text: The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers in 1931. Following studies 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 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.