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Consecutive Pictet–Spengler Condensations toward Bioactive 8‐Benzylprotoberberines: Highly Selective Total Syntheses of (+)‐Javaberine A, (+)‐Javaberine B, and (–)‐Latifolian A
Author(s) -
Kayhan Jenifer,
Wanner Martin J.,
Ingemann Steen,
van Maarseveen Jan H.,
Hiemstra Henk
Publication year - 2016
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201600764
Subject(s) - chemistry , enantiopure drug , regioselectivity , catechol , selectivity , pictet–spengler reaction , stereochemistry , total synthesis , alkaloid , solvent , organic chemistry , enantioselective synthesis , catalysis
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.