A convenient synthesis of regio-specifically 2-alkylated-3-deuteriated-1-aminocyclopropane-1-carboxylic acids

A simple procedure for the large scale preparations of regio-specifically 2-alkylated-3-deuteriated-1-aminocyclopropane-1-carboxylic acids from 1 -deuterio-1,2-dibromoalkanes is described.     

Asymmetric synthesis of substituted 1-aminocyclopropane-1-carboxylic acids via diketopiperazine methodology

Diketopiperazinespirocyclopropane 12 is prepared in > 98% d.e. via the conjugate addition of a phosphorus ylide to (6S)-N,N'-bis(p-methoxybenzyl)-3-methylenepiperazine-2,5-dione 2. Deprotection and hydrolysis of adduct 12 and subsequent peptide coupling demonstrate the applicability of this methodology to the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids for incorporation into novel peptides. A model for the high level of diastereofacial selectivity observed in the cyclopropanation reaction is presented. A highly selective asymmetric approach (> 98% d.e.) to (S)-[2,2-(2)H2]-1-aminocyclopropane-1-carboxylic acid 29 is also reported via a deuterated sulfur ylide addition to acceptor 2.     

Syntheses of 1-alkyl-2-acylindoles, 1-alkyl-2-acylindole-3-carboxylic acids,and their esters,in superbasic media

2-Acylindoles and 2-acylindole-3-carboxylic acids are readily alkylated at the nitrogen atom by haloalkanes in a superbasic medium (DMSO + NaOH). For the carboxylic acids, this reaction may proceed either entirely at the nitrogen atom, or at both the the nitrogen atom and the carboxyl group, depending on the content of water in the medium and the alkali -haloalkane ratio.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 472–482, April, 1996.     

Synthesis of 1-aminocyclopropane-1-carboxylic acid

A three-stage method of synthesizing the natural plant growth regulator 1-aminocyclopropane-l-carboxylic acid by the interaction of cyanoacetic ester with 1,2-dibromoethane has been studied.Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, fax (3712) 89 14 75. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 855—857, November-December, 1995. Original article submitted November 28, 1994.     

Synthesis of racemic cis-1-alkyl- and 1-aryl-2-aminocyclopropanecarboxylic esters

The title cyclic β-amino esters were synthesized stereo- and regioselectively. Starting from the corresponding 1-aryl- and 1-alkylcyclopropane-1,2-dicarboxylates, selective monosaponification and subsequent Curtius reaction leads to certain cis-1-alkyl- and 1-aryl-2-aminocyclopropanecarboxylic esters. These β-aminocyclopropanecarboxylate derivatives (β-ACCs) can be seen as useful building blocks for β-peptides.     

Asymmetric synthesis of substituted 1-aminocyclopropane-1-carboxylic acids from a new chiral glycine equivalent with 3,6-dihydro-2H-1,4-oxazin-2-one structure

Condensation of the new chiral glycine equivalent 10 with aldehydes at room temperature in the presence of K₂CO₃ under solid–liquid phase-transfer-catalysed conditions afforded stereoselectively new chiral (Z)-α,β-didehydroamino acid (DDAA) derivatives with oxazinone structure 14. These systems have been used in diastereoselective cyclopropanation reactions for the synthesis of enantiomerically pure 1-aminocyclopropanecarboxylic acids (ACCs) such as (−)-allo-norcoronamic and (−)-allo-coronamic acids.     

Synthesis and exchange reactions of 5-alkyl-2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acids

An improved preparation of 2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acid 3, a potent inhibitor of dihydroorotase is presented. Trans-5-alkyl-2-oxo-6-thioxohexahydropyrimidine-4-carboxylic acids 12a-c were synthesised via the thiation of the p-methoxybenzyl esters of 5-alkyldihydroorotic acids with Lawesson's reagent followed by subsequent de-protection. The corresponding cisisomers were prepared by reduction of 5-alkyl-6-thioxoorotic acids with zinc in acetic acid. The stability and exchange reactions of 12a-c under physiological conditions were investigated by ultra-violet and ¹H nmr spectroscopy. The attempted synthesis of 16 , a fused cyclopentyl derivative of 3 is also presented.     

Optimized synthesis of 2-substituted 1-halocyclopropane-1-carboxylic acids

The reaction of gem-dichloro- and gem-dibromocyclopropanes with n-butyllithium in THF under argon at–78°С followed by purging the reaction mixture with dry CO₂ was used to synthesize cis- and/or trans-1-halocyclopropane-1-carboxylic acids in 30–56% yields. The yields of the target products could be increased to 76–83% by the addition of an equimolar amount of LiCl to the reaction mixture. The highest salt effect was obtained with lithium chloride generated in situ (88–96%).     

Integrated microreaction system for optical resolution of racemic amino acids

We developed a novel microreaction system for optical resolution of racemic amino acids. This device, which is based on a continuous microfluidic system, consists of an enzyme-immobilized microreactor and a microextractor. Use of the enzyme-microreactor, which was prepared by membrane formation on the microchannel surface, enabled a highly enantioselective reaction for a racemic amino acid derivative. The microextractor provided a laminar flow of two immiscible solutions, which enabled selective extraction of the product. Using this integrated device, we could perform efficient continuous production of optically pure unnatural amino acids.     

