Abstract
Quinocarcin is a pentacyclic tetrahydroisoquinoline alkaloid that was isolated by Takahashi and Tomita in 1983. Quinocarcin exhibited remarkable antitumor activities against a variety of tumor cell lines and its citrate salt (KW2152) has been in clinical trials in Japan. Its potent biological activities and fascinating architecture have attracted attention of many synthetic chemists. We planned a novel strategy for total synthesis of quinocarcin, in which the core tetrahydroisoquinoline structure is constructed via Au(I)-catalyzed intramolecular hydroamination reaction. Although the control of regioselectivity on the hydroamination reaction was a challenging issue of this strategy, we expected the desired 6-endo-dig selectivity might be achieved through appropriate tuning of the catalyst and/or substrate structure. Our synthesis commenced with the preparation of 2,5-cis-pyrrolidine 16 by a cis-selective intramolecular amination of bromoallene 15 develoved by our group. As we anticipated, 2,5-cis-pyrrolidine 16 was obtained with an excellent diastereoselectivity from a diastereomixture of bromoallene 15. After several manipulations, the pyrrolidine 5 with the requisite functionalities was synthesized uneventfully. Next, we embarked model study for construction of the core structure of quinocarcin. When using phenylglycinol-type substrates, undesired 5-exo-dig cyclization is generally favored; however, we found that the desired 6-endo-dig product 20d was obtained exclusively when using dihydrobenzofuran derivative 19d. We elaborated the core structure 32 in three steps from 6-endo-dig product 20d. In conclusion, we have succeeded in tile stereocontrolled synthesis of pyrrolidine 5 and the construction of the core structure of quinocarcin 32. Total synthesis of quinocarcin is underway.
