 26.36 (u), 26.46 (u), 28.24 (u), 29.01
(u), 29.19 (u), 29.60 (d), 52.07 (d), 60.49 (u), 62.00 (u), 62.25 (d),
129.14 (d), 129.50 (d), 129.22 (d), 132.73 (d), 140.44 (u), 160.62 (u),
170.94 (u); IR (KBr) ν 3274 (m), 3061 (m), 2932 (s), 2871 (s), 2802
(w), 1738 (s), 1604 (w), 1446 (s), 1396 (w), 1372 (m), 1313 (s), 1242
(s), 1182 (s), 1131 (s), 1080 (s), 1046 (m), 1024 (m) cm-1; MS (EI)
m/z 498 (M+, 9), 425 (11), 362 (15), 299 (13), 298 (51), 250 (10), 249
(45), 228 (19), 222 (34), 201 (14), 198 (19), 197 (91), 195 (13), 170
(15), 169 (43), 155 (34), 148 (12), 141 (10), 125 (54), 109 (16), 107
(10), 102 (11); Anal. Calcd for C24H38N2O5S2: C, 57.80; H, 7.68; N,
5.62. Found: C, 57.86; H, 7.46; N, 5.40.
1
Z-4b. mp 135 °C; [R]D -159.0 (c 1.01, CH2Cl2); H NMR (400
MHz, CDCl3) δ 0.25-0.40 (m, 1H), 1.00-1.70 (m, 6H), 1.36 (t, J )
7.1 Hz, 3H), 1.37 (s, 9H), 1.91-2.02 (m, 1H), 2.24-2.38 (m, 2H),
2.64 (s, 3H), 3.71-3.79 (m, 1H), 4.19-4.35 (m, 2H), 4.59 (dd, J )
4.3, J ) 9.5 Hz, 1H), 5.45 (d, J ) 9.6 Hz, 1H), 6.50 (s, 1H), 7.51-
7.62 (m, 3H), 7.92-7.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
14.22 (d), 24.22 (d), 25.04 (u), 26.93 (u), 29.11 (d), 30.21 (u), 31.97
(u), 35.38 (u), 42.85 (d), 60.42 (u), 61.19 (d), 61.89 (u), 128.80 (d),
128.94 (d), 131.03 (d), 132.34 (d), 140.12 (u), 161.18 (u), 170.82 (u);
IR (KBr) ν 3125 (w), 3062 (m), 2978 (m), 2923 (s), 2872 (m), 2799
(w), 1738 (s), 1610 (w), 1470 (m), 1447 (m), 1396 (w), 1369 (w), 1342
(m), 1313 (s), 1235 (s), 1207 (s), 1153 (s), 1130 (s), 1114 (s), 1098
(s), 1080 (m), 1016 (m) cm-1; MS (EI) m/z 484 (M+, 3), 363 (12), 209
(17), 208 (100), 180 (19), 156 (12), 136 (24), 125 (15); Anal. Calcd
for C23H36N2O5S2: C, 57.00; H, 7.49; N, 5.78. Found: C, 56.81, H,
7.61, N, 5.65.
(RS)-N,N-Dimethylamino-S-((E,2R,3S)-2-(ethoxycarbonyl-(2-methyl-
propane-2-sulfonyl-amino)-methyl)-cyclohexylidenemethyl)-phenyl-
sulfoxonium-tetrafluoroborate (ent-E-11a). Following GP2, the
reaction of sulfoximine ent-E-4d (311 mg, 0.66 mmol) with Me3OBF4
(108 mg, 0.73 mmol) afforded a mixture (384 mg) of salt ent-E-11a
and sulfoximine ent-E-4d in a ratio of 94:6 (1H NMR) as a colorless
1
E-4b. mp 141 °C; [R]D -115.3 (c 1.29, CH2Cl2); H NMR (400
MHz, CDCl3) δ 1.12 (t, J ) 7.2 Hz, 3H), 1.16-1.31 (m, 11H), 1.46-
1.70 (m, 2H), 1.72-2.08 (m, 5H), 2.61-2.73 (m, 4H), 3.18-3.26 (m,
1H), 3.66-3.78 (m, 1H), 3.85-3.98 (m, 2H), 4.79 (d, J ) 10.4 Hz,
1H), 6.28 (s, 1H), 7.50-7.62 (m, 3H), 7.87-7.95 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.00 (d), 24.00 (d), 25.26 (u), 27.92 (u), 28.39
(u), 29.17 (d), 30.07 (u), 30.17 (u), 52.00 (d), 59.98 (u), 61.38 (u),
61.80 (d), 128.62 (d), 129.07 (d), 132.30 (u), 159.89 (u), 170.33 (u);
IR (KBr) ν 3490 (w),3055 (m), 2990 (m), 2953 (m), 2930 (s), 2901
(m), 2857 (m), 2799 (w), 1755 (s), 1620 (m), 1582 (w), 1447 (s), 1384
(w), 1367 (m), 1321 (s), 1243 (s), 1217 (m), 1189 (m), 1153 (s), 1124
(s), 1109 (s), 1085 (m), 1023 (m) cm-1; MS (EI) m/z 485 ([M+1]+,
37), 411 (11), 333 (15), 332 (40), 285 (34), 284 (100), 262 (14), 232
(11), 231 (59), 215 (21), 214 (79), 213 (21), 210 (18), 209 (15), 208
(77), 184 (50), 183 (100), 182 (21), 181 (47), 180 (12), 156 (23), 141
(18), 136 (36), 135 (13), 134 (39), 125 (62), 117 (11), 109 (15), 107
(24), 106 (14), 105 (11), 102 (47), 93 (11), 91 (20), 80 (14); Anal.
