Metalated 2-alkenylsulfoximines: Efficient solutions for asymmetric d3-synthons

Article abstract of DOI:10.1021/ja9530735

By starting from the 4,5-dihydro-1,2λ⁶,3-oxathiazole 2-oxides 5 and 6 or their enantiomers, a number of enantiopure acyclic and cyclic 2-alkenyl sulfoximines have been prepared. After deprotonation with n-BuLi and transmetalation with chlorotris(isopropoxy)titanium chloride, these sulfoximines can be γ-hydroxyalkylated to the corresponding γ-hydroxy vinyl sulfoximines with high diastereomeric excesses (≥95% de) irrespective of the nature of the added aldehyde. The cyclopentenyl- and cyclohexenylsulfoximines 50a/51a and 50b/51b are demonstrated as the first examples of highly enantioselective solutions for cyclic d³-synthons. From the X-ray structures of 18e, 21, 59, and 62, it can be deduced that the S(S)/R(S)-configured sulfoximines attack the aldehydes nearly exclusively from their Re/Si faces, respectively. A remarkable property of these systems is that this stereochemical interrelation holds also for reactions with chiral aldehydes (reagent control), although here the achievable stereocontrol depends on the relative configuration of the stereogenic centers in the auxiliary. This is especially true for the cyclohexenylsulfoximines 50b and 51b, which require the same absolute configuration at both the sulfur atom and the carbon atom in the side chain of the amino acid based auxiliary. In the case of this intramolecular matched situation, the stereochemical preferences of the chiral aldehyde can be overcompensated nearly completely. This mutual reinforcement of the two stereogenic centers in the sulfoximine moiety accounts for the high degree of reagent control (≥94% de in the acyclic series, ≥95% de with the five-membered ring systems, and ≥97% de with the cyclohexenylsulfoximines) achievable with these 2-alkenylsulfoximines.

Full text of DOI:10.1021/ja9530735

J. Am. Chem. Soc. 1996, 118, 4765-4777
4765
Metalated 2-Alkenylsulfoximines: Efficient Solutions for
Asymmetric d3-Synthons†
Michael Reggelin,* Heinz Weinberger, Matthias Gerlach, and Reinhard Welcker
Contribution from the Institut fu¨r Organische Chemie der Johann-Wolfgang-Goethe-UniVersita¨t
Frankfurt, Marie-Curie-Strasse 11, D-60439 Frankfurt/Main, Germany
ReceiVed September 6, 1995X
Abstract: By starting from the 4,5-dihydro-1,2λ6,3-oxathiazole 2-oxides 5 and 6 or their enantiomers, a number of
enantiopure acyclic and cyclic 2-alkenyl sulfoximines have been prepared. After deprotonation with n-BuLi and
transmetalation with chlorotris(isopropoxy)titanium chloride, these sulfoximines can be γ-hydroxyalkylated to the
corresponding γ-hydroxy vinyl sulfoximines with high diastereomeric excesses (g95% de) irrespective of the nature
of the added aldehyde. The cyclopentenyl- and cyclohexenylsulfoximines 50a/51a and 50b/51b are demonstrated
as the first examples of highly enantioselective solutions for cyclic d3-synthons. From the X-ray structures of 18e,
21, 59, and 62, it can be deduced that the SS/RS-configured sulfoximines attack the aldehydes nearly exclusively
from their Re/Si faces, respectively. A remarkable property of these systems is that this stereochemical interrelation
holds also for reactions with chiral aldehydes (reagent control), although here the achievable stereocontrol depends
on the relative configuration of the stereogenic centers in the auxiliary. This is especially true for the
cyclohexenylsulfoximines 50b and 51b, which require the same absolute configuration at both the sulfur atom and
the carbon atom in the side chain of the amino acid based auxiliary. In the case of this intramolecular matched
situation, the stereochemical preferences of the chiral aldehyde can be overcompensated nearly completely. This
mutual reinforcement of the two stereogenic centers in the sulfoximine moiety accounts for the high degree of reagent
control (g94% de in the acyclic series, g95% de with the five-membered ring systems, and g97% de with the
cyclohexenylsulfoximines) achievable with these 2-alkenylsulfoximines.
Introduction
W. Roush4 have reached this level of sophistication.5 Methods
involving other metals such as lithium are rather limited with
respect to both stereochemical outcome6 and constitutional
flexibility.7 The major problem with the non-boron compounds
is the poor control of the configurational behavior of involved
The asymmetric transfer of a C-3 fragment using chiral,
aracemic allyl organometallics is one of the most important tools
in modern synthetic chemistry.1 Despite this fact, only few
synthetic methods are available where a reagent-controlled
asymmetric conversion is achieved that is characterized by a
predictable stereochemical outcome irrespective of the nature
of the reacting electrophile. Until now only the allylic boron
reagents introduced by H. C. Brown,2 R. W. Hoffmann,3 and
(4) (a) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339-6348. (b) Roush, W.
R.; Hoong, L. K.; Palmer, A. J.; Straub, J. A.; Palkowitz, A. D. J. Org.
Chem. 1990, 55, 4117-4126. (c) Roush, W. R.; Palkowitz, A. D.; Ando,
K. J. Am. Chem. Soc. 1990, 112, 6348-6359. (d) Roush, W. R.; Hoong, L.
K.; Palmer, M. A. J.; Park, J. C. J. Org. Chem. 1990, 55, 4109-4117. (e)
Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem. 1987, 52,
316-318. (f) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc.
1985, 107, 8186-8190. (g) In a recent paper, the Roush group introduced
a new tartramide which exhibits excellent enantioselectivities with achiral
aldehydes. Furthermore it performs much better with â-alkoxy-substituted
chiral aldehydes than the “first generation allylic tartrates” used so far:
Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60, 3806-3813.
(5) There are a number of alternative chiral boron compounds described
in the literature. In a way, they represent variations on the methods
introduced by the already-mentioned authors. Especially successful examples
are described in the following: (a) Garcia, J.; Kim, B.; Masamune, S. J.
Org. Chem. 1987, 52, 4831-4832. (b) Short, R. P.; Masamune, S. J. Am.
Chem. Soc. 1989, 111, 1892-1894. (c) Corey, E. J.; Yu, C,-M.; Kim, S. S.
J. Am. Chem. Soc. 1989, 111, 5496-5498. With the diacetone glucose
modified 2-alkenyl titanium reagents of M. Riediker and R. O. Duthaler,
aldehydes can be allylated with enantiomeric excesses in the range of 80-
90% ee: (d) Riediker, M.; Duthaler, R. O. Angew. Chem. 1989, 101, 488-
490; Angew. Chem., Int. Ed. Engl. 1989, 28, 494. (e) Duthaler, R. O.; Hafner,
A.; Riediker, M. Pure Appl. Chem. 1990, 62, 631-642. (f) Hafner, A.;
Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. J.
J. Am. Chem. Soc. 1992, 114, 2321-2336.
† Abbreviations used: DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; EA,
ethyl acetate; LDMAN, lithium 1-(dimethylamino)naphthalenide; NBS,
N-bromosuccinimide; SET, single electron transfer.
X Abstract published in AdVance ACS Abstracts, May 1, 1996.
(1) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b)
Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, U.K., 1991; Vol. 2, pp 1-49. (c) Roush, W. R.
in Houben-Weyl E 21; Hoffmann, R. W., Ed.; Thieme: Stuttgart, Germany,
1995; in press.
(2) (a) Racherla, U. S.; Liao, Y.; Brown, H. C. J. Org. Chem. 1992, 57,
6614-6617. (b) Brown, H. C.; Bhat, H. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570-1576. (c) Brown, H. C.; Bhat, H. S.; Randad, R. S. J.
Org. Chem. 1987, 52, 319-320. (d) Brown, H. C.; Bhat, H. S. J. Am. Chem.
Soc. 1986, 108, 293-294. (e) Brown, H. C.; Jadhav, P. K. J. Am. Chem.
Soc. 1983, 105, 2092-2093.
(3) (a) Hoffmann, R. W.; Schlapbach, A. Tetrahedron 1992, 48, 1959-
1968. (b) Hoffmann, R. W.; Niel, G.; Schlapbach, A. Pure Appl. Chem.
1990, 62, 1993-1998. (c) Hoffmann, R. W. Pure Appl. Chem. 1988, 60,
123-130. (d) Hoffmann, R. W.; Dresely, S.; Lanz, J. W. Chem. Ber. 1988,
121, 1501-1507. (e) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986,
119, 2013-2024. (f) Hoffmann, R. W.; Dresely, S. Synthesis 1988, 103-
106. (g) Hoffmann, R. W.; Dresely, S. Angew. Chem. 1986, 98, 186-187;
Angew. Chem., Int. Ed. Engl. 1986, 25, 189. Pioneering work in the field
of chiral, aracemic allyl organometallics and the problem of double
stereodifferentiation: (h) Hoffmann, R. W.; Zeiss, H.-J.; Ladner, W.;
Tabche, S. Chem. Ber. 1982, 115, 2357-2370. (i) Hoffmann. R. W.; Zeiss,
H.-J.; Angew. Chem. 1980, 92, 218-219; Angew. Chem., Int. Ed. Engl.
1980, 19, 218. (k) Herold, T.; Schrott, U.; Hoffmann, R. W.; Schnelle, G.;
Ladner, W.; Steinbach, K. Chem. Ber. 1981, 114, 359-374. (l) Hoffmann,
R. W.; Herold, T. Chem. Ber. 1981, 114, 375-383. (m) Hoffmann, R. W.;
Helbig, W. Chem. Ber. 1981, 114, 2802-2807.
(6) (a) Hoppe, D.; Kra¨mer, T. Angew. Chem. 1986, 98, 171-173; Angew.
Chem., Int. Ed. Engl. 1986, 25, 160-162. (b) Zschage, O.; Schwark, J.-R.;
Hoppe, D. Angew. Chem. 1990, 102, 336-337; Angew. Chem., Int. Ed.
Engl. 1990, 29, 296.
(7) (a) Hoppe and co-workers found a remarkable second-order asym-
metric transformation accompanied by enrichment of a crotyllithium species
which is configurationally stable only in the solid state: (a) Zschage, O.;
Hoppe, D. Tetrahedron 1992, 48, 5657-5666. (b) Hoppe, D.; Zschage, O.
Angew. Chem. 1989, 101, 67-69; Angew. Chem., Int. Ed. Engl. 1989, 28,
69-71.
S0002-7863(95)03073-3 CCC: $12.00 © 1996 American Chemical Society

4766 J. Am. Chem. Soc., Vol. 118, No. 20, 1996
Reggelin et al.
Scheme 1. General Structure of a Chiral 2-Alkenylmetal
Reagent
preparation, which distinguishes the tartrate ester solution from
many other asymmetric d3-synthons, and excellent stereochem-
ical properties expected from a solution which is stereoselective
due to the underlying reaction mechanism. Two obvious
difficulties have to be overcome before this approach can be
successfully applied. The first is the problem of preparing
R-chiral 2-alkenyl organometallics in an enantiopure form, and
the second is associated with the question of how to control
their configurational behavior. Circumventing these obstacles
is by no means trivial, and so the constitutional range of these
type of reagents remains rather small.1,3,12 Despite the fact that
with some of these systems the Hoffmann group achieved 1,3-
chirality tranfer rates close to 100%, there are some major
drawbacks even with these reagents:
metallorganic species. Even in the favorable case of dipole
stabilization,8 racemization competes successfully with elec-
trophile uptake. The development of more robust alternative
methods to the boron-based protocols is therefore quite desirable.
There are two different classes of chiral, aracemic allylic
metal compounds (Scheme 1). The first one relies on chirally
modified ligand spheres so that the CR will not become
stereogenic (RR ) H, Class A), and the second class uses the
effective 1,3-chirality transfer9 process operating in R-chiral
2-alkenylboronates (RR * H, Class B) during their reaction with
aldehydes. The most successful reagents among the chiral
ligated boron compounds are H. C. Brown’s terpene based
reagents and the tartrate ester modified 2-alkenylboronates 2
introduced by W. Roush.
The former reagents exhibit excellent diastereo- and enantio-
selectivities in their reactions with a wide range of achiral
aldehydes (83-99% ee).1a,2d,e In allylboration reactions with
chiral, aracemic aldehydes, these reagents tend to overcompen-
sate the stereochemical preferences of the electrophile to an
extent that is seldom reached by other asymmetric allyl transfer
reagents.2b,c On the other hand, only the parent system (RE and
RZ ) H), as well as the Z- and E-configured crotylboranes (RZ
) Me or RE ) Me) are accessible conveniently (although the
“super base chemistry” that is invoked to prepare the C-4 system
is not without peculiarities).3b
These constitutional restrictions do not apply in principle to
the tartrate ester derived boronates,10 although the overwhelming
majority of applications described in the literature also make
use of allyl- and crotyl-derived systems.11 The major drawback
associated with these reagents is the strong dependence of the
achievable isomeric purity of the γ-hydroxyalkylation products
on the nature of the aldehyde.1,4 Furthermore, their ability to
overcome the asymmetric induction exerted by chiral aldehydes
is rather limited,4b,c and therefore, they do not meet the
requirement for reagent control in the construction of chiral
molecular frameworks.
(1) The control of the absolute configuration at CR is a
problem, persistant especially for the most enantioselective
R-methoxy-substituted compounds.3c
(2) The reactivity of R-substituted boronates is reduced in
comparison to unsubstituted boronates, so often the yields, even
under forced reaction conditions (high pressures), are only
moderate.3c Even more serious is the observation that this effect
is particularly bad in mismatched double stereodifferentiation,13
leading to undesirable kinetic resolution effects. This results
in an increase in the amount of the “wrong” diastereomer
produced in the reaction with the chiral aldehyde that is above
the level of the minor enantiomer in the starting material.3c,14
(3) There is no general entry to this class of compounds, and
therefore, almost every change in the substitution pattern of the
nucleophile entails the necessity to develop a new procedure
for its synthesis.
There was thus a need for a set of reagents combining all the
merits of the R-substituted systems without suffering from their
major drawbacks such as diminished reactivity (especially in
the mismatched situations) and the restrictions in constitutional
flexibility caused in part by the difficult control of the absolute
configuration at CR.
Results and Discussion
By following these lines, we developed a new solution for
asymmetric d3-synthons based on the 2-alkenylsulfoximines 1
and 2 (Scheme 2).15 These allylic sulfoximines can be
conveniently synthesized in enantiomerically pure form via the
homochiral cyclic sulfonimidates 3 and 4 introduced by us in
1992.16 These heterocycles, which can be made in large
scale16,17 starting from valine (R ) i-Pr), leucine (R ) i-Bu),
phenylglycine (R ) Ph), or alanine (R ) CH3) in both epimeric
forms, react with a wide range of carbon nucleophiles with a
clean inversion of the configuration at sulfur.16 These oxathia-
zolidine S-oxides therefore provide an efficient entry to the
desired 2-alkenylsulfoximines whose earlier synthesis in ara-
cemic form was a tedious or impossible task. The alternative
electrophilic imination of the corresponding allylic sulfoxides
by mesitylenesulfonylhydroxylamine (MSH),18 that is known
to proceed with retention of configuration,19 is not suitable here
In this sense, the R-chiral 2-alkenylboronates developed by
R. W. Hoffmann are the logical compromise between ease of
(8) (a) Beak, P.; Becker, P. D. J. Org. Chem. 1982, 47, 3855-3861. (b)
Beak, P.; Reitz, D. B. Chem. ReV. 1978, 78, 275-316.
(9) The frequently used term 1,3-chirality transfer is somewhat mislead-
ing. Chirality is a property of the molecule as a whole, so strictly speaking
it is not correct to assign this term to a process describing the correlated
creation and removal of a stereogenic center at two atoms being separated
by a third one. Nevertheless chirality transfer or transmission of chirality
are well-established terms and so we will use them too as handy shortcuts
for the process described above.
(12) Stu¨rmer, R. Angew. Chem. 1990, 102, 62; Angew. Chem., Int. Ed.
Engl. 1990, 29, 59.
(13) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem. 1985, 97, 1; Angew. Chem., Int. Ed. Engl. 1985, 24, 1. (b) Hoffmann,
R. W. Angew. Chem. 1987, 99, 503-517; Angew. Chem., Int. Ed. Engl.
1987, 26, 489.
(14) (a) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986, 119, 2013-
2024. (b) Hoffmann, R. W.; Schlapbach, A. Tetrahedron 1992, 48, 1959-
1968.
(15) Reggelin, M.; Weinberger, H. Angew. Chem. 1994, 106, 489-491;
Angew. Chem., Int. Ed. Engl. 1994, 33, 444-446.
(16) Reggelin, M.; Weinberger, H. Tetrahedron Lett. 1992, 33, 6959-
6962.
(10) Easy accessable vinylic boronates can be homologized by the
Matteson procedure: (a) Sadhu, K. M.; Matteson, D. S.; Hurst, G. D.;
Kurosky, J. M. Organometallics, 1984, 3, 804-806. See also: (b) Matteson,
D. S.; Majumdar, D. Organometallics, 1983, 2, 1529-1535. (c) Matteson,
D. S.; Ray, R.; Rocks, R. R.; Tsai, D. J. Organometallics, 1983, 2, 1536-
1543. (d) Brown, H. C.; Phadke, A. S.; Bhat, N. G. Tetrahedron Lett. 1993,
34, 7845-7848.
(11) Recent examples: (a) Chen, S.-H.; Horvath, R. F.; Joglar, J.; Fisher,
M. J.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 5834-5845. (b) White,
J. D.; Johnson, A. T. J. Org. Chem. 1990, 55, 5938-5940. (c) An
unsuccessful application is described in a total synthesis of FK 506:
Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583-5601.
(17) Reggelin, M.; Welcker, R. Tetrahedron Lett. 1995, 5885-5886.

