Inoue Masayuki, Lee Nayoung, Kasuya Satoshi, Sato Takaaki, Hirama Masahiro, Moriyama Miyako, Fukuyama Yoshiyasu
Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
J Org Chem. 2007 Apr 13;72(8):3065-75. doi: 10.1021/jo0700474. Epub 2007 Mar 14.
(-)-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.
（-）-Merrilactone A [（-）-1]于2000年从八角莲中分离得到，在胎鼠皮质神经元培养物中具有神经突生长活性，因此有望在治疗与阿尔茨海默病和帕金森病相关的神经退行性疾病方面展现治疗潜力。除了其生物学特性外，1的笼状五环骨架带来了有趣的合成挑战。在此，我们报道基于一种新型去对称化策略对merrilactone A [（+）-1]的非天然对映体进行的全合成。手性锂酰胺16g促进了八元内消旋二酮3d的对映选择性跨环羟醛反应，一步确定了1的顺式双环[3.3.0]辛烷骨架中四个手性中心的绝对立体化学。所得化合物4d作为后续构建（+）-1所需官能团操作的平台。令人惊讶的是，合成的merrilactone A的天然和非天然对映体在原代神经元培养物中均能同等程度地促进神经突生长。
