Stereospecific synthesis of new 2,3,4,5-piperidinetetracarboxylic acids and 2,3,5-piperidinetricarboxylic acids

Diels-Alder adducts of 1,2-dihydropyridine with maleic and acrylic acid derivatives were stereospecifically converted by way of RuO₄ oxidation into new r-2,c-3,c-4,c-5-piperidinetetracarboxylic acid, r-2,t-3,t-4,c-5-piperidinetetracarboxylic acid, r-2,c-3,c-5-piperidinetricarboxylic acid, and r-2,t-3,c-5-piperidinetricarboxylic acid.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

Synthesis of N-allyl- and N-acyl-2-vinylindoline

Heating a mixture of (2R*,3R*)- and (2R*,3S*)-2-[(1S*)-1-iodoethyl]-3,5-dimethyl-1-[(2-nitrophenyl) sulfonyl]indolines with N-isopropylpiperidine in xylene resulted in (2S*,3R*)-3,5-dimethyl-1-[(2-nitrophenyl) sulfonyl]-2-vinylindoline. The latter reacted with thiophenol to afford (2S*,3R*)-3,5-dimethyl-2-vinylindoline, whose reaction with allyl halides or acetyl bromide gave rise to N-allyl-, N-propenyl-, or N-acetyl derivatives. Nitration of 1-acetyl-3,5-dimethyl-2-vinylindoline yielded ortho-nitro derivative.     

Reaction of 2,3-diaminomaleonitrile with diones

2,3-Diaminomaleonitrile (DAMN) was allowed to react with 2,6-heptanedione to produce (2Z)-2-amino-3-[(1E)-3-methylcyclohex-2-enylideneamino]but-2-enedinitrile and (2Z)-2-amino-3-[(1Z)-3-methylcyclohex-2-enylideneamino]but-2-enedinitrile. The reaction of DAMN with 2,7-octanedione yielded trans-5,8a-dimethyl-1,5a,6,7,8,8a-hexahydrocyclopenta[e]-1,4-diazepine-2,3-dicarbonitrile. DAMN reacted with 2,8-nonanedione to afford trans- and cis-5,9a-dimethyl-5a,6,7,8,9,9a-hexahydro-1H-benzo[e]-1,4-diazepine-2,3-dicarbonitrile. These compounds were characterized by X-ray crystallography, NMR spectroscopy, and DFT calculations.     

Resolution and conformational analysis of diastereoisomeric esters of cis- and trans-2-(aminomethyl)-1-carboxycyclopropanes

(1R,2S)-, (1S,2R)-, (1R,2R)- and (1S,2S)-2-(Aminomethyl)-1-carboxycyclopropanes, conformationally restricted analogues of the neurotransmitter γ-aminobutyric acid (GABA), have been resolved by chromatographic separation of the corresponding diastereoisomeric esters which were formed between the cis- and trans-2-(acetamidomethyl)-1-carboxycyclopropanes with (R)-(−)-pantolactone. ¹H NMR, semi-empirical conformational analysis, ab initio (DFT) structure and NMR shielding tensor calculations of the cis-diastereoisomers allowed the absolute configuration assignments of the cis-amino acids.     

An approach to an asymmetric synthesis of stemofoline

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxododecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give (1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Efficient synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-ω-iodoalkanoates

The efficient synthesis of four benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-ω-iodoalkanoates {benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-iodopropanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-iodobutanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-iodopentanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-6-iodohexanoate} from natural or protected l-amino acids is described.     

Synthesis of 2-(hydroxyphenylamino)- and 2-(aminophenylamino)-4-methylquinolines and N,N′-bis(4-methylquinolin-2-yl)benzenediamines

2-(Hydroxyphenylamino)- and 2-(aminophenylamino)-4-methylquinolines and N,N′-bis(4-methylquinolin-2-yl)benzenediamines were synthesized by reactions of 2-chloro-4-methylquinolines with o-, m-, and p-aminophenols and o-, m-, and p-phenylenediamines.     