Metalated 2-Alkenylsulfoximines
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4767
Table 1. γ-Hydroxyalkylations of the 2-Alkenylsulfoximines
9/epi-9 and 10/epi-10
Scheme 2. Homochiral 2-Alkenylsulfoximines from Cyclic
Sulfonimidates
Scheme 3 γ-Hydroxyalkylations of Acyclic
2-Alkenylsulfoximinesa,b
a To minimize the amount of redundant information in the schemes
and to improve their readability, the following abbreviations for the
auxiliaries have been introduced:
bReagents: (a) MCH2CHdCHR1, (b) TMS-Cl, Me2EtN, (c) n-BuLi,
-78 °C, THF, (d) ClTi(OiPr)3, 0 °C; (e) R2CHO, (f) saturated
(NH4)2CO3.
a From 1H-NMR-spectroscopic analysis of the crude reaction product.
b The detection limit of the NMR method was assumed to be 2%. If a
ds value is given as g98% no other isomer could be detected.
c Characterized by X-ray structural analysis. d The silylated derivative
(21) has been characterized by X-ray.
because of the rapid [2.3] sigmatropic rearrangement (Mislow
rearrangement)20 which leads to their racemization.21
cycloaliphatic, R,â-unsaturated, and aromatic representatives
(Table 1). Moreover we found that the absolute configuration
induced at C-3 and C-4 depends nearly exclusively on the
absolute configuration of the sulfur atom in the auxiliary. From
these results we deduced the following model for the mechanism
of stereoselection (Scheme 4).
Acyclic 2-Alkenylsulfoximines: Synthesis and Asymmetric
γ-Hydroxyalkylation with Achiral and Chiral Aldehydes.
With the homochiral 2-alkenylsulfoximines in hand, we tried
to achieve the asymmetric transfer of a nucleophilic C-3
fragment as exemplified by the reaction of the open chain
sulfoximine 7, which can be synthesized via the cyclic sulfon-
imidate 6 (Scheme 3).16,15 After deprotonation with n-butyl-
lithium the lithiated intermediate can be transmetallated with
chlorotris(isopropoxy)titanium.22 The titanium reagent thus
obtained reacts with aldehydes, yielding the γ-hydroxy vinyl
sulfoximines 8 with excellent control of both the prochirality
of the double bond as well as the absolute configuration of the
newly created stereogenic centers at C-3 and C-4. This is true
for all aldehydes tested including aliphatic, branched aliphatic,
Deprotonation of the neutral compounds 9 or 10 (derived from
18; epi-9 and epi-10 were synthesized via 5, Scheme 2) yields
the lithiated species 11 or 12, which was shown to be
configurationally labile15,23 (see below). The diastereomer
differentiating transmetalation with chlorotris(isopropoxy)tita-
nium should lead to the titanium compounds 13/14 or 15/16.
In the case of their configurational stability, the efficiency of
this differentiation should be conserved in the diastereomeric
excess of the individual titanium compound. Assuming this to
be true, then the addition of the aldehyde should proceed via
the already-mentioned 1,3-chirality transfer and produce the
enantiomerically pure γ-hydroxy vinyl sulfoximines 17/18 or
19/20.
(18) (a) Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda, M.
J. Org. Chem. 1973, 38, 1239-1241. (b) Review: Tamura, Y.; Minami-
kawa, J.; Ikeda, M. Synthesis 1977, 1-17.
(19) Johnson, C. R.; Kirchhoff, R. A.; Corkins, H. G. J. Org. Chem.
1974, 39, 2458-2459.
(20) (a) Bickart, F. W.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow,
K. J. Am. Chem. Soc. 1968, 90, 4869-4876. (b) Hoffmann, R. W.;
Goldmann, S.; Maak, N.; Gerlach, R.; Frickel, F.; Steinbach, G. Chem.
Ber. 1980, 113, 819-830. (c) Goldmann, S.; Hoffmann, R. W.; Maak, N.;
Geueke, K.-J. Chem. Ber. 1980, 113, 831-844.
(21) Beside this stereochemical problem this allyl sulfoxide-allyl
sulfenate rearrangement hampers even the synthesis of racemic 2-alkenyl-
sulfoximines. In the electrophilic imination of allyl phenyl sulfoxide by
MSH the corresponding racemic sulfoximine was obtained with only 29%
yield (Pyne, S. G.; Boche, G. Tetrahedron 1993, 49, 8449-8464).
(22) (a) Reetz, M. T. Top. Curr. Chem. 1982, 106, 1-54. (b) Reetz, M.
T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986.
Therefore in this scheme the decisive step from a stereo-
chemical point of view is the diastereomer differentiation during
transmetalation. This would be the ideal situation in which the
influence of structural properties of the reacting aldehyde is
minimal, thus setting up optimal conditions for a reagent-
controlled reaction.
(23) Gais, H.-J.; Erdelmeier, I.; Lindner, H. J.; Vollhardt, J. Angew. Chem.
1986, 98, 914-915; Angew. Chem., Int. Ed. Engl. 1986, 25, 938.

4768 J. Am. Chem. Soc., Vol. 118, No. 20, 1996
Scheme 4. Mechanistic Considerations
Reggelin et al.
Scheme 6. Stereoconvergence
methylpropanal. In the case of configurational lability, the
carbon atom adjacent to sulfur should no longer be stereogenic,
so that both isomers of the starting material should generate
the same organometallic species 23. Transtitanation, followed
by 1,3-chirality transfer during electrophile uptake will result
in a mixture of the γ-hydroxy vinyl sulfoximines 24 and 25,
whose deviation from 1:1 reflects both the effectiveness of the
diastereomer differentiation and the transmission of chirality.9
If, in contrast, the lithium compound is configurationally
stable on the time scale of the subsequent reaction with the
aldehyde, then the 1:1 ratio of the neutral compounds 22 and
epi-22 should translate into the same ratio for both metalated
forms.27 Therefore the composition of the starting epimeric
mixture should be conserved in the corresponding composition
of the mixture of the product vinylsulfoximines 24 and 25.
What we found indeed was a highly stereoconvergent process
that was compatible with a configurationally labile lithium
intermediate. No trace of isomers of 24 could be detected.
Furthermore NMR studies at -78 °C in THF-d8 followed by
distance geometry calculations (ensemble distance bounds
driven dynamics, ensemble DDD28) on the distance data
obtained from the quantitative analysis of NOESY spectra do
support these conclusions from the chemical experiments.
Details of this work will be published elsewhere.
On the basis of on our current knowledge about the
configurational behavior of the titanium compound, we cannot
rule out the possibility of it being configurationally labile. The
only argument against this is the invariance of the diastereo-
selectivity of the reaction with respect to the structure of the
aldehyde. With a configurationally labile titanium system the
stereochemical outcome depends on the efficiency of diastere-
omer differentiation as effected by the aldehyde. Due to the
different properties (steric demand, electronic structure) of these
aldehydes, one would expect a dependency of the observed
diastereomeric excess on the nature of the electrophile. This
is not the case, and so we prefer the model of a configurational
stable titanium species.
Scheme 5. Open Chain Adducts Characterized by X-ray
Structural Analysis
Indeed we found that all reactions of the titanated species
proceed with complete regio- and diastereocontrol irrespective
of the aldehyde (Table 1).15,24 The relative and the absolute
configurations of the products derived from both epimeric forms
of the starting 2-alkenylsulfoximines have been confirmed by
X-ray structural analysis of 18e and 21 (Scheme 5).15,25
As can be deduced from the 3,4-anti-configuration of the
newly created stereogenic centers, the relatiVe topicity of attack
is as expected from the six-membered ring transition state
model,1,26 like (lk) in both cases. Moreover, the absolute topicity
of the nucleophile/electrophile approach corresponds exclusively
to the absolute configuration at sulfur. The C chirality in the
side chain plays only a minor role here, although this situation
changed with chiral aldehydes as will be discussed below. The
S configuration at sulfur in the starting sulfoximines entails a
Re,Re process, whereas the RS-configured sulfoximines attack
the aldehydes solely from the Si face.
In order to prove the above-mentioned hypothesis concerning
the configurational behavior of the lithium intermediate, we
synthesized the 1-methyl-substituted derivative 22 by reacting
allyllithium with our sulfur(VI) electrophile 5 and trapping of
the intermediate carbanionic species with methyl iodide (Scheme
6). The 1:1 mixture of the silylated methallylsulfoximines 22/
epi-22 was deprotonated as usual, transmetallated with chloro-
tris(isopropoxy)titanium, and reacted with 1.5 equiv of 2-
(27) This argument holds only under the assumption that the reaction
with the titanium electrophile is highly stereoselective. Although there is
evidence for this to be true it is not necessarily the case. Hoppe and co-
workers have observed that the stereochemical outcome of electrophilic
substitution reactions involving benzylic and allylic carbanions is highly
dependent on the nature of the electrophile: (a) Carstens, A.; Hoppe, D.
Tetrahedron 1994, 50, 6097-6108. (b) Hoppe, D.; Carstens, A.; Kra¨mer,
T. Angew. Chem. 1990, 102, 1455-1456; Angew. Chem., Int. Ed. Engl.
1990, 29, 1424-1425. (c) Zschage, O.; Schwark, J.-R.; Kra¨mer, T.; Hoppe,
D. Tetrahedron 1992, 48, 8377-8388. (d) Zschage, O.; Hoppe, D.
Tetrahedron 1992, 48, 8389-8392. For studies on the stereochemistry of
the electrophilic substitution reaction with stannanes see: (e) Fleming, I.;
Rowley, M. Tetrahedron Lett. 1985, 3857-3858. For theoretical work in
the field see: (f) Jemmis, E. D.; Chandrasekhar, J.; Schleyer, P. v. R. J.
Am. Chem. Soc. 1979, 101, 527-537.
(28) (a) Kenmink, J.; van Mierlo, C. P. M.; Scheek, R. M.; Creighton,
T. E. J. Mol. Biol. 1993, 230, 312-322. (b) Mierke, D. F.; Scheek, R. M.;
Kessler, H. Biopolymers 1994, 34, 559-563. For the first application of
ensemble DDD to obtain relative configurations from NOESY data, see:
Reggelin, M.; Ko¨ck, M.; Conde-Frieboes, K.; Mierke, D. F. Angew. Chem.
1994, 106, 822-824; Angew. Chem., Int. Ed. Engl. 1994, 33, 753-755.
(24) In a very recent publication, Gais et al. used N-methylated derivatives
of these titanated 2-alkenylsulfoximines for asymmetric γ-hydroxyalkyla-
tions. Moreover it was demonstrated that the obtained vinyl sulfoximines
can be converted to C-silylated homoallylic alcohols by a stereoselective
nickel-catalyzed rearrangement reaction: Gais, H.-J.; Mu¨ller, H.; Decker,
J.; Hainz, R. Tetrahedron Lett. 1995, 7433-7436.
(25) Structural details of the vinyl sulfoximine 18e (CSD-57981) have
been published: Berger, B.; Bolte, M. Acta Crystallogr. 1994, C50, 1281-
1282. The corresponding data for the compounds 21, 59, and 62 will be
submitted to Acta Crystallogr. and are part of the supporting information.
(26) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1989, 111, 1236-1240.

