Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds through the Alkylation of Anodically Prepared α‑Amino Nitriles

α-Amino nitrile <b>2a</b> was conveniently prepared in two individual steps from chiral hexafluorophosphate salt isoquinolinium (−)-<b>8b</b> including anodic cyanation as an efficient means to activate the sp³ C1–H bond of the THIQ nucleus. The lithiation of <b>2a</b> 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 <i>N</i>-Boc-1-alkyl-THIQs (+)-<b>10a</b>–<b>g</b> in up to 97:3 er’s after removal of the chiral auxiliary group. Examination of the ORTEP view of THIQ (+)-<b>1f</b> revealed that the newly created stereogenic center had an absolute <i>S</i> configuration. Likewise, (−)-xylopinine was synthesized in four workup steps in an overall 63% yield from α-amino nitrile (+)-<b>2b</b>. In this process, crystallization of an enantioenriched mixture (90:10) of (−)-norlaudanosine with 1 equiv of (−)-<i>N</i>-acetyl-l-leucine afforded the leucinate salt (+)-<b>13</b> (99:1 dr). Similarly, (+)-salsolidine was displaced from its (−)-DBTA salt (−)-<b>12</b> in 99:1 er, which was determined by proton and carbon NMR spectroscopy in the presence of thiophosphinic acid (+)-<b>14</b> as the chiral solvating agent