Syn-Selective Vinylogous Kobayashi Aldol Reaction

Abstract

The Kobayashi aldol reaction has become a prominent transformation in polyketide syntheses. This methodology takes advantage of the directing effects of the Evans auxiliary and allows the stereoselective incorporation of a four carbon segment with two additional methyl branches establishing an anti-relationship between the two newly formed chiral centers. So far this transformation was restricted to anti-aldol products. We present here a modified protocol that provides the corresponding aldol product with high syn-selectivity.

The vinylogous Mukaiyama aldol reaction (VMAR) in natural product synthesis

“…Using this particular orchestration of transformations, they were capable of generating the Z-congured silyl ketene N,O-acetal. 14 The subsequent VMAR produced the expected syn-aldol product and in parallel to the chelationcontrolled VMARs, aldehydes that are capable of chelating TiCl 4 generated the anti-aldol product (Fig. 91).…”

The Impact of the Mukaiyama Aldol Reaction in Total Synthesis

“…[19] After four decades of continued development, both diastereoselective and enantioselective versions of the reaction have evolved. [20] A practical auxiliary-based method was developed by the group of Kobayashi, [21] and later extended by the groups of Hosokawa [22] and Kalesse; [23] this method uses silicon dienolates of type 33 to simultaneously configure one double bond and up to two stereocenters. The efficiency of this vinylogous aldol addition was demonstrated independently by De Brabander and co-workers [24] and Nicolaou, Chen, and co-workers [25] in the total synthesis and structural revision of palmerolide A (34, Scheme 8), a marine macrolide that exhibits potent and selective activity against melanoma cancer cells.…”

Structure Elucidation and Total Synthesis of Kulkenon

“…[7] We envisaged that the syn configuration between C24 and C25 could be generated through the syn-selective Kobayashi aldol reaction, recently developed in our group (Scheme 1). [8] For the synthesis of the "eastern" fragment 4 we employed our syn-selective variation of Kobayashis vinylogous Mukaiyama aldol reaction. The transformation of isovaleraldehyde (6) with Z-N,O-keteneacetal 5 provided alcohol 7 in 82 % yield and d.r.…”