Synthesis of optically active copoly(vinylamine–vinylalcohol) containing a pair of adeninyl and thyminyl pendant groups

Preparation of novel model polymers of polynucleotides with copoly(vinylamine–vinylalcohol) [P(Vam–Val)] backbone and a pair of adeninyl and thyminyl pendant groups is described. At first, direct, low temperature esterification was used to attach (?) and (±)-2-(thymin-1-yl)propionic acid [(?)TPA and (±)TPA], to the N–Cbz protected hydroxy polymer P(Vamz–Val) which was prepared by selective N-protection of N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarboximide (CbzONB) with P(Vam–Val), at the hydroxy group via an ester bond. Two novel precursors P(Vamz–Ve(?)T) and P(Vamz–Ve(±)T) were obtained. Then the Cbz protecting group of P(Vamz–Ve(?)T) and P(Vamz–Ve(±)T) were removed by hydrobromic acid to give the hydrobromide salt of P(Vam–Ve(?)T) and P(Vam–Ve(±)T), respectively. Finally, the attachment of (±)-2-(adenine-9-yl)propionic acid [(±)APA] to linear P(Vam–Ve(?)T) and P(Vam–Ve(±)T) by selective N-acylation with N-hydroxy-5-norbornene-2,3-dicarboximide (HONB). This procedure gave the corresponding P(Vam–Val) having a pair of adeninyl and thyminyl pendant groups, such as P(Va(±)Ad–Ve(?)T) and P(Va(±)Ad–Ve(±)T). In contrast to the corresponding polymer models, the related segment model compounds were also prepared from threo-2-amino-4-pentanol without N-blocking-deblocking operations. The segment model compounds including four stereoisomers of highly optical purities, were separated and purified by reverse phase HPLC technique.     

Synthesis of polyamide containing optically active thymine derivative as a grafted pendant

A new route to polyamides containing optically active thymine groups as pendants has been established. The method is based on the grafting of (–) and (±)-2-(thymin-1-yl)propionic acid [(–) and (±) TPA] onto a polyamide containing hydroxyl groups. The hydroxy polyamide was prepared by selective N-acylation of an active diester of N-hydroxy-5-norborene-2,3-dicarboxamide (HONB), N,N'-(isophthaloyl-dioxy)-bis(5-norbornene-2,3-dicarboximide) (IPBONB), with 1,3-diamino-2-hydroxypropane (AHP). Model compounds (?) and (±)-(1,3-dibenzoylamino-2-propyl)2-(thymin-1-yl)propionate[(?) and (±) (BAPTP)] were prepared by direct, low-temperature esterification before synthesizing the polymer.     

Syntheses of polyethylenimine containing asymmetric nucleic acid base derivatives as grafted pendants

Preparations of new model polymers of polynucleotides with linear polyethylenimine (PEI) backbones and optically active nucleic acid base derivatives as pending side chains are described. (±)-2-(Thymin-1-yl)propionic acid (II) and (±)-2-(adenin-9-yl)propionic acid (IV) were synthesized. These carboxylic acid derivatives were grafted onto PEI at the imino nitrogen by the p-nitrophenyl active ester method. The enantiomeric pairs of II were optically resolved with quinine to yield (?) and (+)-2-(thymin-1-yl)propionic acid (VII and VIII). VII and VIII were grafted onto PEI through amide bond by direct coupling with diethylphosphoryl cyanide to give optically active graft polymers. The related monomer and dimer model compounds were also prepared by the same method from diethylamine and dimethylethylene diamine, respectively.     

Synthesis of polyesters containing nucleic acid base derivatives as pending side chains

Preparations of four diol monomers containing nucleic acid bases and the corresponding model polymers of polynucleotides with linear polyester backbone and nucleic acid base derivative as pending side chains are described. N-(1′,3′-Dihydroxy-2′-methyl-2′-propyl)-2-(thymin-l-yl)propionamide ( Ia , HMPTPA), N-(1′,3′-dihydroxy-2-methyl-2′-propyl)-2-(uracil-l-yl)propionamide ( Ib , HMPUPA), and their isomers, N-(β,β′-dihydroxyethyl)-2-(thynin-1-yl)propionamide ( IIa , HETPA) and N-(β,β′-dihydroxyethyl)-2-(uracil-1-yl)propionamide ( IIb , HEUPA) were synthesized through the selective N-acylation of 2-methyl-2-amino-1,3-propanediol and diethanolamine with 2-(thymin-1-yl)propionic acid (TPA) and 2-(uracil-1-yl)propionic acid (UPA), respectively, by the active amide-benzotriazole method. Diol monomers I and II were polycondenzed with active amide of benzotriazole such as 1,1′-(isophthaloyl)bisbenzotriazole (IPBBT) in the presence of triethylamine and in DMF at 60°C, giving polyesters containing thymine and uracil derivatives as the side group. Prior to polymer synthesis, an O-acylation of Ia using the active monoamide l-benzoylbenzotriazole was carried out as a model compound study.     

