The reaction of methyl pyrrole-2-carboxylate with epoxides

Potassium methyl pyrrole-2-carboxylate and styrene oxide are shown to yield trans-1-styrylpyrrole-2-carboxylic acid (dry conditions) and 1-(2-hydroxy-2-phenylethyl)pyrrole-2-carboxylic acid (moist conditions). The hydroxy acid yields 1H-3-phenyl-3,4-dihydropyrrolo[2.1-c]-[1.4]oxazin-1-one, on treatment with polyphosphoric acid. Vinyl acids were also obtained from the potassium pyrrole ester and ethylene oxide, propylene oxide, and cis- and trans-stilbene oxide; the latter two compounds yielded stereospecific products. A pyrrolo[2.1-c]-[1.4]benzoxazinone was obtained from cyclohexene oxide. The photo chemical isomerization of the trans-1-styryl acid and the attempted conversion into lactones is described.     

On the easy oxidation of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid to its disulfide dimer

The physical and spectroscopic data of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid are reviewed and the synthesis of (R)-di-[2-(N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid disulfide is described. The product resulting from the conjugate addition of the dithioacid to 2(5H)-furanone is also characterised.     

Strategy for synthesis of the isoleucine conjugate of epi-jasmonic acid

The TES ether of 2-((1R,2S,3R)-3-hydroxy-2-((Z)-pent-2-enyl)cyclopentyl)acetic acid (5, equal to the reduction product of epi-jasmonic acid) derived from (1R,4S)-4-hydroxycyclopent-2-enyl acetate (19) in 13 steps was activated by using isobutyl chloroformate and was subjected to condensation with isoleucine at room temperature for 48 h. The product was desilylated and oxidized to the isoleucine conjugate of epi-jasmonic acid in 68% yield over three steps. Similarly, allo-isoleucine conjugate of epi-jasmonic acid and three isoleucine conjugates of ent-epi-jasmonic acid, jasmonic acid, and ent-jasmonic acid were synthesized.     

First asymmetric synthesis of an acyclic β,β-dialkylated-γ-aminobutyric acid

Enantiomerically pure (R)-γ-amino-β-benzyl-β-methylbutyric acid, an acyclic β,β-dialkyl GABA derivative, is efficiently synthesised from (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate by a sequence based on benzylation, Arndt-Eistert homologation and nitrile reduction. Benzylation of (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate using potassium carbonate under not strictly anhydrous conditions occurs diastereoselectively to afford (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl (S)-2-cyano-2-methyl-3-phenylpropanoate, the key chiral intermediate from which the desired γ-amino acid is obtained in five steps in 65% overall yield.     

Asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by a new aminophosphine phosphinite ligand derived from ketopinic acid

A new chiral aminophosphine phosphinite N,O-bis(diphenylphosphino)-(1S,2R)-1-(N-methylamino) methyl-2-hydroxyl-7,7-dimethylbicyclo[2.2.1]heptane was synthesized from ketopinic acid and its application to the asymmetric hydrogenation of dehydroamino acid derivatives examined.     

Lipase-mediated kinetic resolution of rigid clofibrate analogues with lipid-modifying activity

The lipase-catalysed kinetic resolution of methyl esters of (±)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid, (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-2-carboxylic acid, and (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-3-carboxylic acid, rigid analogues of clofibrate, was effected with fair to moderate enantioselectivities (E=1.0–4.8), enantiomeric excesses of up to 86% and workable reaction rates. Enantiomerically pure (R)- and (S)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acids were obtained by fractional crystallisation of the diastereomeric salts of the corresponding racemic acid with (+)- and (−)-amphetamine from ethanol; the absolute configuration of the products were established by chemical correlation.     

Enantioselective synthesis of m-carboranylalanine, a boron-rich analogue of phenylalanine

The enantiomers of the highly lipophilic α-amino acid m-carboranyl-alanine [3-(1,7-dicarba-closo-dodecaborane(12)-1-yl)-2-aminopropanoic acid], a carborane containing analogue of phenylalanine, have been synthesised via hydroxyamination of the N-acyl derivative formed from 3-(m-carboranyl)propionic acid [3-(1,7-dicarba-closo-dodeca-borane(12)-1-yl)-2-propanoic acid] and Oppolzer's camphor sultam. The enantiomeric excess of both enantiomers of the amino acid was >98%. (S)-Configuration was assigned to the (+)-enantiomer (CH₃OH, 589 nm).     

