Diastereoselective synthesis of enantiopure acyclic ss,ss -disubstituted vinylsulfoxides

Article abstract of DOI:10.1021/ol800368g

Thermal elimination of sulfenic acid from enantiopure ss,ss -disubstituted bis-sulfoxides allows the stereoselective synthesis of enantiopure acyclic ss,ss -disubstituted vinylsulfoxides. This mild and stereospecific synthesis provides either (E) or (Z) v

Full text of DOI:10.1021/ol800368g

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1917-1920
Diastereoselective Synthesis of
Enantiopure Acyclic ꢀ,ꢀ′-Disubstituted
Vinylsulfoxides
Franck Brebion, Jean-Philippe Goddard, Louis Fensterbank,* and Max Malacria*
UPMC- UniV. Paris 06, Laboratoire de Chimie Organique, UMR 7611, Institut de
Chimie Mole´culaire, FR 2769, case 229, 4 place Jussieu,
75252 Paris Cedex 05, France
louis.fensterbank@upmc.fr; max.malacria@upmc.fr
Received February 18, 2008
ABSTRACT
Thermal elimination of sulfenic acid from enantiopure ꢀ,ꢀ′-disubstituted bis-sulfoxides allows the stereoselective synthesis of enantiopure
acyclic ꢀ,ꢀ′-disubstituted vinylsulfoxides. This mild and stereospecific synthesis provides either (E) or (Z) vinylsulfoxides in high yields and
is compatible with acid or base sensitive functional groups.
Vinylsulfoxides are valuable intermediates in asymmetric
synthesis as demonstrated by the many studies concerning
their use as inductors of chirality.1 For example, they are
efficient partners in Diels-Alder reactions,2 [2 + 2] and 1,3-
dipolar cycloadditions,3 Pauson-Khand reactions4and [3,3]-
sigmatropic shift5 and are powerful Michael acceptors in
radical or anionic conditions.2a,6 Vinylsulfoxides have also
served as precursors of functionalized allenes whether by a
radical or an organometallic route7 and as monomers for
anionic polymerization to give asymmetric star polymers.8
Recently, also, an enantiopure vinylsulfoxide has been used
as a key building block in the total synthesis of (+)-
aspidospermidine.9 Whereas numerous syntheses of enan-
tiopure ꢀ-monosubstituted vinylsulfoxides have been devel-
oped,10 only few methods allow the regio- and stereoselective
preparation of their ꢀ,ꢀ′-disubstituted analogues and espe-
cially in acyclic series.11 These methods are based mainly
on the addition of an organometallic species (Cu,11a,e Zn,11c
(3) [2 + 2]: (a) Bienayme´, H.; Guicher, N. Tetrahedron Lett. 1997, 38,
5511–5514. (b) Loughlin, W. A.; Rowen, C. C.; Healy, P. C. J. Org. Chem.
2004, 69, 5690–5698. (c) Loughlin, W. A.; Rowen, C. C.; Healy, P. C.
Synthesis 2005, 2220–2226, and references therein1,3-Dipolar: (d) Chaigne,
F.; Gotteland, J.-P.; Malacria, M. Tetrahedron Lett. 1989, 30, 1803–1806.
(e) Midura, W. H.; Krysiak, J. A.; Mikolajczyk, M. Tetrahedron 1999, 55,
14791–14802. (f) Garcia Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org.
Chem. 2002, 67, 981–987. (g) Louis, C.; Hootele, C. Tetrahedron:
Asymmetry 1997, 8, 109–131.
(4) Rivero, M. R.; Alonso, I.; Carretero, J. C. Chem.-Eur. J. 2004, 10,
5443–5459, and references cited thereins.
(5) (a) Marino, J. P. Pure Appl. Chem. 1993, 65, 667–674. (b) Alayrac,
C.; Fromont, C.; Metzner, P.; Anh, N. T. Angew. Chem., Int. Ed. 1997, 36,
371–374.
(1) For recent reviews: (a) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003,
103, 3651–3705. (b) Pellissier, H. Tetrahedron 2006, 62, 5559–5601.
(2) (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717–1760, and references
cited therein. (b) Carren˜o, M. C.; Garcia-Cerrada, S.; Urbano, A.
Chem.-Eur. J. 2003, 9, 4118–4131, and references cited therein.
(6) (a) Lacoˆte, E.; Delouvrie´, B.; Fensterbank, L.; Malacria, M. Angew.
Chem., Int. Ed. 1998, 37, 2116–2118. (b) Marino, J. P.; Viso, A.; Lee,
J.-D.; Fernandez de la Pradilla, R.; Fernandez, P.; Rubio, M. B. J. Org.
Chem. 1997, 62, 645–653. (c) Srikanth, G. S. C.; Castle, S. L. Tetrahedron
2005, 61, 10377–10441, and references cited therein.
10.1021/ol800368g CCC: $40.75
Published on Web 04/12/2008
2008 American Chemical Society

