Approaches to the total synthesis of chaetochalasin A

Abstract

Chaetochalasin A is a complex natural product whose biosynthesis may involve two domino Diels–Alder reactions. Approaches to the total synthesis of chaetochalasin A using this approach have been studied. Methyl (6R,8S,2Z,4E,10E,12E,14E)-6,8,10,14-tetramethylhexadeca-2,4,10,12,14-pentaenoate was identified as a key intermediate and was synthesized from (E)-1-bromo-4-tert-butyldimethylsilyloxy-2-methylbut-2-ene using diastereoselective alkylations of derivatives of (+)-pseudoephedrine to introduce the stereogenic centres, a modified Julia reaction to prepare the conjugated triene and a phosphonate condensation to provide the (2Z)-alkene. However, during the synthesis, facile geometrical isomerisation of the (14E)-trisubstituted and (2Z)-double-bonds was observed and attempts to incorporate this pentaene into a synthesis of chaetochalasin A led to the formation of mixtures of products. The analogous ethyl 6,8,10,14-tetramethylhexadeca-4,10,12,14-tetraenoate [that lacks the (2Z)-double-bond] was incorporated into a Diels–Alder precursor by acylation of a valine-derived N-acylpyrrolidinone followed by oxidative elimination of the corresponding 3-(phenylselanyl)pyrrolidinone. However, preliminary studies of the macrocycle-forming Diels–Alder reaction for a synthesis of chaetochalasin A were complicated by (E,Z)-isomerisation of the (10E)-double-bond of the conjugated triene and three Diels–Alder adducts were isolated and characterised. Further studies of this approach to chaetochalasin A will require an alternative procedure for the generation of the acylpyrrolinone in the presence of the acid sensitive conjugated triene.