A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

Novel octulosonic acid derivatives in the composite Smallanthus sonchifolius

Two novel octulosonic acid derivatives with a 6,8-dioxabicyclo[3.2.1]octane skeleton that are major water-soluble phenolic compounds were found in the roots of Smallanthus sonchifolius. The structures of these compounds were determined to be (1R,2S,3S,4R,5S,7R)-4-hydroxy-7-hydroxymethyl-3-[3-(3,4-dihydroxyphenyl)-1-oxo-2-propenyloxy]-6,8-dioxabicyclo[3.2.1]octan-5-carboxylic acid (4-O-caffeoyl-2,7-anhydro-d-glycero-β-d-galacto-oct-2-ulopyranosonic acid) and (1R,2S,3R,4R,5S,7R)-2,4-dihydroxy-7-hydroxymethyl-2,3-bis[3-(3,4-dihydroxyphenyl)-1-oxo-2-propenyloxy]-6,8-dioxabicyclo[3.2.1]octan-5-carboxylic acid (4,5-di-O-caffeoyl-2,7-anhydro-d-glycero-β-d-galacto-oct-2-ulopyranosonic acid) by MS, NMR and CD spectral analyses.     

Synthesis of aromatic carbamates derivatives with a chromen-2-one fragment

Condensation of methyl N-(3-hydroxyphenyl)carbamate with ethyl trifluoromethylacetoacetate, 2-methoxyethyl acetoacetate in the presence of conc. sulfuric acid, and also with acetonedicarboxylic acid formed in situ from citric acid under the action of conc. sulfuric acid afforded chromene derivatives. The esterification of 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}acetic acid with methanol in the presence of TsOH provided the corresponding ester. The oxidation of its α-methylene group with selenium dioxide led to the formation of methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}-2-oxo-acetate entering into a condensation with o-phenylenediamine resulting in a derivative with a dihydroquinoxaline fragment. The reaction of phenyl N-(4-formylphenyl)carbamate with 3-acetyl-2H-chromen-2-one in butanol in the presence of catalytic quantity of piperidine and acetic acid furnished 4-[(E)-3-oxo-2H-chromen-3-yl)-1-propenyl]phenyl N-phenylcarbamate.     

Synthesis of (S)-, (R)-, and (rac)-2-amino-3,3-bis(4-fluorophenyl)propanoic acids and an evaluation of the DPP IV inhibitory activity of Denagliptin diastereomers

The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective, cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then decomposed to isolate the target amino acid (S)-1 (ee >99%) and ligand (S)-BPB, which can be reused in subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates (S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were investigated. These findings are important in the design and synthesis of DPP IV inhibitors.     

Preparation of single-enantiomer semiochemicals using 2-methoxy-2-(1-naphthyl)propionic acid and 2-methoxy-2-(9-phenanthryl)propionic acid

Enantioresolution of 3-octanol, 6-methyl-5-hepten-2-ol (sulcatol), and 1-octen-3-ol was conducted using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) and (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid (M9PP acid). In each case, the diastereomeric esters obtained were readily separated by HPLC. The stereochemistry of the esters could be assigned from their respective ¹H NMR analyses. Solvolyses of the esters gave enantiopure alcohols and acids. MαNP and M9PP acids displayed almost equivalent properties in ¹H NMR anisotropy. The chiral resolving ability of M9PP acid was slightly superior to that of MαNP acid in HPLC.     

Chelation of manganese(II) with quinaldic acids. An NMR relaxation study

Manganese(II) enhanced spin-lattice relaxation rates (1/T_1p) of ¹H and ¹³C nuclei in quinoline-2-carboxylic acid, 8-methoxyquinoline-2-carboxylic acid, 8-hydroxyquinoline-2-carboxylic acid, 8-aminoquinoline-2-carboxylic acid, and 6-(hydroxymethyl)pyridine-2-carboxylic acid were measured in aqueous solution at various temperatures. Relative metal-nucleus distances were calculated from the r^?6 dependence of 1/T_1p. The results indicate that the Mn²⁺ ion in the 8-methoxyquinaldic acid chelate is coordinated to the carboxyl oxygen atom and the nitrogen atom but not t the methoxyl oxygen atom.     

Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (?)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-dihydroxycyclooctanecarboxylic acid (?)-12 was prepared by using the OsO₄-catalyzed oxidation of Boc-protected amino ester (?)-5. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and ³J(H,H) coupling constants) and X-ray crystallography.     

