Stereoselective formation of a P-P bond in the reaction of 2-alkoxy-2-thio-1,3,2-oxathiaphospholanes with O,O-dialkyl H-phosphonates and H-thiophosphonates

A new method for the formation of organohypophosphates containing a P-P bond under mild conditions, based on the DBU-assisted reaction of 2-alkoxy-2-thio-1,3,2-oxathiaphospholanes with O,O-dialkyl H-phosphonates or H-thiophosphonates, has been elaborated. The resulting triesters of P(1)-thio- and P(1),P(2)-dithiohypophosphoric acids, respectively, having O-methyl or O-ethyl groups, can be selectively dealkylated to form the corresponding di- or monoesters. Appropriately protected 2'-deoxyguanosine-3'-O-(2-thio-1,3,2-oxathiaphospholane) was converted into the corresponding P(1)-thio- and P(1),P(2)-dithiohypophosphate esters in a highly stereoselective manner (98%+ and 90%+, respectively).     

Oxathiaphospholane Approach to the Synthesis of Conjugates of Amino Acids Methyl Esters with Nucleosides

Based upon 1,3,2-oxathiaphospholane chemistry, 5'-O-derivatization of nucleosides with the O-methyl esters of amino acids was performed and corresponding conjugates were obtained in satisfactory yield.     

An oxathiaphospholane approach to one-pot phosphorothioylation of isoprenoid alcohols

[reaction: see text] Allyl, isopentenyl, geranyl, citronellyl, farnesyl, and phytyl alcohols were transformed in good yield (>60%) into their phosphorothioates via a DBU-assisted 1,3,2-oxathiaphospholane ring-opening condensation with 2-(2-cyanoethoxy)-2-thiono-1,3,2-oxathiaphospholane, a reagent that is stable and easy to handle, followed by subsequent removal of the 2-cyanoethyl group from the intermediate phosphorothioate diester under basic conditions.     

5-氟尿嘧啶N1-甲酰基氨基酸、短肽的合成及抗肿瘤活性

5-氟尿嘧啶N¹-甲酰氯分别与Gly、Val、Leu、Ile、Phe、Asp和Glu的苄酯反应,制备了7种5-氟尿嘧啶-N¹-甲酰基氨基酸苄酯。氢解后得到了相应的5-氟尿嘧啶N¹-甲酰氨基酸。将其进一步与氨基酸甲酯或二肽甲酯缩合,制备了5-氟尿嘧啶N¹-甲酰基二肽甲酯和三肽甲酯。5-氟尿嘧啶-N¹-甲酰基二肽甲酯也可采用5-氟尿嘧啶-N¹-甲酰氯与二肽甲酯直接反应制备。     

Synthesis of pyrimidine derivatives of amino acids using pig liver esterase and pancreas lipase.

The parent methyl ester of the N-1 substituted 5-chloropyrimidinone is hydrolysed by pig liver esterase to the corresponding carboxylic acid. The acid chloride was made with PCl5 in toluene, and coupling with benzyl and methyl esters of selected L-amino acids to the corresponding amides was done in dichloromethane in the presence of triethylamine. The benzyl and methyl ester protecting groups were hydrolysed with pancreas lipase or esterase in a pH-stat to yield the corresponding carboxylic acids.     

Azides of N-substituted aziridine-2-carboxylic acids. Reaction with methyl esters of amino acids

The corresponding azide was obtained by nitrosation of 1-benzylaziridine-2-carboxylic acid hydrazide. Reaction of the azide with methyl esters of amino acids gave N-(1-benzyl-2-aziridinylcarbonyl)-substituted methyl esters of amino acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1350–1352, October, 1980.     

A convenient route to N-[2-(Fmoc)aminoethyl]glycine esters and PNA oligomerization using a Bis-N-Boc nucleobase protecting group strategy

A simple and practical synthesis of the benzyl, allyl, and 4-nitrobenzyl esters of N-[2-(Fmoc)aminoethyl]glycine is described starting from the known N-(2-aminoethyl)glycine. These esters are stored as stable hydrochloride salts and were used in the synthesis of peptide nucleic acid monomers possessing bis-N-Boc-protected nucleobase moieties on the exocyclic amino groups of ethyl cytosin-1-ylacetate, ethyl adenin-9-ylacetate and ethyl (O(6)-benzylguanin-9-yl)acetate. Upon ester hydrolysis, the corresponding nucleobase acetic acids were coupled to N-[2-(Fmoc)aminoethyl]glycine benzyl ester or to N-[2-(Fmoc)aminoethyl]glycine allyl ester in order to retain the O(6) benzyl ether protecting group of guanine. The Fmoc/bis-N-Boc-protected monomers were successfully used in the Fmoc-mediated solid-phase peptide synthesis of mixed sequence 10-mer PNA oligomers and are shown to be a viable alternative to the currently most widely used Fmoc/Bhoc-protected peptide nucleic acid monomers.     

