開催日: 2017/09/20 - 2017/09/22
Hexahydropyrroloindole alkaloids possess structural diversity and a broad range of biological activities. Among these compounds, (+)-gliocladin C (1), produced by a strain of microorganism, Gliocladium roseum found in the sea hare Aplysia kurodai, is known to possess potent cytotoxicity against murine P388 lymphocytic leukemia cells (ED50 = 2.4 µg/mL). Moreover, the analogous compounds T988 A-C (2a-c), isolated from the New Zealand fungi Tilachlidium sp. (CANU-T988) by Munro and co-workers in 2004, are known to possess a potent cytotoxicity against cultured P388 leukemia cells. These compounds are composed of di- or triketopiperazine skeleton in conjunction with the pyrroloindole skeleton including a quaternary carbon center with indolyl group at the 10b position. These intriguing structural features have inspired a number of synthetic chemists to develop synthetic routes. Herein, we report our recently completed total syntheses of 1 and 2a-c via AgNTf2-mediated Friedel-Crafts alkylation and α-bromination on the diketopiperazine ring. Diketopiperazine 18 was derived from L-tryptophan methyl ester 14 and D-serine derivative 15 through condensation and formation of the diketopiperazine ring. Treatment of 18 with NBS in CH2Cl2 gave bromopyrroloindoline 12 high stereoselectively. We found that the judicious choice of solvent was crucial for the high stereoselectivity of this bromocyclization. Indole adduct 19 was then obtained in excellent yield by treatment of bromopyrroloindoline 12 with AgNTf2 in the presence of 5-bromoindole. After several conversions including oxidative cleavage of the terminal olefin, we achieved the total synthesis of (+)-gliocladin C (1). Furthermore, we developed a synthetic route to T988s via 21 as the synthetic intermediate. For chemoselective C-H oxidation at the C11a position, we found that the control of stereochemistry of the C3 position was crucial. Thus, we succeeded in α-bromination of 23 with NBS in the presence of AIBN under the microwave irradiation to obtain enamine 25 in quantitative yield. Finally, the total synthesis of (+)-T988 C (2a) and the first total synthesis of (+)-T988 A (2c) and (+)-T988 B (2b) were accomplished via formation of the disulfide bridge.