Copper (I)-catalyzed carbon-hydogen insertion reactions of diazoesters: an asymmetric approach to the mitosene ring system

Abstract

The mitomycins are common targets of natural product synthesis due to their antitumor properties and synthetically challenging structures. Especially prolific are investigations toward the synthesis of mitomycin C (1), which is currently used in the treatment of cancer. From these studies emerged interest in a related compound, FR900482 (2), the isolation and structure determination of which were reported in 1987 by workers from the Fujisawa Pharmaceutical Company. In initial studies, FR-900482 was superior to mitomyicin C in potency and suppression of side effects. To date, three syntheses of FR-900482 have been described, but only one has led to an optically active product. The 1,2-disubstituted mitosene, or pyrrolo[1,2-a]indole, ring system (cf. 4) has proven to be a useful intermediate in synthetic approaches to mitomycin K (3) and FR-900482. One asymmetric approach to this ring system is through the formation of a bond between C9 and C9a. This can be effected by a stereoselective intramolecular carbon-hydrogen (C-H) insertion reaction of a meso diazoester. The objective of this research is to enhance die stereoselective construction of the mitosene ring system via the C-H insertion reaction of a diazoester. To do this, chiral catalysts and chiral auxiliaries may be used, both separately (enantioselective and disatereosele,ctive, respectively) and together (double diastercoselective). Previous investigations have found that copper(I) catalysts were superior to rhodium(II) catalysts in the decomposition of the diazoester, and that the (-)-menthol chiral auxiliary provided little enhancement in stereoselectivity. In continuation of that study, diazoesters of (-)-(R)pantolactone and (-)-8-phenylmenthol have been examined. Decomposition of the pantolactone ester with rhodium(H) acetate did show diasteroselectivity (32% d.e.). However, no matched pair of chiral auxiliary and chiral copper-(I) catalyst was observed.