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

Abstract : 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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01367242
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Submitted on : Thursday, September 15, 2016 - 5:18:00 PM
Last modification on : Thursday, March 5, 2020 - 3:33:43 PM

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L. Benmekhbi, F. Louafi, T. Roisnel, J.-P. Hurvois. Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds through the Alkylation of Anodically Prepared α-Amino Nitriles. Journal of Organic Chemistry, American Chemical Society, 2016, 81 (15), pp.6721--6739. ⟨10.1021/acs.joc.6b01419⟩. ⟨hal-01367242⟩

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