Consecutive Pictet–Spengler Condensations toward Bioactive 8‐Benzylprotoberberines: Highly Selective Total Syntheses of (+)‐Javaberine A, (+)‐Javaberine B, and (–)‐Latifolian A

Abstract

Enantiopure 8‐benzylprotoberberines were synthesized by two consecutive Pictet–Spengler (PS) condensations with protected 3,4‐dihydroxyphenylacetaldehydes. The first PS to (+)‐(R)‐norprotosinomenine was optimized to 90 % ee with 5 mol‐% of (R)‐TRIP as chiral Brønsted acid (> 99 % ee after trituration). The second PS did not require any catalyst, and its regioselectivity was strongly dependent on the solvent: 99:1 para selectivity was obtained in trifluoroethanol leading to (+)‐javaberine A; 81:19 ortho selectivity was reached in apolar aprotic solvents for the synthesis of (+)‐javaberine B. Complete, natural diastereoselectivity was observed in the second PS. Through selective catechol oxidation the spirocyclic alkaloid (–)‐latifolian A was prepared from protected (+)‐javaberine A.