Calcd for C23H36N2O5S2: C, 57.00; H, 7.49; N, 5.78. Found: C, 56.79;
H, 7.76; N, 5.66.
1
oil. H NMR (400 MHz, CDCl3) δ 1.04 (t, J ) 7.1 Hz, 3H), 1.34 (s,
9H), 1.53-1.91 (m, 4H), 1.96-2.08 (m, 1H), 2.28-2.45 (m, 2H), 2.95-
3.04 (m, 1H), 3.11 (s, 6H), 3.34-3.43 (m, 1H), 3.59 (dq, J ) 7.1 Hz,
J ) 10.7 Hz, 1H), 3.73 (dq, J ) 7.2, J ) 10.7 Hz, 1H), 4.30 (t br, J
) 10.4 Hz, 1H), 5.12 (d br, J ) 10.17 Hz, 1H), 6.96 (s br, 1H), 7.79-
7.87 (m, 2H), 7.92-7.98 (m, 1H), 8.11-8.17 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 14.15 (d), 20.56 (u), 24.39 (d), 27.26 (u), 28.52 (u),
29.41 (u), 37.87 (d), 49.89 (d), 57.74 (d), 60.54 (u), 61.96 (u), 114.00
(d), 129.13 (d), 130.75 (u), 131.45 (d), 137.32 (d), 170.10 (u), 176.67
(u).
(RS)-N,N-Dimethylamino-S-((Z,2R,3S)-2-(ethoxycarbonyl-(2-methyl-
propane-2-sulfonyl-amino)-methyl)-cyclohexylidenemethyl)-phenyl-
sulfoxonium-tetrafluoroborate (ent-Z-11a). Following GP2, the
reaction of sulfoximine ent-Z-4d (380 mg, 0.81 mmol) with Me3OBF4
(133 mg, 0.89 mmol) afforded a mixture (468 mg) of salt ent-Z-11a
and sulfoximine ent-Z-4d in a ratio of 93:7 (1H NMR) as a colorless
oil. 1H NMR (400 MHz, CDCl3) δ 0.85-0.98 (m, 1H), 1.29-1.48 (m,
(-)-(Z,SS,2S,3R)- and (-)-(E,SS,2S,3R)-(2-(N-Methyl-S-phenyl-
sulfonimidoyl-methylene)-cyclooctyl)-(2-methylpropane-2-sulfonyl-
9
13250 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Unsaturated, Fused Bicyclic Proline Analogues
A R T I C L E S
2H), 1.36 (t, J ) 7.1 Hz, 3 H), 1.41 (s, 9H), 1.67-1.85 (m, 1 H),
1.94-2.05 (m, 1H), 2.11-2.22 (m, 1H), 2.60-2.78 (m, 2H), 3.08 (s,
6H), 3.49-3.57 (m, 1H), 4.20-4.32 (m, 2H), 4.40 (t, J ) 10.4 Hz,
1H), 5.36 (d, J ) 10.2 Hz, 1H), 7.22 (s, 1H), 7.80-7.88 (m, 2H), 7.90-
7.96 (m, 1H), 8.18-8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
14.05 (d), 19.27 (u), 24.04 (d), 28.62 (u), 29.03 (u), 35.05 (u), 37.42
(d), 41.60 (d), 57.10 (d), 60.30 (u), 62.12 (u), 115.02 (d), 128.74 (d),
130.76 (u), 131.26 (d), 136.84 (d), 169.76 (u), 176.83 (u).
(34); Anal. Calcd for C15H25NO4S: C, 57.12; H, 7.99; N, 4.44. Found:
C, 57.00; H, 8.11; N, 4.40.
(-)-(1S,11R)-2-(2-Methyl-propane-2-sulfonyl)-2,3,5,6,7,8,9,9a-oc-
tahydro-1H-cyclo-octa[c]pyrrole-1-carboxylic Acid Ethyl Ester (2b).
