Use of activation methods for organozinc reagents

Alkylation of the isoquinoline skeleton in the 1-position

Noscapine comes of age.

Diastereoselective Hydroxyalkylations in Position 1 of Tetrahydroisoquinolines and Synthesis of Aporphine, Protoberberine, and Pathalide Alkaloids



Unsubstituted and 6,7-dialkoxy-N-pivaloyl-tetrahydroisoquinolines 1–3 are converted to 1-bromomagnesium derivatives by sequential treatment with t-BuLi (−75°/THF) and MBr2.OEt2. Addition of the metalated tetrahydroisoquinolines to aliphatic or aromatic aldehydes occurs with relative topicity ul (Scheme 2). The 1-hydroxyalkylated 2-pivaloyl-tetrahydroisoquinolines a of u-configuration thus obtained (14 examples) can be converted to free aminoalcohols c of either l-or u-configuration (9 examples; Scheme 3). The depivaloylation with retention ( u-c) is best achieved by heating in EtOH/KOH, the conversion to 1-aminoalcohols l-c by treatment with CF3COOH/(CF3CO)2O ( l,-pivalates l-b), followed by alkaline saponification or by LiAlH4 reduction of the esters. The configuration of the products is assigned by 1H-NMR spectroscopy, by X-ray crystal structure analysis, by chemical correlation, and by comparison of the chemical properties of the l- and the u-isomers. The diastereoselective hydroxybenzylation of the tetrahydroisoquinoline is used for short syntheses of ushinsunine/oliveroline (Scheme 4), β-hydrastine, and ophiocarpine/epiopliocarpine (Scheme 6; aporphine, phthalide, and protoberberine alkaloids, respectively).

Diasteroselektive Hydroxyalkylierungen in 1-Stellung von Tetrahydroisochinolinen und Synthese von Aporphin-, Protoberberin- und Phthalid-Alkaloider

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. A crystallization of enantioenriched (−)-crispine A (90:10 er) with 1 equiv of (−)-DBTA afforded the tartrate salt (−)-14 (≥98:2 dr) in 81% yield. The absolute S configuration of (−)-crispine A was simply deduced from examination of the X-ray data of tartrate salt (−)-14. Likewise, the natural (+)-crispine A was prepared in seven workup steps in an overall 30% yield, and reciprocal crys...

Electrochemical Synthesis and Chemistry of Chiral 1-Cyanotetrahydroisoquinolines. An Approach to the Asymmetric Syntheses of the Alkaloid (−)-Crispine A and Its Natural (+)-Antipode

Novel zinc-promoted alkylation of iminium salts. New synthesis of benzylisoquinoline, phthalidylisoquinoline, and protoberberine alkaloids and related compounds

Kimihiko Nagami

Papers

Novel zinc-promoted alkylation of iminium salts. New synthesis of benzylisoquinoline, phthalidylisoquinoline, and protoberberine alkaloids and related compounds

A new synthetic method of nitrogen heterocycles through a novel annulation