Synthesis and Chemical Constitution of Diphenoxyphosphoryl Derivatives and Phosphonium Salts as Coupling Reagents for Peptide Segment Condensation

The reactions of diphenoxyphosphoryl chloride ((PhO) 2 P(O)Cl) and different chlorophosphonium salts ([R 3 PCl]X, R = (CH 3 ) 2 N, pyrrolidine, X = PF 6 m , BF 4 m ), respectively, with 7-aza-1-hydroxybenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), hydroximinomalonitrile (HOxDCO), and ethyl hydroximinocyanoacetate (HOxO) are described. The structures of the new compounds, which are useful coupling reagents for epimerization-free peptide segment condensation, are discussed on the basis of their 1 H, 13 C, 31 P NMR, and IR spectra. The reactions of (PhO) 2 P(O)Cl lead to mixtures of O - and N -phosphorylated isomers of varying ratios. Contrary, reactions of chlorophosphonium salts yield exclusively one isomer.     

An Improved Method for the Synthesis of N-Phenoxyacetylribonucleosides

N-phenoxyacetylribonucleosides were prepared efficiently from the reaction of ribonucleosides with phenoxyacetylchloride and 1,2,4-triazole(for adenosine and cytidine) or 1-hydroxybenzotriazole (for guanosine).     

Spectrophotometric, EPR and kinetic characterisation of the >N-O* radical from 1-hydroxybenzotriazole, a key reactive species in mediated enzymatic oxidations

Characterisation of the aminoxyl (>N-O*) radical BTNO, generated from 1-hydroxybenzotriazole (HBT) by the one-electron oxidant CAN (a Ce(IV) salt), confirms BTNO as the reactive intermediate in oxidations run with the laccase/HBT system.     

Synthesis of Substituted 3H-Indole-modified b-Cyclodextrin

The hydrophobic cavities of cyclodextrins and the inclusion with various organic molecules in the aqueous solution make them useful in chemical and biological activities1, one of which is the modified cyclodextrins acting as indicators of molecular recognition. Cyclodextrins, which are spectroscopically inert, can be converted into spectroscopically active compounds by modifing one or two of the hydroxy groups with appropriate chromophores, and used as molecular sensor due to the capability of…     

O-selectivity and utility of phosphorylation mediated by phosphite triester intermediates in the N-unprotected phosphoramidite method

Previously, O-selective phosphorylation on polymer supports in the N-unprotected phosphoramidite method could not be carried out because the amino groups of dA and dC have high reactivity toward tervalent phosphorus(III)-type phosphitylating reagents. In this paper, we developed a new coupling strategy named the "activated phosphite method" in which the phosphitylation is mediated by phosphite triester intermediates 1. Application of 1-hydroxybenzotriazole as the promoter to the solid-phase synthesis resulted in excellent O-selectivity of more than 99.7%. This O-selectivity was explained by the frontier molecular orbital interactions between the reactive intermediates and the nucleophiles such as the amino or hydroxyl groups of nucleosides. Furthermore, longer oligonucleotides were synthesized not only by a manual operation but also by a DNA synthesizer. The utility of our new method was demonstrated by the successful synthesis of a base-labile modified oligodeoxyribonucleotide having 4-N-acetyldeoxycytidine residues. Finally, DNA 20-mers containing dA or dC could be synthesized in good yields by use of a combined reagent of 6-trifluoromethyl-1-hydroxybenzotriazole and benzimidazolium triflate.     

A new approach to the synthesis of phosphotriester intermediates of nucleosides and nucleic acids

Aryl phosphorodichloridates can be converted by means of 1-hydroxybenzotriazole into an effective phosphorylating agent, which can be applied to the synthesis of phosphotriester intermediates of nucleic acids.     

