Synthesis of macrocyclic precursors of lankacidins using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure

Abstract

In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones and their participation in Stille coupling reactions have been investigated. 1- tert-Butyldimethylsilyl-4-(2-iodoethenyl)azetidinone was found to undergo a Stille coupling reaction with a 3-hydroxy-1-tributylstannylhepta-1,5-diene to give an acceptable yield of the corresponding conjugated diene but the analogous reaction with a 3- tert-butyldimethylsilyloxy-1-tributylstannylhepta-1,5-diene was unsuccessful. A series of 4-[( E)-2-iodoprop-1-enyl]azetidinones, a ring-opened ester and a lactone were also found to undergo Stille reactions with 3-tributylstannylprop-2-enol albeit with variable yields. Asymmetric syntheses of methyl (2 R,3 R,5 S)-3- tert-butyldimethylsilyloxy-2-methyl-5-(2-trimethylsilylethoxy)methoxy-6-oxohexanoate, (3 R,4 S)-1- tert-butyldimethylsilyl-4-[( E)-2-iodoprop-1-enyl]-3-methylazetidin-2-one, and (5 S,2 E,6 E)-5- tert-butyldimethylsilyloxy-2-methyl-1-phenylsulfonyl-7-tributylstannylhepta-2,6-diene and their incorporation into macrocyclic precursors of the lankacidins were then investigated. Key reactions were a Julia reaction between the aldehyde and the sulfone to form the 12,13-double-bond, a stereoselective acylation of the azetidinone, and formation of macrocycles using intramolecular Stille reactions in the presence of a free hydroxyl group at C(8) (lankacidin numbering).