Polymer-bound oxathiaphospholane: a solid-phase reagent for regioselective monothiophosphorylation and monophosphorylation of unprotected nucleosides and carbohydrates

Two polymers bound to N,N-diisopropylamino-1,3,2-oxathiaphospholane were reacted with unprotected carbohydrates and nucleosides in the presence of 1H-tetrazole, followed by oxidation with tert-butyl hydroperoxide or sulfurization with Beaucage's reagent. The 1,3,2-oxathiaphospholane ring-opening with 3-hydroxypropionitrile, followed by treatment with DBU, afforded the corresponding monophosphate and monothiophosphate derivatives, respectively, through the elimination of polymer-bound ethylene episulfide. Reactions using this strategy offer the advantages of high regioselectivity, monosubstitution, and facile isolation and recovery of products.     

Synthesis of methyl esters of 5-amino-4-(substituted amino)-2-methylthio-7H-pyrrolo[2,3d]-pyrimidine-6-carboxylic acids

The optimum route for the synthesis of methyl esters of N-[(4-substituted amino)-5-cyano-2-methylthiopyrimidin-6-yl]amino acids (which are starting materials for preparing the methyl esters of the corresponding 5-amino-4-(substituted amino)pyrrolo[2,3-d]pyrimidine-6-carboxylic acids) is via subsequent reactions of 4,6-dichloro-2-methylthiopyrimidine-5-carbonitrile with amines and methyl glycinate. In some examples, the reaction of methyl N-(4-chloro-2-methylthio-6-pyrimidinyl)aminoacetate with amines occurs to give the corresponding acid amides. The previously unknown synthesized derivatives of pyrimidin-6-yl amino acids and 4,5-diaminopyrrolo[2,3-d]pyrimidine- 6-carboxylic acids possess fungicidal properties.Vilnius University, Vilnius 2006, Lithuania. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 7, pp. 955–961, July, 2000.     

Polymer-supported O-alkylisoureas: useful reagents for the O-alkylation of carboxylic acids

Polymer-supported O-alkylisoureas were prepared by reaction of an alcohol with a polymer-supported carbodiimide under copper(II) catalysis. These reagents were used to transform carboxylic acids into the corresponding methyl, benzyl, allyl, and p-nitrobenzyl esters in a highly chemoselective manner in high yields and in very high purity after simple resin filtration and solvent evaporation. The reactions could be carried out using both conventional or microwave heating, with reaction times as short as 3-5 min in the latter case, without compromising yield, purity, or chemoselectivity. Unfortunately, the corresponding solid-supported tert-butyl isoureas could not be prepared.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. X. synthesis of 5-substituted ethyl or methyl 4-isoxazolecarboxylates and methyl 4-(2,2-dimethyl-1-oxopropyl)-5-isoxazolecarboxylate

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with hydroxylamine hydrochloride in methanol solution afforded in high yields the relative esters of 5-substituted 4-isoxazolecarboxylic acids II . These esters were hydrolyzed generally with concentrated hydrochloric acid-acetic acid mixtures to the corresponding carboxylic acids in satisfactory yields. Ethyl or methyl esters II isomerized with sodium ethoxide or methoxide, respectively, to the corresponding esters or hemiesters of 2-cyano-3-oxoalkanoic acids generally in excellent to satisfactory yields. Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate with hydroxylamine hydrochloride afforded in moderate yield methyl 4-(2,2-dimethyl-1-oxopropyl)-5-isoxazolecarboxylate, which was converted by acid hydrolysis as above to 4-t-butyl-4-hydroxyfuro[3,4-d]isoxazol-6-(4H)-one.     

