G. V. Grishina

Synthesis and Stereochemistry of 3-Hydroxy-1,2,3,6-tetrahydropyridines

A series of 1-benzyl-3-hydroxy-1,2,3,6-tetrahydropyridines, multipurpose synthons for fine organic synthesis and potential antiviral compounds, was prepared by the rearrangement of a number of 1-benzyl-3,4- epoxypiperidines under treatment with lithium amides. 3,4-Epoxypiperidines were obtained by oxidation of 1,2,5,6- tetrahydropyridines trifluoroacetates with a trifluoroperacetic acid. Convenient synthetic routes were found and developed. A conformation analysis of the series of stable 3,4-epoxypiperidines and 3-hydroxy-1,2,3,6- tetrahydropyridines was carried out.

trans-4-amino-3-hydroxypiperidines. Regio- and stereoselective synthesis

Abstracttrans-4-Amino-1-benzyl-3-hydroxypiperidines were synthesized by regio- and stereoselective amination of a series of 1-benzyl-3,4-epoxypiperidines with primary and secondary aliphatic, aromatic, and heterocyclic amines in the presence of lithium perchlorate. The regio- and stereoselectivity of the amination process is ensured by specific activation of the oxirane ring in epoxypiperidine derivatives. Lithium cation is coordinated simultaneously at the piperidine nitrogen atom and oxirane oxygen atom, which leads to greater extension of the C4-O bond as compared to C3-O, so that nucleophilic attack is directed at the C4 atom of the piperidine ring.

Chiral 4-piperidones and their bicyclic analogs. Strategy of stereoselective synthesis (review)

The principal stereoselective paths of synthesis and the stereochemistry of chiral 4 piperidones and their bicyclic analogs are examined critically in this article.

A simple and convenient route to 1,2,3,4,5,6,7,8-octahydro-1,6-naphthyridines

Abstract A simple and convenient synthetic approach to the new series of 1,2,3,4,5,6,7,8-octahydro-1,6-naphthyridines 1a-j has been developed. This was achieved via a one-pot process combining metalated 4-piperidinonimine alkylation and intramolecular cyclization.

Preparation of enantiomeric pure (−)-(3R,4S)-1-benzyl-3,4-epoxypiperidine and enriched (−)-(R)-1-Benzyl-3-hydroxy-1,2,3,6-tetrahydropyridine by kinetic separation of (±)-1-benzyl-3,4-epoxypiperidine under the action of chiral lithium amides

Enantiomeric pure (−)-(3R,4S)-1-benzyl-3,4-epoxypiperidine and (−)-(R)-1-benzyl-3-hydroxy-1,2,3,6-tetrahydropyridine with enantiomeric excess 61.9% were obtained by kinetic separation of (±)-1-benzyl-3,4-epoxypiperidine under the action of lithium salt (+)-(S)-2-[(pyrrolidin-1-yl)methyl]pyrrolidine. The sterical direction of the kinetic separation of (±)-1-benzyl-3,4-epoxypiperidine and absolute configurations of the target products were established.

A simple diastereoselective synthesis of chiral nonracemic aliphatic amines

An efficient procedure has been developed for the diastereoselective synthesis of chiral aliphatic amines (diastereoisomeric excess >96%) from (1S)-N-(1-methylethylidene)-1-phenylethylamine, i.e., Schiff base derived from the simplest ketone (acetone) and (1S)-1-phenylethylamine. The procedure includes successive lithiation, alkylation, and reduction and is characterized by high regioselectivity in the formation of alkylated syn-Z-imines. Hydride reduction of the prochiral C=N bond in the latter gives mainly optically active aliphatic amines with R configuration. All reactions are performed as a one-pot process without isolation of intermediate products.

Synthesis and conformational study of 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines

A new class of endocyclic enamines, 1,6-disubstituted 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines, was synthesized from 4-piperidone imines by successive subjecting the latter to lithiation with lithium diethylamide, to alkylation with 1-bromo-3-chloropropane, and to intramolecular cyclization. All stages were carried out as a unique process without isolation of the intermediate compounds. A thorough optimization of the process conditions, workup, and product storage was carried out. The conformational study of 1,6-disubstituted 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines was performed.

3,3-disubstituted piperidin-4-ones. Conformational analysis by NMR and circular dichroism methods

Using1H and13C NMR spectroscopy, we have established the conformational inhomogeneity of chiral 3, 3-disubstituted pipe ridin-4-ones. The conformer with an equatorial methyl group on the C(3) atom predominates in the conformational equilibrium. For (1′S, 3S)-1-(l phenylethyl)-3-(2-cyanoethyl)- and 1,3-dimethylpiperdin-4-ones, we found1H NMR spectral parameters which may serve as criteria for conformational homogeneity of piperidin-4-one molecules. The conformational composition of the (3S)-enantiomers of 1,3-dimethyl-3-(2-cyanoethyl)-and 1,3-dimethyl-3-(2-carbomethyl)piperidine-4-ones was also estimated on the basis of theoretical analysis of the circular dichroism spectra in solvents of different polarities.

Asymmetric synthesis and stereochemistry of chiral cis - and trans -3-alkyl-4-aminopiperidines

Chiral nonracemic 3-substituted cis- and trans-4-aminopiperidines, which are precursors of anilidopiperidine analgesics, were obtained by diastereoselective synthesis from 1-methyl- and 1-benzyl-4-[(S)-1-phenylethyl]iminopiperidines, using the following reaction sequence: metalation with lithium diethylamide, alkylation with alkyl halides, and hydride reduction or hydrogenation over Raney nickel. The steric direction of the reaction, three-dimensional structure, preferred conformation, and absolute configuration of the resultant aminopiperidines were determined.

Amination of meso-bromophenyl(polyalkyl)porphyrins: Synthesis of porphyrins containing a hydroxypiperidine fragment

Abstract5,15-Bis(4-bromophenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin and 5-(4-bromophenyl)-13,17-dibutyl-2,3,7,8,12,18-hexamethylporphyrin were synthesized, and their palladium-catalyzed amination with a number of cyclic secondary amines, including hydroxypiperidines, was studied [Pd(OAc)2, ligand, THF or dioxane, t-BuONa, 80–100°C]. The reactions of the meso-bromophenylporphyrins with piperidine and morpholine gave the corresponding amination products in quantitative yield. The amination with hydroxypiperidines required excess amine (3 equiv per bromine atom) and excess base (6–8 equiv) and was accompanied by formation of hydrodebromination products; in the reactions with the bis(bromophenyl)derivative, mixed products resulting from amination at one phenyl group and reductive debromination at the other were also formed. The yields of the amination products varied from good {75–50% in the reactions with 4-hydroxypiperidine and trans-3-hydroxy-4-[4-(2-fluorophenyl)piperazin-1-yl]piperidine} to moderate (20–50%, 3-hydroxypiperidine) and poor [11–25%, trans-3,4-dihydroxypiperidine and trans-3-hydroxy-4-(4-hydroxypiperidin-1-yl)piperidine].