The Asymmetric Total Synthesis of (+)-Reticuline

The synthesis of the title compound was accomplished via chiral formamidines in 5 steps (30.4% overall) and 98.6% ee.The isoquinoline alkaloid, reticuline 1 was first isolated in 19301 and again in 1939.2The absolute configurafion was reported in 19593 and total syntheses have been numero~s.~However, except for studies by Yamada-and Noyoria all syntheses of 1 yielded racemic products.We now describe an enicient route to this important alkaloid (a biosynthetic precursor to thebaine, codeine, and mophinew) using asymmetrlc methodology previously developed In our laboratory.Although Bmssi4 has described an expedient synthesis of (+)-I and noneticuline (NH-analog) the method requires a resolution, via the tartaric add san.9The present synthesis vnii provide (+)-1 in the natural configuration (S) and in greater than 98.6% enant~omenc excess thus making this pivotal alkaloid available in optically active form.The scheme utilized is a further extension of methodology involving chiral tormamidines to reach a number of isoquin~line.~~morphinan.1'indole.12and pyrrolidine13 alkaloids.Starting with the phenethylamine 2 , derived from van~ilin, nitromethane, and lithium aluminum hydride, the known14 tetrahydroisoquinoiine 3 was formed in 75% yield.The valinoi I-butyl ether formamidinel3 was then introduced by heating with tetrahydro~soquinoline 3 in toluene anording 4 in 88% yield.The key StereOSeleCtivBStep was accomplished by treating 4 with tbutyllithium at -78% to generate the lithiated Species 5 to which the benzyl bromide was then introduced at -l0O0C.h sifu removal of the chiral auxiliary gave the 1-benzylisoquinoiine 6 in 7096 yield for the process.n h i s paper is dedicated to Professor D.