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Article

Catalytic Enantioselective Alkylative Aldol Reaction: Efficient Multicomponent Assembly of Dialkylzincs, Allenic Esters, and Ketones toward Highly Functionalized δ-Lactones with Tetrasubstituted Chiral Centers

Supporting Info

Kounosuke Oisaki, Dongbo Zhao, Motomu Kanai,* and Masakatsu Shibasaki*

Contribution from the Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0013, Japan

J. Am. Chem. Soc., 2007, 129 (23), pp 7439–7443

DOI: 10.1021/ja071512h

Publication Date (Web): May 16, 2007

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, mshibasa@mol.f.u-tokyo.ac.jp

Abstract

A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized δ-lactones were produced in the presence of a catalytic amount of the Cu(OAc)₂−DIFLUORPHOS complex through three-component assembly of dialkylzincs, allenic esters, and unactivated ketones. This CAMCR constructs two C−C bonds and one tetrasubstituted chiral center simultaneously. Conjugate addition of alkylcopper species to an allenic ester produced highly active copper enolate in situ, and the successive asymmetric aldol addition to ketones followed by lactonization afforded the desired products. The addition of MS4A and Lewis base (Ph₂SO, DMSO, or HMPA) is important for obtaining a high yield, with suppression of the undesired α-addition pathway. Control/crossover experiments suggest that the addition of a Lewis base facilitated the retro-aldol reaction of the α-adducts (proofreading effect). The ketone and copper enolate generated through the retro-aldol reaction were converted to the desired lactone through the γ-aldol pathway, which was trapped by irreversible lactone formation.