Recent Advances in Asymmetric Aldol Reaction of Masked Acetoacetic Esters Promoted by Ti(IV) / BINOL: A New Methodology, Non-Linear Effects and Autoinduction

Abstract

Aldol condensation of synthetic equivalents of acetacetic esters allows the formation of a polyfunctional C5 fragment and the corresponding aldols have proven to be versatile key-intermediates in the synthesis of complex, biologically active natural products. O-silyldienolates 1 and 2 can be considered among the most popular masked acetacetic esters and in these last years the silyl dienolate 1a (R1 = R2 = Me), deriving from commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-one, has been used in a variety of aldol reactions (based on the employment of Ti(IV), or Cu(II), chiral complexes) taking place with high efficiency and enantioselectivity; on the contrary, the highly oxygenated diene 2 (Chans diene) has been essentially used in the synthesis of racemic aldols by TiCl4 catalysis. The aldol condensation of the synthetic equivalents of acetoacetic ester 1-2 can be conveniently performed in the presence of a chiral Ti(O-i-Pr)4 / BINOL complex under catalytic conditions. The reported procedure is of particular synthetic value since the addition of masked acetoacetic esters proceeds efficiently with aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes too. In the course of the investigation on the mechanistic aspects of the reaction, positive non-linear effects have been observed; rather interestingly, the mode of preparation and the concentration of the catalyst has been found to exert a marked influence on the non linear effects. Furhermore, the occurence of a concomitant auto-inductive process with amplification of the enantiomeric excess in the aldol reaction of 2 has been pointed out. Keywords: aldols, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, BINOL complex, TiCl4