Determination of the absolute configuration of an unexpectedly stable N-silylated isomer isolated en route to the trinem antibiotic GV129606

The unexpected (3S,4R)-3-[(R)-1-(hydroxy)ethyl]-4-[(2′R,6′S)-1′-oxo-2′-(N-benzyloxy-N-methyl)aminocyclohexen-6′-yl]-1-(t-butyl-dimethylsilyl)azetidin-2-one was one of the main reaction products of the Lewis acid catalysed condensation of (3S,4R)-3-[(R)-1-(t-butyl-dimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one with 1-trimethylsilyloxy-6-(N-benzyloxycarbonyl-N-methylamino)cyclohexene. Its absolute configuration was established by NMR experiments on the corresponding, conformationally rigid, acetonide derivative.     

Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics

Syntheses of N-Boc (S)-4-(diethylphosphono)-(α-methyl)phenylalanine [Boc-(α-Me)Phe(4-PO₃Et₂)-OH] (9) and N-Boc (S)-2-amino-6-(diethylphosphono)tetralin-2-carboxylic acid [Boc-Atc(6-PO₃Et₂)-OH] (18) are reported as conformationally-constrained phosphotyrosyl mimetics suitably protected for peptide synthesis. Both syntheses proceeded through chiral arylhalides that are converted to arylphosphonates by palladium-catalyzed cross coupling with diethylphosphite. These amino acid analogues may be useful in the study of cellular signal transduction processes.     

A diastereodivergent strategy for the asymmetric syntheses of (−)-martinellic acid and (−)-4-epi-martinellic acid

Asymmetric syntheses of (−)-martinellic acid and (−)-4-epi-martinellic acid were achieved in 20 steps from commercially available starting materials using a diastereodivergent strategy. The conjugate addition of lithium (R)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (E)-3-[2′-(N,N-diallylamino)-5′-bromophenyl]propenoate and alkylation of the resultant β-amino ester with methyl bromoacetate were used as the key steps to install the C(9b) and C(3a) stereogenic centres, respectively. Subsequent cyclisation to the corresponding pyrroloquinolin-2-one and reduction of the C(4)-carbonyl group was followed by two complementary procedures for olefination and concomitant intramolecular Michael addition, which gave both C(4)-epimers of this tricyclic molecular architecture in >99:1 dr. Subsequent elaboration of these templates provided access to (−)-martinellic acid and, for the first time, (−)-4-epi-martinellic acid.     

A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary

The synthesis of levetiracetam and its enantiomer by deracemization of (±)-2-bromobutyric acid using either (S)- or (R)-N-phenylpantolactam as chiral auxiliaries, followed by S_N2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described.     

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.     

Synthesis and steric structure of N″-(arylmethylidene)-N″′-(1-methyl-3-phenylprop-2-yn-1-ylidene)thiocarbonohydrazides

Thiocarbonohydrazones derived from aromatic aldehydes reacted with 4-phenylbut-3-yn-2-one in aqueous acetic acid (20°C, 2 h) to produce previously unknown N″-[(E-s-cis)-arylmethylidene]-N″′-[(Z-s-trans)-1-methyl-3-phenylprop-2-yn-1-ylidene]thiocarbonohydrazides with high chemo-, regio-, and stereoselectivity. The steric structure of N″-[(E-s-cis)-benzylidene]-N″′-[(Z-s-trans)-1-methyl-3-phenylprop-2-yn-1-ylidene]thiocarbonohydrazide in crystal and in solution was studied by X-ray analysis and IR and NMR spectroscopy.     

Electroreductive five- and six-membered cyclization of aromatic β- and γ-imino esters derived from (S)-aspartic acid and (S)-glutamic acid

The electroreduction of aromatic β-dimethylcarbamoyl-β-imino esters, prepared from (S)-aspartic acid, in the presence of chlorotrimethylsilane gave five-membered cyclized products, 1-benzoyl-4-hydroxy-5-aryl-N,N-dimethylpyrrolidine-2-carboxamides and 5-(dimethylcarbamoyl)-2-aryl-1H-pyrrol-3-yl benzoates, depending on the post-treatment after the electroreduction. The electroreduction of aromatic γ-dialkylcarbamoyl-γ-imino and γ-methoxylmethyl-γ-imino esters, prepared from (S)-glutamic acid, and following transformation gave six-membered cyclized products, 1-benzoyl-5-hydroxy-N,N-dialkyl-6-phenylpiperidine-2-carboxamides and 3-hydroxy-6-(methoxymethyl)-2-phenylpiperidin-1-yl)(phenyl)methanones, respectively.     

