33 多環式アルカロイド群の分岐型迅速合成プロセス : 生合成を模倣した構造多様化戦略(口頭発表の部)

抄録

Indole alkaloids composed of elaborated cyclic arrays have been one of the most valuable resources for discovering biologically active substances. To gain concise and flexible access to alkaloid analogs possessing natural and unexploited skeletons, we are developing a synthetic process based on divergent cyclizations inspired by the biogenic strategy generating structural diversity of natural products. With intentions to emulate the biosynthetic proposal of iboga and aspidosperma alkaloids, we designed a common dihydropyridine precursor 3 for divergent Diels-Alder reactions in either of two ways: (1) the dihydropyridine reacts as a diene leading to the iboga-type skeleton; (2) the dihydropyridine serves as a dienophile to form the aspidosperma-type skeleton. First of all, we developed an original protocol for constructing sensitive 1,6-dihydropyridine (DHP) rings employing a cationic Cu(I) catalyst. Next, the key precursor 21 for the Cu(I)-catalyzed DHP synthesis was successfully prepared through conjugate addition of the common intermediate 25 with methyl propiolate 20 and concomitant Hofmann elimination. The Cu(I)-catalyzed 1,6-DHP cyclization and subsequent Diels-Alder cycloaddition under mild conditions (45℃) allowed a cascade synthesis of iboga-type skeleton 28. Meanwhile, divergent cyclization proceeded to furnish ngouniensine-type skeleton 29 by the simple modification of reaction temperature (100℃). Furthermore, the reaction site of 25 with 20 was altered depending on the solvents to produce a distinct precursor for the Cu(I)-catalyzed cyclization, which allowed successful construction of a novel tetracyclic skeleton 31. We also achieved total synthesis of (±)-catharanthine 34 through protecting group-free 9-step sequence in order to demonstrate applicability and potential of the currently developed synthetic process efficiently generating complexity and diversity of natural product relevant scaffolds in a programmable fashion.