EPC‐Synthesis of Tetrahydroisoquinolines by Diastereoselective Alkylation at the 1‐Position of Phenylalanine‐Derived Precursors. Synthesis of the Alkaloid (+)‐Corlumine

The 1,2,3,4‐tetrahydro‐ N ‐pivaloyl‐isoquinoline‐3‐carboxylic acids 1d , 2d , and 3d , derived from ( R )‐ or ( S )‐phenylalanine, ( S )‐dopa, and ( S )‐α‐methyldopa, respectively, are doubly deprotonated with ( tert ‐butyl)lithium in THF and alkylated at the 1‐position (products 5 – 10 ). The major diastereoisomers formed are the result of electrophilic attack from the face opposite to the carboxylate group (rel. topicity ul ‐1,3). Even the addition to benzaldehyd (→ 7,8 ) is highly stereoselective ( one of four diastereoisomers is formed exclusively (300‐MHz 1 H‐NMR analysis)), if MgBr 2 etherate is added prior to the electrophile. Some of the obtained amino‐acid derivatives are decarboxylated by anodic oxidation in MeOH (→ 11 , 12 , 17 ) and NaBH 3 CN reduction, and converted to the known 1‐methyl‐ and 1‐benzyltetrahydroisoquinolines ( 15 , 16 ) of > 95% ee as well as to the phthalide isoquinoline alkaloid (+)‐corlumine of ≥80% ee. The synthetic approach described here is compared with other methods of synthesizing enantiomerically pure 1‐substituted tetrahydroisoquinolines (and thus an important group of alkaloids, Scheme 1 ).