Te11d) to an acetylenic sulfoxide and proceed in good yield
and stereoselectively. However, they are essentially limited
to the formation of C-C bonds12 and are not compatible
with bases or reducing agent sensitive functional groups.
Acyclic vinylsulfoxides substituted by a heteroatom (O, N,
S) in the ꢀ position have also drawn a lot of attention, but
only a few syntheses are stereoselective. In this context, there
is still a need to develop a mild and neutral synthesis which
enables us to prepare acyclic ꢀ,ꢀ′-disubstituted vinylsulfox-
ides bearing not only alkyl and aryl but also heteroatomic
substituents in good yield and with high stereocontrol.
investigate further this reaction as a potential new access to
acyclic ꢀ,ꢀ′-disubstituted vinylsulfoxides.
In a first step, we tested the viability of our approach by
studying the reactivity and the diastereoselectivity of the
ꢀ-elimination. Our systems differ from others by the presence
of a tertiary stereogenic carbon, and we designed different
precursors to investigate its influence. The diastereoselectivity
was examined from two diastereomeric bis-sulfoxides 1a15a
and 2, prepared, respectively, by addition of MeCu·LiI and
Me3ZnLi on an alkylidene bis-sulfoxide. When heated at 70
°C in toluene, 1a and 2 gave vinylsulfoxides 3a and 4,
respectively, in high yield (Scheme 1). The double bond
We recently reported the diastereoselective Michael ad-
dition of nucleophiles and radicals onto alkylidene bis-
sulfoxides13 affording enantiopure ꢀ,ꢀ′-disubstituted bis-
sulfoxides.14,15 In the course of these studies, we noticed
some adducts were prone to spontaneously ꢀ-eliminate a
molecule of sulfenic acid at room temperature to generate
ꢀ,ꢀ′-disubstituted vinylsulfoxides (Scheme 1).14,15 Although
the ꢀ-elimination of sulfenic acid has been extensively
studied16 and has found applications for the synthesis of
alkenes or R,ꢀ-unsaturated carbonyls,17 only a limited
number of examples involved bis-sulfoxides.18 Interestingly,
Trost described two examples of condensation of the lithium
anion of bis(phenylsulfinyl)-methane with a primary alkyl
halide followed by in situ elimination of sulfenic acid to
afford only E vinylsulfoxides.19 This encouraged us to
Scheme 1. Thermolysis of Diastereomeric ꢀ,ꢀ′-Disubstituted
Bis-Sulfoxides: A Stereospecific Reaction
configurations were attributed by NOE and 13C NMR
γ-effect.20 These reactions are completely stereospecific with
regard to the carbon stereogenic center, and in both experi-
ments, no trace of the other diastereomer was detected.
The ꢀ-elimination proceeded quite rapidly at moderate
temperature,21 and we examined if the steric strain in the
starting material might play a significant role. Thus, we
prepared bis-sulfoxide 5 by Meerwein-Ponndorf-Verley
reduction of the adequate alkylidene bis-sulfoxide with
lithium ethoxide, as well as 6 by condensation of the lithium
anion of (SS,SS)-bis(p-tolylsulfinyl)methane onto 5-bro-
mopentene. When heated at 70 °C, 5 and 6 afforded only
the corresponding (E) vinylsulfoxides 7 and 8, respectively,
but with moderate yield and extended reaction time (Scheme
2). So the steric strain induced by both sulfoxide moieties
and the substituents on the ꢀ-carbon would ease the elimina-
tion reaction, a finding which was already rationalized for
simple sulfoxides by a steric destabilization of the starting
material and release of the steric strain in the transition
state.16
(7) (a) Mourie`s, V.; Delouvrie´, B.; Lacoˆte, E.; Fensterbank, L.; Malacria,
M. Eur. J. Org. Chem. 2002, 1776–1787. (b) Varghese, J. P.; Knochel, P.;
Marek, I. Org. Lett. 2000, 2, 2849–2852. See also: (c) Sklute, G.; Amsallem,
D.; Shabli, A.; Varghese, J. P.; Marek, I. J. Am. Chem. Soc. 2003, 125,
11776–11777.
(8) Zhao, Y.; Higashihara, T.; Sugiyama, K.; Hirao, A. J. Am. Chem.
Soc. 2005, 127, 14158–14159.
(9) Marino, J. P.; Rubio, M. B.; Cao, G.; De Dios, A. J. Am. Chem.
Soc. 2002, 124, 13398–13399.
(10) Chernysheva, N. A.; Gusarova, N. K.; Trofimov, B. A. Russ. J.
Org. Chem. 2000, 36, 1–23.
(11) (a) Truce, W. E.; Lusch, M. J. J. Org. Chem. 1978, 43, 2252–
2258. (b) Alonso, I.; Carretero, J. C. J. Org. Chem. 2001, 66, 4453–4456.
(c) Maezaki, N.; Sawamoto, H.; Yoshigami, R.; Suzuki, T.; Tanaka, T. Org.
Lett. 2003, 5, 1345–1347. (d) Xu, Q.; Huang, X.; Ni, J. Tetrahedron Lett.
2004, 45, 2981–2984. (e) Xu, Q.; Huang, C.-Y. Tetrahedron Lett. 2004,
45, 5657–5660.
(12) Only rare examples of intermolecular addition of heteroatomic
nucleophiles onto substituted acetylenic sulfoxides have been reported. See:
(a) McMullen, C. H.; Stirling, C. J. M. J. Chem. Soc. (B) 1966, 121, 7–
1220. (b) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.; Suzuki, T.;
Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68, 5550–
5558.
(13) For the synthesis of alkylidene bis-sulfoxides see: Delouvrie´, B.;
Najera, F.; Fensterbank, L.; Malacria, M. J. Organomet. Chem. 2002,
643-644, 130–135.
(14) Brebion, F.; Vitale, M.; Fensterbank, L.; Malacria, M. Tetrahedron:
Asymmetry 2003, 14, 2889–2896
.
(15) (a) Brebion, F.; Delouvrie´, B.; Najera, F.; Fensterbank, L.; Malacria,
M.; Vaissermann, J. Angew. Chem., Int. Ed. 2003, 42, 5342–5345. (b)
Brebion, F.; Goddard, J.-P.; Louis Fensterbank, L.; Malacria, M. Synthesis
2005, 2449–2452. (c) Brebion, F.; Goddard, J.-P.; Gomez, C.; Fensterbank,
L.; Malacria, M. Synlett 2006, 713–716. (d) For recent work on bis-sulfinyl
derivatives: Goddard, J.-P.; Gomez, C.; Brebion, F.; Beauvie`re, S.;
Scheme 2. Thermolysis of ꢀ-Monosubstituted Bis-Sulfoxides
Fensterbank, L.; Malacria, M. Chem. Commun. 2007, 2929–2931
.
(16) (a) Cubbage, J. W.; Guo, Y.; McCulla, R. D.; Jenks, W. S. J. Org.
Chem. 2001, 66, 8722–8736, and references cited therein. (b) McCulla,
R. D.; Jenks, W. S. J. Org. Chem. 2003, 68, 7871–7879.
(17) (a) Trost, B. M. Chem. ReV. 1978, 78, 363–382. (b) Trost, B. M.
Acc. Chem. Res. 1978, 11, 453–461.
(18) (a) Carretero, J. C.; Garcia Ruano, J. L.; Martin Cabrejas, L. M.
Tetrahedron: Asymmetry 1997, 8, 409–416. (b) Boivin, J.; Chauvet, C.;
Zard, S. Z. Tetrahedron Lett. 1992, 33, 4913–4916.
(19) Trost, B. M.; Bridges, A. J. J. Org. Chem. 1975, 40, 2014–16.
1918
Org. Lett., Vol. 10, No. 10, 2008