Following GP3, the reaction of sulfoximine Z-11b (645 mg, 1.06 mmol)
with DBU (175 µL, 1.17 mmol) yielded the protected R-amino acid
2b (297 mg, 81%) as a slowly crystallizing white solid and sulfinamide
12 (134 mg, 74%) as a colorless oil. mp 67 °C; [R]365 -60.3 (c 0.39,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J ) 7.1 Hz, 3H, Et),
1.39 (s, 9H, t-Bu), 1.40-1.51 (m, 4H), 1.53-1.75 (m, 4H), 2.06-2.26
(m, 2H, 5-H), 3.26 (m br, 1H, 9a-H), 4.11 (d br, J ) 12.9 Hz, 1H,
3-H), 4.14-4.24 (m, 3H, Et, 3-H), 4.70 (d br, J ) 8.5 Hz, 1H, 1-H),
5.50-5.58 (m, 1H, 4-H); 13C NMR (100 MHz, CDCl3) δ 14.22 (d),
24.32 (d), 24.92 (u), 25.10 (u), 28.23 (u), 29.47 (u), 25.64 (u), 43.13
(d), 54.46 (u), 60.75 (u), 61.27 (u), 65.53 (d), 120.84 (d), 139.03 (u),
170.80 (u); IR (capillary) ν 2979 (s), 2928 (s), 2858 (s), 1743 (s), 1458
(s), 1394 (m), 1373 (m), 1320 (s), 1189 (s), 1153 (s), 1127 (s), 1051
(s) cm-1; MS (CI, isobutane) m/z 344 ([M+H]+, 83), 224 (100); Anal.
Calcd for C17H29NO4S: C, 59.44; H, 8.51; N, 4.08. Found: C, 59.47;
H, 8.33; N, 3.93.
(SS)-N,N-Dimethylamino-S-((Z,1R,2S)-2-(ethoxycarbonyl-(2-methyl-
propane-2-sulfonyl-amino)-methyl)-cyclooctylidenemethyl)-phenyl-
sulfoxonium-tetrafluoroborate (Z-11b). Following GP2, the reaction
of sulfoximine Z-4c (530 mg, 1.06 mmol) with Me3OBF4 (173 mg,
1.17 mmol) afforded a mixture (645 mg) of salt Z-11b and sulfoximine
1
Z-4c in a ratio of 96:4 (1H NMR) as a colorless oil. H NMR (400
MHz, CDCl3) δ 0.72-0.86 (m, 1H), 0.98-1.13 (m, 1H), 1.13-1.26
(m, 1H), 1.27-1.58 (m, 5H), 1.39 (m, 12H), 1.85-2.10 (m, 2H), 2.46-
2.58 (m, 1H), 2.78-2.88 (m, 1H), 3.16 (s, 6H), 3.55-3.65 (m, 1H),
4.26-4.41 (m, 3H), 5.06 (d, J ) 10.2 Hz, 1H), 7.19 (s, 1H), 7.82-
7.89 (m, 2H), 7.91-7.99 (m, 1H), 8.23-8.29 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 14.17 (d), 22.97 (u), 24.09 (u), 24.58 (u), 27.62 (u),
33.61 (u), 35.05 (u), 24.09 (d), 37.39 (d), 44.58 (d), 60.70 (u), 62.51
(u), 62.61 (d), 117.15 (d), 128.78 (d), 131.26 (d), 130.16 (u), 136.85
(d), 169.64 (u), 181.99 (u).
