Development of a synthesis of lankacidins: stereoselective synthesis of the δ-lactone fragment

Abstract

Electrophiles react at C(3) stereoselectively on the less hindered face of the enolate derived from the 4-substituted azetidinone 5 to give products in which the new substituent is trans to the (tert-butyldimethylsilyloxymethyl) group at C(4). Aldol addition with 3-(tert-butyldimethylsilyloxy)propanal gave the alcohols 27 and 29, ratio 80 : 20, which were separated as mixtures at C(1′). Oxidation, followed by exchange of protecting groups, gave the 3-(1′-oxopropyl)azetidinones 39 and 41 which, on selective monodesilylation, were converted into the δ-lactones 43 and 44. The benzyloxymethyl protected 3-(hydroxyalkyl)azetidinones 40 and 42 were similarly prepared and gave the δ-lactones 43 and 44 on hydrogenolysis. The stereochemistry of the major δ-lactone 43 corresponds to that of the lankacidins at C(2) and C(3). The 3-(1′-oxopropyl)azetidinone 26, which has additional substituents at C(16) and C(17)(Isnkacidin numbering), was similarly prepared.