ASYMMETRIC-SYNTHESIS OF BENZOQUINOLIZIDINES - A FORMAL SYNTHESIS OF (-)-EMETINE

Chiral formamidines affixed to tetrahydroisoquinoline derivatives affords the appropriate precursor 9 to various benzo[a]quinolizidines 2 and 3 and dibenzo[a,g]quinolizidines 4 in modest to high optical purity. Both 3 and 4 have been utilized in total syntheses of natural emetine 1, thus the route herein constitutes a formal total synthesis of 1. Furthermore, Mannich cyclizations of 1-alkylisoquinolines 18a-c proceeded with or without loss of absolute stereochemistry at the C-1 position. Explanation for this behavior is based upon whether a [3,3] rearrangement or a Mannich reaction takes place. The former results in virtually complete racemization of 18, whereas the latter totally conserves the chirality in 18. Finally, 1-alkynylisoquinolines of high optical purity were transformed, via the Overman protocol, to alkylidine benzo[a]quinolizidines 24 in good yield and to our knowledge, high enantiomeric excess.