Chemical behavior of ortho-hydroquinone-based bis(pyrazol-1-yl)methane ligands in the presence of palladium(II) chloride

The synthesis, structural characterization, and coordination behavior of ditopic ortho-hydroquinone-based bis(pyrazol-1-yl)methane ligands (ortho-(OH)₂C₆H₃-4-CHpz₂, ortho-(OH)₂C₆H₃-4-CH(3-Phpz)₂, and ortho-(OH)₂C₆H₃-4-CH(3-tBupz)₂) with pyrazole, 3-phenylpyrazole, and 3-tert-butylpyrazole as donors are described. The reaction of a soluble PdCl₂-source with ortho-(OH)₂C₆H₃-4-CHpz₂ in acetonitrile yielded the related square-planar N,N-coordinated Pd(II) dichloride complex, whereas treatment of ortho-(OH)₂C₆H₃-4-CH(3-Phpz)₂ or ortho-(OH)₂C₆H₃-4-CH(3-tBupz)₂ with PdCl₂ in acetonitrile resulted in degradation of these ligands. The Pd(II) complexes trans-(3-PhpzH)₂PdCl₂ and trans-(3-tBupzH)₂PdCl₂ were isolated and fully characterized including X-ray diffraction analyses.     

A mild and efficient cyanosilylation of ketones catalyzed by a Lewis acid-Lewis base bifunctional catalyst

A new family of bifunctional catalysts (N-oxides-Ti(OⁱPr)₄ (2:1)) containing a Lewis acid and a Lewis base was developed and applied to the catalytic cyanosilylation of ketones. Utilizing rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex as catalysts, the cyanosilylation products were obtained in 42-97% yield. Based on experimental phenomena and kinetic studies, a catalytic cycle was proposed to explain the remarkable activities of these catalysts. Investigations indicated that rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex should promote the reaction via a dual activation of the ketone by the titanium and TMSCN by the N-oxide.     

Diastereoselective reduction of β-keto carbonyl compounds by cultured plant cells

The diastereoselective reduction of β-keto carbonyl compounds such as 2-benzamidomethyl-3-oxobutanoates and 2-methyl-2-(2-propenyl)cyclopentan-1,3-dione by cultured cells of higher plants was investigated. The reduction of the 2-benzamidomethyl-3-oxobutanoates by Parthenocissus tricuspidata diastereoselectively produced the (2R,3S)-2-benzamidomethyl-3-hydroxybutanoates, whereas the reduction by Gossypium hirsutum gave the (2S,3S)-2-benzamidomethyl-3-hydroxybutanoates. The (2R,3S)/(2S,3S) predominance in the reduction with Nicotiana tabacum, Glycine max, and Catharanthus roseus was reversed by the change in the structure of the alkoxyl group in the substrate. On the other hand, the reduction of 2-methyl-2-(2-propenyl)cyclopentan-1,3-dione by P. tricuspidata produced (2R,3S)-3-hydroxy-2-methyl-2-(2-propenyl)cyclopentan-1-one, whereas the reaction by N. tabacum, G. max, C. roseus, and G. hirsutum gave (2S,3S)-3-hydroxy-2-methyl-2-(2-propenyl)cyclopentan-1-one.     

Synthesis of all the stereoisomers of 6-methyl-2-octadecanone, 6,14-dimethyl-2-octadecanone, and 14-methyl-2-octadecanone, the components of the female-produced sex pheromone of a moth, Lyclene dharma dharma

All of the stereoisomers of the components of the female-produced sex pheromone of a moth, Lyclene dharma dharma, were synthesized. They are (R)- and (S)-6-methyl-2-octadecanone, (6R,14R)-, (6R,14S)-, (6S,14R)-, and (6S,14S)-6,14-dimethyl-2-octadecanone, and (R)- and (S)-14-methyl-2-octadecanone. Enantiomers of citronellal and methyl (S)-3-hydroxy-2-methylpropanoate were the starting materials, and olefin cross metathesis was employed as the key reaction.     

