Synthetic approaches to the skeleton of crinine-type alkaloids from isoquinoline and the total synthesis of (?)-crinine

Abstract

The crinine-type alkaloids, which have the 5,10b-ethanophenanthridine skeleton as the core structure, represent an important sub-class of the family of Amaryllidaceae alkaloids. Considering the obvious structural relationship between the crinine-type alkaloids and the isoquinoline nucleus, a synthetic strategy involving the construction of the crinane skeleton from isoquinoline would be a logical approach. In order to realize this goal, a novel methodology to prepare 4,4-disubstituted 1,4-dihydroisoquinolines through boron-activated enamine chemistry has been developed in our lab. This method provides not only a quaternary carbon center at C-4 but also an imine group that can be further functionalized. A systemic investigation of the reductive alkylation of isoquinoline using boron-activated enamine chemistry was performed in order to examine the scope of this methodology for preparing 4,4-disubstituted isoquinoline derivatives. Various functional groups including simple alkyls, allyl, protected alcohols, protected aldehydes, and esters were successfully introduced at C-4 of the 1,4-dihydroisoquinoline product. Additionally, several spiro compounds and imines with two different substituents at C-4 were also synthesized. Based on this method, (?)-crinine was efficiently prepared in 9 steps in 14.4% overall yield for the first time from 6,7-methylenedioxyisoquinoline using an AB-->D-->C sequence. This method was then applied to build the skeletons of delagoenine and delagoensine - two very unusual alkaloids possessing a hemiaminal function in the D-ring.