Synthesis of marasin and 9-Me-marasin (nona- and deca-6,8-diyne-2,4-dienol)

Abstract

3, 4-Pentadienol was protected with ethyl vinyl ether and regioselectively (70%) deprotonated at the terminal position by treatment with BuLi in THF at low temperature. Starting from the so obtained lithium compound, Marasin (nona-6,8-diyne-3,4-dienol) (1a) and 9-Me-Marasin (deca-6,8-diyne-3,4-dienol) (1b) were prepared by two metal-mediated synthetic routes. Route A involves transmetallation of the lithium compound with LiCuBr{2}, followed by reaction with Me{3}Si-C@?C-C@?C-l or Me-C@?C-C@?C-l. Route B involves transmetallation with ZnCl{2}, followed by a palladium-catalyzed coupling reaction with Me{3}Si-C@?C-C@?C-Br or Me-C@?C-C@?C-Br. Before removal of the protecting groups the yield of C-C coupled products, Me{3}Si-C@?C-C@?C-CH@?C@?CH-CH{2}CH{2}OCH(Me)OEt and Me-C@?C-C@?C-CH@?C@?CH-CH{2}CH{2}-OCH(Me)OEt (6a and 6b) was 95 % via route A. Route B afforded (6a) and for (6b) in 75% and 50 % yield, respectively. After removal of the trimethylsilyl group with AgNO{3} and the acetal group with trace of acid, (1a) and (1b) were obtained by route A in 20 % and 65 % overall yield, respectively, and by route B in 13 % and 30 % overall yield, respectively. The antibiotic activity of both compounds was tested against Staphylococcus aureus and the MIC (Minimal Inhibiting Concentration) for Marasin was 0.2 (fesol|@mg/ml) 9-Me-marasin was not active suggesting that the free acetylene function of the allenediyne is essential for the antibiotic activity.