Total Synthesis and Structural Revision of (±)-Tricholomalides A and B

摘要

A focus of our laboratory is the total synthesis and evaluation of small-molecule natural products possessing neurotrophic activity. Such compounds may serve as promising lead agents in the treatment of neurodegenerative disease, the progression of which is marked by diminishing levels of neuronal support. In this context, we took note of a report by Ohta and co-workers of a class of neurotrophically active diterpenes termed the tricholomalides. Isolated from the mushroom tricholoma sp., tricholomalides A-C were found to induce neurite outgrowth in rat pheochromocytoma cells at micromolar levels. The promising neurotrophic activity and complexity of the target structures prompted us to undertake the syntheses of tricholomalides A and B. As shown below, in the course of our total synthesis effort, we found that the structures of tricholomalides A (1') and B (2') had been misassigned. Our revised assignments are shown as structures 1 and 2 (Scheme 1). We describe below the total syntheses of tricholomalides A (1) and B (2) using chemistry recently developed in our laboratory.