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Total Synthesis and Bioactivity of an Unnatural Enantiomer of Merrilactone A:  Development of an Enantioselective Desymmetrization Strategy

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posted on 2007-04-13, 00:00 authored by Masayuki Inoue, Nayoung Lee, Satoshi Kasuya, Takaaki Sato, Masahiro Hirama, Miyako Moriyama, Yoshiyasu Fukuyama
(−)-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. Here, we report the total synthesis of the unnatural enantiomer of merrilactone A [(+)-1], based on a novel desymmetrization strategy. The chiral lithium amide 16g promoted an enantioselective transannular aldol reaction of eight-membered meso-diketone 3d, establishing the absolute stereochemistries of four chiral centers of the cis-bicyclo[3.3.0]octane framework of 1 in a single step. The obtained compound 4d served as a platform for the subsequent functional group manipulations necessary for the construction of (+)-1. Surprisingly, both the natural and unnatural enantiomers of synthetic merrilactone A equally promoted neurite outgrowth in primary neuronal cultures.