Synthesis of protoberberines using a silyl-directed Pictet–Spengler cyclization

Abstract

Five naturally-occurring protoberberines have been synthesized in enantioenriched form by alkylation by two different 2-trimethylsilylbenzyl chlorides of four tetrahydroisoquinolines, derivatized with Meyers' formamidine valinol methyl ether chiral auxiliary. Silyl-directed Pictet–Spengler cyclization of the ensuing 3,4-dimethoxy-2-trimethylsilylbenzyl tetrahydroisoquinolines leads to four of the target protoberberines in excellent yield and complete regioselectivity. In the fifth case, the 3,4-methylenedioxy analog gives a mixture of protoberberine and a product of ring closure at C6 of the benzyl moiety in a 3:4 ratio.