A new synthetic approach directed towards the synthesis of naturally occurring 2-alkyl-tetrahydroquinolines is described. The C-C bonds in the α position relative to the nitrogen atom were formed by the reversal of the polarity of the C=N bond of α-amino nitrile 6, which was prepared electrochemically from 1-(phenylethyl)-tetrahydroquinoline. A NaBH 4 -mediated reductive decyanation process furnished benzylic amines 16a-d as mixtures of diastereomers (50-

α-Amino nitrile 2a was conveniently prepared in two individual steps from chiral hexafluorophosphate salt isoquinolinium (-)-8b including anodic cyanation as an efficient means to activate the sp(3) C1-H bond of the THIQ nucleus. The lithiation of 2a was carried out in THF at -80 °C in the presence of LDA to produce a stable α-amino carbanion which was condensed on a large variety of alkyl halides. The resulting quaternary α-amino nitriles were subjected to a stereoselective reductive decyanation in ethanol in the presence of NaBH4 as the hydride donor to yield N-Boc-1-alkyl-THIQs (+)-10a-g in up to 97:3 er's after removal of the chiral auxiliary group. Examination of the ORTEP view of THIQ (+)-1f revealed that the newly created stereogenic center had an absolute S configuration. Likewise, (-)-xylopinine was synthesized in four workup steps in an overall 63% yield from α-amino nitrile (+)-2b. In this process, crystallization of an enantioenriched mixture (90:10) of (-)-norlaudanosine with 1 equiv of (-)-N-acetyl-l-leucine afforded the leucinate salt (+)-13 (99:1 dr). Similarly, (+)-salsolidine was displaced from its (-)-DBTA salt (-)-12 in 99:1 er, which was determined by proton and carbon NMR spectroscopy in the presence of thiophosphinic acid (+)-14 as the chiral solvating agent.

The stereoselective convergent total syntheses of both enantiomers of the tetrahydroisoquinoline (THIQ) alkaloid crispine A are described. The THIQ precursors (-)-6 (90:10 dr) and (-)-11 (85:15 dr) were prepared from the alkylation-reduction sequence of a common α-amino nitrile (+)-4 derivative that has been conveniently prepared by anodic cyanation. Elaboration of the pyrrolidine ring of the title compound was cleanly achieved by two efficient ring closures methods involving (a) the displacement of a halogen atom and (b) the formation of a cyclic iminium cation to afford (-)-crispine A in 90% and 85% yields, respectively. A crystallization of enantioenriched (-)-crispine A (90:10 er) with 1 equiv of (-)-DBTA afforded the tartrate salt (-)-14 (≥98:2 dr) in 81% yield. The absolute S configuration of (-)-crispine A was simply deduced from examination of the X-ray data of tartrate salt (-)-14. Likewise, the natural (+)-crispine A was prepared in seven workup steps in an overall 30% yield, and reciprocal crystallization with (+)-DBTA afforded the enantiomeric tartrate salt (+)-14 in a ≥98:2 dr. Both enantiomers of crispine A were liberated from their respective DBTA salts in ≥98:2 er's which were determined by proton and carbon NMR spectroscopy, utilizing (R)-(+)-tert-butylphenylphosphinothioic acid (+)-15 as chiral solvating agent.