Simple Diastereoselectivity of the BF 3 ‚OEt 2 -Catalyzed Vinylogous Mukaiyama Aldol Reaction of 2-(Trimethylsiloxy)furans with Aldehydes Carlos Silva Lo ´pez, Rosana A Ä lvarez, Bele ´n Vaz, Olalla Nieto Faza, and A Ä ngel R. de Lera* Departamento de Quı ´mica Orga ´ nica, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Galicia, Spain qolera@uvigo.es Received January 21, 2005 A comprehensive scan of the transition state space for the reaction of 2-(trimethylsiloxy)furan and methacrolein (24 combinations) offered a satisfactory explanation of the high like diastereoselectivity obtained experimentally in the Mukaiyama vinylogous aldol reaction of these and related partners. It was determined that the syn-γ-hydroxyalkylbutenolides are formed preferentially following a g + orientation of the two reactants with the aldehyde in the s-trans conformation. Diastereoselectivity is shown to be caused by a combination of subtle effects favoring the formation of the like product. 1. Introduction The Lewis acid-promoted condensation of trialkylsilyl enol-ethers with carbonyl compounds to produce cross- aldol products was reported by Mukaiyama and co- workers in 1974. 1 Synthetically appealing features of these so-called latent enolate aldol reactions are their regioselectivity (reaction at the C R -position), the great variety of carbonyl compounds or their masked forms that can be used as partners 2 often displaying chemoselectiv- ity (acetals, ketals, ortho esters, and aminoacetals), and the diastereoselectivity derived from the use of a scope of catalysts, promoters, or additives. Recent developments have focused on the enantiocontrol of the process through incorporation of enantiopure ligands on the Lewis acid. All of these features have contributed to the promotion of the Mukaiyama aldol reaction to its present status as a powerful C-C bond-forming process. 3 As a general trend, O-silylated dienolates (extended enolates) derived from both cyclic and acyclic R,- unsaturated carbonyl compounds react at the γ-posi- tion, 4,5 although exceptions are known. 6 The vinylogous aldol 7 reaction has the interest of the synthetic com- munity because of the increased complexity of the δ-hy- droxy-R,-unsaturated carbonyl adduct, with two stere- ocenters and a stereogenic double bond, relative to the aldol counterpart. 2-(Trimethylsiloxy)furan 1a, the prototype of the con- formationally constrained extended enolates, exhibits the general reactivity pattern for its Lewis acid-induced condensation with aldehydes, ketones, and acetals to produce butenolides, 8 a common scaffold in natural products. Butyrolactones (annonaceous acetogenins) 9 and unsaturated derivatives (γ-alkylidenebutenolides, 10 such as vitamin C and pulvinic acids) are well-known members of this group. Interestingly, the corresponding lithium dienolate, generated upon treatment of the precursor butenolide * To whom correspondence should be addressed. Fax: 34986812556. (1) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503-7509. (2) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 6, 527-530. (3) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389. (4) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 4, 319-322. (5) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 11, 1201-1202. (6) Fleming, I.; Lee, T. V. Tetrahedron Lett. 1981, 22, 705-708. (7) Casiraghi, G.; Zanardi, F. Chem. Rev. 2000, 100, 1929-1972. (8) Asaoka, M.; Yanagida, N.; Ishibashi, K.; Takei, H. Tetrahedron Lett. 1981, 22, 4269-4270. (9) Figade `re, B. Acc. Chem. Res. 1995, 28, 359-365. (10) Bru ¨ ckner, R. J. Chem. Soc., Chem. Commun. 2001, 141-152. 3654 J. Org. Chem. 2005, 70, 3654-3659 10.1021/jo0501339 CCC: $30.25 © 2005 American Chemical Society Published on Web 03/29/2005