Parallel kinetic resolution of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 3-alkyl-cispentacin derivatives

The double mutual kinetic resolution of tert-butyl (RS)-3-benzyl-cyclopentene-1-carboxylate with a 50 : 50 mixture of lithium (RS)-N-benzyl-N-alpha-methylbenzylamide and lithium (RS)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide gives, after protonation with 2,6-di-tert-butylphenol, a 50 : 50 mixture of the readily separable N-benzyl-(1SR,2RS,3RS,alphaRS)- and N-3,4-dimethoxybenzyl-(1SR,2RS,3RS,alphaRS)-beta-amino esters in >98% de in each case. This product distribution indicates that these amides react at very similar rates and with no mutual interference to furnish readily separable products, and are thus ideal for parallel kinetic resolution. The efficient parallel kinetic resolution (E > 65) of a range of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates with a pseudoenantiomeric mixture of homochiral lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide gives, after separation and N-deprotection, a range of carboxylate protected 3-alkyl-cispentacin derivatives in >98% de and >95% ee.     

Kinetic resolution and parallel kinetic resolution of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 5-alkyl-cispentacin derivatives

Conjugate addition of lithium dibenzylamide to methyl 5-isopropyl, 5-phenyl- and 5-tert-butyl-cyclopentene-1-carboxylates occurs with high levels of substrate control (>88% de), with preferential addition to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the stereodirecting 5-alkyl substituent. Treatment of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with both lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide and lithium (+/-)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide indicates significant enantiorecognition in their mutual kinetic resolutions, with preferential addition anti- to the 5-alkyl substituent, giving the 1,2-syn-1,5-anti-arrangement (E >16) after enolate protonation anti- to the amino functionality. The kinetic resolution of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with lithium (S)-N-benzyl-N-alpha-methylbenzylamide, and their efficient parallel kinetic resolution with a pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide are also demonstrated, giving a range of 5-alkyl-cispentacin derivatives in >98% de and high ee after N-deprotection.     

Parallel kinetic resolution of tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates for the asymmetric synthesis of 3-oxy-substituted cispentacin and transpentacin derivatives

tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent-1-ene-carboxylates display excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide. A 50 : 50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide allows for the efficient parallel kinetic resolution of the tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates, affording differentially protected 3-oxy-substituted cispentacin derivatives in high yield and >98% de. Subsequent N-deprotection and hydrolysis provides access to 3-oxy-substituted cispentacin derivatives in good yield, and in >98% de and >98% ee, while stereoselective epimerisation and subsequent deprotection affords the corresponding transpentacin analogues in good yield, and in >98% de and >98% ee.     

Regio-specific synthesis of new 1-(tert-butyl)-1H-pyrazolecarboxamide derivatives

Regio-specific and non-regiospecific condensation reactions on 1,3-dicarbonyl compounds rendered 1,3,5-trisubstituted pyrazoles. Herein, the control of regio-specificity was a significant improvement in pyrazole research. A high yield acylation of poorly nucleophilic aryl amines, which resulted in mono- or diacylated products depending on the reaction conditions, is described. As a result, a library of potentially bioactive compounds was obtained.     

Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate

Conjugate addition of lithium dibenzylamide to tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate and an excess of lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 +/- 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in > 98% de and 98 +/- 1% ee. Selective epimerisation of tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate by treatment with KO'Bu in 'BuOH gives tert-butyl (1S,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in > 98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in > 98% de and 97 +/- 1% ee.     

Synthesis of benzyl and tert-butyl 3-(2-methoxycarbonylethyl)-4-methylpyrrole-2-carboxylates from methyl 4-oxobutanoate

Condensation of methyl 4-oxobutanoate with nitroethane in the presence of 4-dimethylaminopyridine, followed by treatment with acetic anhydride, afforded a nitroacetoxyester 10b . Subsequent reaction with isocyanoacetate esters and DBU in refluxing tetrahydrofuran gave the synthetically valuable pyrroles 1a and 1b.     

