Gábor Dörnyei

Studies aiming at the synthesis of morphine. II. Studies on phenolic coupling of N-norreticuline derivatives

Abstract The synthesis of salutaridine derivatives via phenolic coupling on norreticuline derivatives can be performed in improved yields, using non-metallic oxidizing agents. The assumption of a coordination effect in the preformation of the desired structure is, thus, unnecessary.

Validation of high-affinity binding sites for succinic acid through distinguishable binding of gamma-hydroxybutyric acid receptor-specific NCS 382 antipodes

Gamma-hydroxybutyric acid (GHB) binding to multiple sites for the tricarboxylic acid cycle intermediate succinic acid (SUC) has been disclosed recently. In order to better characterize these targets, distinguishable binding of GHB receptor-specific NCS 382 antipodes to [(3)H]-SUC or [(3)H]-GHB labelled sites in rat brain synaptic membranes was explored. Eutomer binding parameters suggest identity of the high-affinity target for SUC with a synaptic GHB receptor subtype.

Inhibition of γ-aminobutyric acid uptake by bicuculline analogues

Abstract Enantiomers of norbicuculline, (+)[1S,9R] and (−)[1R,9S]erythro-1-[1′-(4′,5′-methylenedioxyphthalidyl)]-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and of the N-methyl derivatives {(+)[1S,9R] and (−)[1R,9S]bicuculline} were found to inhibit the progress of the γ-aminobutyric acid transporter-mediated uptake of 40 μM [ 14 C ]γ-aminobutyric acid into native plasma membrane vesicles from the rat cerebral cortex at 30°C. The values for the dissociation constants of the reversible inhibition, relative to (+)[1S,9R]bicuculline, in order of increasing inhibition, were: (−)[1R,9S]bicuculline, 3.3; (+)[1S,9R]-bicuculline, 1.0; (−)[1R,9S]norbicuculline, 0.4≈(+)[1S,9R]norbicuculline; guvacine, 0.02. The norbicucullines have higher potencies than (+)[1S,9R]bicuculline for the γ-aminobutyric acid transporter, in contrast to the relative potencies of these inhibitors for the inhibition of function and γ-aminobutyric acid binding of the γ-aminobutyric acid type A receptor.

New routes to clavine-type ergot alkaloids. Part 1. First total synthesis of three natural products : (+)- setoclavine, (+)-isosetoclavine, (-)-9,10-dihydroisosetoclavine, and structure correction of the latter

The double bond in ring D of (+)-9,10-didehydro-6-methylergolin-8-one (2) was reduced selectively by catalytic hydrogenation to yield (-)-6-methylergolin-8-one (6). Grignard reaction of 6 has been performed with methylmagnesium iodide to afford two isomers (5 and 7). The main isomer having an 8a-methyl group at C8 with a C/D-trans junction (5; (-)-dihydroisosetoclavine) proved to be identical with the natural product, hence its name and structure should be corrected. As a minor isomer (7) a C/D-cis clavine derivative was also isolated which can be regarded as unnatural (+)-8α-hydroxy-costaclavine. (+)-Setoclavine (8) and (+)-isosetoclavine (9) have also been prepared from 2, thus achieving the first total synthesis of these natural products. Detailed structure elucidation of 5-9 has been carried out as well.

Chemistry of indoles carrying a basic function. Part 8: A new approach to the ergoline skeleton

Starting from N-pivaloyl-Uhles ketone a new synthetic approach to the ergoline skeleton has been elaborated. Ring D of the tetracyclic skeleton was formed by an intramolecular Dieckmann-condensation of a diester, obtained in a Reformatsky reaction of a properly substituted derivative of N-pivaloyl Uhles ketone followed by elimination of water.

Cyclopropanation of carbon-carbon double bonds in ring d of ergot alkaloids

Some ergot alkaloid derivatives containing a double bond in ring D have been reacted with diazomethane/palladium diacetate reagent to result in formation of a fused cyclopropane ring. This procedure proved to be generally applicable for cyclopropanation of Ergot alkaloids.

AN INTRIGUING CASE OF THE RETRO-MICHAEL REACTION

Abstract In the course of Michael addition of carbanions, derived from malononitrile or cyanoacetic ester, to a nitrostyrol retro reaction has also been observed. Depending on the reaction conditions any of the two compounds formed can be obtained as main product. The entire process has been thoroughly investigated.

Chapter 2 The Morphine Alkaloids

Publisher Summary The morphinans represent a large group of alkaloids, related to the isoquinoline alkaloids. This chapter explores that the first representative of the morphinan group of alkaloids, morphine, was discovered 200 years ago. Many significant advances have been made in the isolation, structure elucidation, and chemistry of the morphinan alkaloids. The chapter focuses on the occurrence, isolation, structure elucidation, synthesis, transformations, reactions, biogenesis, and pharmacological activity of morphinan alkaloids. It discusses that because of the great medicinal importance of the morphinan alkaloids, as well as of codeine and semisynthetic derivatives, intensive research has been directed toward finding an effective and commercially feasible total synthesis for these compounds. The chapter also reviews that the biogenesis of morphine alkaloids has been the subject of numerous studies. Finally, it discusses conversion of the dihydrothebainone product of Grewe cyclization to codeine and morphine; the transformation of the biomimetic intermediate salutaridine and its derivatives; and semisynthetic approaches resulting in 14-hydroxy morphinan derivatives with high medicinal importance.

Chapter 2 Corynantheine, Yohimbine, and Related Alkaloids

Publisher Summary This chapter describes the corynantheine–yohimbine group of monoterpene indole alkaloids with greater emphasis on their chemistry including structural elucidations, synthesis, transformations, reactions, spectroscopy, and pharmacology. The simplest member of the indolo[2,3-a]quinolizine alkaloid group has been found in Dracontomelum magniferum B1; it possesses structure (−)-1. The structures of vincarpine and dihydrovincarpine are determined on the basis of their spectral data and via some derivatives obtained by either catalytic or hydride reduction. Pharmacological investigation of a great number of C- 18-acyloxy analogs of reserpine showed that alteration at this site of the molecule exerts smaller or greater modification of the original activity. In comparison with other spectroscopic methods, 13 C-NMR spectroscopy affords the most valuable information for the stereochemical and conformational analysis of quinolizidine compounds. Among naturally occurring compounds the indole alkaloids play important roles as biologically active substances. Yohimbine is a sympathicolytic agent, and yohimbine and its naturally occurring diastereomers can be used as valuable tools for the subclassification of α-adrenoceptors, including the differentiation between the high and low affinity sites.