The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers[3] in 1931. Following studies[4][5] where the synthesis of the key lactonic amide intermediate (structure 4 in figure) was the most troublesome, the major breakthrough was achieved in 1981 when J. R. Falck and co-workers[6] reported a four-step total synthesis of hydrastine from simple starting materials. The key step in the Falck synthesis was using a Passerini reaction to construct the lactonic amide intermediate 4.
Starting from a simple phenylbromide variant 1, alkylation reaction with lithium methylisocyanide gives the isocyanide intermediate 2. Reacting isocyanide intermediate 2 with opianic acid 3 initiated the intramolecular Passerini reaction to give the key lactonic amide intermediate 4. The tetrahydro-isoquinolin ring was formed by first a ring-closure reaction under dehydration conditions using POCl3 and then a catalyzed hydrogenation using PtO2 as the catalyst. Finally, hydrastine was synthesized by installing the N-methyl group via reductive amination reaction with formaldehyde.
^Hope E, Pyman FL, Remfry FG, Robinson R (1931). "XXXI.—A synthesis of hydrastine. Part I". J. Chem. Soc.: 236–247. doi:10.1039/JR9310000236. ISSN0368-1769.
^Haworth RD, Pinder AR (1950). "360. A new route to the phthalide-isoquinoline bases, and a synthesis of (–)-hydrastine". J. Chem. Soc.: 1776–1780. doi:10.1039/JR9500001776. ISSN0368-1769.
(what is this?) (verify)