(-)-(1R,9S)-2,3,5,6,7,7a-Hexahydro-1H-isoindole-1-carboxylic Acid
Ethyl Ester (ent-1). To a solution of ent-2a (196 mg, 0.62 mmol) in
CH2Cl2 (27 mL) was added CF3SO3H (20.5 mL of 0.1 M in CH2Cl2)
at -30 °C. After the mixture had been stirred for 45 min at -30 °C,
saturated aqueous NaHCO3 (60 mL) was added. The mixture was
extracted with CH2Cl2 (100 mL) and the combined organic phases were
dried (MgSO4) and concentrated in vacuo. Purification of the remaining
brown oil by flash chromatography (EtOH/n-hexane, 2:1) gave the
R-amino acid ester ent-1 (101 mg, 83%) as a light yellow oil. [R]436
-49.6 (c 0.38, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.92 (dq, J )
13.4, J ) 2.7 Hz, 1H), 1.27 (t, J ) 7.2 Hz, 3H), 1.42-1.56 (m, 1H),
1.78-1.91 (m, 1H), 1.91-2.13 (m, 3H), 2.49 (s br, 1H), 2.79 (s br,
1H), 3.56 (d br, J ) 13.7 Hz, 1H), 3.75 (d br, J ) 13.7 Hz, 1H), 3.96
(d, J ) 8.8 Hz, 1H), 4.08-4.24 (m, 2H), 5.53 (s br, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.34 (d), 22.13 (u), 24.62 (u), 24.72 (u), 42.48
(d), 50.02 (u), 60.36 (u), 63.22 (d), 117.67 (d), 139.39 (u), 174.04 (u);
IR (capillary) ν 3363 (w), 2933 (s), 2859 (s), 1733 (s), 1447 (m), 1370
(-)-(1R,9S)-2-(2-Methyl-propane-2-sulfonyl)-2,3,5,6,7,7a-hexahy-
dro-1H-isoindole-1-carboxylic Acid Ethyl Ester (ent-2a). From ent-
E-11a and DBU: Following GP3, the reaction of sulfoximine ent-E-
11a (384 mg, 0.66 mmol) with DBU (109 µL, 0.73 mmol) yielded the
protected R-amino acid ent-2a (168 mg, 80%) as a slowly crystallizing
white solid and sulfinamide ent-12 (85 mg, 76%) as a colorless oil of
g99% ee. From ent-Z-11a and DBU: Following GP3, the reaction of
sulfoximine ent-Z-11a (468 mg, 0.81 mmol) with DBU (134 µL, 0.89
mmol) provided ent-2a (195 mg, 76%). From ent-E-11a and LiN(H)-
t-Bu: To a solution of freshly distilled tBuNH2 (from CaH2) (52 µL,
0.48 mmol) in THF (5 mL) was added at -78 °C n-BuLi (300 µL,
0.48 mmol of a 1.6 M in n-hexane) dropwise. Then the solution was
allowed to warm to room temperature and stirring was continued for
10 min. The solution of LiN(H)t-Bu was added dropwise at -78 °C to
a solution of ent-E-11a (253 mg, 0.44 mmol) in THF (20 mL). After
the mixture had been stirred at -78 °C for 1 h, it was warmed to room
temperature and stirring was continued for 10 h. Then saturated aqueous
NH4Cl (30 mL) was added and the mixture was extracted with CH2-
Cl2. The combined organic phases were dried (MgSO4) and concentrated
in vacuo. Purification by flash chromatography (Et2O/n-hexane, 1:1)
afforded ent-2a (107 mg, 77%). ent-2a. mp 64 °C; [R]365 -21.5 (c
(w), 1336 (w), 1185 (s), 1102 (m), 1024 (w), 819 (w), 794 (w) cm-1
;
MS (EI) m/z 195 (M+, 10), 123 (10), 122 (100), 94 (30); HRMS calcd
for C11H17NO2 195.125929, found 195.125959.
Acknowledgment. Financial support of this work by the
Deutsche Forschungsgemeinschaft (Collaborative Research
Center “Asymmetric Synthesis with Chemical and Biological
Methods” SFB 380 and Graduate Program “Methods in Asym-
metric Synthesis” GK 440) and the Gru¨nenthal GmbH, Aachen,
is gratefully acknowledged. We thank Dr. Jan Runsink and Dr.
Marcel Schleusner for NOE experiments and Cornelia Ver-
meeren for the HPLC separations.
1
1.11, CH2Cl2); H NMR (400 MHz, CDCl3) δ 0.85-0.97 (dq, J )
13.3, J ) 2.7 Hz, 1H, 7-Hax), 1.27 (t, J ) 7.1 Hz, 3H, Et), 1.38 (s, 9H,
t-Bu), 1.42-1.55 (m, 1H, 6-Hax), 1.81-1.91 (m, 1H, 6-Heq), 1.94-
2.14 (m, 3H, 5-H, 7-Heq), 2.91 (s br, 1H, 7a-H), 4.10-4.24 (m, 3H,
Et, 3-H), 4.26-4.37 (d br, J ) 12.6 Hz, 1H, 3-H), 4.58 (d br, J ) 8.5
Hz, 1H, 1-H), 5.62 (s br, 1H, 4-H); 13C NMR (100 MHz, CDCl3) δ
14.26 (d), 21.55 (u), 24.03 (u), 24.22 (d), 24.45 (u), 43.14 (d), 52.99
(u), 60.70 (u), 61.30 (u), 65.55 (d), 119.69 (d), 135.89 (u), 170.99 (u);
IR (CHCl3) ν 2981 (m), 2938 (s), 2876 (m), 1742 (s), 1480 (m), 1457
(m), 1395 (w), 1376 (w), 1321 (s), 1231 (w), 1193 (s), 1130 (s), 1054
(s), 1023 (m) cm-1; MS (CI, isobutane) m/z 316 ([M+H]+, 100), 196
Supporting Information Available: 1H and 13C NMR spectra
of ent-1. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA030324Y
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13251