Synthesis of labeled 1-amino-2-methylenecyclopropane-1-carboxylic acid, an inactivator of 1-aminocyclopropane-1-carboxylate deaminase

1-Amino-2-methylenecyclopropane-1-carboxylic acid (2-methylene-ACC) is an irreversible inhibitor for a bacterial enzyme, 1-aminocyclopropane-1-carboxylate (ACC) deaminase, which catalyzes the conversion of ACC to alpha-ketobutyrate and ammonia. The inactivation has been proposed to proceed with the ring scission induced by an addition of an enzyme nucleophile, resulting in the formation of a reactive turnover product that then traps an active-site residue. To gain further insight into this unique enzymatic reaction, the tritiated 2-methylene-ACC was prepared and incubated with ACC deaminase to locate and identify the entrapped amino acid residue. The synthesis of this radiolabeled compound and the results of its incubation with ACC deaminase are reported in this paper.     

Lipase-catalyzed kinetic resolution of racemic 1-(10-alkyl-10H-phenothiazin-3-yl)ethanols and their butanoates

The synthesis of both enantiomers of 1-(10-alkyl-10H-phenothiazin-3-yl)ethanols and their butanoates by enantiomer-selective acylation of racemic alcohols with the lipase from Pseudomonas fluorescens (L-AK) or/and by methanolysis of the corresponding racemic esters with lipase B from Candida antarctica (CaL-B) is described. The absolute configuration of the enantiomerically pure enantiomers was determined by X-ray crystallography.     

Ethylene biosynthesis by 1-aminocyclopropane-1-carboxylic acid oxidase: a DFT study

The reaction catalyzed by the plant enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO) was investigated by using hybrid density functional theory. ACCO belongs to the non-heme iron(II) enzyme superfamily and carries out the bicarbonate-dependent two-electron oxidation of its substrate ACC (1-aminocyclopropane-1-carboxylic acid) concomitant with the reduction of dioxygen and oxidation of a reducing agent probably ascorbate. The reaction gives ethylene, CO(2), cyanide and two water molecules. A model including the mononuclear iron complex with ACC in the first coordination sphere was used to study the details of O-O bond cleavage and cyclopropane ring opening. Calculations imply that this unusual and complex reaction is triggered by a hydrogen atom abstraction step generating a radical on the amino nitrogen of ACC. Subsequently, cyclopropane ring opening followed by O-O bond heterolysis leads to a very reactive iron(IV)-oxo intermediate, which decomposes to ethylene and cyanoformate with very low energy barriers. The reaction is assisted by bicarbonate located in the second coordination sphere of the metal.     

Crystal structure and mechanistic implications of 1-aminocyclopropane-1-carboxylic acid oxidase--the ethylene-forming enzyme

The final step in the biosynthesis of the plant signaling molecule ethylene is catalyzed by 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO). ACCO requires bicarbonate as an activator and catalyzes the oxidation of ACC to give ethylene, CO2, and HCN. We report crystal structures of ACCO in apo-form (2.1 A resolution) and complexed with Fe(II) (2.55 A) or Co(II) (2.4 A). The active site contains a single Fe(II) ligated by three residues (His177, Asp179, and His234), and it is relatively open compared to those of the 2-oxoglutarate oxygenases. The side chains of Arg175 and Arg244, proposed to be involved in binding bicarbonate, project away from the active site, but conformational changes may allow either or both to enter the active site. The structures will form a basis for future mechanistic and inhibition studies.     

New data on derivatives of 1-alkoxyaziridine-2-carboxylic acids

Esters of β-alkoxyamino-α-bromopropionic acids were obtained by reaction of α,β-dibromopropionic acid esters with alkoxyamines in the presence of triethylamine at 20°C for 1 month. When the products are refluxed in acetonitrile in the presence of triethylamine, they are converted to aziridines. Selective amidation of the alkoxyaziridines with excess dimethylamine in absolute methanol in the presence of sodium methoxide leads to enrichment with the cis isomer. The parameters of inversion of the nitrogen atom in the alkoxyaziridines were determined. Communication 20 from the series “Asymetric Unbridged Nitrogen”; see [1] for communication 19. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 212–215. February, 1980.     

Kinetic resolution of racemic alcohols with chiral carboxylic acids and dicyclohexylcarbodiimide

The DCC-esterification method has been used to kinetically resolve racemic mixtures of alcohols. With simple chiral carboxylic acids, such as O-aryl lactic acids, in the presence of various basic catalysts, mixtures of the enantiomerically enriched alcohols (e.e. <50%) and the corresponding esters (d.e.<70%) have been obtained.     

A new method for production of chiral 2-aryl-2-fluoropropanoic acids using an effective kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids

We report a new method for the preparation of chiral 2-aryl-2-fluoropropanoic acids, including 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), by the kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids using enantioselective esterification. By applying pivalic anhydride (Piv2O) as a coupling agent, bis(α-naphthyl)methanol [(α-Np)2CHOH] as an achiral alcohol, and (+)-benzotetramisole (BTM) as a chiral acyl-transfer catalyst, a series of racemic 2-aryl-2-fluoropropanoic acids were kinetically separated to afford the optically active carboxylic acids and the corresponding esters with good to high enantiomeric excesses. This technology can provide a convenient approach to furnish the chiral α-fluorinated drugs containing quaternary carbons at the α-positions in the 2-aryl-2-fluoropropanoic acid structure.     

A trans-tetrahydrobenzoxanthene receptor for the resolution of racemic mixtures of sulfonylamino acids

An enantioselective cleft-type receptor for sulfonylamino acids has been prepared and its use for the resolution of the amino acid racemic mixture is shown.     

Fluorocinnoline derivatives. II. Synthesis and antibacterial activity of fluorinated 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic acids

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-1,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alkyl-6,8-difluoro- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17-35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin.