Diastereoselective retrosynthesis of blastmycinone, using selective enolisation methods and a consideration of the FelkinAnh model.

(Oops, please ignore the drawing accident where a butyl group changes to a pentyl group. It doesn't affect any of the chemistry discussed.)

#chemistry #organicchemistry #ochem #orgo #retrosynthesis



This synthesis is a way for me to highlight a few of the issues involved in choosing aldol reactions as a synthetic plan, which are a very relevant strategy in polyketide chemical synthesis. The 1,3dioxygenation pattern recurs throughout nature, and although the ideas presented in this video are far from the only way of constructing this motif, they are methods that mimic biosynthesis (socalled biomimetic reactions). To a trained chemist, this motif is associated strongly with aldol reaction and enolate type disconnections.

There are two ester disconnections that help to simplify this retrosynthetic analysis back to a linear system. The relative stereochemistry setup here is well suited to aldol methodology explored extensively by organic chemists in the 1980s and 1990s by Prof David Evans and Prof Ian Paterson and many many others at the time. I haven't presented models for diasteroselectivity here but intend to do so in future videos on this aldol topic.

There are several ways to control absolute and relative stereochemistry. Using an Evans auxiliary (oxazolidone derived) is a powerful way of making a chiral enolate that is great at diastereodifferentiation the Z enolate (cis enolate) will always lead to the 1,2syn aldol products across the newly formed carboncarbon bond. The aldehyde component that lends itself to an aldol disconnection here is quickly derived from the chiral pool using lactic acid. If no chiral enolate is used in the aldol reaction, the diastereoselectivity is still possible to achieve. This can be explained by using the polar FelkinAnh model, where the electronegative atom is adopting the "Rlarge" perpendicular position; in this conformation the aldehyde is most reaction. Good diastereoselectivity is achieved, in all cases, by ensuring kinetic control is in operation.