P-47 Platensimycinの全合成研究(ポスター発表の部)

抄録

Platensimycin was isolated from a strain of Streptomyces platensis by a Merck research group as a novel broad spectrum Gram-positive antibiotic. It inhibits bacterial grouwht by selectively inhibiting condensing enzyme FabF in the fatty acid synthesis pathway. Because of its unique mode of action, platensimycin showa no cross-ersistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-resistant enterococci. Platensimycin consists of an unusual 3-amino-2,4-dihydroxybenzoic acid polar domain linked through an amide bond to a relatively lipophilic, compact, tetra-cyclic core. Its attractive biological activity and intriguing structure prompted us to embark on the synthesis of platensimycin. Starting from a known carboxilic acid (9), Diels-Alder precursor 7 was prepared in 5 steps via iodolactonization, epoxidation, regioselective epocide opening with Et_2/AlCN/DME and elimination. Although the Diels-Alder reaction of 7 with Danishefsky's diene was unsuccessful, the reacton of 7 with Rawal's diene 10 proceeded smoothly under mild conditions (CH_2Cl_2, 40℃), giving 6 as a single diastereomer. After protection of the enone carbonyl group of 6 by Noyori's protocol, the resulting acetal 11 was converted into TBS-protected Weinreb's amide intermediate 12, which was then exposed to MeMgCl to afford ketone 5 in excellnt overall yield. The Wittig olefination of 5 and subsequent reduction of the nitrile group of the resultind product 13 gave olefinic aldehyde 14, the methylenation of which furnished RCM precursor 4. Treatment of 4 with the Grubb's second generation catalyst gave cyclization product 15. Finally, exposure of 15 to aqueous acidic conditions brought about deprotection of the two protecting groups as well as the cyclization to afford the targeted tetacyclic core structure (2) of platensimycin. Although we have completed the synthesis of 2, some of the steps, including the RCM reaction, need improvement in chemical yield. At present, we are also trying other synthetic routes involving several types of radical cyclization reactions.