Optical resolution by preferential crystallization of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid

The racemic structure of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid [(1RS,3RS)-1] was examined based on the melting point, solubility, and IR spectrum, with the aim of optical resolution by preferential crystallization. (1RS,3RS)-1 was indicated from these results to exist as a conglomerate. The successive optical resolution by preferential crystallization of (1RS,3RS)-1 yielded (1S,3S)- and (1R,3R)-1 with optical purities of 85--95% at 66--81% degrees of resolution, which were fully purified by recrystallization.     

An example of ultrasonic activation in the synthesis of ethyl 3-(R-imino)adamantyl-1-carboxylates

Russian Journal of General Chemistry -     

Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis of ethyl-5-(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4-carboxylates

A series of pyrazole-4-carboxylates have been synthesised using indium bromide catalyst and the cyclisation of respective 3-substituted-isoquinolinylhydrazines 1 into their corresponding ethyl-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoates 3 in ethanol solvent under ultrasonic irradiation at 90?°C for 30 min. The regio-selective cyclisation products were efficiently provided by indium bromide catalyst and are confirmed by nuclear Overhauser effect spectroscopy?Cnuclear magnetic resonance (NOESY?CNMR) studies.     

1-(3-吡唑基)薁-3-甲酸甲酯类衍生物的合成

室温下,1-乙酰基薁-3-甲酸甲酯与N,N-二甲酰胺缩甲醛缩合后再与肼或苯肼反应,合成了6个新的1-(3-吡唑基)薁类衍生物,其结构经1HNMR,MS和元素分析表征。并对反应机理进行了探讨。     

Novel Synthesis of 5-Amino-3-bromo-1-(tert-butyl)-1H-pyrazole-4-carbonitrile: A Versatile Intermediate for the Preparation of 5-Amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides

A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.     

Synthesis and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by ¹H-, ¹³C-, and ¹⁵N-NMR spectroscopy and HRMS investigation.     

3, 6-Di(tert-butyl)-o-benzoquinone fluoroalkylated derivatives

Russian Chemical Bulletin - A reaction of perfluoroalkyltrimethylsilanes with 3, 6-di(tert-butyl)-o-benzoquinone was used to obtain new perfluoroalkyl-substituted sterically hindered...     

Enzyme-catalysed improved resolution of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol

Resolutions of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol 1 using various enzymes were performed. Among them, Pseudomonas fluorescens resolved it with moderate stereoselectivity (E=13) and reacted faster with the (S)-enantiomer. To optimize enzyme-catalysed reaction conditions for the resolution, the effect of solvents and additives was studied. In n-hexane:ethyl acetate (9:1), both reaction rate and selectivity were high. When pyridine, potassium carbonate and molecular sieves were used as additives, the enantiomeric excess of the (R)-enantiomer was 99, 99 and 98% at 52–60% conversion, respectively. However, in diisopropyl ether, the enantiomeric excess of unreacted alcohol (R)-1 was up to 99% at 70% conversion without additives.     

Preparation of methyl (1R,2S,5S)- and (1S,2R,5R)-2-amino-5-tert-butyl-cyclopentane-1-carboxylates by parallel kinetic resolution of methyl (RS)-5-tert-butyl-cyclopentene-1-carboxylate

Comparison of the kinetic and parallel kinetic resolutions of methyl (RS)-5-tert-butyl-cyclopentene-1-carboxylate allows for the efficient synthesis of both (1R,2S,5S)- and (1S,2R,5R)-enantiomers of methyl 2-amino-5-tert-butyl-cyclopentane-1-carboxylate.     

Urea as leaving group in the synthesis of 3-(tert-butyl)perhydro-1,5,3-dithiazepine

The new compound 3-(tert-butyl)perhydro-1,5,3-dithiazepine has been synthesised from 5-(tert-butyl)perhydro-1,3,5-triazin-2-one in 45% yield. In the reaction, urea acts as the leaving group being exchanged for the S-CH₂-CH₂-S fragment of the product.     

Preparation of (RS)-5-Amino-3-carboxypentanoic Acid (1)

(RS)-5-Amino-3-carboxypentanoic acid (1) was prepared by a Wittig reaction of N-benzoylglycinal (3) with the phosphorane (4), followed by catalytic hydrogenation and acid hydrolysis.