A conventional new procedure for N-acylation of unprotected amino acids

The preparation of amide derivatives (4) by N-acylation of unprotected alpha-amino acids is easily achieved via readily available benzotriazolyl carboxylates (2a-d) or succinimidyl carboxylates (2e-f). These intermediates (2) are prepared from reaction of carboxylic acids (1) with 1-hydroxybenzotriazole (HO-Bt) or N-hydroxysuccinimide (HO-Su) in the presence of equimolar amounts of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCI). The overall yields of the target compounds (4) were excellent, and this two-stage procedure could be applicable as an alternative procedure for one-pot reaction.     

A convenient and efficient synthesis of C-carbamoyl-1,2,3-triazoles from alkyl bromide by a one-pot sequential addition: conversion of ester to amide using Zr(Ot-Bu)4

A convenient and efficient one-pot sequence has been developed for the synthesis of C-carbamoyl-1,2,3-triazoles from alkyl bromide using (i) sodium azide, (ii) methyl propiolate and copper iodide, and (iii) amines, zirconium tert-butoxide, and 1-hydroxybenzotriazole, under microwave irradiation. The sequential reactions in one-pot provided the desired C-carbamoyl-1,2,3-triazoles in excellent yields.     

New method of preparation of carboxy-protected amino acid conjugates of glycyrrhizinic acid

A method for preparation of carboxy-protected amino acid conjugates of glycyrrhizinic acid with the use of N-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and methyl esters of L-amino acids (phenylalanine, tyrosine, leucine, isoleucine, and methionine) in 85–90% yield was developed. The structure of the prepared compounds was confirmed by IR and ¹³C NMR spectra.     

The activation of N-hydroxy compounds by μ-oxo-bis-[tris-(dimethylamino)-phosphonium] bis-tetrafluoroborate

A study is made of the effect of 1-hydroxybenzotriazole on μ-oxo-bis-[tris(dimethylamino)-phosphonium]-bis-tetrafluoroborate 1 during amide bond formation. The reagent 1 is used to activate phenylhydroxamic acid towards a Lossen-type rearrangement and bring about Beckmann rearrangement of ketoximes under mild conditions. Both syn- and anti-benzaldoxime give benzonitrile by elimination.     

Shorter puromycin analog synthesis by means of an efficient Staudinger-Vilarrasa coupling

An efficient Staudinger-Vilarrasa coupling generates amides from azides and 1-hydroxybenzotriazole esters of amino- or hydroxy acid derivatives in very high isolated yields and purity. New puromycin analogs, mostly putative biosynthetic intermediates, were synthesized in nine steps from adenosine.     

Attachment of drugs to polyethylene glycols

Polyethylene glycol (PEG) was used as a carrier polymer for the attachment, via end groups, of drugs such as penicillin V, aspirin, amphetamine, quinidine and atropine. For this purpose, methods were developed for the functionalization of PEG; PEG-NH₂, PEG-COOH and PEG-NCO were prepared. Use was made of dicyclohexyl carbodiimide together with 4-dimethylamino pyridine or 1-hydroxybenzotriazole for the coupling reactions.     

A new reagent for polypeptide synthesis: mu-oxo-bis-(tris-(dimethylamino)-phosphonium)-bis-tetrafluoroborate.

The products 1 and 2 (X = OTs) have been isolated from the reaction between hexamethylphosphortriamide and p-toluene sulfonic anhydride and the latter converted into μ-oxo-bis-[tris-(dimethylamino)-phosphonium]-bis-tetrafluoroborate 2 (X = BF₄). This is a practical reagent for the formation of the peptide link. Where racemisation is possible via oxazolone formation this can be decreased by the addition of 1-hydroxybenzotriazole or N-hydroxysuccinimide. These additives may also increase the efficiency of condensation at glycine and proline residues.     

S-4-methylphenyl-o,o-bis[1-benzotriazolyl] phosphorothioate: a versatile phosphorylating agent

The phosphorylating agent obtained by treatment of S-4-methylphenyl phosphorodichloridothioate with 1-hydroxybenzotriazole can not only be applied for the introduction of polyphosphate functions at the terminal ends of nucleic acids, but also for the formation of 3′-5′-phosphotriester linkages.     

