Total Synthesis of Merrilactone A.

Abstract

(-)-Merrilactone A [(-)-1], isolated from Illicium merrillianum in 2000, possesses neurite outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. Apart from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. In this account, we describe the total synthesis of (+)- and (-)-merrilactone A, based on two novel strategies. Both strategies employed, as a key step, a transannular aldol reaction of eight membered diketone to construct the core cis-bicyclo [3.3.0] octyl system of 1. In the first generation total synthesis, the 2, 6-bis (trifluoromethyl) benzyl group served as a long-range stereocontrolling element for synthesis of the enantiopure bicyclo [3.3.0] octane frame-work of (-)-1. On the other hand, asymmetric aldol reaction was developed in the second generation synthesis to build the fused core of (+)-1 in a more consice manner. The obtained key intermediates were utilized as a platform for the subsequent functional group manipulations necessary for construction of (-)- and (+)-1. Surprisingly, both the natural and unnatural enantiomers of 1 equally promoted neurite outgrowth in primary neuronal cultures.