5602
J. Am. Chem. Soc. 2001, 123, 5602-5603
Asymmetric Synthesis of â-Mercapto Carboxylic
Acid Derivatives by Intramolecular Sulfur Transfer
in N-Enoyl Oxazolidine-2-thiones Promoted by Lewis
Acids
Claudio Palomo,*,† Mikel Oiarbide,† Flavia Dias,†
Aurelio Ortiz,† and Anthony Linden‡
Figure 1. General principles of the new strategy: (1) attachment of a
chiral auxiliary; (2) intramolecular reaction promoted by an additive,
which also alters the auxiliary; (3) detachment of the product and of the
modified auxiliary; and (4) regeneration of the original auxiliary.
Departamento de Qu´ımica Orga´nica I
Facultad de Qu´ımica,UniVersidad del Pa´ıs Vasco
Apdo. 1072, 20080 San Sebastia´n, Spain
Organisch-chemisches Institut der UniVersita¨t Zu¨rich
Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland
ReceiVed March 22, 2001
ReVised Manuscript ReceiVed May 8, 2001
â-Heterosubstituted carbonyl compounds are widespread in
natural products, and their synthesis has attracted much interest.
Unlike â-oxy and â-amino carbonyl compounds, which are
accessible through many different approaches, â-thio carbonyl
compounds can only be reached through a very narrow range of
synthetic routes.1 For instance, while the aldol and the Mannich
methodologies have been profusely developed in the former cases,
the aldol strategy involving thioaldehydes is of very limited use,
because of the poor electrophilicity of thioaldehydes, among other
reasons.2 The general practice so far documented for the prepara-
tion of â-thio carbonyl compounds is the conjugate addition of
thiols to R,â-unsaturated carbonyl systems. In recent years both
diastereo- and enantioselective versions of this approach have been
addressed with success. In the diastereoselective methods,3 a chiral
auxiliary is typically attached to the enoyl substrate prior to the
intermolecular attack of a thiol,4 while in the enantioselective
cases,5 both enoyl derivatives and enones have been reacted with
thiols in the presence of chiral ligand-metal complexes. Common
to both strategies is the use of arenethiols as the nucleophile.6 In
consequence, aryl sulfides are obtained, from which the dearyl-
ation process to yield the eventually desired free thiol is not always
straightforward. We report herein on a conceptually new strategy
for the asymmetric synthesis of â-mercapto carboxylic acids and
alcohols that formally effects the conjugate addition of simple
“SH-” to enoyl imides in a highly stereocontrolled way. The new
Figure 2. Possible course of the reaction from III to VI.
synthetic concept is outlined in Figure 1. This development is
founded upon the effective asymmetric induction that could
reasonably be expected in such an intramolecular process (I to
give II), even if the stereogenic unit is remote from the bond-
forming atoms.7
To put this idea into practice, we succeeded in carrying out
the reaction of N-enoyl oxazolidine-2-thiones III, Figure 2, with
some Lewis acids to yield, after hydrolysis, the corresponding
â-mercapto carbonyl adducts VI. Our idea was inspired by the
well-documented tendency for allyl thiocarbamates and thioureas
to undergo electrocyclic intramolecular rearrangements.8 Given
the assumption that N-enoyl oxazolidine-2-thiones III upon
complexation with a Lewis acid would render species IV, a
subsequent electrocyclic cyclization followed by hydrolysis to VI,
as described in Figure 2, is a plausible conjecture.
Accordingly, see Table 1, it was found that 0.01-0.05 M
solutions of substrates 1-4 in methylene chloride react smoothly
with SnCl4 at -78 °C in a few hours to afford, after simple
aqueous workup, adducts 5-8. As the results in the table show,
this unprecedented transformation is general for both aromatic
and aliphatic R groups and successfully tolerates structurally
different oxazolidine-2-thiones. Nevertheless, the presence of
aromatic groups in the substrate has a significant influence on
the reaction outcome. In fact, when R is an aromatic group, the
initially formed solid in the reaction9 did not evolve unless the
reaction mixture was allowed to reach room temperature. The
essentially perfect diastereocontrol exerted during the process for
R ) aliphatics (entries a-c, i-k, and n-o), regardless of the
auxiliary employed, is, however, lowered for the aromatic cases
(entries d-h, l, and m), presumably due to the higher reaction
temperatures used.10
† Universidad del Pa´ıs Vasco.
