Synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters

Cross coupling protocols were applied for the synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl esters. Stille conditions produced the corresponding products in reasonable yields. Samarium iodide reduction of the resulting coupling products produced the 2β-carbomethoxy-3α-aryl-8-oxabicyclo[3.2.1]octane diastereoisomers as the major, and the 2β-carbomethoxy-3β-aryl-8-oxabicyclo[3.2.1]octane diastereoisomer as the minor products. Both diastereomers manifested inhibition of the dopamine (DAT) and serotonin (SERT) transporters, with some selectivity for SERT inhibition.     

Synthesis of orthogonally protected 3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid--a versatile building block for the synthesis of cocaine analogues

An eight-step synthesis of an orthogonally protected 3,8-diazabicyclo[3.2.1]octane from commercially available pyroglutamic acid was developed. The target compound can be used as a versatile building block for combinatorial synthesis of pharmacologically useful compounds and features a hidden α-, β-, δ- and ε-amino acid, which can also be seen as an example of a new class of cocaine analogues.     

Alpha,gamma-diamino acids: asymmetric synthesis of new constrained 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids

The synthesis of two new diastereomeric 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids exo- and endo-8,9 is reported using exo- and endo-norbornene amino acids as chiral building blocks. This method provides a fast access to optically pure amino acids 8 and 9 which can be considered both alpha,gamma- and alpha,delta-diamino acids containing sterical constraints and characterized by alpha,alpha-disubstitution.     

An efficient route to all stereoisomeric enantiopure 6-amino-3-alkyl-3- azabicyclo[3.2.1]octane-6-carboxylic acids

A single-step synthesis on a gram scale of four pure stereoisomers of the 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acid was carried out using (R)-1-phenylethylamine to confer chirality. The phenylethyl group, and the p-methoxy group linked to the N-atom, are easily removed by hydrogenolysis to afford the corresponding NH-3 derivatives. A series of N-3-alkyl compounds were prepared by way of a "one-pot" deprotection-alkylation procedure starting from the above key compounds. Their biological activity has been evaluated on the GABA receptor.     

Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part VII: synthesis of some 6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids and esters

Abstract  

A series of ethyl 2-(substituted)-9-cyclopropyl-4-fluoro-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylates has been prepared from ethyl 7,8-diamino-1,4-dihydroquinoline-3-carboxylate via thermally induced reactions with model alkanoic acids or via microwave-assisted cyclocondensation with some arene carboxaldehydes. Acid-catalysed hydrolysis of the resulting ester derivatives furnished the corresponding imidazoquinoline-7-carboxylic acids. The structures of these new acid and ester derivatives are based on microanalytical and spectral (IR, MS, and NMR) data.     

Synthesis and properties of 2,7-diazabicyclo[2.2.2]octane-3,8-diones and -3,8-dithiones

In an alkaline medium, 3,4-dihydropyridin-2(1H)-ones form 2,7-diazebicyclo[2.2.2]-octane-3,8-diones, which are thiolated to the corresponding dithiones. The alkylation of the last proceeds at the sulfur atoms with the formation of 2,7-diazabicyclo[2.2.2]octa-2,7-dienes.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 620–625, May, 1989.     

Synthesis of 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitriles and -6-carboxylic acid esters

Dieckmann ring closure reactions of 4-[(2-cyanoethyl)substituted amino]-2-phenyl-5-pyrimidinecarboxylates (Ha-f) afforded several 5,6,7,8-tetrahydro-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitriles (IIIa-f). The open-chain intermediates (IIa-f) were prepared by dechloroamination of 5-carbethoxy-4-chloro-2-phenylpyrimidine (1a) with several 3-substituted amino- propionitriles. Alkylation of the sodium salt of 5,6,7,8-tetrahydro-8-methyl-5-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6- carbonitrile (IIIa) with methyl iodide in DMF resulted in methylation at C-6 to afford IV. Tosylation of IIIa in pyridine gave the corresponding tosyl ester (V) of the enolic form. Oxidative dehydrogenation at the 6,7-position resulted when IIIa reacted with thionyl chloride, affording 5,8-dihydro-8-methyl-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitrile (VII). Dechloroamination of la or 5-carbethoxy-4-chloro-2-methylthiopyrimidine (Ib) with ethyl 3-ethylaminopropionate followed by Dieckmann cyclization of the resulting open-chain intermediates gave the corresponding ethyl 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates IX'a and IX'b, respectively. These exist predominately in the enol form and undergo alkylation and oxidation reactions similar to IIIa.     