Stereoselective conjugate addition reactions of lithium amides to α,β-unsaturated chiral iron acyl complexes [(η-C5H5)Fe(CO)(PPh3)(COCHCHR)]

Conjugate addition of achiral lithium dimethylamide to the chiral iron cinnamoyl complexes (S,E)- and (S,Z)-[(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHPh)] proceeds with high diastereoselectivity, with this protocol being used to establish unambiguously the absolute configuration of Winterstein’s acid (3-N,N-dimethylamino-3-phenylpropanoic acid) as (R). The highly diastereoselective conjugate addition of lithium N-benzyl-N-trimethylsilylamide to a range of α,β-unsaturated iron acyl complexes, followed by in-situ elaboration of the derived enolate by either alkylation or aldol reactions is also demonstrated, facilitating the stereoselective synthesis of both cis- and trans-β-lactams. This methodology has been used to effect the formal asymmetric syntheses of (±)-olivanic acid and (±)-thienamycin. Addition of chiral lithium amides derived from primary and secondary amines to the iron crotonyl complex [(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHMe)] indicates that lithium N-α-methylbenzylamide shows low levels of enantiorecognition, while lithium N-3,4-dimethoxybenzyl-N-α-methylbenzylamide and lithium N-benzyl-N-α-methylbenzylamide show high levels of enantiodiscrimination. The high level of observed enantiorecognition was used to facilitate a kinetic resolution of (RS)-[(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHMe)] with homochiral lithium (R)-N-3,4-dimethoxybenzyl-N-α-methylbenzylamide. Further mechanistic studies show that conjugate additions of (RS)-lithium N-benzyl-N-α-methylbenzylamide to either the (RS)- or homochiral iron crotonyl complex show 2:1 stoicheiometry, while homochiral lithium N-benzyl-N-α-methylbenzylamide shows 1:1 stoicheiometry.     

Synthesis and investigation of anti-inflammatory and anticonvulsant activities of novel coumarin-diacylated hydrazide derivatives

A number of novel coumarin derivatives synthesized by the reaction of 3-carbonyl chloride coumarin with some substituted aryl acid hydrazides to investigate their anti-inflammatory and anticonvulsant activities. Carrageenan (0.1 ml of 1%, w/v) was injected subplantarly in the right paw of rats to induce an acute model of inflammation. Anti-inflammatory efficacy was evaluated for 5 hours at 3 different dosages 5, 10, 25 mg/kg. After that, the changes in the level of paw edema volumes and percentage inhibition of all groups were observed and the most effective coumarin derivative was found as N'-(2-hyroxybenzoyl)-2-oxo-2H-chromene-3-carbohydrazide. In addition, N’-(2-oxo-2H-chromene-3-carbonyl)nicotinohydrazide, (E)-N’-(3-(4-hydroxyphenyl)acryloyl)-2-oxo-2H-chromene-3-carbohydrazide, and N’-(5-amino-2-hydroxybenzoyl)-2-oxo-2H-chromone-3-carbohydrazide showed their anti-inflammatory effects in a dose-dependent manner. On the other hand, pentylenetetrazole (PTZ, 80 mg/kg, i.p.)-induced seizure model was used to investigate the anticonvulsant activities of six newly synthesized coumarin derivatives in mice. Hybrid compound of salicylic acid hydrazide and 3-carbonyl chloride coumarin (8d) was found the most promising anticonvulsant agent among all treatment groups according to the onset of seizure and survival rate. Moreover, (E)-N'-cinnamoyl-2-oxo-2H-chromene-3-carbohyrazide (8b) and (E)-N'-(3-(4-hyroxyphenyl)acryloyl)-2-oxo-2H-chromene-3-carbohydrazide (8c) has potential anticonvulsant efficiency in low doses (30 mg/kg). The anticonvulsant effect of these coumarin derivatives may be through enhanced GABA-mediated inhibition in the brain.     

Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones into N-(α-ketoacyl)anthranilic acids

N-(α-Ketoacyl)anthranilic acids were prepared by oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones by using paraperiodic acid (H₅IO₆) or sodium periodate (NaIO₄). The optimisation of the reaction conditions is described as well as the utilisation of N-(α-ketoacyl)anthranilic acids in the preparation of anthranilic acid hydrochlorides.     

Synthesis of pseudopeptidic (S)-6-amino-5-oxo-1,4-diazepines and (S)-3-benzyl-2-oxo-1,4-benzodiazepines by an Ugi 4CC Staudinger/aza-Wittig sequence

Sequential Ugi reaction between p-substituted arylglyoxals, alkylamines, cyclohexyl isocyanide and 3-azido-(S)-2-(tert-butoxycarbonylamino)propanoic acid, followed by a Staudinger/aza-Wittig cyclization in the presence of triphenylphosphine, gave rise to enantiomerically pure N-cyclohexyl 4-alkyl-2-aryl-5-oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamides, that can be useful for new drug design. By the same sequence, p-substituted benzaldehydes, 2-aminobenzophenone, cyclohexyl isocyanide and (S)-3-phenyl-2-azidopropionic acid gave rise to N-cyclohexyl 2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-arylacetamides.     

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.     