Isomerization of S-2-hydroxyalkyl esters of phosphorus acids

Conclusions Based on the³¹P NMR spectral data, the isomerization of the S-2-hydroxyalkyl esters of thiophosphoric and thiophosphonic acids to the corresponding 2-mercaptoalkyl esters of phosphoric and phosphonic acids proceeds with the formation of stable intermediate compounds, which, in all probability, contain the 1,3,2-thiaoxaphospholane ring. The 2-mercaptoalkyl esters of phosphorus acids decompose to either the dialkylphosphoric or phosphonic acid and alkylene sulfide. Compounds of the 1,3,2-thiaoxaphospholane series are not formed during the decomposition.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2142–2144, September, 1978.     

Synthesis of nucleoside boranophosphoramidate prodrugs conjugated with amino acids

[structure: see text] Nucleoside boranophosphates and nucleoside amino acid phosphoramidates have been shown to be potent antiviral and anticancer agents with the potential to act as nucleoside prodrugs. A combination of these two types of compounds results in a boranophosphoramidate linkage between the nucleoside and amino acid. This new class of potential prodrugs is expected to possess advantages conferred by both types of parent compounds. Two approaches, specifically the H-phosphonate and oxathiaphospholane approaches, are described here to synthesize nucleoside boranophosphoramidate prodrugs conjugated with amino acids. The H-phosphonate approach involves a key intermediate, silylated nucleoside amino acid phosphoramidite 6, prepared from a series of reactions starting from nucleoside H-phosphonate in the presence of condensing reagent DPCP. Due to the lengthy procedure and the difficulties in removing DPCP from the final products, we switched to the oxathiaphospholane approach in which the DBU-assisted oxathiaphospholane ring-opening process constituted a key step for the generation of nucleoside amino acid boranophosphoramidates 24. We demonstrate that this key step did not cause any measurable C-racemization of boranophosphorylated amino acids 22. Diastereomers of compounds 24a-f were separated by RP-HPLC. An "adjacent"-type mechanism is proposed to explain the diastereomer ratio in the final products obtained via the oxathiaphospholane approach. A tentative assignment of configuration for the diastereomers was carried out based on the mechanism, molecular modeling, and (1)H NMR. Conclusively, the oxathiaphospholane methodology proved to be more facile and efficient than H-phosphonate chemistry in the preparation of the nucleoside amino acid boranophosphoramidate analogues that are promising as a new type of antiviral prodrugs.     

Convenient synthesis of nucleoside borane diphosphate analogues: deoxy- and ribonucleoside 5'-P(alpha)-boranodiphosphates

The nucleoside boranophosphates, having one of the nonbridging phosphate oxygens substituted with a borane (BH(3)) group, have shown potential therapeutical applications as aptamers, antisense agents, and antiviral prodrugs. An oxathiaphospholane approach, which does not require exocyclic amine protection of the nucleobase, has been successfully developed to efficiently synthesize 5'-P(alpha)-boranodiphosphates of 2'-deoxythymidine, adenosine, guanosine, and uridine. The approach involves a key intermediate, the borane complex of nucleoside 5'-O-1,3,2-oxathiaphospholane 16, that undergoes a ring-opening reaction catalyzed by 1,4-diazabicyclo[5.4.0]-undec-7-ene to form the protected nucleoside 5'-P(alpha)-boranodiphosphate 18. Treatment of 18 with ammonium hydroxide yielded diastereoisomeric mixtures of nucleoside 5'-P(alpha)-boranodiphosphates 5. This oxathiaphospholane approach ensures the availability of nucleoside 5'-P(alpha)-boranodiphosphate analogues needed for antiviral drug research.     

New approach to preparation of N-acylphosphoramido(thio)(seleno)ates

N-[2-(X)-1,3,2-Oxathiaphospholane] derivatives (X = S, Se, O) of carboxamides were prepared and their DBU-assisted reaction with alcohols led to the corresponding O-alkyl-N-acylphosphoramido(thio)(seleno)ates. Their structures were confirmed by MS analysis and ¹H and ³¹P NMR spectroscopy. Independently N-acylphosphoramidoselenoates were converted to N-acylphosphoramidates by treatment with tert-butylperoxytrimethylsilane. The oxathiaphospholane approach was also applied to the synthesis of derivatives having N-prolylphosphoramido(thio)(seleno)ate linkages on the 5′-OH group of AMP.     

