Soluble polymer-supported chemoenzymatic synthesis of the C-21-C-27 fragment of the bryostatins

A chemoenzymatic synthesis of the C-21-C-27 fragment of the marine macrolid e family of bryostatin antibiotics is presented. The approach commences fro m achiral starting materials and has as its crucial step the enzymatic reso lution of a racemic mixture of soluble polymer-supported alcohols (syn-10 a nd syn-11). The immobilized lipase from Candida antarctica (Novozym 435) ca talyzes the enantioselective acetylation of syn-10 (in 40% conversion and > 99% ee), allowing isolation of the key intermediate (R)-14 in enantiomerica lly pure form following its cleavage from the poly(ethylene) glycol (PEG) s caffold. The PEG matrix is both compatible with the multipolymer enzymatic transformation and allows for rapid purification and facile NMR characteriz ation of all intermediates throughout the synthesis.