Diastereoselective Synthesis of (-)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid via Morpholinone Derivatives.

A simple and convenient synthesis of (-)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is described, applying a combination of two synthetic methods: the Petasis reaction and Pomeranz-Fritsch-Bobbitt cyclization. The diastereomeric morpholinone derivative N-(2,2-diethoxyethyl)-3-(3,4-dimethoxyphenyl)-5-phenyl-1,4-oxazin-2-one formed in the Petasis reaction was further transformed into 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid via Pomeranz-Fritsch-Bobbitt cyclization, a classical method of synthesis leading to the tetrahydroisoquinoline core. We review important examples of applications of the Pomeranz-Fritsch process and its modifications in the synthesis of chiral tetrahydroisoquinoline derivatives that have been published in the past two decades.

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004-2015.

In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet-Spengler, the Bischler-Napieralski, and the Pomeranz-Fritsch-Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1-N2, N2-C3, C1-N2/N2-C3, and C1-N2/C4-C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

Density functional theory calculations of the optical rotation and electronic circular dichroism: the absolute configuration of the highly flexible trans-isocytoxazone revised.

Ab initio calculations of the optical rotation (OR) and electronic circular dichroism (ECD) for a series of trans-diastereomers of the natural cytokine modulator cytoxazone 1-4 have been performed by density functional theory (DFT). The calculation of OR and ECD curves provides, after critical assessment, a reliable method for the assignment of absolute configuration of these conformationally flexible molecules. The effects of the level of theory used for calculations, changes of conformer equilibrium, and the solvent influence on the geometry and values of calculated OR data are discussed, leading to the conclusion that the most frequently used B3LYP/6-31G(d) method is not adequate for prediction of the absolute configuration of this type of highly flexible molecules. The absolute configurations of levorotatory trans-isocytoxazone 2 and analogues 1, 3, and 4 have been established as (-)-(4S,5S)-trans-1-4; i.e., it is in opposition to the previously published configuration (-)-(4R,5R)-trans-2.

Two optically active isoquinoline derivatives.

In the two title optically active tetrahydroisoquinoline derivatives, namely 3-hydroxymethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-2-ium bromide methanol hemisolvate, C(16)H(18)NO(+).Br(-).0.5CH(3)OH, (IIb), and 2-formyl-3-hydroxymethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, C(17)H(17)NO(2), (III), the absolute configurations have been confirmed as 3R,4R by structure refinement using Bijvoet-pair reflections. The hydroxymethyl and phenyl groups in (IIb) are oriented in equatorial and pseudo-equatorial positions, respectively, whereas in (III), the corresponding groups are in axial and pseudo-axial positions, respectively; the hydroxymethyl and phenyl groups are trans with respect to one another in both structures. The heterocyclic rings in (IIb) and (III) adopt envelope conformations inverted with respect to each other. In both structures, the molecules are linked through hydrogen bonds.