Asymmetric hydrogenation of (E)-α,β-bis(N-acylamino)acrylates catalyzed by a rhodium complex with trans-chelating chiral diphosphine ligand

The asymmetric hydrogenation of (E)-α,β-bis(N-acylamino)acrylates was promoted by a rhodium complex bearing a trans-chelating chiral diphosphine ligand (R,R)-(S,S)-PrTRAP, providing the corresponding optically active (2S,3R)-2,3-bis(N-acylamino)carboxylates with 79–82% ee. The 2,3-bis(N-acylamino)carboxylates isolated were readily hydrolyzed under acid to afford (2S,3R)-2,3-diaminocarboxylic acids in 95% yield without epimerization.     

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.     

[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20-100 °C, 10-60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77-83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59-63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.     

Asymmetric synthesis of anti-diastereoisomers of β-heterocycle substituted (S)-α-aminobutyric acids

A new efficient method for the asymmetric synthesis of β-heterocycle substituted (2S,3S)-α-aminobutyric acids through the diastereoselective addition of 5-thioxo-4-allyl-1,2,4-triazoles, containing various substituents at the 3-position, to the CC double bond of (E)- and (Z)-dehydroaminobutyric acid in the Ni^II complexes of their Schiff base with chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide [(S)-BPB], (S)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide [(S)-3,4-DCBPB], (S)-N-(2-benzoylphenyl)-1-(3,4-dimethylbenzyl)pyrrolidine-2-carboxamide [(S)-3,4-DMBPB], and (S)-N-(2-benzoylphenyl)-1-(2-chlorobenzyl)pyrrolidine-2-carboxamide [(S)-2-CBPB] has been elaborated upon. The nucleophilic addition proceeds with high diastereoselectivity with a preferential formation of (S,S,S)-diastereoisomers. After decomposition of a mixture of diastereomeric complexes, optically active β-heterocycle substituted (2S,3S)-α-aminobutyric acids with high diastereomeric purity (de >98%) were isolated.     

Synthesis of both enantiomers of baclofen using (R)- and (S)-N-phenylpantolactam as chiral auxiliaries

Esterification of racemic 4-nitro-3-(4-chlorophenyl)butanoic acid with (R)- or (S)-N-phenylpantolactam as the chiral auxiliary allowed us to obtain the (3R,3′R)- or (3S,3′S)-nitro esters with >98:2 dr after column chromatography. Hydrolysis of the resulting diastereopure nitro esters gave the corresponding enantiopure nitro acids, which were readily converted in high yields into either (R)- or (S)-baclofen hydrochloride.     

Palladium-catalyzed construction of amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions

The palladium catalyzed regio- and diastereo-selective allylic alkylation of (R)-2-acetoxy-4-aryl-3-butene with N-(diphenylmethylidene)glycinate and N-(diphenylmethylidene)alaninate occurred. The stereochemistry was controlled by the use of o-(diphenylphosphino)carboxylic acid, and produced new amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions.     

Seven membered ring chelates derived from γ-hydroxyamides and triphenyltin or diphenylboron

N-Benzyl-4-hydroxy-butyramide (1), 4-hydroxy-N-[(R)-1-phenyl-ethyl]-butyramide (2), and (R)-4-hydroxy-2-methyl-N-[(R)-1-phenyl-ethyl]-butyramide (3a) were used to prepare new diphenylboron and triphenyltinoxy compounds: diphenylborinic acid 3-benzylcarbamoyl-propyl ester (4), diphenylborinic acid 3-[(R)-1-phenyl-ethylcarbamoyl]-propyl ester (5) and diphenylborinic acid (R)-3-[(R)-1-phenyl-ethylcarbamoyl]-butyl ester (6), N-benzyl-4-triphenyltinoxy-butyramide (7), 4-triphenyltinoxy-N-[(R)-1-phenyl-ethyl]-butyramide (8), and (R)-4-triphenyltinoxy-2-methyl-N-[(R)-1-phenyl-ethyl]-butyramide (9). The X-ray diffraction analysis of a crystalline structure of the new γ-hydroxyamide 3a is reported, as well as that of the first example of a crystalline structure where a diphenylborinic ester forms a seven membered chelate, by a carbonyl coordination to boron (4). Structural studies of tin and boron esters were performed by NMR. The CO internal coordination to tin atoms, affording seven membered rings, was observed by ¹¹⁹Sn NMR experiments at low temperature.     

A new route to (±)-erythro-roccellic acid and chaetomellic anhydride C through functional rearrangement, promoted by n-propylamine or CH3ONa/CH3OH, of N-propyl-3-chloro-4-dichloromethyl-3-dodecylpyrrolidin-2-one

The rearrangement of a trichloro-pyrrolidin-2-one, prepared by the CuCl-TMEDA catalyzed atom transfer radical cyclization of N-alkyl-N-(3-chloro-2-propenyl)-2,2-dichloromyristamide, with n-propylamine or CH₃ONa/CH₃OH, is the key step of a new, short and inexpensive route to chaetomellic anhydride C and (±)-erythro-roccellic acid.