Metalated 2-Alkenylsulfoximines
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4769
In summary, the chiral sulfonimidoyl moiety provides an
allylic carbon nucleophile with all the properties needed to make
it a powerful instrument of stereocontrol in reactions with
aldehydes.
Scheme 7. Reagent Control: Acyclic Sulfoximinesa-c
(1) It acidifies the R-hydrogens to allow for easy deproto-
nation.
(2) It guarantees the configurational lability of the generated
organolithium compound as far as the stereogenic CR is
concerned while maintaining the configurational integrity of the
double bond (if RZ, RE * H).29
(3) The auxiliary is fixed at a pseudoaxial position in the
transition state involving reactions with a carbonyl compound
by interaction with the metal to ensure the uniform prochirality
of the developing double bond between C-1 and C-2 and the
absolute configurations at C-3 and C-4 (both aspects of
stereocontrol are interrelated by the transition state model).1b,3e
(4) It exerts excellent asymmetric induction.
(5) The nature of the auxiliary is such that the constitutional
flexibility of the starting material is maximal. This includes
the possibility to incorporate the allylic moiety into a carbocyclic
ring system as discussed below.
Acyclic 2-Alkenylsulfoximines: Reactions with r-Chiral
Lactaldehydes. On the basis of on this analysis and the results
from the achiral aldehyde addition experiments described above,
we expected the addition of chiral, aracemic aldehydes to be
insensitive to the chirality sense of the electrophile. To prove
a The terms im and imm denote intramolecular matched and
intramolecular mismatched relative configurations in the auxiliary. In
the matched case with both stereogenic centers (located at the S atom
of the sulfoximine and the C atom of the valine moiety) having the
same sense of chirality, mutual reinforcement of the asymmetric
induction exerted by the auxiliary takes place and a maximum of
stereocontrol is achieved (see 28/29 and 32/33). In the intramolecular
mismatched case (imm), the two centers interact in an unfavorable way
which leads to diminished stereocontrol. This latter case is particularly
obvious for the anti-Cram products 30 and 31. b Uncomplete isolation.
c Reagents: (a) n-BuLi, -78 °C, THF, (b) ClTi(OiPr)3, 0 °C, (c) 34 or
ent-34, (d) saturated (NH4)2CO3.
30
this hypothesis we reacted the SS and RS configured allylic
sulfoximines 9 and epi-9, as well as the corresponding E-
crotylsulfoximines 10 and epi-10 with both antipodes of the
TBS-protected 2-hydroxypropanals 34 and ent-34 (Scheme 7).
As expected from the results with the achiral aldehydes, the
configuration of the stereogenic centers at C-3 and C-4 in the
resulting vinyl sulfoximines 26-33 is again dominated by the
sense of chirality of the sulfur atom in the starting sulfoximine.
In all cases the RS/SS-configured nucleophiles attack the
aldehyde predominantly from the Si/Re face, respectively. A
closer look at the diastereoselectivities given in Scheme 7 reveals
the following details:
Scheme 8. Fluoride-Induced Cyclization
(1) As expected, the highest de values (g98%) are observed
in the cases where the facial selectivity of the sulfoximine
reagent matches the 1,2-asymmetric induction exerted by the
aldehyde (intermolecular matched pair, Cram products 26, 27
and 32, 33).
(2) The lowest level is observed in those intermolecular
mismatched situations (anti-Cram) in which the relative con-
figuration of the two stereogenic centers in the auxiliary is unlike
(ul; 30, ds ) 80%; 31, ds ) 84%). In the remaining two cases,
the high level of reagent control (de ) 94% for the anti-Cram
product 28 and de g 98% for the anti-Cram product 29)
observed is obviously related to the like stereochemistry (here
SS, SC) in the sulfoximines 9 and 10. In this case both
stereogenic centers contribute in a synergistic manner to the
overall diastereofacial selectivity of the nucleophile. It is
therefore this mutual reinforcement (intramolecular matched
generality of the method. All possible absolute configurations
of the two stereogenic centers in the allyl-based addition
products and all four 3,4-anti-configured isomers of the crotyl-
based systems can be prepared with at least 94% ds irrespective
of the sense of chirality in the electrophile (reagent control).
The vinyl sulfoximines 26-33 were isolated as highly viscous
oils, and therefore, no single crystals suitable for X-ray structural
analysis could be obtained. In the course of our efforts to
determine their absolute configuration by alternative means, we
found a new fluoride-induced cyclization reaction31 that lead
to highly substituted tetrahydrofurans which are structurally
related to muscarine derivatives (Scheme 8).
i
situation, m) that enables the system to overcompensate the
stereochemical preferences of the aldehyde (see also below).
Since this intramolecular matched situation can be generated
easily by a proper choice of the stereochemistry in the amino
acid part of the auxiliary, there are no restrictions on the
It is known from extensive 13C-NMR spectroscopic studies
on muscarine derivatives that the chemical shifts of the 5-methyl
group as well as C-4 are sensitive to the relative configuration
at C-5 and C-4.32 In the 4,5-cis derivatives both carbons
resonate ca. 4 ppm upfield from their counterparts in the
corresponding 4,5-trans-configured compounds. In order to take
(29) The prochirality of the double bond determines the relative topicity
of the nucleophile/electrophile approach and plays therefore a major role
in the control of the relative configuration at C-3 and C-4 in the addition
product.
(30) The terms SX and RX are descriptors used to describe the sense of
chirality (S or R) at heteroatom positions (X). This nomenclature has been
introduced by D. J. Cram: Cram, D. J.; et al. J. Am. Chem. Soc. 1970, 92,
7369-7384.
(31) Reggelin, M.; Weinberger, H. Manuscript in preparation.
(32) (a) De Amici, M.; De Micheli, C.; Molteni, G.; Pitre´, D.; Carrea,
G.; Riva, S.; Spezia, S.; Zetta, L. J. Org. Chem. 1991, 56, 67-72. (b) Knight,
D. W.; Shaw, D.; Fenton, G. Synlett 1994, 295-296. For the sake of
convenience, the numbering used in the acyclic compounds is retained here.

4770 J. Am. Chem. Soc., Vol. 118, No. 20, 1996
Reggelin et al.
Scheme 9. Definition of Type I and Type II
Scheme 10. Synthesis of Type I Cycloalkenylsulfoximinesa
Cycloalkenylsulfoximines
advantage of these findings, we cyclized all eight possible
γ-hydroxy vinyl sulfoximines (starting from 9/epi-9, 10/epi-10
and the enantiomeric aldehydes 34/ent-34) and analyzed their
13C-NMR spectra. As expected we found two groups of four
compounds each. The first group is made up of compounds
with an average chemical shift of 13.96 ( 0.16 ppm for the
5-methyl group, and the second one contains compounds with
an average chemical shift of 19.00 ( 0.11 ppm for that carbon
atom. On the basis of these statistically highly significant
differences (t-score ) -52.7, P(t) ) 3.14 × 10-9), we assigned
the 4,5-cis configuration to the members of group one and the
4,5-trans configuration to the derivatives in group two. These
results, together with the known absolute configuration of the
aldehydes used, enabled us to assign the absolute configuration
of the γ-hydroxy vinyl sulfoximines 26-33 as indicated in
Scheme 7.
Cyclic 2-Alkenylsulfoximines: Synthesis and Reactions
with Achiral and Chiral Aldehydes. The proposed mechanism
of stereoselection together with the achieved high diastereomeric
excess in the above-mentioned γ-hydroxyalkylations prompted
us to pursue the possibility of incorporating the allylic fragment
into a cyclic system (Scheme 9). The connection of RZ with
RR in the acyclic sulfoximines incorporates the complete allylic
moiety into the ring, thus leading to the 2-cycloalkenylsulfox-
imines 37 (type I cycloalkenylsulfoximines). Connecting the
substituents RE and Râ, on the other hand, leads to the
(cycloalkenylmethyl)sulfoximines 38 being only the double bond
of the allylic fragment part of the carbocyclic ring system (type
II cycloalkenylsulfoximines). Examples of the successful
application of chiral endocyclic allylic compounds of type I as
allyl transfer reagents have been described by H. C. Brown’s
group. They reacted 2-cyclohexenylisopinocampheylborane
with aldehydes, yielding the expected homoallylic alcohols with
very high enantiomeric excesses.33 The analogous seven- and
eight-membered ring systems do not behave as well due to
difficulties in controlling the regiochemistry of the hydroboration
of the underlying 1,3-dienes. Asymmetric allylic transfer based
on the 2-cycloalkenylmethyl type II of reagents has, to the best
of our knowledge, not been described.34 Therefore we decided
to explore the synthetic potential of our sulfoximines in these
fields.
a Reagents: (a) t-BuLi, (b) ent-5, (c) Me3SiCl, Me2NEt.
pounds with triple bonds are involved which render the synthesis
of cyclic starting materials with ring sizes smaller than eight
impossible.3c,f
(2) The overall process is stereoconvergent; there is no need
to control the stereogenic 1-position in 37 (or 38 if RR * H).
(3) The synthesis of both cyclic systems is straightforward
and highly flexible, starting from readily available allylic halides
or ketones (see below).
Type I 2-Cycloalkenylsulfoximines. The most efficient
entry to the hitherto unknown endocyclic 2-alkenylsulfoximines
41a-d with the complete allylic moiety incorporated in the ring,
uses the selenium-lithium exchange reaction introduced by H.
Reich et al.35 (Scheme 10). The allylic bromides 39a-d,
prepared by allylic bromination of the alkene precursor with
NBS, were treated with diphenyldiselenide under reductive
conditions in ethanol,36 producing the corresponding 2-cycloal-
kenylselenides 40a-d in good to excellent yields. Lithio-
deselenization of these intermediates with t-BuLi, followed by
reaction with the sulfonimidate ent-5, gives the desired enan-
tiomerically pure endocyclic allylsulfoximines 41a-d in good
yields. This method of generating the allylic carbon nucleophile
is much more effective than the reductive desulfurization process
of the corresponding sulfides with SET reagents as proposed
by Cohen et al.37 With LDMAN38 as the reducing agent and
2-cyclohexenyl sulfide, we obtained only 31% of the unprotected
precurser of 41a instead of the 61% accessible by the selenium
route.39
In order to study the potential use of these cyclic allylic
sulfoximines in asymmetric γ-hydroxyalkylation reactions, we
protected the hydroxy group in the side chain by silylation. As
described for the acyclic derivatives, the sequence starts with a
deprotonation of the substrate dissolved in THF at -78 °C.
Attempts to achieve proton abstraction with weaker bases as
Grignard reagents (we tried t-BuMgCl and AllMgBr) and
lithium hexamethyldisilazide were, as opposed to the acyclic
systems, not successful. After lithiation, the resulting lithium
compound was either treated directly with the electrophile or
transmetallated and then reacted with the aldehyde. Because
of the observation that the six-membered ring, as well as the
10- and 12-membered ring systems gave unsatisfactory results
with respect to both yield and stereochemical outcome, we
focused our studies on the TBS-protected cyclooctenylsulfox-
imide 41e (Scheme 11).
The 2-alkenylsulfoximine solution for an asymmetric d3-
synthon is particularly well suited to accomplish this aim for
the following reasons:
(1) Unlike the homochiral R-substituted boron systems,3 the
synthesis of 37 or 38 does not rely on synthetic protocols
involving the Matteson procedure,10 whose constitutional and
stereochemical outcome is highly dependent on the nature of
the applied vinyllithium derivative.3g Furthermore no com-
The reaction of lithiated 41e with pivaldehyde results in the
formation of only two of the eight possible products (90% yield,
(35) (a) Reich, H. J.; Bowe, M. D. J. Am. Chem. Soc. 1990, 112, 8994-
8995. (b) Reich, H. J.; Medina, M. A.; Bowe, M. D. J. Am. Chem. Soc.
1992, 114, 11003-11004. Reich, H. J.; Ringer, J. W. J. Org. Chem. 1988,
53, 455-457.
(36) Reich, H. J.; Ringer, J. W. J. Org. Chem. 1988, 53, 455-457.
(37) (a) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152-161.
(b) Cohen T.; Guo, B.-S. Tetrahedron 1986, 42, 2803-2809.
(38) Cohen, T.; Sherbine, J. P.; Matz, J. R.; Hutchins, R. R.; McKenry,
B. M.; Wiley, P. R. J. Am. Chem. Soc. 1984, 106, 3245-3252.
(39) Reggelin, M.; Gerlach, M. Unpublished results.
(33) (a) Brown, H. C.; Bhat, K. S.; Jadhav, P. K. J. Chem. Soc., Perkin
Trans. I 1991, 2633-2638. (b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J.
Am. Chem. Soc. 1985, 107, 2564-2565.
(34) Intramolecular (2-cycloalkenylmethyl)stannane-aldehyde cyclization
reactions with racemic substrates have been described by S. Denmark: (a)
Denmark, S. E.; Weber, E. J. J. Am. Chem. Soc. 1984, 106, 7970-7971.
(b) Denmark, S. E.; Weber, E. J.; Wilson, T. M.; Willson, T. M. Tetrahedron
1989, 45, 1053-1065.

