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

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 sp3 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.