SYNTHESIS OF γ-GLUTAMYLPHOSPHONODIDEPEPTIDES

Abstract

γ-Glutamylphosphonodidepsipeptides 3a-f were obtained by condensation of α-t-butyl or α-benzyl ester of optically active N-benzyloxycarbonyl-glutamic acid with di-p-nitrobenzyl 1-hydroxymethanephosphonate, (+) dibenzyl 1-hydroxy-2-methylpropanephosphonate and (-) dibenzyl 1-hydroxy-3 methylbutanephosphonate. Dicyclohexylcarbodiimide in the presence of 4-(N,N-dimethylamino)- pyridine and 1-hydroxybenzotriazole in methylene chloride was used as a condensing agent for compounds 3a-c. Compounds 3d-f were obtained by means of the dicyclohexylcarbodiimide method in the presence of 4-(N, N-dimethylamino)pyridine in carbon tetrachloride. Protecting groups were removed by conventional methods.     

Synthesis of polymer-bound 4-acetoxy-3-phenylbenzaldehyde derivatives: applications in solid-phase organic synthesis

Aminomethyl polystyrene resin was reacted with 4-(5'-formyl-2'-hydroxyphenyl)benzoic acid and 4-(5'-formyl-2'-hydroxyphenyl)phenyl propionic acid, respectively, in the presence of 1-hydroxybenzotriazole and 1,3-diisopropylcarbodiimide to yield polymer-bound benzaldehydes. The phenolic group in resins was acetylated with acetic anhydride to afford two polymer-bound 4-acetoxybenzaldehydes. The reductive amination of polymer-bound linkers by amines and sodium triacetoxyborohydride, followed by sulfonylation with arylsulfonyl chloride derivatives in the presence of pyridine and the cleavage with TFA/DCM/H2O, produced pure sulfonamides.     

Synthesis of aromatic polyamides by 1-hydroxybenzotriazole-catalyzed polycondensation of active aromatic diesters with aromatic diamines

Catalytic actions of various additives were studied in the polycondensation of di(4-nitrophenyl) isophthalate with bis(4-aminophenyl) ether in N-methyl-2-pyrrolidone, and 1-hydroxybenzotriazole (HOBt) was found to be a highly effective catalyst that yielded high-molecular-weight polyamide. In addition to the polycondensation of the 4-nitrophenyl ester, the polymerization of negatively substituted phenyl esters like di(2,4,5-trichlorophenyl) isophthalate was also accelerated by HOBt. For the HOBt-catalyzed aminolysis of esters a bifunctional concerted mechanism that involves an eight-membered transition state was proposed.     

Synthesis of conformationally locked versions of puromycin analogues

Conformationally locked North and South versions of puromycin analogues built on a bicyclo[3.1.0]hexane pseudosugar template were synthesized. The final assembly of the products was accomplished by the Staudinger-Vilarrasa coupling of the corresponding North (2 and 3) and South (6 and 7) 3'-azidopurine carbanucleosides with the Fmoc-protected 1-hydroxybenzotriazole ester of 4-methoxy-L-tyrosine. North azides 2 and 3 were reported earlier. The 3'-azido intermediates 6 and 7 that are necessary for the synthesis of the South puromycin analogues are described herein for the first time.     

Reaction between nucleoside base residues and the phosphorylating agent derived from 1-hydroxybenzotriazole and 2-chloroprenyl phosphorodichloridate

In the presence of 1-methylimidazole, 2-$\text{N}$-acyl guanine (as in $\text{4a}$), thymine (as in $\text{5a}$) and uracil (as in $\text{5b}$) residues react readily with the phosphorylating agent derived from 2-chlorophenyl phosphorodichloridate ($\text{1a}$) and 1-hydroxybenzotriazole.