3,4-dihydro-6,7-dimethoxy-4-methyl-3-oxo-qinoxaline-2-carbonyl azide as a highly sensitive fluorescence derivatization reagent for primary,secondary and tertiary alcohols in high-performance liquid chromatography

3,4-Dhydro-6,7-dimethoxy-4-methyl-3-oxo-quinoxaline-2-carbonyl azide is a highly senstive fluorescence derivatization reagent for primary, secondary and tertiary alcohols for high-performance liquid chromatography. Reaction conditions are optimized with benzyl alcohol, n-hexanol, cyclohexanol and 2-methyl-2-butanol. The reagent reacts with the alcohols in benzene to produce the corresponding fluorescent carbamic acid esters, which can be separated on a reversed-phase column YMC Pack C₈ with aqueous methanol as eluent. the detection limits for the alchols are 2–5 fmol per 10-μl njection. The reagent also reacts with hydroxysteroids with primary, secondary and/or tertiary alcoholic group(s) to form fluorescent derivatives. Hydroxycarboxylic acids and phenols do not give any chromatographic peaks.     

Molecular diversity via amino acid derived alpha-amino nitriles: synthesis of spirocyclic 2,6-dioxopiperazine derivatives

[reaction: see text] Chiral spirocyclic 2,6-dioxopiperazines were synthesized from amino acid derived alpha-quaternary alpha-amino nitriles via H(2)SO(4)-promoted cyano hydration, followed by base-mediated cyclization and N-alkylation. This methodology, requiring the previous preparation of the amino nitrile by a modified Strecker reaction, was applied to Phe, Trp, Pro, Asp, Glu, and Ser derivatives. In the case of the Trp-derived amino nitrile the major product of the treatment with H(2)SO(4) was not the expected carboxamide, but a new tetracyclic indoline derivative containing the novel heterocyclic system hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indole, as a result of a domino tautomerization. The treatment of this indoline derivative with refluxing 1 N HCl led to a Trp-derived 2,6-dioxopiperazine. The 2,6-dioxopiperazine ring opened under the reaction conditions of methyl ester saponification, giving N-(carboxyalkyl)amino acid derivatives. Therefore, the synthesis of 2,6-dioxopiperazines containing free carboxylic acids from the respective methyl esters required transesterification to benzyl esters, followed by hydrogenolysis.     

Transformations of 2-(2-thiocyanatoalkoxy)-1,3,2-dioxaphospholanes

In contrast to the case of 2-(2-haloalkoxy)-1,3,2-dioxaphospholanes, the coordination of the phosphorus atom in analogous esters with an SCN group is altered under mild conditions involving the sulfur atom with formation of spirophosphoranes with a 1,3,2-oxathiaphospholane fragment.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 950–951, April, 1991.     

Selective Alkaline Protease Catalyzed Hydrolysis of Peptide Esters

Procedures for preparing C-terminal free peptides from hydrolysis of its corresponding methyl or benzyl esters catalyzed by alkaline protease has been developed. N-protected peptides having side-chain ester protecting groups or successive hydrophobic amino acid residues in its sequence are hydrolyzed selectively at C-terminal only and leave other bonds (β and γ- ester or peptide bonds) intact. Compounds which cause a side reaction in base mediated saponification could be hydrolyzed safely by this procedure. Products of this hydrolysis are useful intermediates for fragments coupling in the solid phase peptide synthesis.     

Phosphonic-Acid Analogues of the N-Acetyl-2-deoxyneiiraniinic Acids: Synthesis and Inhibition of Vibrio cholerae Sialidase

The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N-acetyl-2-deoxyneuraminic acids 5 and 6 . Thus, hydrogenation and benzylation of methyl N-acetyl-2,3-didehydro-2-deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O-benzylated benzyl and methyl esters 9 and 10 , the partially O-benzylated benzyl and methyl esters 11 and 12 , and the fully O-and N-benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15 . Oxidative decarboxylation of 15 with Pb(OAc)₄ gave a 1:9 mixture of the α-and β-D-glycero-D-galacto-acetates 16 and 17 . Phosphonoylation of 17 with P(OMe)₃ and Me₃SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19 , which were deprotected to give the (4-acetamido-2,4-dideoxy-D-glycero-α-and β-D-galacto-octopyranosyl)phosphonic acids 3 and 4 , respectively. The acid 6 was obtained by epimerization of the tert-butyl ester 23 with lithium N-cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (K_i 5.5 10_-5 M) and 4 (K_i 2.3.10^?4 M ) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N-acetyl-2-deoxyneuraminic acids 5 (K_i 2.3 10^?3 M ) and 6 . Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5 , possessing an equatorial COOH group is an inhibitor.