The synthesis,configuration, and conformation of cis- and trans-3-amino-3,4-dihydro-1-hydroxy-4-methylcarbostyrils and other configurationally related compounds

The cis- and trans-3-amino-3,4-dihydro-1-hydroxy-4-methylcarbostyrils (Ia and Ib) were synthesized by catalytic hydrogenation of erythro- and threo-α-amino-β-(o-nitrophenyl)butyric acid hydrochlorides, IIIa and IIIb, respectively, under acidic conditions. The free bases of IIIa and IIIb were catalytically hydrogenated under neutral conditions to yield the erythro- and threo-α-amino-β-(o-aminophenyl)butyric acids (VIa and VIb), which were converted by acidification to their corresponding lactams, cis- and trans-3-amino-3,4-dihydro-4-methylcarbostyrils, IIa and IIb. The erythro and threo isomers of α-amino-β-(o-nitrophenyl)-butyric acid were prepared and separated by liquid chromatography via a diastereomeric mixture of (V) of methyl α-acetamido-β-(o-nitrophenyl)butyrates. The configurations and conformational assignments of the cyclic hydroxamic acids Ia and Ib were first established by analysis of the proton nmr spectra. In turn, the configurations of the o-nitroaromatic amino acids IIIa and IIIb were assigned as well as the other structurally related compounds (VIa, VIb, IIa and IIb) derived therefrom.     

Highly efficient and selective biocatalytic acylation studies on triazolylsugars

Different acid anhydrides (of C₂ to C₇ aliphatic fatty acids and benzoic acid) have been used to study the selective acylation of primary/secondary hydroxyl groups in 2-phenyl-4-(d-threo-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-erythro-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-arabino-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole and 2-phenyl-4-(d-lyxo-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole in the presence of Candida antarctica lipase B in diisopropyl ether. Among the different acid anhydrides, butanoic anhydride was found to be the most efficient acylating agent (for butanoylation); for acetylation, vinyl acetate gave the best results. The reactions with both these acylating agents were highly selective and efficient yielding exclusively the monoacylated products in 95-99% yields in 1-5 h.     

Reactivity of 3H-1,2,4-dithiazole-3-thiones and 3H-1,2-dithiole-3-thiones as sulfurizing agents for oligonucleotide synthesis

The reactivity of 5-amino-3H-1,2,4-dithiazole-3-thiones substituted at their amino group and 5-amino-3H-1,2-dithiole-3-thiones substituted at their amino group and C4 toward compounds containing P(III) atoms has been studied. N,N-Disubstituted-N′-(3-thioxo-3H-1,2,4-dithiazol-5-yl)methanimidamides were selected as novel efficient sulfur transfer reagents suitable for DNA and RNA synthesis.     

An efficient and stereodivergent synthesis of threo- and erythro-β-methylphenylalanine. Resolution of each racemic pair by semipreparative HPLC

threo and erythro diastereoisomers of the constrained amino acid (βMe)Phe can be obtained separately on a multigram scale through a three-step synthesis from the corresponding Z and E isomers of 2-phenyl-4(α-phenylethylidene)-5(4H)-oxazolone. The 5(4H)-oxazolones are readily available from acetophenone and hippuric acid. The four enantiomerically pure isomers of β-methylphenylalanine, (2R,3R)-(βMe)Phe, (2S,3S)-(βMe)Phe, (2R,3S)-(βMe)Phe and (2S,3R)-(βMe)Phe, have been prepared by HPLC resolution of the racemic precursors methyl threo (or erythro)-2-benzamide-3-phenylbutanoates.     

Diastereoselective Mukaiyama aldol reaction of (N-alkyl) isatins with 2-(trimethylsilyloxy)furan by using lanthanum triflate

An efficient vinylogous Mukaiyama aldol reaction (VMAR) of 2-(trimethylsilyloxy)furan with various (N-alkyl)isatins is described in the presence of lanthanum(III) triflates (5 mol %). The reaction proceeds rapidly and affords the corresponding 3-hydroxy-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one in high yields with good diastereoselectivities (threo:erythro ratio up to ≤95:5).     

An efficient and general enantioselective synthesis of some isoxazole-containing analogues of the neuroexcitant glutamic acid

Isoxazole amino acids are an important class of neuroexcitant which are difficult to prepare in enantiopure form. Diastereoselective alkylation of the enantiomerically pure glycine derivative, tert-butoxycarbonyl-2-(tert-butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI) with 4-bromomethyl-2-methoxymethyl-5-methylisoxazolin-5-one 5 or 5-bromomethyl-4-bromo-3-methoxyisoxazole, gives intermediates which under mild hydrolysis conditions produce the amino acids (S)- and (R)-bromohomoibotenic acid and (S)- and (R)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid with e.e. >99%.     

