Development of a synthesis of lankacidins: an investigation into 17-membered ring formation

Abstract

Studies are reported concerning the synthesis of macrocyclic analogues of the lankacidins. The long-chain trienylphosphonate 33 has been synthesized as a mixture of epimers at C(7), by a convergent route which involved alkylation of ethyl 2-methyl-3-oxobutanoate 10 by the 10-(tert-butyldimethylsilyloxy)-3,9-dimethyldeca-2,4,8-trienyl chloride 11 to give 27 followed by an aldol addition to the aldehyde 12. Stereoselective reduction then gave the 1,3-syn-diol 35 which was protected as its acetonide 36. However, it did not prove possible to hydrolyse the 1,3-dioxolane ring in 36 to reveal the keto phosphonate grouping and leave the acetonide component intact. To avoid this problem, acrolein was added to the alkylated keto ester 27 to give the aldol product 40 as a mixture of diastereoisomers. Stereoselective reduction gave the 1,3-syn-diols 41 and 42, in a ratio of 75:25, which were separated and taken through to the δ-lactones 47 and 48. The lactone 47 corresponds to the C(14)–C(12) fragment of the lankacidins, and the diol 41 is an advanced intermediate for a synthesis of a 17-membered macrocyclic analogue of the lankacidins. The diols 41 and 42 were protected as their acetonides 43 and 44 and these were taken through to the 16-formyl-2-oxophosphonates 7 and 57. Cyclisations into the cycloheptadeca-2,4,8,10-tetraenones 8 and 58 were carried out using potassium carbonate in the presence of 18-crown-6 in toluene at 100 °C. Alternative conditions for the cyclisations were less successful as were attempts to cyclise the halogeno sulfones 62 and 63 although the 17-acetoxy sulfone 64 was cyclised using tetrakis(triphenylphosphine)palladium(0) and 1,3-bis(triphenylphosphino)propane, but only in a modest yield (18%). Deprotection and reduction of the cyclised products have been briefly investigated.