[3+2] Cycloaddition-mediated synthesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester

1,3-Dipolar cycloaddition reactions are fundamental processes in organic chemistry. Herein we report [3+2] annulation of thiomethylacrylate 2 and azomethine ylide precursor 3 towards the synthesis of novel 3-methylsulfanyl-pyrrolidine 5. Alternatively, we have also explored the alkylation of 7 with dimethyldisulfide/LDA for the introduction of thiomethyl group towards the synthesis of 5 in moderate to good yields. Efficacy of these two routes under various conditions/catalysts for the synthesis of 5 is presented.     

Synthesis of 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids and anti-convulsant properties of the corresponding amides

Novel 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids have been made via [3+2]cycloaddition to alkyne 2. A number of the corresponding amides are anti-convulsant in mice.     

Bromination of 2,7-diaza-1-methyl-5-phenylbicyclo[2.2.2]octane-3,8-dione

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1143–1144, August, 1993.     

An improved synthesis of [1H]-isoindolin-1-one-3-carboxylic acid

Preparation of the title compound in one operation from commercially available phthalaldehydic acid in 34% yield is described.     

Rearrangement of 2-aminofuro[3,2-b]pyridine-3-carboxylic esters

Ethyl 2-aminofuro[3,2-b]pyridine-3-carboxylate rearranges with sodium ethoxide in ethanol to 2-oxo-3-cyano-2,3-dihydro[3,2-b]furopyridine; the corresponding p-nitrophenyl ester undergoes the same rearrangement by dilute aqueous sodium hydroxide. In the first case it was possible to isolate the labile intermediate, which was shown to be the hemiacetal of the above mentioned cyanolactone.     

Synthesis and structure of hydroxyl acids of general structure 7,7-alkenyl/alkynyl-5-hydroxymethyl-6-oxabicyclo[3.2.1]octane-1-carboxylic acid

The open-ended hollow tubular structure formed by inclusion of water molecules in the packing of the hydroxyl acid 1 (R1 = CH2OH, R2 = ethyl groups) led to the synthesis and structural study of their unsaturated analogues. In this article we report on a general and practical large-scale synthesis of hydroxyl acids that possess alkenyl and alkynyl appendages. Substitution of the ethyl groups in 1 with unsaturated two-carbon appendages has a different effect on the molecular structure and on the hydrogen-bonding pattern. No variation has been induced by substitution of only one ethyl group with a vinyl one, although the substitution of both ethyl groups with vinyl or acetylene appendages has the greatest effect on the molecular structure and results in different hydrogen-bonding motifs.     

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, Part VI [1]. Synthesis and X-ray structure of model indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylic esters

Cyclocondensation reaction of ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate with 1-methylisatin produced a separable mixture of the corresponding indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates, of which the latter isomer predominates. On the other hand, interaction with 1H-isatin or 5-chloroisatin gave the respective indolo[2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates as the sole regiospecific products. The structures of these new pentacyclic derivatives are based on microanalytical, spectral (IR, MS, and NMR) and X-ray crystal structure data.     

Synthesis of unnatural amino acids: (S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid

(S,S,S)-2-Azabicyclo[3.3.0]octane-3-carboxylic acid 1, a structural element of the very potent ACE inhibitor HOE 498, is readily available via a diastereo selective synthesis starting from serine or cystine.