A practical synthesis of new S,N-disubstituted derivatives of 5-(4-methylpiperidino)methyl-2-thiouracil

5-(4-Methylpiperidino)methyl-2-thiouracil (1) has been obtained via the Mannich reaction between 2-thiouracil, paraformaldehyde, and a cyclic secondary amine such as 4-methylpiperidine (4-MP) in ethanol. New S,N(1)-di-o-(m- and p-)bromo-(nitro-) benzyl-substituted derivatives have been synthesized successfully in the reactions of 1 with the corresponding o-(m- and p-)bromobenzyl bromides or o-(m- and p-) nitrobenzyl chlorides in DMF solution in the presence of K₂CO₃. The opposite method of synthesis, that is, the reaction between 2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyluracils and 2-o-(m- and p-)nitrobenzylthio-1-o-(m- and p-) nitrobenzyluracils (8), with paraformaldehyde and 4-methylpiperidine in ethanol failed, indicating the important role of the enol form of 2-thiouracil for the Mannich reaction to be successful.     

Photochemistry of β-(4-sydnonyl)-o-divinylbenzene: competitive cis-trans isomerization and photolysis

New cis- and trans-3-aryl-4-[2-(2-vinylphenyl)ethenyl]sydnones 2, aryl = phenyl, p-tolyl were prepared and transformed on irradiation in the presence of acrolein to a pyrazoline derivative that aromatized during isolation to trans-1-tolyl-3-[2-(2-vinylphenyl)ethenyl]pyrazole 7 and trans-5-formyl-1-tolyl-3-[2-(2-vinylphenyl)ethenyl]pyrazole 8.     

Novel pyrrolo[1,2-a][3.1.6]benzothiadiazocine ring synthesis. Unusual Truce-Smiles type rearrangement of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl(or sulfinyl)}acetone

Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone with sodium hydroxide with or without zinc gave 1-(2-nitrophenyl)(1H-pyrrol-2-ylsulfonyl)methane by a Truce-Smiles type of transformation and 1-(2-nitrophenyl)-2-methylsulfonylpyrrole by deacetylation. Similar treatment of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfinyl}acetone gave only 1-(2-nitro-phenyl)(1H-pyrrol-2-ylsulfinyl)methane. 1-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetone, 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}-1-phenyl-ethan-1-one or 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetonitrile were reductively cyclised with sodium borohydride and 5% palladium-on-carbon into 6-methyl(or phenyl)-5,6-dihydro-7H-pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-ol or 6-amino-5H-pyrrolo[1,2-a][3.1.6]benzothiadiazocine-7-oxide, respectively.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Two-photon induced fluorescence of novel dyes

Three novel compounds, trans-2-[p-(N-ethyl-N-(hydroxyethyl)amino)styryl]-N-methylbenzothiazolium iodide (1), trans-2-[p-(N-ethyl-N-(hydroxyethyl)amino)styryl]-1′,3′,3′-trimethylindolium iodide (2), and trans-2-[p-(N,N-dimethylamino)styryl]-1′,3′,3′-trimethylindolium iodide (3), were synthesized and their two-photon induced fluorescence behavior was studied. Under excitation by 1064 nm laser irradiation, the solutions of these compounds exhibit two-photon induced fluorescence with λ_max at 639, 666 and 665 nm for 1, 2 and 3 respectively.     

New ceramides from the flower of Albizia julibrissin

A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as(2S,3S,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-1,3,4-triol (Ⅰ) and 1-O-β-D-glucopyranosyl-(2S,3S,4R,8E)-2-[(2'R)-hydroxy-hexade-canoylamino]-8-tetracosene-1,3,4-triol (H) on the basis of chemical and spectroscopic studies.     

Arthrobacter sp.: a lipase of choice for the kinetic resolution of racemic arylazetidinone precursors of taxanoid side chains

The native strain of Arthrobacter sp. (MTCC 5125) bearing a lipase has been found to be the most effective in the kinetic resolution of racemic arylazetidinones for producing cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-phenyl-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thienyl)-2-azetidinone, and cis-3-acetoxy-4-(t-butyl)-2-azetidinone products. The resolved compounds, which were obtained in high enantiopurity are important intermediates of amino acid side chains of paclitaxel as well as a new generation of taxanoids. The use of co-solvents dramatically improved the resolution efficacy of the lipase.