Metalated 2-Alkenylsulfoximines
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4771
Scheme 11. Hydroxyalkylation of a Type I
Scheme 12. Synthesis of
Cyclooctenylsulfoximinea
(2-Cyclopentenylmethyl)sulfoximinesa
a Reagents: (a) transmetalation with ClTi(OiPr)3, or MgBr2‚OEt2 or
ZnCl2‚OEt2, (b) acetone or pivalaldehyde.
54:46)40 NMR-spectroscopic analysis revealed exclusive γ-at-
tack and control of the absolute configuration of one of the two
newly created stereogenic centers by the chiral sulfur moiety.
No constitutional isomer (from R-attack) was detected, which
is in contrast to observations in the acyclic series.41 In the latter,
the lithium compound reacts, as expected, nearly exclusively
in the R-position with diastereoselectivities too low to be of
preparative value.41b,c Due to the fact that only two of the four
possible diastereomers from the γ-attack were observed, we
were interested to find out which of the two centers is under
control. Therefore we repeated the experiment with the non-
prochiral acetone as electrophile, thus removing the stereogenic
character from C-4 (R1 ) R2 ) Me). Again two diastereomeric
products (43, epi-43) were formed (90% yield, 66:34), this time
with (almost) no diastereocontrol. To our surprise, we must
conclude that stereocontrol is effective at the carbinol center
(C-4) only. The interrelation of the absolute configuration at
positions 3 and 4, which has been observed in the acyclic series15
and was interpreted as being a consequence of the 1,3-chirality
transfer process involving a six-membered pericyclic transition
state, is now decoupled. This leads us to the conclusion that
the above-mentioned mode of stereoselection is no longer valid
here.
a Reagents: (a) n-BuLi, -78 °C, (b) cyclopentanone or cyclohex-
anone, (c) TMSOTf.
Table 2. γ-Hydroxyalkylations of the
(2-Cyclopentenylmethyl)sulfoximines 50a and 51a
In order to improve the observed diastereoselection, we
studied the influence of different metals. The results were
disappointing: Irrespective of the nature of the metal [ClTi-
(OiPr)3: 21% yield with pivaldehyde, two diastereomers (53:
47); MgBr2‚OEt2: 34% yield with pivaldehyde, two diastere-
omers (ca. 50:50); ZnCl2‚OEt2: 45% yield with pivaldehyde,
two diastereomers (ca. 50:50)], both chemical yields and
stereoselection were in a range that is not very useful for
synthetic applications.
As a result we switched to the 2-cycloalkenylmethyl systems
38 (type II reagents, Scheme 9), derivatives of which have been
prepared by Gais et al. as chiral, aracemic substrates for cuprate-
mediated allylic substitution reactions.42
Type II Cycloalkenylsulfoximines. By starting from cy-
clopentanone (n ) 1) or cyclohexanone (n ) 2) and the methyl-
substituted sulfoximine 44 (or its S-epimer 45), which in turn
is easily accessible in 95% (92% for 45) yield from the
corresponding sulfonimidate,16 we synthesized the desired allylic
sulfoximines 50 and 51 in a “one-pot” sequence (Scheme 12).
The lithium salts of the ketone addition products 46 and 47
were reacted with trimethylsilyl triflate followed by n-butyl-
lithium-induced elimination of the silicon moiety. The olefins
primarily formed are the ones with the exocyclic double bond
a From 1H-NMR-spectroscopic analysis of the crude reaction product.
b The detection limit of the NMR method was assumed to be 2%. If a
ds value is given as g98%, no other isomer could be detected.
(48, 49) which can be isomerized to the target endocyclic
sulfoximines 50 and 51 by further addition of n-butyllithium at
room temperature. By following this protocol, the isolation of
the intermediate silyl ether, followed by isomerization with
lithium- or potassium methoxide,42 was not necessary. With
this convenient entry to (2-cycloalkenylmethyl)sulfoximines at
hand, we started to explore their potential use as solutions for
cyclic, asymmetric d3-synthons. To do so we reacted the
titanated derivatives of 50a and 51a with a variety of aldehydes
(Table 2).
We were delighted to see that the chemistry of these
(cyclopentenylmethyl)sulfoximines behaved as that of our
acyclic sulfoximines. The regioselectivity is complete (no trace
of R-adduct can be detected), the diastereocontrol is excellent
(ds g 93%, in most cases ds g 98%), and the yields are even
higher than with the acyclic compounds.
(40) The configuration on the two newly created stereogenic centers has
not been determined.
(41) (a) Reggelin, M.; Weinberger, H. Unpublished results. Examples
with racemic allylsulfoximines: (b) Harmata, M.; Claassen R. J., II.
Tetrahedron Lett. 1991, 32, 6497-6500. (c) Pyne, S. G.; Boche, G.
Tetrahedron 1993, 49, 8449-8464.
(42) (a) Gais, H.-J.; Mu¨ller, H.; Bund, J.; Scommoda, M.; Brandt, J.;
Raabe, G. J. Am. Chem. Soc. 1995, 117, 2453-2466. (b) Bund, J.; Gais,
H.-J.; Erdelmeier, I. J. Am. Chem. Soc. 1991, 113, 1442-1444.
Provided with these encouraging results from the achiral
aldehyde addition experiments, documented in Table 2, we were
next interested in the amount of reagent control which may be
achievable with these cyclic allyl transfer reagents. As in the

4772 J. Am. Chem. Soc., Vol. 118, No. 20, 1996
Reggelin et al.
Scheme 13. Reagent Control:
(2-Cyclopentenylmethyl)sulfoximines
Figure 1. XRAST drawing of a part of the solid state structure of 59
showing the hydrogen bond between the oxygen atom of the sulfon-
imidoyl moiety and the OH-group at C-4. The double bond between
C-1 and C-2 is cis-configured, and the substituent at C-3 in the
cyclohexane ring introduced by the aldehyde addition adopts an axial
position.
Scheme 15. Proof of the Absolute Configuration by X-ray
Scheme 14. Reagent Control:
(2-Cyclohexenylmethyl)sulfoximines
relative configuration of the stereogenic centers in the auxiliary.
Even more than in the acyclic series it is absolutely necessary
to react the aldehyde with the intramolecular matched auxiliary
(im) (i.e., lk relative configuration). Not only does this guarantee
a high level of stereocontrol even in the intermolecular,
mismatched case, leading to the anti-Cram product 59 with 97%
ds, but also the yield is increased from moderate 42% (same
aldehyde, intramolecular mismatched auxiliary, product 61) to
excellent 90%.
The absolute configuration of the products, as indicated in
Table 2, as well as in Scheme 14, has been confirmed by X-ray
structural analysis of the bicyclic ether 62, again obtained by
the already-mentioned fluoride-induced cyclization procedure,
and the cyclic vinyl sulfoximine 59 (Scheme 15).43 In ac-
cordance with the results in the acyclic series, here again we
observe a strong preference of the titanated sulfoximine to attack
the aldehyde from the Re face if the sulfur is S-configured and
Vice Versa. Furthermore, the new double bond between C-1
and C-2 in the cyclic addition product 59 is Z-configured which,
together with the absolute configuration at C-3 and C-4, fits
well into the picture of a pericyclic six-membered transition
state. From these results we conclude that even with these cyclic
substrates this model accounts for the stereochemical outcome
of the reaction. A remarkable feature of the structure of the
vinyl sulfoximine 59 is the hydrogen bond between the 4-OH
group and the sulfoximine oxygen being embedded in an eight-
membered ring system (d ) 2.185 Å, Figure 1). None of the
open chain sulfoximines studied so far (see 18e and 21, Scheme
5) by crystal structural analysis is comparable to 59 in this
respect. In the dihydroxy sulfoximine 18e, a hydrogen bond
exists between the sulfoximine oxygen and the side chain
hydroxy group (d ) 2.054 Å), and in the monosilylated
compound 21, no hydrogen bond can be observed at all.
acyclic series described above, both antipodes of the silyl-
protected lactaldehydes 34 and ent-34 were reacted with the
two S-epimeric sulfoximines 50a and 51a (Scheme 13).
Unlike the corresponding experiments with the acyclic
sulfoximines, the diastereoselectivities observed are high (ds
g 95%) irrespective of both the sense of chirality in the
electrophile and the relative configuration of the stereogenic
centers in the auxiliary. Thus the absolute configuration at C-3
and C-4 is controlled by the reagent alone with no additional
demands on the relative configuration of its stereogenic centers.
Next we were interested in the diastereocontrol achievable
in the six-membered ring systems 50b and 51b (Scheme 14).
These were synthesized using the one-pot procedure described
above (Scheme 12) with 69% yield for the SS-configured and
52% yield for the RS-configured sulfoximines (51b and 50b,
respectively). In complete contrast to the five-membered ring
systems, here we observe again a very strong influence of the
(43) An R-methylated derivative of the bicyclic ether 62 can be converted
to a vinyl-substituted 2-oxabicyclo[3.3.0]octane with complete retention of
the configuration at the sulfur atom: Reggelin, M.; Gerlach, M. Manuscript
in preparation.

Metalated 2-Alkenylsulfoximines
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4773
Scheme 16. Intramolecular Matched Stereochemistry Entails
Efficient Reagent Control
The bicyclic sulfoximine 63 has been synthesized from the
epimeric mixture of the 1-methyl-substituted sulfoximine derived
from 50a via our hydroxyalkylation-cyclization procedure. It
can be methylated with methyl triflate, yielding the correspond-
ing S-aminooxosulfonium salt which was converted without
isolation to the desulfurized vinyl-substituted 2-oxabicyclooctane
64 with 70% yield. The sulfinamide 65 was generated as a
pure diastereomer, and comparison with an authentic sample48
showed that it has been formed with complete retention at the
sulfur atom.
Conclusion. Open chain allylic sulfoximines are available
in enantiomerically pure state from the nucleophilic displace-
ment reaction of cyclic sulfonimidates. They can be deproto-
nated with lithium bases, yielding configurationally labile
organometallic intermediates which can be titanated with high
diastereomer differentiation. These titanium compounds, sus-
pected to be uniformly configured and configurationally stable
at the time scale of electrophile uptake, react with a variety of
achiral aldehydes to form the corresponding γ-hydroxy vinyl
sulfoximines with diastereoselectivities exceeding 95% irrespec-
tive of the nature of the aldehyde.
For complete reagent control in the reactions with R-chiral
aldehydes, it is necessary to apply the amino acid modified
sulfonimidoyl moiety with both stereogenic centers in the same
absolute configuration. This like relative configuration entails
a mutual reinforcement of the diastereofacial selectivity strong
enough to overcome the stereochemical bias exerted by the
chiral electrophile.
This effect is operative not only in the acyclic series but also
in the metalated (2-cycloalkenylmethyl)sulfoximines. It is the
first example of asymmetric allyl transfer reagents of this
structural type. In the six-membered ring systems, as well as
in the acyclic series, the stereochemical outcome and the
chemical yield is strongly dependent on the relative configu-
ration of the stereogenic centers of the auxiliary. The need for
this intramolecular matched relationship is not a restriction to
the generality of the method because it is easily established by
a proper choice of the chirality of the underlying amino acid.
Scheme 17. Removal of the Auxiliarya
a Reagents: (a) MeOTf, -20 °C, (b) DBU, 0 °C, (c) saturated NH4Cl.
As stated above, the necessity to use the auxiliary with the
lk stereochemistry is by no means a restriction of the method.
Consequently, if it is necessary to generate the stereotriade as
depicted in the vinyl sulfoximine 61 (Scheme 14) with high
isomeric purity and yield, it is just necessary to switch the
absolute configuration in the side chain of the auxiliary from R
to S (i.e., replace (R)-valine by (S)-valine, Scheme 16).
By switching from the RC- (51b, Scheme 14) to the SC-
configured sulfoximine epi-51b (Scheme 16) and reacting it with
ent-34 will lead to the addition product ent-59 with a correct
configured stereotriade with ds ) 97% and a yield of 90%. This
must necessarily be the case because the product generated is
just the enantiomer of 59, which has been synthesized with the
given selectivity and yield (Scheme 14). Changing the system
from the intramolecular mismatched to the matched situation
opens up a pathway which is enantiomorphic to the one leading
to isomer 59. Every stereotriade depicted in Scheme 14 can
therefore be synthesized with at least 97% ds and 80% yield.
Removal of the Auxiliary. Sulfoximines can be regarded
as aza analogs of sulfones. Therefore many of the reactions
known for this latter class of compounds can be applied to
manipulate sulfoximines too. Of particular importance are
desulfurization procedures that are coupled with the formation
of new functionalities accompanied by C-C bond formation.
This is exemplified by the early examples of nucleophilic
alkylidene transfer via S-aminooxosulfonium ylides44 and, more
recently, by allylic substitution reactions of 2-alkenylsulfox-
imines45 and nickel-mediated cross-coupling reactions of vinylic
sulfoximines.46 Finally, the thermal extrusion of chiral, aracemic
N,S-dimethylsulfoximine from the corresponding â-hydroxysul-
foximines, is a useful method for the resolution of racemic
ketones.47
Experimental Section
All manipulations except workup and chromatographic purification
were performed in an atmosphere of dry, oxygen-free argon with
Schlenk and syringe techniques. Solvents were purified and dried prior
to use by distillation from an appropiate drying agent. Diethyl ether
(Et2O) and tetrahydrofuran (THF) were distilled from sodium ben-
zophenone ketyl. Dichloromethane (CH2Cl2) was distilled from calcium
hydride. Starting materials were obtained from commercial sources
and used without further purification unless otherwise stated. The assay
from n-BuLi was obtained by titration with menthol in THF in the
presence of 1,10-phenanthroline.49 Chlorotris(isopropoxy)titanium
(ClTIPT) was prepared by literature procedures,22 distilled at 8 mbar
with exclusion of moisture and stored at 4 °C as a hexane solution
(1.0 mmol/g). Analytical thin-layer chromatography (TLC) was
performed on Macherey Nagel & CO precoated TLC plates (SilG/UV
245). Flash chromatography was performed with E. Merck silica gel
60 (15-40 µm). Melting points were determined by a Gallenkamp
apparatus and are uncorrected. 1H and 13C NMR were recorded on
Bruker AMX 400, WH 270, and AC 250 instruments. 1H-NMR and
13C-NMR spectra are reported in ppm relative to tetramethylsilane.
Optical rotations were measured with a Perkin Elmer 241 polarimeter.
IR spectra were recorded on a Perkin Elmer 1310 spectrometer.
Diastereoselectivities of the γ-hydroxyalkylation products were deter-
Our method is based on a DBU-induced reductive elimination
of the sulfur moiety from S-aminooxosulfonium intermediates
(Scheme 17).
(44) (a) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95,
7418-7423. (b) Johnson, C. R.; Schroeck, C. W.; Shanklin, J. R. J. Am.
Chem. Soc. 1973, 95, 7424-7431. (c) Johnson, C. R.; Lockard, J. P.
Tetrahedron Lett. 1971, 48, 4589-4592.
(45) (a) Gais, H.-J.; Mu¨ller H.; Bund, J.; Scommoda, M.; Brandt, J.;
Raabe, G. J. Am. Chem. Soc. 1995, 117, 2453-2466. (b) Bund, J.; Gais,
H.-J.; Erdelmeier, I. J. Am. Chem. Soc. 1991, 113, 1442-1444.
(46) (a) Gais, H.-J.; Erdelmeier, I. J. Am. Chem. Soc. 1989, 111, 1125-
1126. (b) Gais, H.-J.; Mu¨ller, H.; Decker, J.; Hainz, R. Tetrahedron Lett.
1995, 7433-7436. (c) Gais, H.-J.; Lenz, D.; Raabe, G. Tetrahedron Lett.
1995, 7437-7440.
1
mined from the H-NMR spectra of the crude products.
General Procedure for the Synthesis of 2-Cycloalkenylphenylse-
lenides 40a-d. Diphenyldiselenide (1.0 equiv) was dissolved in boiling
(48) Prepared by methylation of the C-epimeric sulfinamide described
in ref 16.
(49) Vedejs, E. J. Org. Chem. 1978, 43, 188-190.
(47) (a) Johnson, C. R.; Zeller, J. R. J. Am. Chem. Soc. 1982, 104, 4021.
(b) Poupart, M.-A.; Paquette, L. A. Tetrahedron Lett. 1988, 29, 269-272.

