開催日: 2017/09/20 - 2017/09/22
(+)-Gracilamine (1), isolated from Galanthus gracilis by Ünver and Kaya in 2005, is a member of amaryllidaceae alkaloid, which possesses seven stereogenic centers involving all carbon quaternary stereocenter at C3 on the unprecedented pentacyclic core structure (A to D rings). Since the synthetically challenging structure of 1, many synthetic efforts have been investigated, and so far total synthetic works (including formal synthesis) have been reported from five research groups of Ma, Gao, Snyder, Yu and Banwell, respectively. But no enantioselective synthesis of 1 has been reported, and the absolute configuration of 1 is not known. Herein, we disclose an enantioselective synthetic (+)-gracilamine (1) based upon a diastereoselective dearomative phenolic coupling reaction and regioselective intramolecular aza-Michael reaction. In our synthetic process, organocatalytic aza-Friedel-Crafts reaction developed by our group was efficiently applied for the construction of stereocenter at C9a, whose stereochemistry allowed us to control the remaining stereocenters in 1. Asymmetric aza-Friedel-Crafts reaction with sesamol (4) and N-Boc aldimine 17 was examined in the presence of catalyst (R,R)-2. Under the previously developed conditions, aza-Friedel-Crafts reaction took place smoothly, and desired 18 was obtained in 94% yield with 91% ee, which was increased to be 99% ee after recrystallization with hexane. The construction of B and E rings included C3a stereocenter were achieved by diastereoselective dearomative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction of phenol 22. Then, D ring was constructed by means of intramolecular Mannich-type reaction of ketone 30 with α-keto ester 7. Finally, (+)-gracilamine (1) was obtained by reduction of ketone, detosylation and methylation of amino group. The optical rotation of our synthetic 1 [[α]25 D = +16.4 (c 0.11)] showed good agreement with previously report data [[α]25 D = +21.8 (c 0.13)].