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 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.

Electrochemical access to 8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-7-carbonitrile. Application to the asymmetric syntheses of (+)-myrtine and alkaloid (+)-241D.

The total syntheses of both enantiomers of trans-quinolizidine (+)-myrtine and cis-2,4,6-trisubstituted piperidine alkaloid (+)-241D are reported here. Our approach was based on the N-Boc-directed metalation of enantiopure 4-piperidone (-)-11, which was prepared in four steps from α-amino nitrile 6 through a stereoselective alkylation-reduction decyanation process. α-Amino nitrile 6 was prepared at the anode through electrochemical oxidation of 4-piperidone (+)-5.

Electrochemical synthesis and chemistry of chiral 1-cyanotetrahydroisoquinolines. An approach to the asymmetric syntheses of the alkaloid (-)-crispine a and its natural (+)-antipode.

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.

Synthesis of tetrahydroisoquinoline alkaloids via anodic cyanation as the key step.

We report a new route to tetrahydroisoquinoline (THIQ) alkaloids involving the alkylation of alpha-aminonitrile 2 as a key step. The latter compound was prepared by anodic cyanation of the corresponding tertiary amine 1. Reductive decyanation of alpha-aminonitriles 6a-c proceeded diastereoselectively (up to 95% de) to deliver the C1-substituted alkaloids precursors 9a-c.