Preparation of the both enantiomers of threo-2-amino-3-methylhexanoic acid by enzymatic resolution and their conversion to optically active forms of threo-4-methylheptan-3-ol,a pheromone component of the smaller european elm bark beetle

The both enantiomers of threo-2-amino-3-methylhexanoic acid were prepared by resolving its racemic N-acetate with Aspergillus acylase. The amino acid enantiomers were converted to optically active forms of threo-4-methylheptan-3-ol, a pheromone component of Scolytus multistriatus.     

An efficient approach to d-threo-3-hydroxyaspartic acid for the synthesis of novel l-threo-oxazolines as selective blockers of glutamate reversed uptake

An efficient, stereoselective synthetic strategy to d-threo-3-hydroxyaspartic acid was developed. Starting from l-(2S,3S)-N-benzoyl-3-hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the d-trans-isomer, which was hydrolyzed to give d-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from d-threo-3-hydroxyaspartic acid, l-threo-oxazolines can be stereoselectively synthesized.     

Absolute configuration of (−)-4-methylheptan-3-ol,a pheromone of the smaller european elm bark beetle,as determined by the synthesis of its (3R,4R)-(+)- and (3S,4R)-(+)-isomers

Nerol and geraniol were stereoselectively converted to (±)-threo- and (±)-erythro-4-methylheptan-3-ol respectively. (R)-(+)-Citronellic acid was converted to a mixture of (3R,4R)-(+)-threo- and (3S,4R)-(+)-erythro-isomers which was separable by GLC. These syntheses established the absolute configuration of the naturally occurring (?)-4-methylheptan-3-ol to be 3S,4S.     

Stepwise solid phase synthesis of uridylylated viral genome-linked peptides using uridylylated amino acid building blocks

The uridylylated amino acid building blocks 2-cyanoethyl-(N^α-9-fluorenylmethoxy-carbonyl-tyrosin-4-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate and 2-chlorophenyl-(N^α-fluorenyl-methoxycarbonyl-serin-3-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate have been used successfully in an on-line SPPS of the VPgpU from the polio, coxsackie and cowpea mosaic virus.     

Syntheses, characterization, X-ray crystal structures and emission properties of five oxovanadium(V) complexes with pyridyl/pyrimidyl-pyrazole derived ditopic ligands

Four oxovanadium(V) complexes of heterocycle based ditopic ligands PyPzOAP (N-[amino(pyridin-2-yl)methylidene]-5-methyl-1-(pyridin-2-yl)-1H-pyrazole-3-carbohydrazonic acid), PyPzOAPz (N-[amino(pyrazin-2-yl)methylidene]-5-methyl-1-(pyridin-2-yl)-1H-pyrazole-3-carbohydrazonic acid), PymPzOAP (N-[amino(pyridin-2-yl)methylidene]-1-(4,6-dimethylpyrimidin-2-yl)-5-methyl-1H-pyrazole-3-carbohydrazonic acid) and PyPzCAP (5-methyl-1-(pyridin-2-yl)-N′-[1-(pyridin-2-yl)ethylidene]-1H-pyrazole-3-carbohydrazide) and a binuclear (di-μ-oxo) oxovanadium(V) complex of the ligand PymPzCAP (1-(4,6-dimethylpyrimidin-2-yl)-5-methyl-N′-[1-(pyridin-2-yl)ethylidene]-1H-pyrazole-3-carbohydrazide) have been investigated. The ligands act as uninegative NNO tridentates donors for the VO₂⁺ ion exhibiting their monotopicity. The ligands show varying emission properties due to the presence of fluophoric groups like 1-(2-pyridyl)pyrazole or 1-(2-pyrimidyl)pyrazole. The vanadium(V) complexes show fluorescence quenching with respect to the used ligands to a varying extent. The complexes were characterized by UV-Vis, IR, cyclic voltammetry and X-ray crystallography.     

