A Triple-Aldol Cascade Reaction for the Rapid Assembly of Polyketides

摘要

Polyketides have long provided synthetic organic chemists with a variety of complex architectures to construct and develop new chemical tools for, and provided medicine with, many useful drugs. About 1% of polyketides display drug activity, which is five times the average for natural products. A common strategy in the synthesis of polyketides is the cross-aldol reaction, although it can be complicated by uncontrolled oligomerization and dehydration reactions. There has been significant advances in the development of the asymmetric aldol and allylation reactions of aldehydes. However, further manipulations, such as alcohol protection or redox reactions, are often required before the next iteration can proceed. Therefore, there has been increasing interest in one-pot cascade aldol reactions , however, only one example successfully proceeded to the third aldol iteration, and in low yields, Inspired by the seminal work of Mukaiyama et al. , our research group reported an aldol cascade reaction using tris(trimethylsilyl)silyl enol ethers, such as the easily prepared 1,to give versatile aldehyde products 2 (Scheme 1). Moreover, these aldehydes can be treated with Grignard or polyhalomethyllithium reagents in the same reaction pot to generate mono-protected diols. The formation of these compounds is highly diastereoselec-tive because of the extreme steric bulk of the tris(trimethyl-silyl)silyl group. Significantly, further addition of 1 to 2 is strictly prevented, because of the steric bulk of the (TMS)3SiNTf2·2 complex.