‡ Universita¨t Zu¨rich (X-ray analyses).
(1) Leading references, see: (a) Baird, C. P.; Rayner C. M. J. Chem. Soc.,
Perkin Trans. 1 1998, 1973. (b) Procter D. J. J. Chem. Soc., Perkin Trans. 1
1999, 641.
(2) See, for instance: (a) Heathcock, C. H. Aldrichim. Acta 1990, 23, 99.
(b) Usov, V. A.; Timokhina, L. V.; Voronkov, M. G. Russ. Chem. ReV. 1990,
59 (4), 378. (c) Zhang, X.-M.; Malick, D.; Petersson, G. A. J. Org. Chem.
1998, 63, 5314. For a review on C-S bond formation, see: (d) Kondo, T.;
Mitsudo, T.-a. Chem. ReV. 2000, 100, 3205.
(3) For leading references, see: (a) Wu, M.-J.; Wu, C.-C.; Tseng, T.-C. J.
Org. Chem. 1994, 59, 7188. (b) Tsai, W.-J.; Lin, Y.-T.; Uang, B.-J.
Tetrahedron: Asymmetry 1994, 5, 1195. (c) Tomioka, K.; Muraoka, A.; Kanai,
M. J. Org. Chem. 1995, 60, 6188. (d) Taber, D. F.; Gorski, G. J.; Liable-
Sands, L. M.; Rheingold, A. L. Tetrahedron Lett. 1997, 38, 6317. (e) Miyata,
O.; Shinada, T.; Ninomiya, I.; Naito, T. Tetrahedron 1997, 53, 2421. (f) Lin,
C.-H.; Yang, K.-S.; Pan, J.-P.; Chen, K. Tetrahedron Lett. 2000, 41, 6815.
(4) For a case of diastereoselective, reagent-controlled, addition of thiols
to enones, see: Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J.
Am. Chem. Soc. 2000, 122, 1927.
(5) (a) Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H.
Tetrahedron Lett. 1977, 2181. (b) Kobayashi, N.; Iwau, K. J. Am. Chem. Soc.
1978, 100, 7071. (c) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981,
103, 417. (d) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363. (e)
Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am. Chem. Soc. 1997,
119, 12974. (f) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem.
Soc. 1998, 120, 4043. (g) Tomioka, K.; Okuda, M.; Nishimura, K.; Manabe,
S.; Kanai, M.; Nagaoka, Y.; Koga, K. Tetrahedron Lett. 1998, 39, 2141. (h)
Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675.
(i) Saito, M.; Nakajima, M.; Hashimoto, S. Tetrahedron 2000, 56, 9589.
(6) Reactions with benzyl thiol as the nucleophile have been documented
in ref 5f.
(7) For more information on this subject, see: Tokoroyama, T. Chem. Eur.
J. 1998, 4, 2397.
(8) Selected examples: (a) Hayashi, T. Tetrahedron Lett. 1974, 339. (b)
Nakai, T.; Ari-Izumi A. Tetrahedron Lett. 1976, 2335. (c) Soledade, M.;
Pedras, C.; Okanga, F. I. Chem. Commun. 1998, 67. For a recent paper dealing
with a very similar cyclization of homoallylic systems, see: (d) Hari, A.;
Miller, B. L. Org. Lett. 2000, 2, 3667.
(9) Upon the addition of the Lewis acid to a solution of the corresponding
oxazolidine-2-thione in methylene chloride, a white solid slowly appears, which
redissolves on stirring for 5-10 min at the same temperature (-78 °C) for R
) aliphatics. This precipitate remains unaltered for R aromatics, unless the
mixture is warmed close to room temperature.
10.1021/ja015860+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/19/2001