Synthesis of polyurethanes containing nucleic acid base derivatives as grafted pendants and their precursor amino functionalized polyurethane

A new route to polyurethanes containing nucleic acid base derivatives as grafted pendants have been established. The method is based on the grafting of 2-(thymin-1-yl)propionic acid (TPA) or 2-(adenin-9-yl)propionic acid (APA) onto amino functionalized polyurethane, poly[2-amino-2-methyl-1,3-propylene methylene bis(4-phenyl carbamate)] (PU-NH₂, IX ) at the primary amino group by the N-hydroxy compound of active ester technique. Two novel polymer models of polynucleic acid—poly[2-(2′-(thymin-1′-yl) propionamido)-2-methyl-1,3-propylene methylene bis(4-phenylcarbamate)] (PU–NHT, X ) and poly[2-(2′-(adenin-9′-yl)propionamido)-2-methyl-1,3-propylene methylene bis(4-phenylcarbamate)] (PU–NHA-40, XI )—were obtained. The amino functional polyurethane was prepared by the following three step reactions; (1) Selective N-protection of N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarbonimide (CbzONB) with 2-amino-2-methyl-1,3-propanediol gave the N-protecting diol monomer 2-benzyloxycarbonylamino-2-methyl-1,3-propanediol (CbzAMP); (2) N-Protecting polurethane poly(2-benzyloxycarbonylamino-2-methyl-methyl-1,3) propylene methylene bis(4-phenylcarbamate) (PU–NHCbz, VIII ) was obtained by the polyaddition of 4,4′-diphenyl-methane diisocyanate (MDI) with CbzAMP. (3) Deprotection of PU–NHCbz produced amino polyurethane PU-NH₂. Prior to polymer synthesis, the amidation of APA with 3-aminoheptane or diethylamine were carried out as a model reaction study and the related monomer model compounds were prepared by the same methods.     

Synthèse de deux nouveaux acides amines phénoliques comportant un cycle 1,2,4-oxadiazole

Synthesis of two phenolic amino acids containing the 1,2,4-oxadiazole ring The synthesis of α-amino-β [3-(p-hydroxyphenyl)-1,2,4, oxadiazol-5-yl]propionic acid (9) and its β-amino isomer (10) (see scheme 3) is reported. By condensation of p-benzyloxy-benzamide oxime and N-benzyloxycarbonyl asparagine the derivatives 4 and 5 (see scheme 1) are obtained leading after deprotection to 9 and 10 . The synthesis of N-carboxyanhydride of 4 (6) and its corresponding amino acid (7) and amide (8) is also described.     

Synthesis of poly(vinylamine) containing asymmetric nucleic acid base derivatives as grafted pendants

The preparations of new model polymers of polynucleotides with stereoregular poly(vinylamine) (PVAm) backbones and an optically active nucleic acid base derivative as a pending side chain are described. The grafting of (±)-, (+)-, and (?)-2-(thymin-1-yl) propionic acid to linear PVAm prepared either by hydrolysis of poly(vinyl acetamide) or poly(vinyl-t-butyl carbamate) has proven to be more difficult than the case of polyethyleneimine. This may be due to a combination of the low solubility and steric factors of PVAm. PVAm formed a complex with oximes such as ethyl-2-hydroxyimino cyanoacetate (EHICA), which activates the amino group of PVAm; it became soluble in polar solvents and gave higher percent graft. These carboxylic acid derivatives were grafted onto PVAm through amide bonds by direct coupling with sulfonic acid esters of hydroxybenzotriazoles to give optically active graft polymers. These coupling agents were found to be much superior reagents than DEPC regarding racemization. The related monomer and dimer model compounds were also prepared by the same method from 3-aminopentane and (?)-, (+)-, and meso-2,4-diaminopentane, respectively. The dimer models were separated and purified by HPLC to give models for isotactic, heterotactic, and syndiotactic polymer models. The enantiomeric purity of the optically active monomer model was determined by 360-MHz NMR spectroscopy using optically active shift reagents.     

