The chemoenzymatic and enantioselective synthesis of biologically active resorcylic acid lactones (RALs)

Abstract

Modular total syntheses of the biologically active resorcylic acid lactones (RALs) L-783.277 (1) and L-783.290 (128) are reported. The three key buildings blocks employed for this purpose were the aromatic 133, the enantiopure alcohol (R)-25 or (R)-166 and the protected diol 127. The building blocks (R)-25, (R)-166 and 127 were prepared by chemoenzymatic methods with the last of these being derived from the cis-1,2-dihydrocatechol 82 (X = Cl) which is itself obtained through the whole-cell biotransformation of chlorobenzene. These building blocks have been linked to one another using Heck and Mitsunobu chemistries and the fourteen-membered macrolide rings formed using either a RCM reaction (as applied to compound 132) or through intramolecular addition of an acetylide anion to a tethered Weinreb amide (as applied to compound 165). Attempts to extend the RCM-based route to the RAL aigialomycin C (131) are also described. -- provided by Candidate.