The Synthesis Of Hexadeca-heptaenoate Tert-butyldimethylsiloxane

Amphotericin B, a polyene macrolide antibiotic, was originally isolated from Streptomyces nodosus, and it can be strong inhibiting fungus. Studies have shown, it wide antifungal spectrum, strong activity, and for the majority of deep fungus with antibacterial activity. So far, Amphotericin Bis still the drug of choice for the treatment of critically ill deep fungal infections. Owing to its complex structure and important pharmacological activity, thus causing the world famous biochemist and organic synthetic chemists interested in research. Only the Nicolaou K. C. study group has completed the asymmetric synthesis of this molecule by far, but the reported synthetic route is long and cumbersome, difficult to derivatization, relatively harsh reaction conditions.As part of the total synthesis of Amphotericin B, the simple and effective synthetic route of the hexadeca-heptaenoate tert-butyldimethylsiloxane was explored and designed via the retrosynthetic analysis in this dissertation, by studying on the isomerization of the alkyne derivatives in the transition metal catalyzed at home and abroad. The1,7-octadiyne, using as the starting material, was deprotonated using methyllithium and then treated with methyl chloroformate to provide the methyl nona-2,8-diynoate (80%) and its best reaction temperature is-78℃, which was isomerized to the (2E,4E)-methyl nona-2,4-dien-8-ynoate when heated with triphenylphosphine, dimethylsulfoxide and acetic acid in toluene(77%), and it’s the best. The carboxylate functionality was reduced using DIBALH at-78℃into the (2E,4E)-nona-2,4-dien-8-yn-l-o1(90%), which was then protected with TBSCl to gave the tert-butyldimethyl((2E,4E)-nona-2,4-dien-8-yn-1-yloxy)silane in95%yield. After deprotonation with butyllithium at low temperature, the carbanion was treated again with methyl chloroformate at the same temperature. The second isomerization was realized using tributylphosphine in ethanol (50%) and the carboxylate functionality was again reduced with DIBALH to the corresponding alcohol (90%), which was then oxidized to the aldehyde with TEMPO and phenyl iododiacetate (70%). Subsequent olefmation by treating the above aldehyde with the phosphonate at-78℃afforded the heptaene intermediate(the yield is50%to take account of the aldehyde), which is properly functionalized for further transformations. The hexadeca-heptaenoate tert-butyldimethylsiloxane was finished by the conventional reactions in25steps. The structure of target product and intermediates was confirmed by1H NMR and13C NMR.The route used by most of traditional reaction, and the reaction condition is very warm, without the need for high temperature and high pressure equipment, and for the one step synthesis of Amphotericin B under foundation.