Epimeric Isopavine N-Oxides from Roemeria refracta

Roemeria refracta DC. (Papaveraceae) of Turkish origin yielded two novel epimeric N-oxides, (?)-(5R, 11S,14R)-reframidine N-oxide ( = (?)-(5R, 11S,14R)-11,12-dihydro-14-methyl-11,5-(iminomethano)-5H -cyclohepta[1, 2-f: 4, 5-f′]bis[1,3]benzodioxole 14-oxide; 1 ) and (?)-(5R, 11S, 14S)-reframidine N-oxide ( = (?)-(5R, 11S, 14S)-11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxole 14-oxide; 2 ). The isolated (?)-roelactamine ( = (?)-11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxol-15-one, 4 ) is the first natural isopavinoid incorporating a lactam group. The epimeric (?)-15-(2-oxopropyl)reframidines ( = (?)-1-[11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxol-15-y1]propan-2-ones; 5/6 ) and the epimeric (?)-ethyl (reframidin-15-yl)acetates ( = (?)-ethyl [11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxol-15-y1]acetates; 7/8 ) are probably artifacts. (±)-Coclaurine ( 9 ), (±)-N-methylcoclaurine ( 10 ), (?)-roemeridine ( 11 ), and N-feruloyltyramine ( 12 ) are also isolated from R. refracta together with the previously reported bases. Specific ¹³C-NMR assignments are reported for the first time for the isopavines.     

1H- und 13C-NMR.-spektroskopische Untersuchungen an den vier diastereomeren (±)-Dihydropalustraminsäure-methylestern; Strukturkorrelation mit (−)-Dihydropalustraminsäure-methylester sowie mit dem Alkaloid Palustrin. 14. Mitteilung über Schachtelhalmalkaloide

¹H-and¹³C-NMR. spectra of methyl esters of the diastereomeric (±)-dihydropalustramic acids; structural correlation of (?)-dihydropalustramic acid with the alkaloid palustrin Unambiguous assignment of cis-trans configuration at the piperidine ring of the four diastereomeric methyl esters of the (±)-dihydropalustramic acids is based on the interpretation of ¹H- and ¹³C-NMR. data. (?)-Dihydropalustramic acid, the important degradation product of the alkaloid palustrin is shown to be threo-cis-[6-(1-hydroxypropyl)-2-piperidyl]acetic acid. The same conclusion holds for palustrin and dihydropalustrin. Therefore, palustrin is threo-cis-17-(1-hydroxy-propyl)-1,5,10-triazabicyclo[11.4.0]heptadec-15-en-11-one.     

An expedient synthesis of (±)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid hydrobromide via a 3-bromoisoxazole intermediate

The excitatory, amino acid ±2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid hydrobromide was prepared in gram quantities in an 3.3% overall yield from methylbut 2-ynoate. The key step was the facile preparation of methyl 3-bromo-5-methylisoxazole-4-carboxylate.     

Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl 1,2,4-triazole derivative as a selective GlyT1 inhibitor

Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile 1, a novel GlyT1 inhibitor. The diastereomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acid 7 with (1R,2S)-(?)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.     

Synthesis of Polypropionate Fragments Containing Tertiary-Alcohol Moieties. Cross-aldolisations with lithium enolates of 7-oxabicyclo[2.2.1]heptan-2-one derivatives

The Diels-Alder adduct of 2,4-dimethylfuran to 1-cyanovinyl (1′R)-camphanate ((+)-(1R,2S,4R)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′R)-camphanate ((+)- 1 )) was converted into (+)-2,7-dideoxy-2,4-di-C-methyl-L -glycero- ((+)- 6 ) and -D -glycero-L -altro-heptono-1,4-lactone ((+)- 7 ), into (?)-(3R,4R,5R,6S)-3,4:5,7-bis(isopropylidenedioxy)-4,6-dimethylheptan-2-one ((?)- 22 ), and into (+)-(2R,3R,4R,5S,6S)-3,4:5,6-bis(isopropylidenedioxy)-2,4-dimethylheptanal ((+)- 34 ). Condensation of ((+)- 34 with the lithium enolate of (?)-(1R,4R,5S,6R)-6-exo-[(tert-butyl)dimethylsilyloxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1] heptan-2-one ((?)- 38 ; derived from (+)- 1 ) gave a 3:2 mixture of aldols (+)- 39 and (+)- 40 (mismatched pairs of a α-methyl-substituted aldehyde and (E)-enolate) whereas the reaction of (±)- 34 with (±)- 38 gave a 10:1 mixture of aldols (±)- 41 and (±)- 39 . A single aldol, (?)- 44 , was obtained to condensing (+)- 34 with the lithium enolate of (+)-(1S,4S,5S,6S)-5-exo-(benzyloxy)-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptan-2-one ((+)- 43 ; derived from (?)-(1S,2R,4S)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′S)-camphanate ((?)- 3 )). All these cross-aldolisations are highly exo-face selective for the bicyclic ketones. The best stereochemical matching is obtained when the lithium enolates and α-methyl-substituted aldehydes can realize a ‘chelated transition state’ that obeys the Cram and Felkin-Anh models (steric effects). Polypropionate fragments containing eleven contiguous stereogenic centres and tertiary-alcohol moieties are thus prepared with high stereoselectivity in a convergent fashion. The chiral auxiliaries ((1R)- and (1S)-camphanic acid) are recovered at the beginning of the syntheses.     