Reaction of methyl (2E)-3-dimethylamino-2-(1H-indol-3-yl)-propenoate with ureas: facile entry into the polycyclic meridianin analogues with uracil structural unit

Methyl (2E)-3-dimethylamino-2-(1H-indol-3-yl)-propenoate was prepared simply and efficiently in two steps from 3-indoleacetic acid employing N,N-dimethylformamide dimethylacetal (DMFDMA). Upon treatment of (2E)-3-dimethylamino-2-(1H-indol-3-yl)-propenoate with various (thio)ureas in the presence of an acid 2-(1H-indol-3-yl)-3-(3-substituted(thio)ureido)propenoates were obtained in high yields. A base promoted cyclization of these (thio)ureidopropenoate derivatives afforded 5-(indol-3-yl)-3-substituted-pyrimidine-2,4-diones which represent a new family of meridianine analogues.     

Reaction of N-substituted 2-oxochromen-3-carboxamides with bromoderivatives of zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxoalkanoates and zinc

Zinc enolates obtained from ethyl 2,2-dialkyl-4,4-dibromo-3-oxobutanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides forming ethyl 3-{1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoate isomer with a Z-position of methine hydrogens. Zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides to give rise to esters of 3-{1-alkyl-1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa-[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoic acid as isomers with the E-position of the methine proton and the alkyl substituent. The reaction carried out in the presence of small quantities of THF and HMPA leads to the formation of 9c-alkyl-2-R³-9b,9c-dihydro-5-oxa-2-azacyclopenta[2,3]-cyclopropa[1,2-a]naphthalene-1,3,4-triones. Zinc enolates from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc with the secondary amides of 2-oxochromen-3-carboxylic acid form alkyl 3-{2-oxo-1a-(piperidinocarbonyl)-and 3-{6-R¹-1a-(morpholinocarbonyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-R²,R²-3-oxopropanoates as single geometrical isomers.     

Synthesis of kairomones and their analogs from 2-acylcyclohexane-1,3-diones with an unsaturated acyl side chain

Natural 2-[(9Z)-1-oxooctadec-9-en-1-yl]-, 2-[(9Z,12Z)-1-oxooctadeca-9,12-dien-1-yl]-, and 2-[(9Z,12Z,15Z)-1-oxooctadeca-9,12,15-trien-1-yl]cyclohexane-1,3-diones (components of flour moth Ephestia kuehniella kairomones) and some their analogs were synthesized from cyclohexane-1,3-diones and long-chain unsaturated carboxylic acid chlorides.     

Asymmetric Diels–Alder reaction using a new chiral β-nitroacrylate for enantiopure trans-β-norbornane amino acid preparation

The main nitronorbornene adduct derived from the asymmetric Diels–Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic β-amino acid (1S,2R,3R,4R)-trans-β-norbornane amino acid 9. The enantiomer (1R,2S,3S,4S)-9 could be obtained by the same synthetic route by using the chiral auxiliary (R)-1.     

Synthesis of (1H-pyrrol-2-ylsulfanyl)alkanoic acids

(1-Benzyl-1H-pyrrol-2-ylsulfanyl)acetic acid, 2- and 3-(1-benzyl-1H-pyrrol-2-ylsulfanyl)propionic acids, 1,1′-[1,4-phenylenebis(methylene)]bis[(1H-pyrrol-2-ylsulfanyl)acetic acid], and 1,1′-(hexane-1,6-diyl)bis-[(1H-pyrrol-2-ylsulfanyl)acetic acid] were synthesized for the first time by reactions of 1-benzyl-1H-pyrrole, 1,1′-[1,4-phenylenebis(methylene)]bis(1H-pyrrole), and 1,1′-(hexane-1,6-diyl)bis(1H-pyrrole) with thiourea, iodine, and the corresponding halogen-substituted alkanoic acids. 1-(4-Nitrophenyl)-1H-pyrrole failed to react with thiourea and iodine.     

Multienzymatic preparation of 3-[(1R)-1-hydroxyethyl]benzoic acid and (2S)-hydroxy(phenyl)ethanoic acid

The use of two oxidoreductases (an aldoketo reductase from Escherichia coli JM109 and an alcohol dehydrogenase from Lactobacillus brevis) has demonstrated that it is possible to prepare enatiomerically pure diols in a one-pot operation. The reactions were applied to the synthesis of (1R)-1-[3-(hydroxymethyl)phenyl]ethanol and (1S)-1-phenylethane-1,2-diol, using a two-step procedure. The yield is nearly quantitative and the enantiomeric purity is greater than 95%. A third step has been introduced by adding a cell biocatalyst showing dihydrodiol dehydrogenase activity from Pseudomonas fluorescens N3. This allows for the preparation of 3-[(1R)-1-hydroxyethyl]benzoic acid and (2S)-hydroxy(phenyl)ethanoic acid.