藤本 克巳 三共(株), 活性物質研究所, 副主任研究員
OHMORI Ken Assistant Professor, Tokyo Institute of Technology, 理工学研究科, 助手 (50282819)
MATSUMOTO Takashi Associate Professor, Tokyo Institute of Technology, 理工学研究科, 助教授 (70212222)
藤本 克己 三共(株), 活性物質研究所, 副主任研究員
FUJIMOTO Katsumi Sankyo Co.
|Budget Amount *help
¥10,200,000 (Direct Cost : ¥10,200,000)
Fiscal Year 1999 : ¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1998 : ¥2,300,000 (Direct Cost : ¥2,300,000)
Fiscal Year 1997 : ¥4,900,000 (Direct Cost : ¥4,900,000)
An efficient and flexible synthetic route to the furaquinocins, a new class of antibiotics which show cytotoxic activity against HeLa S3 and B16 melanoma cells but no antimicrobial activity, was developed. These compounds pose new synthetic challenges due to their unique hybrid structure composed of the polyketide-derived naphthoquinone and the isoprenoid side chain, including (1) stereocontrol of three contiguous stereogenic centers at C-2, C-3 (quaternary), and C-10, (2) selective construction of the densely functionalized naphthoquinone, and (3) establishment of the sterically congested aromatic-isoprenoid hybrid structure.
Stereocontrolled construction of two of the three contiguous stereogenic centers, including a quaternary chiral center, was effected by the 1,2-rearrangement of optically active epoxy alcohol armed with the cobalt-complexed alkyne as the migrating group. The alkyne in the resulting homopropargyl alcohol, after decoordination of the cobalt, effectively worked as the C2 unit for constructing the naphthofuran skeleton by an electrocyclic benzannulation. The third chiral center was constructed by stereoselective methylenation of the aldehyde, adjacent to the quaternary chiral center, by a sulfur ylide. Through the resulting epoxide as the common intermediate, total syntheses of furaquinocin D, furaquinocin A, furaquinocin B, and furaquinocin H were achieved in a convergent manner.
Biological activity test revealed that some of the synthetic intermediates exhibit potent cyctocidal activities comparable to natural furaquinocins, which provides a valuable information for designing new synthetic antitumor agents.