4774 J. Am. Chem. Soc., Vol. 118, No. 20, 1996
Reggelin et al.
benzene (4 mL/mmol), and ethanol was added until turbity started.
Sodium borohydride (2.0 equiv) was added in batches, until the yellow
solution turned colorless. After refluxing for 15 min, the solution was
treated with 2.0 equiv of the corresponding bromocycloalkene 39a-d
which had been prepared by following literature procedures50 and
refluxed for another 2 h. Then 10% aqueous KOH (2 mL/mmol) was
added, and the organic solvents were removed at ambient temperature
under reduced pressure. The residual two-phase system was extracted
with ether (3 × 50 mL), the combined extracts were dried over MgSO4,
and concentrated, and the crude product was distilled in Vacuo.
rac-2-Cyclohexenylphenylselenide (40a): yield 11.0 g (85%); bp
118-120 °C, 0.01 mbar; RF ) 0.19 (hexane, neat); 1H NMR (270 MHz,
CDCl3) δ 1.554-2.090 (m, 4-6 H2), 3.966 (m, 3-H), 5.744 (m, 1-H),
5.858 (m,2-H), 7.222-7.279 (m, o-H2, p-H), 7.551 (m, m-H2); 13C NMR
(100 MHz, CDCl3) δ 19.60, 24.86, 29.39, 41.10, 127.17, 127.71, 128.89,
129.64, 130.65, 134.05. Anal. Calcd for C12H14Se: C, 60.76; H, 5.95.
Found: C, 60.51; H, 5.90.
rac-2-Cyclooctenylphenylselenide (40b): yield 15.1 g (96%); bp
140-142 °C, 0.01 mbar; RF ) 0.34 (hexane, neat); 1H NMR (270 MHz,
CDCl3) δ 1.279-2.231 (m, 4-8 H2), 4.236 (m, 3-H), 5.632 (m, 1-H,
2-H), 7.238 (m, o-H2, p-H), 7.505 (m, m-H2); 13C NMR (100 MHz,
CDCl3) δ 26.16, 26.39, 26.56, 29.24, 36.28, 39.78, 126.95, 130.24,
128.83, 133.59, 133.19, 134.43. Anal. Calcd for C14H18Se: C, 63.39;
H, 6.84. Found: C, 63.18; H, 6.58.
[SS,1RS,N(1R)]-N-[1-[[(Trimethylsilyl)oxy]methyl]-2-methylpro-
pyl]-S-cyclooct-2-en-1-yl-S-(4-methylphenyl)sulfoximine (41b): yield
2.66 g (79%); [R]20D ) 139.00° (c ) 0.82, CH2Cl2); RF ) 0.40 (ether/
1
hexane ) 1:3); νmax (cm-1) ) 1240, 1090 (NdSdO); H NMR (270
MHz, CDCl3) δ 0.003, 0.027 (2 × s, OSi(CH3)3), 0.846-0.927 (m,
NCHCH(CH3)2), 1.200-2.325 (m, 4-8 H2, NCHCH(CH3)2), 2.355,
2.364 (2 × s, p-CH3), 2.915 (m, NCH), 3.489, 3.614 (2 × m, NCHCH2),
3.941, 4.078 (2 × m, 1-H), 5.475-5.794 (m, 2-H, 3-H), 7.253 (d, m-H2),
7.693(d, o-H2); 13C NMR (100 MHz, CDCl3) δ -0.52, 16.05, 16.20,
20.81, 20.90, 21.40, 24.81, 24.90, 25.48, 25.66, 26.28, 26.38, 28.59,
28.91, 28.98, 29.24, 29.35, 29.65, 61.09, 61.14, 63.59, 64.78, 65.27,
65.31, 124.13, 125.03, 129.31, 129.40, 129.69, 130.09, 132.95, 133.09,
134.93, 135.31, 142.73, 142.88. Anal. Calcd for C23H39NO2SSi: C,
65.51; H, 9.32; N, 3.32. Found: C, 65.24; H, 9.14; N, 3.16.
[SS,1RS,N(1R)]-N-[1-[[(Trimethylsilyl)oxy]methyl]-2-methylpro-
pyl]-S-cyclodec-2-en-1-yl)-S-(4-methylphenyl)sulfoximine (41c): yield
1.35 g (61%); [R]20D ) 113.60° (c ) 0.61, CH2Cl2); RF ) 0.55 (ether/
1
hexane ) 1:2); νmax (cm-1) ) 1250, 1100 (NdSdO); H NMR (270
MHz, CDCl3) δ -0.002, 0.019 (2 × s, OSi(CH3)3), 0.884, 0.951 (2 ×
d, NCHCH(CH3)2), 1.239-2.272 (m, 4-10 H2, NCHCH(CH3)2), 2.394,
2.417 (2 × s, p-CH3), 2.948 (m, NCH), 3.473, 3.627 (2 × m, NCHCH2),
4.128, 4.349 (2 × ddd, 1-H), 5.215-5.614 (m, 2-H, 3-H), 7.243 (d,
m-H2), 7.649 (d, o-H2); 13C NMR (100 MHz, CDCl3) δ -0.53, -0.51
(OSi(CH3)3), 15.47, 15.76, 20.45, 20.54, 20.77, 20.84, 20.93, 21.23,
21.42, 24.55, 24.59, 24.61, 24.75, 25.25, 25.28, 26.58, 26.98, 27.04,
27.16, 28.89, 28.94, 29.13, 61.08, 61.28, 63.85, 64.89, 64.96, 65.25,
123.85, 124.95, 129.05, 129.11, 130.10, 130.33, 131.73, 131.83, 134.87,
135.42, 142.70, 142.89. Anal. Calcd for C25H43NO2SSi: C, 66.76;
H, 9.64; N, 3.11. Found: C, 66.72; H, 9.44; N, 3.22.
rac-2-Cyclodecenylphenylselenide (40c): yield 4.5 g (71%); bp
158-160 °C, 0.01 mbar; RF ) 0.33 (hexane, neat); 1H NMR (270 MHz,
CDCl3) δ 1.210-2.423 (m, 4-10 H2), 4.500 (m, 3-H), 5.279 (m, 1-H),
5.445 (m, 2-H), 7.256 (m, o-H2, p-H), 7.527 (m, m-H2); 13C NMR (100
MHz, CDCl3) δ 20.58, 24.22, 25.48, 25.61, 26.72, 31.61, 34.44, 41.07,
126.98, 128.68, 129.08, 132.39, 134.13, 134.80. Anal. Calcd for C16-
H22Se: C, 65.52; H, 7.56. Found: C, 65.34; H, 7.49.
[SS,1RS,N(1R)]-N-[1-[[(Trimethylsilyl)oxy]methyl]-2-methylpro-
pyl]-S-cyclododec-2-en-1-yl-S-(4-methylphenyl)sulfoximine (41d):
yield 0.91 g (61%); [R]20 ) 93.70° (c ) 2.82, CH2Cl2); RF ) 0.60
rac-2-Cyclododecenylphenylselenide (40d): yield 5.8 g (39%); bp
156-170 °C, 0.01 mbar; RF ) 0.38 (hexane, neat); 1H NMR (270 MHz,
CDCl3) δ 1.019-2.134 (m, 4-12 H2), 3.775 (m, 3-H), 5.109-5.438
(m, 1-H, 2-H), 7.179-7.620 (m, phenyl-H); 13C NMR (100 MHz,
CDCl3) δ 21.82, 22.68, 24.14, 24.38, 24.72, 25.34, 26.10, 26.36, 33.36,
39.77, 126.93, 128.56, 129.11, 132.63, 135.16, 136.04. Anal. Calcd
for C18H26Se: C, 67.27; H, 8.15. Found: C, 67.40; H, 8.07.
General Procedure for the Synthesis of 2-Cycloalkenylsulfox-
imines 41a-d. To a well-stirred solution of the corresponding
2-cycloalkenylphenylselenide (2.0 equiv, 40a-d) in dry Et2O (3 mL/
mmol) at -78 °C was added dropwise via syringe t-BuLi (1.5 equiv,
1.6 M in n-hexane). After 45 min, 1.0 equiv of the cyclic sulfonimidate
ent-5 was introduced to the resultant yellow reaction mixture. The
reaction mixture was stirred at that temperature until no further change
in the composition of the mixture could be detected by TLC (60-80
min), quenched with saturated aqueous NH4Cl (5 mL/mmol), and
extracted with ether (3 × 10 mL). After the organic layer has been
dried with MgSO4 and concentrated in Vacuo, the crude product was
dissolved in dry CH2Cl2 (3 mL/mmol) and treated with chlorotrimeth-
ylsilane (1.5 equiv) and EtMe2N (2.0 equiv) at 0 °C. The reaction
mixture was kept at 0 °C for 15 min, after which the temperature was
raised to room temperature for another 60 min. Finally the reaction
mixture was poured onto ice and extracted with CH2Cl2 (3 × 10 mL).
The combined extracts were dried over MgSO4 and concentrated in
Vacuo, and the residue was purified by flash chromatography (eluent:
Et2O/n-hexane).
D
(ether/hexane ) 1:2); νmax (cm-1) ) 1240, 1120 (NdSdO); 1H NMR
(270 MHz, CDCl3) δ 0.026 (s, OSi(CH3)3), 0.895, 0.918 (2 × d,
NCHCH(CH3)2), 1.003-2.331 (m, 4-12 H2, NCHCH(CH3)2), 2.408
(s, p-CH3), 2.930 (m, NCH), 3.504, 3.626 (2 × m, NCHCH2), 4.386
(m, 1-H), 5.123-5.727 (m, 2-H, 3-H), 7.257 (d, m-H2), 7.623 (d, o-H2);
13C NMR (100 MHz, CDCl3) δ -0.56, -0.52, 15.91, 20.88, 21.43,
23.72, 24.05, 24.23, 24.38, 24.67, 25.17, 25.33, 25.79, 25.98, 26.07,
26.57, 29.08, 31.38, 32.67, 37.51, 61.37, 63.31, 65.32, 123.77, 129.13,
130.26, 130.44, 131.45, 134.38, 134.61, 139.68, 142.63. Anal. Calcd
for C27H47NO2SSi: C, 67.87; H, 9.91; N, 2.93. Found: C, 67.81; H,
9.75; N, 2.69.
[SS,1RS,N(1R)]-N-[1-[[(tert-Butyldimethylsilyl)oxy]methyl]-2-
methylpropyl]-S-cyclooct-2-en-1-yl-S-(4-methylphenyl)sulfox-
imine (41e). By deviating from the general procedure given above,
41e was prepared with tert-butyldimethylchlorosilane and 0.3 equiv
of DMAP: yield 1.02 g (69%); [R]20D ) 128.50° (c ) 1.04, CH2Cl2);
RF ) 0.54 (ether/hexane ) 1:3); νmax (cm-1) ) 1230, 1110 (NdSdO);
1H NMR (270 MHz, CDCl3) δ 0.008, 0.035 (2 × s, OSi(CH3)2), 0.873
(s, OSiC(CH3)3), 0.924, 0.938 (2 × d, NCHCH(CH3)2), 1.291-2.412
(m, 4-8 H2, NCHCH(CH3)2), 2.449 (s, p-CH3 ), 2.978 (ddd, NCH),
3.574 (m, NCHCH2), 4.004, 4.151 (2 × ddd, 1-H), 5.574 (m, 2-H),
5.773 (m, 3-H), 7.319 (d, m-H2), 7.737 (d, o-H2); 13C NMR (100 MHz,
CDCl3) δ -5.54, -5.32, 16.09, 18.24, 20.78, 21.45, 24.84, 24.92, 25.95,
26.31, 26.40, 26.61, 26.66, 28.68, 28.94, 29.06, 29.27, 29.66, 61.08,
61.12, 63.49, 65.85, 124.14, 125.06, 129.33, 129.73, 130.12, 132.95,
133.12, 135.52, 142.73, 142.89. Anal. Calcd for C26H45NO2SSi: C,
67.73; H, 9.77; N, 3.02. Found: C, 67.19; H, 9.51; N, 2.92.
General Procedure for the Reaction of the Lithiated Cyclooc-
tenylsulfoximine 41e with Carbonyl Electrophiles. To a well-stirred
solution of 41e (1.0 equiv) in dry THF (3 mL/mmol) under argon at
-78 °C was added dropwise via syringe n-BuLi (1.1 equiv, 1.6 M in
n-hexane). After reaction for 15 min at -78 °C, the electrophile
(pivaldehyde or acetone, 2.0 equiv) was introduced to the resultant
orange reaction mixture. The reaction solution was monitored by TLC,
quenched with saturated aqueous NH4Cl (10 mL/mmol), and extracted
with ether (3 × 10 mL). After being dried with MgSO4, the residue
was purified by flash chromatography (eluent: ether/hexane).
[SS,N(1R),1R*,3R*]-1-[1-[N-[1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]cyclooct-
[SS,1RS,N(1R)]-N-[1-[[(Trimethylsilyl)oxy]methyl]-2-methylpro-
pyl]-S-cyclohex-2-en-1-yl-S-(4-methylphenyl)sulfoximine (41a): yield
201 mg (51%); [R]20D ) 29.30° (c ) 0.96, CH2Cl2); RF ) 0.46 (ether/
1
hexane ) 1:2); νmax (cm-1) ) 1230, 1100 (NdSdO); H NMR (270
MHz, CDCl3) δ 0.034, 0.042 (2 × s, OSi(CH3)3), 0.921, 0.930 (2 × d,
NCHCH(CH3)2), 1.311-2.150 (m, 4-6 H2, NCHCH(CH3)2), 2.418 (s,
p-CH3), 2.925, 2.996 (2 × ddd, NCH), 3.494, 3.631 (2 × dd, NCHCH2),
3.849 (ddd, 1-H), 5.858-6.099 (m, 2-H, 3-H), 7.283 (d, m-H2), 7.685-
(d, o-H2); 13C NMR (100 MHz, CDCl3) δ -0.57, 16.48, 16.75, 18.66,
18.83, 21.45, 23.38, 23.58, 24.38, 24.52, 28.13, 28.34, 28.93, 29.02,
61.62, 61.74, 62.16, 62.63, 65.42, 65.56, 119.91, 121.83, 129.23, 129.45,
130.28, 130.53, 133.47, 133.53, 133.78, 134.03, 143.18. Anal. Calcd
for C21H35NO2SSi: C, 64.08; H, 8.96; N, 3.56. Found: C, 64.32; H,
8.73; N, 3.47.
(50) Cope, A. C.; Estes, L. L. J. Am. Chem. Soc. 1950, 72, 1128-1132.
1-en-3-yl]-2,2-dimethylpropan-1-ol (42): yield 179 mg (43%); [R]20
D

