Synthesis of the AB ring system of clifednamide utilizing Claisen rearrangement and Diels–Alder reaction as key steps

In order to construct the functionalized AB ring system of clifednamide, member of the class of macrocyclic tetramicacid lactams, a synthesis was developed which utilized an Ireland–Claisen rearrangementand an intramolecular Diels–Alder reaction. Starting from di-O-isopropylidene- D-mannitolthe allyl carboxylate precursor for the sigmatropic rearrangement was prepared. This rearrangement proceeded diastereoselectively only in the presence of an allyl silyl etherinstead of the parent enonein the side chain, as suggested by deuteration experiments. A subsequent Diels–Alder reactionyielded the target ethyl hexahydro-1H- indene-carboxylate with high diastereoselectivity. Quantum-chemical investigations of this intramolecular Diels–Alder reactionsupport the proposed configuration of the final product.