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

• Published in: Journal of organic chemistry 2016-08, Vol.81 (15), p.6721-6739
• Main Authors: Benmekhbi, Lotfi, Louafi, Fadila, Roisnel, Thierry, Hurvois, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Chemical Sciences
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.6b01419

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.