Metalated 2-Alkenylsulfoximines
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4775
) 70.78° (c ) 0.77, CH2Cl2); RF ) 0.07 (Et2O/hexane ) 1:3); νmax
acetate/hexane ) 1:1); νmax (cm-1) ) 1220, 1110 (NdSdO); 1H NMR
(270 MHz, CDCl3) δ 0.018, 0.038 (2 × s, OSi(CH3)2), 0.864 (s, OSiC-
(CH3)3), 0.866, 0.874 (2 × d, NCHCH(CH3)2), 1.887 (m, NCH-
CH(CH3)2), 2.431 (s, p-CH3), 2.925 (ddd, NCH), 3.073 (s, S-CH3), 3.631
(dd, NCHCH2), 7.315 (d, m-H2), 7.821 (d, o-H2); 13C NMR (100 MHz,
CDCl3) δ -5.38, -5.27, 16.95, 20.47, 18.32, 21.44, 25.60, 29.67, 45.04,
61.88, 66.38, 128.56, 129.57, 137.60, 143.12. Anal. Calcd for C19-
H35NO2SSi: C, 61.74; H, 9.54; N, 3.79. Found: C, 61.73; H, 9.45;
N, 3.61.
General Procedure for the Synthesis of the (Cycloalkenylmethyl)-
sulfoximines 50a/51a and 50b/51b. To a well-stirred solution of
methylsulfoximine 44 or 45 (1.0 equiv) in dry THF (3 mL/ mmol)
under argon at -78 °C was added dropwise via syringe n-BuLi (1.2
equiv, 1.6 M in n-hexane). The resulting yellow solution was stirred
for 30 min at that temperature and then treated with the corresponding
cycloalkanone (1.6 equiv). After 10 min the pale yellow solution was
allowed to warm to room temperature and was stirred for another 2.5
h. The mixture was recooled to -78 °C, at which point TMS triflate
(2.5 equiv) was added. Again the mixture was warmed up to room
temperature, stirred for 3.5 h, cooled to -78 °C, and treated with n-BuLi
(2.0 equiv, 1.6 M in n-hexane). After 30 min, the dry ice/acetone bath
was removed and stirring was continued for 18 h at ambient temper-
ature. Aqueous workup (NH4Cl) yielded a crude product which was
purified by flash chromatography (Et2O/hexane).
1
(cm-1) ) 3460 (OH), 1240, 1100 (NdSdO); H NMR (270 MHz,
CDCl3) δ 0.007, 0.026 (2 × s, OSi(CH3)2), 0.865 (s, OSiC(CH3)3),
0.915 (m, C(CH3)3, NCHCH(CH3)2), 1.098-2.137 (m, 4-8 H2,
NCHCH(CH3)2), 2.406 (s, p-CH3), 2.559 (br s, 1-OH), 2.930 (ddd,
NCH), 2.755, 3.290 (2 × m, 3-H, 1-H), 3.609 (d, NCHCH2), 7.211 (d,
2-H), 7.246 (d, m-H2), 7.778 (d, o-H2); J1,3 ) 5.2 Hz, J3,2 ) 10.7 Hz;
13C NMR (100 MHz, CDCl3) δ -5.10, -5.02, 17.00, 20.38, 18.65,
21.70, 25.05, 26.23, 27.00, 30.14, 27.15, 29.93, 35.84, 35.93, 38.70,
61.66, 66.05, 82.76, 129.52, 129.72, 136.83, 140.44, 140.94, 142.78.
Anal. Calcd for C31H55NO3SSi: C, 67.70; H, 10.08; N, 2.55. Found:
C, 67.77; H, 10.06; N, 2.35.
[SS,N(1R),1R*,3S*]-1-[1-[N-[1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]cyclooct-
1-en-3-yl]-2,2-dimethylpropan-1-ol (4-epi-42): yield 195 mg (47%);
[R]20 ) 72.50° (c ) 0.80, CH2Cl2); RF ) 0.16 (Et2O/hexane ) 1:3);
D
ν
max (cm-1) ) 3450 (OH), 1260, 1080 (NdSdO); 1H NMR (270 MHz,
CDCl3) δ -0.035, -0.001 (2 × s, OSi(CH3)2), 0.841 (s, OSiC(CH3)3),
0.908 (m, C(CH3)3, NCHCH(CH3)2), 1.014-2.376 (m, 4-8 H2,
NCHCH(CH3)2), 2.416 (s, p-CH3), 2.976 (ddd, NCH), 3.423 (br s,
1-OH), 2.727, 4.453 (2 × m, 3-H, 1-H), 3.521, 3.719 (2 × dd,
NCHCH2), 7.149 (d, 2-H), 7.261 (d, m-H2), 7.658 (d, o-H2); J1,3
)
11.3 Hz, J3,2 ) 9.9 Hz; 13C NMR (100 MHz, CDCl3) δ -5.08, -4.89,
17.23, 20.48, 18.64, 21.45, 25.15, 26.38, 27.03, 30.23, 27.33, 28.67,
29.84, 35.60, 35.88, 39.03, 60.53, 65.63, 102.84, 129.58, 129.73, 136.80,
140.36, 142.38, 143.08. Anal. Calcd for C31H55NO3SSi: C, 67.70;
H, 10.08; N, 2.55. Found: C, 67.83; H, 9.93; N, 2.38.
(+)-[SS,N(1R)]-N-[1-[[(tert-Butyldimethylsilyl)oxy]methyl]-2-
methylpropyl]-S-(cyclopent-1-en-1-ylmethyl)-S-(4-methylphenyl)sul-
foximine (51a): yield 2.31 g (80%); [R]20 ) 57.30° (c ) 1.11,
D
[SS,N(1R),3RS]-1-[1-[N-[1-[[(tert-Butyldimethylsilyl)oxy]methyl]-
2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]cyclooct-1-en-3-
yl]-1-methylethan-1-ol (43/3-epi-43): yield 218 mg (90%); RF ) 0.25
(Et2O/hexane ) 1:3); 1H NMR (270 MHz, CDCl3) δ -0.052, -0.022
(2 × s, OSi(CH3)2: major), 0.005, 0.020 (2 × s, OSi(CH3)2: minor),
0.818 (s, OSiC(CH3)3: major), 0.856 (s, OSiC(CH3)3: minor), 0.918,
0.966 (2 × d, NCHCH(CH3)2: major), 1.176, 1.181 (2 × s, 1-CH3,
2-H3: major), 1.241-2.392 (m, 4-8 H2, NCHCH(CH3)2, 1-OH), 2.391
(s, p-CH3: major), 2.758 (ddd, 3-H: major), 2.891 (ddd, NCH: minor),
2.979 (ddd, NCH: major), 3.548, 3.695 (2 × dd, NCHCH2: major),
6.998 (d, 2-H: major), 7.004 (d, 2-H: minor), 7.249 (d, m-H2), 7.688
(d, o-H2 major), 7.786 (d, o-H2 minor); 13C NMR (100 MHz, CDCl3)
δ -5.44, -5.37, -5.35, -5.28, 15.79, 21.03, 18.25, 21.40, 25.92, 26.07,
26.48, 27.02, 27.18, 27.67, 25.42, 29.57, 29.84, 30.12, 31.67, 48.60,
48.94, 61.01, 61.72, 65.75, 65.94, 71.89, 72.09, 129.30, 129.33, 129.45,
136.51, 136.75, 140.76, 141.22, 141.46, 142.53, 142.65. Anal. Calcd
for C29H51NO3SSi: C, 66.75; H, 9.85; N, 2.68. Found: C, 66.51; H,
9.72; N, 2.43.
General Procedure for the Nucleophilic Ring Opening of the
Cyclic Sulfonimidates 5 and 6. To a well-stirred solution of the
sulfonimidate (5/6 or their enantiomers, 1.0 equiv) in dry THF (3 mL/
mmol) under argon at -78 °C was added dropwise via syringe MeLi
(1.5 equiv, 1.6 M in Et2O). After the reaction had stopped (monitored
by TLC), saturated aqueous NH4Cl (10 mL/mmol) was added and usual
workup yielded a crude product which was dissolved in CH2Cl2 (5
mL/mmol). tert-Butyldimethylchlorosilane (1.5 equiv), EtMe2N (2.0
equiv), and DMAP (0.3 equiv) were added, and after stirring for 18 h
at room temperature, the mixture was poured onto ice and extracted
with CH2Cl2 (3 × 10 mL). The crude product was purified by flash
chromatography (eluent: ethyl acetate/hexane).
CH2Cl2); RF ) 0.40 (Et2O/hexane ) 1:3); νmax (cm-1) ) 1220, 1110
(NdSdO); 1H NMR (270 MHz, CDCl3) δ -0.020, 0.006 (2 × s, OSi-
(CH3)2), 0.837 (s, OSiC(CH3)3), 0.898 (d, NCHCH(CH3)2), 1.734-
2.228 (m, 3-5 H2, NCHCH(CH3)2), 2.413 (s, p-C H3), 2.957 (ddd,
NCH), 3.567, 3.660 (2 × dd, NCHCH2), 3.960 (s, SCH2), 5.361 (br s,
2-H), 7.264 (d, m-H2), 7.692 (d, o-H2); 13C NMR (100 MHz, CDCl3)
δ -5.39, -5.30, 16.46, 20.69, 18.53, 21.46, 23.66, 32.68, 35.07, 25.97,
29.41, 59.56, 61.77, 66.16, 129.19, 129.61, 132.87, 134.39, 135.40,
142.96. Anal. Calcd for C24H41NO2SSi: C, 66.16; H, 9.48; N, 3.21.
Found: C, 66.32; H, 9.26; N, 3.10.
(-)-[RS,N(1R)]-N-[[(1-tert-Butyldimethylsilyl)oxy]methyl]-2-meth-
ylpropyl]-S-(cyclopent-1-en-1-ylmethyl)-S-(4-methylphenyl)sulfox-
imine (50a): yield 2.11 g (76%); [R]20D ) -2.50° (c ) 1.00, CH2Cl2);
mp 87.2 °C; RF ) 0.42 (Et2O/hexane ) 1 : 2); νmax (cm-1) ) 1240,
1
1120 (NdSdO); H NMR (270 MHz, CDCl3) δ -0.043, -0.032 (2
× s, OSi(CH3)2), 0.844 (s, OSiC(CH3)3), 0.904, 0.978 (2 × d, NCHCH-
(CH3)2), 1.600-2.389 (m, 3-5 H2, NCHCH(CH3)2), 2.417 (s, p-CH3),
3.080 (ddd, NCH), 3.491 (dd, NCHCH2), 3.860, 4.039 (2 × d, SCH2),
5.396 (br s, 2-H), 7.264 (d, m-H2), 7.755 (d, o-H2); 13C NMR (100
MHz, CDCl3) δ -5.43, -5.35, 16.69, 19.99, 18.34, 21.46, 23.69, 32.69,
35.06, 25.97, 29.91, 59.04, 61.05, 65.72, 129.20, 129.44, 132.62, 134.58,
136.62, 142.97. Anal. Calcd for C24H41NO2SSi: C, 66.16; H, 9.48;
N, 3.21. Found: C, 66.39; H, 9.33; N, 3.38.
(-)-[RS,N(1R)]-N-[1-[[(tert-Butyldimethylsilyl)oxy]methyl]-2-
methylpropyl]-S-(cyclohex-1-en-1-ylmethyl)-S-(4-methylphenyl)sul-
foximine (50b): yield 513 mg (52%); [R]20 ) -4.26° (c ) 1.64,
D
CH2Cl2); mp 63.1 °C; RF ) 0.40 (Et2O/hexane ) 1:3); νmax (cm-1) )
1260, 1060 (NdSdO); 1H NMR (270 MHz, CDCl3) δ -0.012, 0.002
(2 × s, OSi(CH3)2), 0.875 (s, OSiC(CH3)3), 0.937, 1.013 (2 × d,
NCHCH(CH3)2), 1.455-2.195 (m, 3-6-H2, NCHCH(CH3)2), 2.449 (s,
p-CH3), 3.113 (ddd, NCH), 3.567, 3.536 (2 × dd, NCHCH2), 3.654,
3.837 (2 × d, SCH2), 5.328 (br s, 2-H), 7.295 (d, m-H2), 7.784 (d,
o-H2); 13C NMR (100 MHz, CDCl3) δ -5.18, -5.10, 16.94, 20.23,
18.59, 21.70, 21.85, 22.94, 26.22, 30.16, 25.88, 29.11, 61.19, 65.46,
65.98, 127.55, 129.38, 129.90, 132.41, 136.77, 143.13. Anal. Calcd
for C25H43NO2SSi: C, 66.76; H, 9.64; N, 3.11. Found: C, 66.64; H,
9.36; N, 3.08.
(-)-[RS,N(1R)]-N-[1-[[(tert-Butyldimethylsilyl)oxy]methyl]-2-
methylpropyl]-S-methyl-S-(4-methylphenyl)sulfoximine (44): yield
7.01 g (95%); [R]20D ) -43.20° (c ) 0.82, CH2Cl2); RF ) 0.55 (ethyl
acetate/hexane ) 2:1); νmax (cm-1) ) 1230, 1130 (NdSdO); 1H NMR
(270 MHz, CDCl3) δ -0.038, -0.027 (2 × s, OSi(CH3)2), 0.846 (s,
OSiC(CH3)3), 0.908, 0.978 (2 × d, NCHCH(CH3)2), 2.005 (m,
NCHCH(CH3)2), 2.429 (s, p-CH3), 3.016 (ddd, NCH), 3.053 (s, S-CH3),
3.458, 3.542 (2 × dd, NCHCH2), 7.313 (d, m-H2), 7.860 (d, o-H2); 13
C
(+)-[SS,N(1R)]-N-[[(1-tert-Butyldimethylsilyl)oxy]methyl]-2-meth-
ylpropyl]-S-(cyclohex-1-en-1-ylmethyl)-S-(4-methylphenyl)sulfox-
imine (51b): yield 408 mg (69%); [R]20D ) 49.62° (c ) 0.66, CH2Cl2);
RF ) 0.45 (Et2O/hexane ) 1:3); νmax (cm-1) ) 1220, 1060 (NdSdO);
1H NMR (270 MHz, CDCl3) δ 0.018, 0.022 (2 × s, OSi(CH3)2), 0.869
(s, OSiC(CH3)3), 0.911, 0.917 (2 × d, NCHCH(CH3)2), 1.476-1.999
(m, 3-6 H2, NCHCH(CH3)2), 2.441 (s, p-CH3), 2.973 (ddd, NCH),
3.590, 3.697 (2 × dd, NCHCH2), 3.747 (s, SCH2), 5.290 (br s, 2-H),
NMR (100 MHz, CDCl3) δ -5.44, -5.34, 16.64, 20.02, 18.34, 21.43,
25.96, 29.76, 44.74, 61.20, 65.67, 128.56, 129.65, 138.06, 143.26. Anal.
Calcd for C19H35NO2SSi: C, 61.74; H, 9.54; N, 3.79. Found: C, 61.98;
H, 9.36; N, 4.05.
(+)-[SS,N(1R)]-N-[1-[[(tert-Butyldimethylsilyl)oxy]methyl]-2-
methylpropyl]-S-methyl-S-(4-methylphenyl)sulfoximine (45): yield
3.38 g (92%); [R]20 ) 99.80° (c ) 1.21, CH2Cl2); RF ) 0.57 (ethyl
D

