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

(−)-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.