Potentiometric and viscosimetric titration of poly(N-acyldehydroalanines) containing asymmetric nucleic acid base derivatives as pendant groups

The potentiometric and viscosimetric titration curves of poly(N-acetyldehydroalanine) (PNAcDHA) were compared with those of the nucleic acid base-containing dehydroalanine backbone polymers poly{(+ ?) and (?)? [2-(thymin-1-yl]{propanoamido}propenoic acid} (PTDHA and P(?)TDHA)). The behavior of PNAcDHA was similar to polyacids such as poly(acrylic acid), but PTDHA and P(?)TDHA displayed very strong nearest neighbor interactions, since the pH curves had an additional inflection at half neutralization that was sensitive to the ionic strength of the medium and the viscosity curves showed little expansion of the polymer coil with increasing ionization. NAcDHA–TDHA copolymers were prepared which showed similar behavior. These results suggested that PTDHA and P(?)TDHA were extended and conformationally restricted in aqueous solution compared to PNAcDHA, findings that agreed with the results of spectroscopic studies of these polymers.     

Synthesis of isonipecotinoyl analogues of aminopterin and folic acid

The preparation of isonipecotinoyl analogues of aminopterin and methotrexate is described. Condensation of diethyl N-isonipecotinoyl-L-glutamate 4 with 2-amino-5-bromomethyl-3-cyanopyrazine 5 afforded diethyl N-(N-[(2-amino-3-cyanopyrazin-5-yl)methyl]isonipecotinoyl)-L-glutamate 6 . Cyclisation of 6 with guanidine followed by blocking group hydrolysis afforded N-([N-(2,4-diaminopteridin-6-yl)methyl]isonipecotinoyl)-L-glutamic acid 8 . Coupling of N-(2-amino-4(3H)ioxopteridin-6-yl]methyl)isonipecotinic acid 11 with diethyl L-glutamate gave diethyl N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamate 12 . Blocking group hydrolysis afforded N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamic acid 13 .     

Synthesis of poly(vinyl alcohol) containing asymmetric nucleic acid base derivatives as grafted pendants

The preparations of new model polymers of polynucleotides with linear poly(vinyl alcohol) (PVA) backbones and an optically active nucleic acid base derivative as a pending side chain are described. (±)-, (+)-, and (?)-2-(thymin-1-yl)propionic acid were grafted onto PVA through ester bonds by direct coupling with dicyclohexylcarbodiimide (DCC) in the presence of highly active catalyst 4-pyrrolidinopyridine (PPY) to give optically active graft polymers. The corresponding monomer and dimer models have been prepared.     

4-Aminofurazan-3-carboxylic Acid Iminoester in Reactions with N,O-Nucleophiles

Reactions of 4-aminofurazan-3-carboxylic acid iminoester with o-aminophenol and ethylenediamine give rise respectively to 4-(1,3-benzoxazol-2-yl)- and 1-(4,5-dihydro-1H-imidazol-2-yl)-1,2,5-oxadiazol-3-amines, with aminoethanol arises 2-[(Z)-1-amino-1-(4-amino-1,2,5-oxadiazol-3-yl)methylideneamino]-1-ethanol. Treating of 3-amino-4-(1H-benzo[d]imidazol-2-yl)-1,2,5-oxadiazole with triethyl orthoformate in acetic anhydride yielded benzo[4,5]imidazo[1,2-c][1,2,5]oxadiazolo[3,4-e]pyrimidine, and alkylation with haloalkanes furnished 3-amino-4-(1-R-benzo[d]imidazol-2-yl)-1,2,5-oxadiazoles.     

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).     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

Preparation and Absolute Configuration of (−)-(E)-α-trans-Bergamotenone

The synthesis, absolute configuration, and olfactive evaluation of (?)-(E)-α-trans-bergamotenone (= (?)-(1′S,6′R,E)-5-(2′,6′-dimethylbicyclo[3.1.1]hept-2′-en-6′-yl)pent-3-en-2-one; (?)- 1 ), as well as its homologue (?)- 19 are reperted. The previously arbitrarily attributed absolute configuration of 1 and of (?)-α-trans-bergamotene (= (?)-(1 S,6R)-2,6-dimethyl-6-(4-methylpent-3-enyl)bicyclo[3.1. 1]hept-2-ene; (?)- 2 ), together with those of the structurally related aldehydes (?)- 3a,b and alcohols (?)- 4a,b , have been rigorously assigned.     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.