Stereospecific access to α-haloalkyl esters via enol ester epoxides and synthesis of a C3-C21 fragment of bastimolide A

We report a 14-step synthesis of a C3-C21 fragment of bastimolides A and B, antimalarial macrocyclic polyketides. A crucial ring-opening reaction of an enol ester epoxide showed previously unexplored reactivity, leading to an asymmetric synthesis of α-haloalkyl esters. The α-haloalkyl ester synthesis was shown to be stereospecific, and provided access to a key α-silyloxyaldehyde to initiate application of configuration-encoded 1,5-polyol synthesis. This strategy established the C11/C15 and C15/C19 remote stereochemical relationships of the bastimolides. The potential of this C3-C21 fragment for coupling to C22-C41 was established using a Mukaiyama aldol reaction with a simple enolsilane.