Development of a synthesis of lankacidins: synthesis of the C(14)–C(6) fragment and introduction of the C(10)–C(13) diene

Abstract

Acylation of the azetidinone 8 using the thioester 17, prepared from dimethyl (S)-malate, gave the (3S,4R)-3-(3′,4′-bis-tert- butyldimethylsilyloxy-1′-oxobutyl)azetidinone 18 which was convened into the N-acylazetidinone 20. Desilylation of this was selective for the primary tert-butyldimethylsilyl groups and gave mixtures of products in which the 7-membered lactone 25 was the major component rather than the 6-membered ring isomer required for a lankacidin synthesis. However, the (3S,4R)-3-(3′-tert-butyldimethylsilyloxy-2′-methyl-1′-oxohex-5-enyl)azetidinone 27 was similarly prepared and hydroxyl-induced azetidinone cleavage of the desilylated N-acyl derivative 30 gave the δ-lactone 31. This lactone gave a complex mixture of products on attempted reduction of the ketone substituent, but the required hydroxy lactone 32 could be obtained directly from the azetidinone 30 using sodium borohydride in ethanol. Introduction of the C(10)–C(13) dienyl fragment into intermediates containing the δ-lactone was complicated by elimination. However, this diene could be introduced into azetidinone precursors of the δ-lactone using keto-phosphonate aldehyde condensations.