Scheme 1
if possible, proceeding with only a catalytic amount of the
chiral inducer and avoiding the use of transition metals.6
With this goal in mind, an alternative disconnection for the
CÀS bond was envisaged inverting the polarity of the
reaction partners and hence starting with a prochiral and
unusual sulfur nucleophile, i.e., a sulfenate salt7 (Scheme 1).
Quenching with alkyl halides to afford racemic com-
pounds is well established.7,8 Diastereoselective versions
involving sulfenates possessing a stereogenic center or
planar chirality have been described with a high degree
of success.9 In contrast, enantioselective variants are lim-
ited to a single precedent from our group,10 in which the
chiral influence of (À)-sparteine was evaluated and furn-
ished a low 29% ee.11,12 We anticipated that the use of a
chiral phase-transfer catalyst 2 (PTC*) could be an alter-
native. Phase-transfer catalysis has already been success-
fully employed for various CÀC and CÀO bond-forming
reactions.13 However, applications to the creation of car-
bonÀsulfur bonds have been surprisingly neglected, and
Figure 1. Commercial phase-transfer catalysts used in this study.
none of them exploit sulfenate species as nucleophile.14 We
wish to describe herein our preliminary results concerning
the development of this unprecedented reaction combining
sulfenate salt chemistry and phase-transfer catalysis.
Sulfenate salts being highly reactive, it is necessary to
generate them in situ. We decided to exploit a methodol-
ogy previously developed by us, which is based on a retro-
Michael reaction initiated by a base (Scheme 1).10 The
mechanistic proposal we suggest for the overall process in
the presence of PTC* involves the following cascade
reactions: (i) upon treatment with an inorganic base,
deprotonation of precursor 1 at the interface of the two
immiscible phases followed by β-fragmentation and lib-
eration of the sulfenate, (ii) cation exchangewith the chiral
ammonium salt to afford a lipophilic species with extrac-
tion to the organic layer, (iii) and finally reaction with the
alkyl halide to give the sulfoxide 3. If a tight ion pair with
the quaternary ammonium salt is formed, we can envision
discrimination of the two enantiotopic lone pairs of the
sulfenate during the final alkylation step and hence for-
mation of an enantioenriched sulfoxide product. Worthy
of note is that all examples already investigated concern
enantiofacial differentiation of double bonds in enolates
or enones.13 The formation of an effective chiral ion pair
in our case remained questionable but is required to
prevent a racemic background pathway.
Accordingly, a model study was initiated with the synth-
esis of tolyl methyl sulfoxide 3aa. Optimization was carried
out on a 0.08 mmol scale using 10 mol % of a commercially
available cinchonidinium salt 2a, possessing a free OH
group, and an anthracenylmethyl substituent on the qui-
nuclidine moiety (Figure 1). The influence of a range of
reaction parameters was examined, including the nature of
the precursor, base, solvent, dilution, and temperature.
Representative results of this thorough screening are given
in Table 1.
A preliminary set of experiments was arbitrarily carried
out at À20 °C with 33% aqueous NaOH solution in
toluene, thus allowing identification of sulfinyl sulfone
1aa (EWG = SO2Ph) as the most appropriate starting
material.15 The anticipated sulfoxide product 3aa was
obtained in 50% yield and 20% ee in favor of the
(R)-enantiomer (entry 1). Although this result is far from
(7) O’Donnell, J. S.; Schwan, A. L. J. Sulfur Chem. 2004, 25, 183–211.
ꢁ
(8) See, for example: (a) Foucoin, F.; Caupene, C.; Lohier, J.-F.;
ꢀ
SopkovaÀde Oliveira Santos, J.; Perrio, S.; Metzner, P. Synthesis 2007,
1315–1324. (b) Singh, S. P.; O’Donnell, J. S.; Schwan, A. L. Org. Biomol
Chem. 2010, 8, 1712–1717.
(9) (a) Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M.-T. Org. Lett.
2002, 4, 3619–3622. (b) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.;
Suzuki, T.; Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003,
68, 5550–5558. (c) Schwan, A. L.; Verdu, M. J.; Singh, S. P.; O’Donnell,
J. S.; Ahmadi, A. M. J. Org. Chem. 2009, 74, 6851–6854.(d) Lohier, J.-F.;
ꢁ
ꢀ
Foucoin, F.; Jaffres, P.-A.; Garcia, J. I.; SopkovaÀde Oliveira Santos, J.;
Perrio, S.; Metzner, P. Org. Lett. 2008, 10, 1271–1274.
ꢁ
(10) Caupene, C.; Boudou, C.; Perrio, S.; Metzner, P. J. Org. Chem.
2005, 70, 2812–2815.
(11) Alkylation of anthraquinone-1-sulfenate with a stoichiometric
amount of an enantiopure sulfonium salt was also reported and afforded
a modest 24% ee: Kobayashi, M.; Manabe, K.; Umemura, K.; Matsuyama,
H. Sulfur Lett. 1987, 6, 19–24.
(12) For the related asymmetric palladium-catalyzed arylation, see:
(a) Maitro, G.; Vogel, S.; Sadaoui, M.; Prestat, G.; Madec, G.; Poli, G.
Org. Lett. 2007, 9, 5493–5496. (b) Maitro, G.; Prestat, G.; Madec, D.;
Poli, G. Tetrahedron: Asymmetry 2010, 21, 1075–1084.
(13) (a) Maruoka, K., Ed. Asymmetric Phase Transfer Catalysis;
Wiley-VCH: Weinheim, 2008. (b) Hashimoto, T.; Maruoka, K. Chem.
Rev. 2007, 107, 5656–5682. (c) Ooi, T.; Maruoka, K. Angew. Chem.,
Int. Ed. 2007, 46, 4222–4266. (d) Jew, S.-s.; Park, H.-g. Chem. Commun.
2009, 7090–7103. (e) Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S.
Tetrahedron 2011, 67, 1725–1762.
(14) Introduction of the sulfur atom was achieved by reaction of a thiol or
ꢀ
ꢀ
a thiosulfonate: (a) Julia, S.; Ginebreda, A.; Guixer, J.; Tomas, A. Tetra-
hedron Lett. 1980, 21, 3709–3712. (b) Colonna, S.; Re, A.; Wynberg, H. J.
Chem. Soc., Perkin Trans. 1 1981, 547–552. (c) Wladislaw, B.; Marzorati,
L.; Biaggio, F. C.; Vargas, R. R.; Bjorklund, M. B.; Zukerman-Schpector,
J. Tetrahedron 1999, 55, 12023–12030. (d) Rodrigues, A.; Wladislaw, B.; Di
Vitta, C.; Pandini Cardhoso Filho, J. E.; Marzorati, L.; Bueno, M. A.;
Olivato, P. R. Tetrahedron Lett. 2010, 51, 5344–5348.
(15) The EWG activating group plays a critical role in the efficiency
of this organocatalytic process. A pKa value around 31 (value in DMSO)
for the R-hydrogen seems to ensure a smooth and efficient release of the
sulfenate, along with the best ee. Use of the more acidifying nitro
substituent (pKa of 17) furnished a faster reaction but with almost no
enantioinduction. See the Supporting Information.
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