4776 J. Am. Chem. Soc., Vol. 118, No. 20, 1996
Reggelin et al.
7.294 (d, m-H2), 7.708 (d, o-H2); 13C NMR (100 MHz, CDCl3) δ -5.14,
-5.05, 16.94, 21.01, 18.51, 21.71, 21.86, 22.94, 26.22, 29.56, 25.86,
29.08, 62.02, 66.00, 66.33, 127.80, 129.38, 129.90, 132.22, 135.27,
143.16. Anal. Calcd for C25H43NO2SSi: C, 66.76; H, 9.64; N, 3.11.
Found: C, 66.88; H, 9.42; N, 3.02.
) 1:2); mp 114.8 °C; νmax (cm-1) ) 3380 (OH), 1230, 1100 (NdSdO);
1H NMR (400 MHz, CDCl3) δ -0.130, -0.101 (2 × s, OSi(CH3)2),
0.791 (s, OSiC(CH3)3), 0.982, 1.037 (2 × d, NCHCH(CH3)2), 1.450-
1.811 (m, 4′-H2, 5′-H2), 2.073 (m, NCHCH(CH3)2), 2.420 (m, 3′-H,
pCH3), 2.769 (ddd, 3′-H), 3.056 (ddd, NCH), 3.400, 3.543 (2 × dd,
NCHCH2), 3.980 (ddd, 1′-H), 4.371 (d, 1-H), 5.969 (br s, 1-OH), 6.334
General Procedure for the γ-Hydroxyalkylation of the (2-
Cycloalkenylmethyl)sulfoximines 50a/b and 51a/b. To a well-stirred
solution of the corresponding 2-cycloalkenylsulfoximine (1.0 equiv)
in dry THF (3 mL/mmol) under argon at -78 °C was added via syringe
n-BuLi (1.2 equiv, 1.6 M in n-hexane). After the mixture was stirred
for 15 min at -78 °C, ClTi(OiPr)3 (1.5 equiv, 1.0 M in n-hexane) was
introduced to the yellow or orange reaction mixture within 5 min. The
brown mixture was allowed to warm to 0 °C, stirred for another 60
min, and finally cooled again to -78 °C at which point the aldehyde
(2.0 equiv) was added. The reaction mixture was stirred until no further
change (TLC) could be observed (ca. 2 h). Then saturated aqueous
(NH4)2CO3 (20 mL/mmol) was added with rapid stirring, and after 30
min, the mixture was extracted with ether (3 × 10 mL). After the
organic layer had been dried with MgSO4 and concentrated, the residue
was purified by flash chromatography (eluent: Et2O/hexane).
(-)-[SS,N(1R),1S,1′R,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsilyl)-
oxy]methyl]-2-methylpropyl]-S-4-(methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]ethan-1-ol (52a): yield (210 mg (82%);
[R]20D ) -36.40° (c ) 0.58, CH2Cl2), RF ) 0.11 (Et2O/hexane ) 1:2);
(s, SCH), 7.261-7.450 (m, phenyl-H, m-H2), 7.884 (d, o-H2); J1,1′
)
8.6 Hz, J1′,5′ ) 2.5 Hz, 8.3 Hz; 13C NMR (100 MHz, CDCl3) δ -5.52,
-5.46, 17.34, 20.02, 18.28, 21.45, 20.68, 29.50, 29.87, 25.92, 33.84,
49.21, 61.19, 65.22, 75.46, 125.18, 127.17, 127.46, 128.62, 143.21,
128.31, 129.67, 138.77, 144.15, 161.83. Anal. Calcd for C31H47NO3-
SSi: C, 68.72; H, 8.74; N, 2.58. Found: C, 68.70; H, 8.75; N, 2.62.
(-)-[SS,N(1R),1R,1′R,2S,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-
1-ol (57): yield 254 mg (79%); [R]20D ) -71.10° (c ) 0.78, CH2Cl2);
RF ) 0.17 (Et2O/hexane ) 1:2), νmax (cm-1) ) 3440 (OH), 1250, 1090
(NdSdO); 1H NMR (400 MHz, CDCl3) δ -0.008, 0.007 (2 × s, OSi-
(CH3)2), 0.011, 0.027 (2 × s, OSi(CH3)2), 0.821, 0.887 (2 × d, NCHCH-
(CH3)2), 0.854, 1.015 (2 × s, OSiC(CH3)3), 1.306 (d, 3-H3) 1.614-
1.994 (m, 4′-H2, 5′-H2, NCHCH(CH3)2), 2.343, 2.657 (2 × dd, 3′-H2),
2.425 (s, pCH3), 2.909 (ddd, NCH), 3.086 (ddd, 1′-H), 3.490 (dq, 2-H),
3.623, 3.710 (2 × dd, NCHCH2), 3.820 (dd, 1-H), 5.061 (br s, 1-OH),
6.545 (s, SCH), 7.292 (d, m-H2), 7.794 (d, o-H2); J1,2 ) 5.2 Hz, J2,3
)
6.2 Hz; 13C NMR (100 MHz, CDCl3) δ -5.40, -5.25, -4.50, -4.27,
16.64, 20.54, 18.03, 18.23, 20.76, 21.44, 21.12, 32.10, 33.40, 25.96,
29.30, 47.36, 62.09, 66.49, 74.02, 76.95, 124.88, 128.54, 129.48, 137.73,
143.09, 164.32. Anal. Calcd for C33H61NO4SSi2: C, 63.51; H, 9.85;
N, 2.24. Found: C, 63.33; H, 9.85; N, 2.08.
ν
max (cm-1) ) 3380 (OH), 1220, 1110 (NdSdO); 1H NMR (400 MHz,
CDCl3) δ 0.025, 0.036 (2 × s, OSi(CH3)3), 0.756, 0.862 (2 × d,
NCHCH(CH3)2), 0.857 (s, OSiC(CH3)3), 1.303 (d, 2-H3), 1.585-1.867
(m, 4′-H2, 5′-H2, NCHCH(CH3)2), 2.329, 2.642 (2 × dd, 3′-H2), 2.396
(s, p-CH3), 2.971 (ddd, NCH), 3.464-3.506 (m, 1′-H, 1-H), 3.667 (dd,
NCHCH2), 5.385 (br s, 1-OH), 6.393 (s, SCH), 7.265 (d, m-H2), 7.800
(d, o-H2); J1,1 ) 3.9 Hz, J1,2 ) 6.4 Hz, J1′,5′ ) 2.8, 6.5 Hz; 13C NMR
(100 MHz, CDCl3) δ -5.37, -5.25, 17.30, 21.22, 18.30, 20.27 (C-2),
21.47, 23.51, 29.60, 29.96, 26.00, 33.71, 50.22, 61.94, 66.60, 69.05,
125.02, 128.64, 129.47, 138.65, 143.06, 163.40. Anal. Calcd for C26-
H45NO3SSi: C, 65.09; H, 9.45; N, 2.92. Found: C, 64.79; H, 9.40;
N, 2.77.
(-)-[SS,N(1R),1R,1′R,2R,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-
1-ol (56): yield 174 mg (45%), [R]20D ) -76.70° (c ) 0.69, CH2Cl2);
RF ) 0.18 (Et2O/hexane ) 1:2), νmax (cm-1) ) 3420 (OH), 1240, 1100
1
(NdSdO); H NMR (400 MHz, CDCl3) δ 0.039, 0.047 (2 × s, OSi-
(CH3)2), 0.831, 0.891 (2 × d, NCHCH(CH3)2), 0.876, 0.928 (2 × s,
OSiC(CH3)3), 1.266 (d, 3-H3) 1.474-2.010 (m, 4′-H2 , 5′-H2, NCH-
CH(CH3)2), 2.311, 2.663 (2 × m, 3′-H2), 2.402 (s, p-CH3), 3.066 (ddd,
NCH), 3.187 (ddd, 1′-H), 3.658 (dd, NCHCH2), 3.738 (dq, 2-H), 3.996
(dd, 1-H), 4.829 (br s, 1-OH), 6.472 (s, SCH), 7.257 (d, m-H2), 7.816
(d, o-H2); J1,2 ) 1.9 Hz, J2,3 ) 6.3 Hz; 13C NMR (100 MHz, CDCl3)
δ -5.38, -5.25, -4.79, -4.31, 17.41, 19.42, 18.08, 18.31, 20.38, 21.44,
20.89, 29.98, 33.69, 25.91, 26.02, 28.56, 43.79, 61.86, 66.92, 70.25,
74.61, 124.90, 128.54, 129.37, 139.08, 142.73, 164.01. Anal. Calcd
for C33H61NO4SSi2: C, 63.51; H, 9.85; N, 2.24. Found: C, 63.56; H,
9.92; N, 2.05.
(+)-[RS,N(1R),1R,1′S,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsilyl)-
oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-1-cyclohexylmethanol (53c): yield 190
mg (74%); [R]20 ) 121.20° (c ) 0.86, CH2Cl2); RF ) 0.15 (Et2O/
D
1
hexane ) 1:2), νmax (cm-1) ) 3390 (OH), 1220, 1100 (NdSdO); H
NMR (400 MHz, CDCl3) δ -0.086, -0.061 (2 × s, OSi(CH3)2), 0.827
(s, OSiC(CH3)2), 0.927, 0.983 (2 × d, NCHCH(CH3)2), 1.182-1.816
(m, cyclohexyl-H, 4′-H2, 5′-H2), 2.011 (dqq, NCHCH(CH3)2), 2.335,
2.650 (2 × dd, 3′-H2), 2.415 (s, pCH3), 2.999 (ddd, NCH), 3.121 (ddd,
1′-H), 3.372, 3.503 (2 × dd, NCHCH2), 3.675 (dd, 1-H), 4.642 (br s,
1-OH), 6.234 (s, SCH), 7.280 (d, m-H2), 7.819 (d, o-H2); J1,1′ ) 8.7
Hz, J1′,5′ ) 2.5 Hz, 8.1 Hz; 13C NMR (100 MHz, CDCl3) δ -5.54,
-5.49, 17.19, 19.90, 18.46, 21.09, 21.37, 25.16, 25.93, 26.32, 26.52,
26.88, 29.62, 29.76, 31.25, 34.07, 44.84, 60.93, 65.22, 75.96, 124.34,
128.49, 129.51, 139.05, 142.90, 163.30. Anal. Calcd for C31H52NO3-
SSi: C, 68.00; H, 9.57; N, 2.56. Found: C, 67.71; H, 9.65; N, 2.48.
(-)-[SS,N(1R),1R,1′R,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsilyl)-
oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-1-phenylmethanol (52e): yield 410 mg
(80%); [R]20D ) -47.10° (c ) 0.86, CH2Cl2), RF ) 0.27 (Et2O/hexane
(+)-[RS,N(1R),1S,1′S,2S,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-
1-ol (55): yield 188 mg (64%); [R]20D ) 134.70° (c ) 0.68, CH2Cl2);
RF ) 0.18 (Et2O/hexane ) 1 : 2), νmax (cm-1) ) 3480 (OH), 1250,
1
1110 (NdSdO); H NMR (400 MHz, CDCl3) δ -0.062, -0.046 (2
× s, OSi(CH3)2), 0.082, 0.097 (2 × s, OSi(CH3)2), 0.834, 0.928 (2 ×
s, OSiC(CH3)3), 0.936, 0.989 (2 × d, NCHCH(CH3)2), 1.267 (d, 3-H3),
1.507-2.073 (m, 4′-H2, 5′-H2, NCHCH(CH3)2), 2.324, 2.662 (2 × m,
3′-H2), 2.412 (s, p-CH3), 3.131 (m, 1′-H, NCH), 3.473 (dd, NCHCH2),
3.786 (dq, 2-H), 3.992 (dd, 1-H), 4.607 (br s, 1-OH), 6.214 (s, SCH),
7.272 (d, m-H2), 7.818 (d, o-H2); J1,2 ) 1.9 Hz, J2,3 ) 6.3 Hz; 13C
NMR (100 MHz, CDCl3) δ -5.47, -5.40, -4.76, -4.31, 16.70, 19.71,
18.07, 18.35, 20.32, 21.41, 21.03, 28.61, 34.13, 25.89, 26.00, 29.49,
43.65, 60.68, 65.62, 69.92, 74.53, 124.39, 128.33, 129.47, 139.40,
142.73, 163.39. Anal. Calcd for C33H61NO4SSi2: C, 63.51; H, 9.85;
N, 2.24. Found: C, 63.44; H, 9.63; N, 2.13.
1
) 1:1), νmax (cm-1) ) 3380 (OH), 1220, 1120 (NdSdO); H NMR
(400 MHz, CDCl3) δ -0.010, -0.003 (2 × s, OSi(CH3)2), 0.740, 0.797
(2 × d, NCHCH(CH3)2), 0.813 (s, OSiC(CH3)3), 1.351-1.789 (m, 4′-
H2, 5′-H2, NCHCH(CH3)2), 2.328, 2.703 (2 × m, 3′-H2), 2.328 (s,
pCH3), 3.013 (ddd, NCH), 3.673 (dd, NCHCH2), 3.836 (ddd, 1′-H),
4.233 (d, 1-H), 6.087 (br s, 1-OH), 6.476 (s, SCH), 7.166-7.366 (m,
phenyl-H, m-H2), 7.787 (d, o-H2); J1,1′ ) 9.1 Hz, J1′,5′ ) 3.1 Hz, 8.6
Hz; 13C NMR (100 MHz, CDCl3) δ -5.33, -5.21, 17.60, 20.34, 18.45,
21.49, 20.67, 29.40, 29.96, 26.05, 33.38, 49.64, 62.18, 66.85, 75.44,
125.95, 127.20, 127.52, 128.38, 143.23, 128.66, 129.58, 138.49, 144.41,
162.97. Anal. Calcd for C31H47NO3SSi: C, 68.72; H, 8.74; N, 2.58.
Found: C, 68.66; H, 8.54; N, 2.52.
(+)-[RS,N(1R),1S,1′S,2R,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-
1-ol (54): yield 989 mg (53%); [R]20 ) 80.00° (c ) 0.69, CH2Cl2);
D
RF ) 0.15 (Et2O/hexane ) 1:2); νmax (cm-1) ) 3400 (OH), 1240, 1110
1
(+)-[RS,N(1R),1S,1′S,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsilyl)-
oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclopent-1′-yl]-1-phenylmethanol (53e): yield 197 mg
(NdSdO); H NMR (400 MHz, CDCl3) δ -0.096, -0.089 (2 × s,
OSi(CH3)2), 0.070, 0.104 (2 × s, OSi(CH3)2), 0.819, 0.890 (2 × s,
OSiC(CH3)3), 0.925, 0.984 (2 × d, NCHCH(CH3)2), 1.301 (d, 3-H3)
1.570-2.014 (m, 4′-H2, 5′-H2, NCHCH(CH3)2), 2.347, 2.653 (2 × m,
(75%), [R]20 ) 57.60° (c ) 0.95, CH2Cl2); RF ) 0.16 (Et2O/hexane
D

