Synthesis of Marasin and 9-Me-Marasin, (Nona- and Deca-6,8-diyne-3,4-dienol).

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 LiCuBr₂, followed by reaction with Me₃Si-CC-CC-l or Me-CC-CC-l. Route B involves transmetallation with ZnCl₂, followed by a palladium-catalyzed coupling reaction with Me₃Si-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, Me₃Si-CC-CC-CHCCH-CH₂CH₂OCH(Me)OEt and Me-CC-CC-CHCCH-CH₂CH₂-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 AgNO₃ 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|μg/ml) 9-Me-marasin was not active suggesting that the free acetylene function of the allenediyne is essential for the antibiotic activity.