To determine the scope of this reaction, we performed the
thermolysis of differently substituted bis-sulfoxides. First,
we examined bis-sulfoxides 1a-g prepared by conjugate
addition of organocopper(I) reagents onto alkylidene bis-
sulfoxides. The ꢀ-elimination proceeded with high yield and
diastereoselectivity with alkyl, aryl, or functionalized sub-
stituents (Table 1). The reaction is finished after 4-11 h and
When heated at 70 °C, 915c and 1015a gave vinylsulfoxides
11 and 12, respectively, with high yield and as unique
products. The absence of double bond isomerization or
epimerization demonstrates the compatibility of this reaction
with base sensitive compounds. To the best of our knowl-
edge, 11 and 12 are the first examples of vinylsulfoxides
bearing a homochiral allylic stereogenic carbon in R position
to an ester. We also applied this reaction to the synthesis of
sulfinyl dienes. So an 8.3:1 mixture of two diastereomers
13M and 13m (epimers at the allylic position),15c differing
only by the absolute configuration of the stereogenic carbon,
gave the two dienes (E,E)-15 and (E,Z)-15 in a ratio of 8.3:
1. Considering the previous results, it is reasonable to assume
that each diastereomer gives only one diene, and the reaction
is stereospecific.
Table 1. Synthesis of ꢀ,ꢀ′-Disubstituted Vinylsulfoxides
In the same conditions, bis-sulfoxide 15 gave vinylsul-
foxide 16 as the main product as indicated by the crude NMR
(Scheme 4). Formally, 16 is equivalent to the addition
Scheme 4. Easy Isomerization into an Allylsulfoxide
a DoublebondconfigurationwasdeterminedbyNOE.b Diastereoselectivity
was determined by NMR. c Reaction is completed after 4-5 h.
is made easier by the formation of a π-conjugated system
(Table , entries 5-7). The diastereoselectivity is complete
except when R1 is an isopropyl group (entries 2 and 3), but
in these examples, the stereoselectivity remains superior to
95:5. Interestingly, the nature of R1 and R2 has no influence
on the double bond configuration, and the sole stereo-
chemistry of the stereogenic carbon seems to play a role
which endows this reaction with a highly predictable
outcome.
product of the malonate anion onto an acetylenic sulfoxide;
such a reaction has never been reported so far. Our attempts
to purify 16 by chromatography on silica or alumina were
unsuccessful and led to the isomerization of the double bond
to afford 17 in 93% yield. No analytical study was carried
out to examine the possible racemization of the sulfur atom
via a [2,3]-shift.22
The lack of efficient and stereoselective synthesis of
acyclic ꢀ,ꢀ′-disubstituted vinylsulfoxides bearing an alkoxy
substituent and the easy access to bis-sulfoxides of type 18
by conjugate addition of alkoxides onto alkylidene bis-
sulfoxides15a prompted us to examine the thermolysis of
diastereomers 18 and 19 as a straightforward synthesis of
vinylsulfoxides 20. The ꢀ elimination reactions took place
but required triethylamine as an additive to scavenge the
The reactivity of Michael adducts of ester enolates on
alkylidene bis-sulfoxides was also investigated (Scheme 3).
Scheme 3
.
Synthesis of Vinyl and Dienyl Sulfoxides Substituted
by an Ester Group
Scheme 5
.
ꢀ,ꢀ′-Disubstituted Vinylsulfoxides Bearing an OR
Moiety
Org. Lett., Vol. 10, No. 10, 2008
1919