Metalated 2-Alkenylsulfoximines
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4777
3′-H2), 2.414 (s, p-CH3), 2.960 (ddd, NCH), 3.107 (m, 1′-H), 3.334
(dd, NCHCH), 3.481 (m, 2-H, NCHCH), 3.846 (dd, 1-H), 4.633 (br s,
1-OH), 6.340 (s, SCH), 7.276 (d, m-H2), 7.800 (d, o-H2); J1,1′ ) 6.2
Hz, J1′,5′ ) 6.6 Hz, 2.6 Hz, J2,3 ) 6.1 Hz, J1,2 ) 4.2 Hz; 13C NMR (100
MHz, CDCl3) δ -5.49, -5.40, -4.48, -4.28, 17.37, 19.94, 18.09,
18.33, 20.65, 21.40, 21.10, 31.52, 34.23, 25.96, 25.98, 29.98, 46.98,
61.23, 65.39, 73.91, 76.59, 124.82, 128.55, 129.58, 138.56, 142.97,
163.58. Anal. Calcd for C33H61NO4SSi2: C, 63.51; H, 9.85; N, 2.24.
Found: C, 63.80; H, 9.76; N, 2.09.
(+)-[RS,N(1R),1S,1′S,2S,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
methylene]cyclohex-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-1-
ol (59): yield 131 mg (90%); [R]20D ) 94.23° (c ) 0.52, CH2Cl2); mp
102.9 °C; RF ) 0.14 (Et2O/hexane ) 1:3), νmax (cm-1) ) 3440 (OH),
1230, 1080 (NdSdO); 1H NMR (400 MHz, CDCl3) δ -0.132, -0.106
(2 × s, OSi(CH3)2), 0.040, 0.071 (2 × s, OSi(CH3)2), 0.792, 0.890 (2
× s, OSiC(CH3)3), 0.891, 0.957 (2 × d, NCHCH(CH3)2), 1.219 (d,
3-H3), 1.267-2.145 (m, 3′-H, 4′-H2, 5′-H2, 6′-H2, NCHCH(CH3)2),
2.415 (s, p-CH3), 2.453 (dd, 3′-H), 2.900 (ddd, NCH), 3.228, 3.434 (2
× dd, NCHCH2), 3.610 (ddd, 1′-H), 3.689 (dd, 1-H), 3.766 (br s, 1-OH),
4.013 (dq, 2-H), 6.445 (s, SCH), 7.261 (d, m-H2), 7.781 (d, o-H2); J1,2
) 1.8 Hz; 13C NMR (100 MHz, CDCl3) δ -5.53, -5.48, -4.80, -4.41,
16.80, 19.97, 18.26, 18.45, 20.38, 21.40, 20.75, 26.97, 28.02, 25.87,
25.91, 29.51, 32.99, 38.97, 60.58, 65.30, 70.52, 72.90, 127.67, 128.31,
129.40, 139.72, 142.58, 160.06. Anal. Calcd for C34H63NO4SSi2: C,
63.99; H, 9.95; N, 2.19. Found: C, 63.92; H, 9.83; N, 2.09.
methylene]cyclohex-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-1-
ol (61): yield 173 mg (42%); [R]20 ) -39.23° (c ) 0.91, CH2Cl2),
D
RF ) 0.09 (Et2O/hexane ) 1:3), νmax (cm-1) ) 3420 (OH), 1240, 1090
(NdSdO); 1H NMR (400 MHz, CDCl3) δ -0.020, 0.001 (2 × s, OSi-
(CH3)2), 0.029, 0.058 (2 × s, OSi(CH3)2), 0.721, 0.842 (2 × d, NCHCH-
(CH3)2), 0.836, 0.891 (2 × s, OSiC(CH3)3), 1.219 (d, 3-H3), 0.923-
2.128 (m, 3′-H, 4′-H2, 5′-H2, 6′-H2, NCHCH(CH3)2), 2.403 (s, p-CH3),
2.477 (ddd, 3′-H), 2.760 (ddd, NCH), 3.653 (m, 1′-H, 1-H, NCHCH2),
4.015 (dq, 2-H), 4.300 (br s, 1-OH), 6.495 (s, SCH), 7.268 (d, m-H2),
7.746 (d, o-H2); J1,2 ) 1.7 Hz, J2,3 ) 6.3 Hz; 13C NMR (100 MHz,
CDCl3) δ -5.55, -5.40, -4.92, -4.68, 16.13, 20.38, 17.82, 18.08,
20.61, 21.31, 20.68, 26.79, 27.78, 25.72, 25.81, 28.87, 32.66, 39.06,
61.62, 66.09, 70.85, 72.73, 127.43, 128.58, 129.19, 138.02, 142.61,
159.87. Anal. Calcd for C34H63NO4SSi2: C, 63.99; H, 9.95; N, 2.19.
Found: C, 63.72; H, 9.86; N, 2.37.
Removal of the auxiliary: To a solution of 156 mg (0.381 mmol)
of the bicyclosulfoximine 63 (1:1 epimeric mixture) in 3 mL of dry
dichloromethane under argon at -20 °C was added via syringe 313
mg (1.905 mmol) of methyl triflate. After being stirred for 5 h at this
temperature, the mixture was warmed to 0 °C and 696 mg (4.572 mmol)
of DBU was added. The reaction mixture was stirred for another 30
min, then 10 mL of saturated aqueous NH4Cl solution was added, the
aqueous phase was extracted three times with dichloromethane (10 mL
each), and the organic extracts dried with MgSO4 and purified by flash
chromatography (eluent: EA/hexane ) 1:5).
(+)-(1S,3R,4S,5R)-4-Hydroxy-3-methyl-1-vinyl-2-oxabicyclo[3.3.0]-
octane (64): yield 45 mg (70%); [R]20D ) 22.61° (c ) 0.12, CH2Cl2);
RF ) 0.48 (EA/hexane ) 1:1), 1H NMR (400 MHz, CDCl3) δ 1.31 (d,
3-CH3), 1.53 (d, 4-OH), 1.66 (m, 7′-H), 1.70-1.90 (m, 8-H2, 9-H2),
1.95 (m, 7-H), 2.48 (ddd, 5-H), 3.75 (dq, 3-H), 3.85 (ddd, 4-H), 5.01
(dd, 2′cis-H), 5.28 (dd, 2′trans-H), 5.96 (dd, 1′-H); J1′,2′cis ) 10.6 Hz,
(-)-[SS,N(1R),1R,1′R,2S,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)(sulfonimidoyl]-
methylene]cyclohex-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-1-
ol (60): yield 123 mg (67%); [R]20 ) -51.11° (c ) 0.50, CH2Cl2);
D
RF ) 0.21 (Et2O/hexane ) 1:3), νmax (cm-1) ) 3500 (OH), 1230, 1110
1
(NdSdO); H NMR (400 MHz, CDCl3) δ 0.002, 0.022 (2 × s, OSi-
J1′,2′trans ) 17.1 Hz, J2′cis,2′trans ) 1.7 Hz, J3,3-CH ) 5.9 Hz, J3,4 ) 8.5 Hz
3
(CH3)2), 0.085, 0.098 (2 × s, OSi(CH3)2), 0.747, 0.848 (2 × d, NCHCH-
(CH3)2), 0.848, 0.895 (2 × s, OSiC(CH3)3), 1.238 (d, 3-H3), 1.125-
2.133 (m, 3′-H, 4′-H2, 5′-H2, 6′-H2, NCHCH(CH3)2), 2.423 (s, p-CH3),
2.461 (dd, 3′-H), 2.777 (ddd, NCH), 3.650 (m, 1′-H, 1-H, NCHCH2),
3.895 (dq, 2-H), 4.090 (br s, 1-OH), 6.444 (s, SCH), 7.293 (d, m-H2),
7.764 (d, o-H2); J1,2 ) 5.3 Hz, J2,3 ) 6.2 Hz; 13C NMR (100 MHz,
CDCl3) δ -5.41, -5.28, -4.50, -4.32, 16.26, 20.51, 18.11, 18.21,
18.64, 21.43, 20.97, 27.48, 27.91, 25.94, 25.95, 28.98, 33.18, 41.19,
61.92, 66.23, 71.94, 73.70, 127.42, 128.71, 129.34, 137.86, 142.89,
159.30. Anal. Calcd for C34H63NO4SSi2: C, 63.99; H, 9.95; N, 2.19.
Found: C, 64.22; H, 10.05; N, 2.25.
J4,OH ) 5.9 Hz J4,5 ) 7.3 Hz, J4,5 ) 7.3 Hz, J5,6′) 5.0 Hz, J5,6) 9.5
Hz; 13C NMR (100 MHz, CDCl3) δ -18.8 (3-CH3), 24.81 (6-C), 26.18
(7-C), 41.04 (8-C), 52.16 (5-C), 78.17 (4-C), 78.66 (3-C), 92.70 (1-
C), 111.61 (2′-C), 142.72 (1′-C). Anal. Calcd for C10H16O2: C, 71.39;
H, 9.53; Found: C, 71.25; H, 9.45.
Acknowledgment. This work has been supported by grants
from the Deutsche Forschungsgemeinschaft (DFG, Re 1007/1-
2/1-4). M.R. thanks the DFG for a Habilitationstipendium (Re
1007/1-1/1-3). H.W. thanks the Graduiertenkolleg der Univer-
sita¨t Frankfurt for a fellowship. Furthermore we would like to
thank Dr. J. Bats and Dr. M. Bolte for their careful work on
the X-ray structures of 21, 59 (J.B.), and 62 (M.B.). We are
indebted to Prof. Dr. C. Griesinger for his generous support.
(+)-[RS,N(1R),1S,1′S,2R,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-4-(methylphenyl)sulfonimidoyl]-
methylene]cyclohex-1′-yl]-2-[(tert-butyldimethylsilyl)oxy]propan-1-
ol (58): yield 248 mg (80%); [R]20 ) 114.85° (c ) 0.51, CH2Cl2);
D
mp 75.8 °C; RF ) 0.09 (Et2O/hexane ) 1:5), νmax (cm-1) ) 3460 (OH),
1250, 1100 (NdSdO); 1H NMR (400 MHz, CDCl3) δ -0.128, -0.099
(2 × s, OSi(CH3)2), 0.064, 0.086 (2 × s, OSi(CH3)2), 0.797, 0.888 (2
× s, OSiC(CH3)3), 0.891, 0.958 (2 × d, NCHCH(CH3)2), 1.213 (d,
3-H3), 0.989-2.131 (m, 3′-H, 4′-H2, 5′-H2, 6′-H2, NCHCH(CH3)2),
2.414 (s, p-CH3), 2.467 (ddd, 3′-H), 2.934 (ddd, NCH), 3.265, 3.442
(2 × dd, NCHCH2), 3.538 (m, 1′-H, 1-OH), 3.741 (dd, 1-H), 3.914
(dq, 2-H), 6.340 (s, SCH), 7.281 (d, m-H2), 7.796 (d, o-H2); J1,2 ) 4.1
Hz, J2,3 ) 6.2 Hz; 13C NMR (100 MHz, CDCl3) δ -5.53, -5.46, -4.54,
-4.36, 16.80, 20.03, 17.94, 18.12, 18.26, 21.41, 20.57, 27.79, 27.84,
25.93, 29.44, 33.22, 40.47, 60.75, 65.27, 71.30, 73.41, 127.29, 128.46,
129.47, 139.37, 142.72, 159.22. Anal. Calcd for C34H63NO4SSi2: C,
63.99; H, 9.95; N, 2.19. Found: C, 64.28; H, 10.04; N, 2.18.
(-)-[SS,N(1R),1R,1′R,2R,2′Z]-1-[2′-[[N-[1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-2-methylpropyl]-S-(4-methylphenyl)sulfonimidoyl]-
Supporting Information Available: Structure determination
summaries for compounds 21, 59, and 62; final atomic
coordinates, general displacement parameters, bond lengths,
bond angles, torsions, and plots; text describing details for the
preparation and analytical data for the acyclic sulfoximines
described in Table 1, Table 2, and Scheme 7 (17a-e, 18a-e,
19a-e, 20a-e, 52b-d,f, 53a,b,d, and 26-33) (54 pages). This
material is contained in many libraries on microfiche, im-
mediately follows this article in the microfilm version of the
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information and Internet access instructions.
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