Heterocyclic N-glycosyl derivatives—XI: Synthesis and NMR conformational study of N-glycosyl benzotriazoles from acetylated glycals

Acid-catalyzed reaction of benzotriazole, 5,6-dimethylbenzotriazole and 5,6-dichlorobenzotriazole with di-O-acetyl-d-xylal in ethyl acetate afforded 1-(4′-O-acetyl-2′,3′-dideoxy-d-glycero-pent-2′-enopyranosyl)benzotriazole derivatives and small amounts of 1,2,3-trideoxy-4-O-acetyl-3-(benzotriazolyl)-d-threo-pent-1-enopyranose derivatives. The reactions using di-O-acetyl-l-arabinal led to the formation of the corresponding 1- and 2-(3′,4′-di-O-acetyl-2′-deoxy-l-erythro-pentopyranosyl)benzotriazole derivatives. In addition the enantiomers of the above 2′, 3′-unsaturated N-glycosyl compounds were also obtained. The configurations and conformations of the products obtained were determined by NMR spectroscopy.     

6,7,14,15-Tetrahydro[1,5]diazocino[1,2-a:6,5-a′]diindole. Synthesis of a novel pentacyclic ring system

In search of new lead structures for potent allosteric enhancers of antagonist binding to muscarinic M₂ receptors, the first representative of a novel heterocyclic ring system, 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a′]diindole, has been synthesized. The new pentacyclic ring skeleton is obtained from [3-(2-dibenzylaminoethyl)indol-2-yl]-acetic acid methyl ester in three steps.     

Simultaneous determination of enantiomeric purity and erythro/threo relationship in chiral 1,2-aminoalcohols by NMR using (R)-(+)-t-butylphenylphosphinothioic acid

The rapid simultaneous determination of enantiomeric purity and erythro/threo relationship for a series of chiral 1,2-aminoalcohols is reported. Complexation with 1 equivalent (R)-(+)-t-butylphenylphosphinothioic acid results in a preferred conformation of the aminoalcohol which in turn causes the interproton dihedral angle to assume either large (threo) or small (erythro) J values. Measurement of the resulting vicinal coupling constant allows easy and rapid assignment of erythro versus threo.     

Synthese und Konfiguration von Methylestern der diastereomeren (±)-3-Amino-2,3-diarylpropansäuren,der (±)-3-Amino-2,3-diarylpropanole und ihrer Derivate

Zusammenfassung Durch Umsetzung von Hydramiden mit am aromatischen Ring m,p-dialkoxysubstituierten Arylessigsäureestern in Gegenwart von wasserfr. AlCl₃ entstehen Gemische aus Estern der (±)-erythro- und (±)-threo-3-Amino-2,3-diarylpropansäuren. Bei der Umsetzung von Piperonalhydramid mit dem Methylester der Homoveratrumsäure konnte lediglich daserythro-Diastereomere isoliert werden.Die diastereomeren Ester wurden zu den jeweiligen (±)-erythro- und (±)-threo-3-Amino-2,3-diaryl-1-propanolen reduziert, die als N,O-Dibenzoylderivate charakterisiert wurden. Ihre relativen Konfigurationen und die der zugehörigen Ester wurden auf Grund der IR-Spektren der diastereomeren Aminopropanole bestimmt. Die NMR-Spektren eines Diastereomerenpaares von Aminopropanolen bestätigen die ihnen chemisch zugeordneten Konfigurationen und ermöglichen den Nachweis auch ihrer bevorzugten Konformationen.

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Synthesis and configuration of methyl esters of the diastereomeric (±)-3-amino-2,3-diarylpropanoic acids, the (±)-3-amino-2,3-diaryl-1-propanols and their derivatives

Reaction of hydramides with m,p-dialkoxysubstituted arylacetates in the presence of anhydrous AlCl₃ generally leads to mixtures of the esters of the (±)-erythro- and (±)-threo-3-amino-2,3-diarylpropanoic acids. However, in the reaction of piperonal hydramide with methyl homoveratrate, only the correspondingerythro-diastereomer was obtained.Reduction of the diastereomeric esters gives the corresponding (±)-erythro- and (±)-threo-3-amino-2,3-diaryl-1-propanols, which can be characterized as N,O-dibenzoyl derivatives. Relative configurations of both alcohols and esters were determined by means of their IR spectra. Configurations were confirmed for one pair of diastereomeric amino alcohols by means of NMR spectra and preferred conformations deduced.

