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.
Inoue
Masayuki
M
Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan. inoue@ykbsc.chem.tohoku.ac.jp
Lee
Nayoung
N
Kasuya
Satoshi
S
Sato
Takaaki
T
Hirama
Masahiro
M
Moriyama
Miyako
M
Fukuyama
Yoshiyasu
Y
D000818:Animals; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002942:Circular Dichroism; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D007783:Lactones; D012717:Sesquiterpenes; C458341:merrilactone A