Scheme 6. Proposition of a Diastereoselectivity Model
sulfenic acid formed during the reaction (Scheme 5). In the
absence of Et3N, only the keto sulfoxide resulting from acidic
cleavage of 21 is isolated in low yield. The stereospecificity
of this reaction is verified one more time, each bis-sulfoxide
leading to a distinct vinylsulfoxide.
similar reasoning explains the formation of 24 starting from
22 (Scheme 6). This model based on steric hindrance explains
the formation of vinylsulfoxides 23 or 24 and why the
stereoselectivity is weakly influenced by the nature of R1 or
R2. Thus, only the configurations of the stereogenic carbon
and sulfur atoms play a part in the diastereoselectivity.
In summary, enantiopure acyclic ꢀ,ꢀ′-disubstituted vinyl
sulfoxides are easily prepared from ꢀ,ꢀ′-disubstituted bis-
sulfoxides. This mild, efficient, and stereospecific synthesis
allows the formation of enantiopure disubstituted vinylsul-
foxides bearing alkyl, aryl, base, or acid sensitive functional
groups. The ease of synthesis of various bis-sulfoxides
confers to this synthesis a broad scope. We envisage pre-
paring vinylsulfoxides that would be substituted by various
heteroatomic substituents (ether, thioether, amines) and
should be interesting ligands in asymmetric catalysis and
promising partners in cycloaddition reactions. Results of
these investigations will be communicated in due course.
To rationalize our results, we propose the following model
of diastereoselectivity (Scheme 6). Taking into consideration
that both sulfoxides may participate to the syn concerted
elimination, we envisaged for 21 the transition states TS1
and TS2. Ai, Bi, and Ci are different views of TSi (i ) 1 or
2). The geometric requirements for the planar five-centered
transition state16 are best depicted in Ai. We propose that
the sulfoxide which does not react adopts a conformation
minimizing the steric interactions between its p-tolyl sub-
stituent and the eclipsed R group as represented in Bi. Due
to steric repulsion between the two p-tolyl groups, TS2 is
destabilized compared to TS1 for which the interaction
between a p-tolyl group and a lone pair is less (see C1). A
(20) Crews, P.; Rodriguez, J.; Jaspars, M. Organic Structure Analysis;
Oxford University Press: New York, Oxford, 1998.
Acknowledgment. We thank Ministe`re de la Recherche,
CNRS, and IUF for financial support.
(21) Unless the elimination of sulfenic acid leads to a π-conjugate
system, a temperature superior to 100 °C and extended reaction times are
often required for simple vinylsulfoxides. For a discussion about factors
influencing the thermal sulfoxide elimination, see ref 16.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(22) Allyl sulfoxides are known to racemize at room temperature via a
[2,3]-sigmatropic shift, known as Evans-Mislow rearrangement. For a
review, see: Braverman, S. In The Chemistry of Sulfones and Sulphoxides;
Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley: London, 1988;
Chapter 14.
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