Development of a new approach for the synthesis of (+)-15-deoxy-Δ12,14-prostaglandin J2 methyl ester based on the [2+2]-cycloadduct of 5-trimethylsilylcyclopentadiene and dichloroketene

Abstract

An asymmetric total synthesis of 15-deoxy-Δ^12,14-prostaglandin J₂ methyl ester is presented. The synthesis begins with the preparation of enantiopure (3aR,6R,6aS)-6-(trimethylsilyl)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-1-one by optical resolution of the [2+2]-cycloadduct of the easily available 5-trimethylcyclopentadiene and dichloroketene in situ. The key steps of the approach: (a) formation of cyclopentenone precursor by the consecutive epoxydation and Peterson-type fragmentation reactions of an allylic TMS-derivative of a suitable cyclopentene intermediate; (b) two-stage construction of the prostaglandin α-chain by Wittig olefinations; (c) alkylation using E-1-lithioheptene with subsequent ω-chain formation by generation of a cross-conjugated system by tandem deprotection and dehydration reactions.