Biomimetic Total Synthesis of Dysoxylum Alkaloids.

A five-step total synthesis of Dysoxylum alkaloids has been achieved using a biomimetic approach from zanthoxylamide protoalkaloids. The synthesis featured a direct amidation and a Bischler-Napieralski reaction to form the dihydroisoquinoline ring, which was then subjected to a Noyori asymmetric transfer hydrogenation to establish the stereogenic center at C-1. Our synthetic sequence provides an important perspective on the biosynthetic origin of Dysoxylum alkaloids, since 6 natural alkaloids and 12 synthetic analogues were obtained with high enantioselectivity and in overall yields up to 68%. In addition, we describe the acute toxicity toward zebrafish embryos of Dysoxylum alkaloids, comparing their toxicity with that of their corresponding zanthoxylamide protoalkaloids and establishing an enantioselectivity-toxicity relationship.