P-29 コルチスタチンAおよびJの全合成(ポスター発表の部)

抄録

Cortistatins are the marine alkaloids which were isolated form the marine sponge Corticium aimplex by Kobayashi et al in 2006. Cortistatins have highly selective anti-proliferative activity against HUVECs. Moreover, these compounds possess unique abeo-9(10-19)-androstane type steroidal skeleton as well as isoquinoline moiety. Owing to potent biological activities and unique structures attract synthetic chemists. Herein, total synthesis of cortistatin A and J are described. Our strategy features a construction of common core structure of cortistatins using Knoevenagel condensation, electocyclic reaction and radical cyclization followed by stereoselective installation of isoquinoline moiety and functionalization of A-ring. First, CD-ring fragment 7 was synthesized in 10 steps from readily available (+)-Hajos-Parrish ketone 8. Treatment of 7 with cyclohexane-1,3-dione 6 in the presence of piperidine afforded the tetracyclic structure 12 via Knoevenagel condensation and electrocyclic reaction. After conversion of 12 into iodide 4, radical cyclization furnished the core structure 3. With the key intermediate 3 in hand, isoquinoline was installed. Ce-mediated nuclephilic attack of lithiated isoquinoline 14 afforded 15. After formation of thiocarbamate, one-pot removal of the thiocarbamate and chloride realized the constructon of isoquinoline moiety with desired stereochemistry. Finally, total synthesis of cortistatin A (1) and J (2) were accomplished by modification of A-ring. Treatment of enone 18 with dimethylamine furnished the 1,4-addition product. Reduction followed by elimination of the corresponding ketone afforded cortistatin J (2). Total synthesis of cortistatin A (1) was achieved following Nicolau/Chen's protocols in 3 steps from 18. In conclusion, we hae developed a highly efficient synthetic route to cortistatin A (1) and J (2).