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Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical Cyclization: Application in the Synthesis of ent‐Tadalafil
Author(s) -
Chiu WeiJung,
Lin YanLiang,
Barve Indrajeet J.,
Sun ChungMing
Publication year - 2021
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.202100506
Subject(s) - chemistry , tadalafil , enantioselective synthesis , intramolecular force , radical cyclization , radical , aryl , halogenation , condensation , medicinal chemistry , intramolecular reaction , combinatorial chemistry , stereochemistry , catalysis , organic chemistry , alkyl , medicine , physics , sildenafil , thermodynamics
An enantioselective synthesis of 1‐substituted tetrahydroisoquinolines from L–Dopa methyl ester through intramolecular aryl radical cyclization is demonstrated. The strategy consists of bromination of ( S )‐2‐amino‐3‐(2‐bromo‐4,5‐dimethoxyphenyl)propanoate followed by condensation with various aldehydes to afford bromoimidate ester. Aryl radicals generated from bromoimidate ester under the radical generating conditions ( n Bu 3 SnH/AIBN) cyclizes via 6‐ endo mode to afford cis ‐1‐substituted tetrahydroisoquinolines exclusively in 99% ee. The utility of this synthetic protocol is demonstrated in the synthesis of (6 S , 12a S ) Tadalafil (5 steps, 21%, 99% ee).