     

Addition of Chiral Glycine,Methionine, and Vinylglycine Enolate Derivatives to Aldehydes and Ketones in the Preparation of Enantiomerically Pure α-Amino-β-Hydroxy Acids

Chiral enolates of imidazolidinones and oxazolidinones from the title amino acids react with carbonyl compounds to afford the corresponding alcohols in excellent yields (see Scheme 5). Furthermore, the addition to aldehydes proceeds with high diastereoselectivity to give, after acid hydrolysis, threo-α-amino-β-hydroxy acids of high enantiomeric purity. Some of the threo-α-amino-β-hydroxy acids prepared in this work are the proteinogenic (S)-threonine ( 26 ), the naturally occurring (S)-3-phenylserine ( 28 ), and (S)-3-hydroxyleucine ( 27 ) as well as the unnatural (S)-4,4,4-trifluorothreonine ( 30 ) and (S)-3-(4-pyridyl)serine ( 31 ). The N-methylamide of (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic acid ( 32 ), the unique amino acid in the immunosuppressive cyclosporine, was prepared by the new method. This report presents also information suggesting that both steric and stereoelectronic effects are responsible for the good stereoselectivities observed.     

Synthesis and screening of some novel substituted indoles contained 1,3,4-oxadiazole and 1,2,4-triazole moiety

A series of novel 3-[5-(1H-indol-3-yl-methyl)-2-oxo-[1,3,4]oxadiazol-3-yl]propionitrile(5),3-[4- amino-3-(1H-indol-3-yl-methyl)-5-oxo-4,5-dihydro-[1,2.4]triazol-1-yljpropionitrile(6),3-[5-(1H- indol-3-yl-methyl)-2-thioxo-[1,3,4]oxadiazol-3-yl]propionitrile(7) and 3-[4-amino-3-(1H-indol-3-yl-methyl) -5-thioxo-4,5-dihydro-[1,2,4]triazol-l -yljpropionitrile(8) were synthesized in good yields from the intermediate(1H-indol-3-yl)-acetic acid N’-(2-cyanoethyl)hydrazide(4).The chemical structures of the newly synthesized compounds were elucidated by their IR,~1H NMR and MS.Further,all the compounds were screened for their antimicrobial activity against Gram-positive,Gram-negative bacteria and also tested their ability toward anti-inflammatory activity.     

3-Oxyanthranilic acid derivatives from Actinomadura sp. BCC27169

Eight new compounds including 9′-[2-amino-3-(4″-O-methyl-α-rhamnopyranosyloxy) phenyl]nonanoic acid (1), 9′-[2-amino-3-(4″-O-methyl-α-ribopyranosyloxy)phenyl] nonanoic acid (2), 11′-[2-amino-3-(4″-O-methyl-α-rhamnopyranosyloxy)phenyl]undecanoic acid (3), 11′-[2-amino-3-(4″-O-methyl-α-ribopyranosyloxy)phenyl]undecanoic acid (4), 8-(4′-O-methyl-α-rhamnopyranosyloxy)-3,4-dihydroquinolin-2(1H)-one (5), 8-(4′-O-methyl-α-ribopyranosyloxy)-3,4-dihydroquinolin-2(1H)-one (6), 8-(4′-O-methyl-α-rhamnopyranosyloxy)-2-methyquinoline (7), and 8-(4′-O-methyl-α-ribopyranosyloxy)-2-methylquinoline (8) were isolated from Actinomadura sp. BCC27169. The chemical structures of these compounds were determined based on NMR and high-resolution mass spectroscopy. The absolute configurations of these monosaccharides were revealed by the hydrolysis of compounds 7 and 8. Compounds 3 and 8 exhibited antitubercular activity at MIC 50 μg/mL. Only compound 3 showed cytotoxicity against KB cell at IC₅₀ 18.63 μg/mL, while other isolated compounds were inactive at tested maximum concentration (50 μg/mL).     

Cycloadditions of chiral carbonyl ylides with imine dipolarophiles as a route to enantiomerically pure α-amino-β-hydroxy acids

The preparation of enantiomerically pure threo-β-amino-α-hydroxy acids via 1,3-dipolar cycloadditions of imine dipolarophiles with the chiral isomünchnone derived from (5R)-5-phenylmorpholin-3-one 1 is described. The cycloadducts were obtained with excellent diastereofacial- and exo-selectivity. Subsequent hydrolysis and chemoselective exocyclic amide cleavage afforded the threo-β-amino-α-hydroxy acids with recovery of the initial chiral auxiliary.     

Parallel Solid-Phase Synthesis of disubstituted 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones

A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimidazole provided following Fmoc elimination free amine. Treatment of the free amine with 1,1′-carbonyldiimidazole or 1,1′-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoins or thiohydantoins were isolated in good yields.