Synthesis of 9-[(2-hydroxy-1-phosphonylethoxy)ethyl]guanine, 1-[(2-hydroxy-1-phosphonylethoxy)ethyl]cytosine and 9-[(2-hydroxy-1-phosphonylethoxy)ethyl] adenine

The acyclic nucleoside phosphonate analogues, 9-[(2-hydroxy-1-phosphonylethoxy)ethyl]guanine 6 , 1-[(2-hydroxy-1-phosphonylethoxy)ethyl]cytosine 7 and 9-[(2-hydroxy-1-phosphonylethoxy)ethyl]adenine 8 , have been prepared by the coupling of a tosylate of the phosphonate side chain 12 with a purine or pyrimidine base followed by deprotection of the blocking groups.     

A New Class of Nucleoside Analogues. Synthesis of N. -Pyrimidinyl-and N9-Purinyl-4′-hydrqxy-3-(Hydsoxymethyl)butanes1 # 2

Interest in non-glycosidic derivatives of the nucleo-bases uracil, theymine, cytosine, adenine and guanine stems from their status as nucleoside analogues. It is noteworty in this connection that the anti-biotics aristeromycin³ and eritadenine⁴ consist of an adenine moiety linked, via N₉ -, to a cyclopentyl or a butiric acid derivative, respectively, in place of the conventional nucleoside sugars. A non-glycoaidic 5-fluorouracil derivative⁵ has been recently reported to be clinically effective in the treatment of Gastrointestinal cancer. In this communication the ficile synthesis of 4-hydroxy-3-(hydroxymethyl)butyl derivatives of the nucleobases (1) is described. These nucleoside analogues are characterized by the special feature that they incorporate two hydroxyl functions in a relationship corresponding to the 3′-and 5′-hydroxy groups of the 2-deodyribose Doiety. Phosphorylationj of the hydroxyl groups or their linkage via phosphodiester of the hydroxyl groups or their linkage via phosphodiester bridges should give nucleotide analogues or novel nucleic acid models. The latter molecular systems constitute a new class of potential anti-mitotic or anti-viral agents. One principle synthetic approach to compounds of general structure 1 was visualized via the intermediacy of 2-(hydroxymethyl) - 4-aminobutanol (2, ReH) which, acting as a common precursor, could be elaborated to the desired pyrimidine or purine derivative, via its amine function. The synthesis of amine 2 was achieved according to the reaction sequence described in Scheme I. Diethyl malonate was coupled with 2,2-dimethoxybromoethane, in presence of sodium ethoxide (EthoH, 170°, autoclave). The resulting diester (3) was reduced with LialH₄ to the corresponding diol (4), which was benzylated (NaH, C₆H₅CH₂Cl) to 5. When 5 was refluxed with NH₂OH.HCl in methanol for 30 min., a mixture of oximes 6a,b (syn- and anti-) and nitrile 7 was isolated. The latter mixture could be directly reduced with LiAlH₄ to amine 2,⁶ in high yield.     

A novel method for the synthesis of 9-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]guanine - a potential antiviral agent

9-[[2-Hydroxy-1-(aminomethyl)ethoxy]methyl]guanine (1a), an amino analogue of 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine (I) which is a potent antiviral agent, has been synthesized $\text{via}$ a multistep-synthesis.     

9-(2-Aryloxyethyl) Derivatives of Adenine - a New Class of Non-nucleosidic Antiviral Agents

New 9-(aryloxyalkyl) derivatives of adenine have been prepared by alkylation of adenine with tosylates, bromides, and -chloro ethers containing terminal aromatic fragments in anhydrous DMF in the presence of potassium carbonate. The compounds of the 9-(2-phenoxyethyl)adenine series appear to be highly reactive against cytomegaloviruses of mankind in vitro, while derivatives of 9-(2-benzyloxyethyl)adenine demonstrate anti-HIV-1 activity. Compounds with shorter or longer chains, and also compounds which do not have aromatic fragments at the ends of the chains, do not possess antiviral activity.     

Synthesis of Enantiomerically Pure Bis(hydroxymethyl)-Branched Cyclohexenyl and Cyclohexyl Purines as Potential Inhibitors of HIV

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-bis(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium aluminum hydride to give the racemic diol (+/-)-7. Resolution of (+/-)-7 via a transesterification process using lipase from Pseudomonas sp. (SAM-II) gave both diols in enantiomerically pure form. The enantiomerically pure diol (S,S)-7was benzoylated and epoxidized to give the epoxide 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene followed by dilute hydrochloric acid gave (1R,4S,5R)-4,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave (1R,4S,5R)-1-acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11). (1R,4S,5R)-1-Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11) was converted to the adenine derivative 12 and guanine derivative 13 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chloropurine, respectively. Hydrogenation of 12 and 13 gave the correspondning saturated adenine derivative 14 and guanine derivative 15. (1R,4S,5R)-4,5-Bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 17 via coupling with 6-chloropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but were found to be inactive. Further biological testings are underway.     

Complexing properties of N-[1,1-bis(hydroxymethyl)ethyl]-and N-[tris(hydroxymethyl)methyl]-β-alanine

Russian Chemical Bulletin - Protolytic and complexing properties of N-[1,1-bis(hydroxymethyl)ethyl]- and N-[tris-(hydroxymethyl)methyl]-β-alanine were estimated using the potentiometry. Values...     

An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis of (+)-4'-deoxycarbapentostatin nucleoside.     

The aminomethylation of adenine,cytosine and guanine

Aminomethylated derivatives of adenine, cytosine and guanine have been isolated and characterized for the first time. These results are important because of the potential for similar adducts being formed transiently between nucleosides and nucleotides, and endogenous aldehydes and amines in vivo, and of the potential use of similar adducts for drug delivery. Mono-alkylated products obtained were from the reaction of adenine with one equivalent of aminomethylating agent derived from amines exhibiting lower basicity (e.g., morpholine and N-methylpiperazine); bis-alkylated products were obtained with agents derived from more basic amines regardless of the stoichiometry. On the other hand, only bis-alkylated products were obtained from the reaction of cytosine or guanine with the aminomethylating agent regardless of the basicity of the secondary amine used or the stoichiometry of the reaction. The mono-alkylated adenine products were alkylated on N-9 while the bis-alkylated cytosine products were alkylated on N-9 and N⁴ and the bis-alkylated adenine products were alkylated on N-9 and N⁶. The adenine and cytosine aminomethyl adducts hydrolyzed rapidly in dilute aqueous solution.     

Synthesis of hydroxymethyl branched [3.2.0]bicyclic nucleosides using a regioselective oxetane ring-formation

Two [3.2.0]bicyclic nucleosides, 35 and 34, with one and two hydroxymethyl substituents, respectively, have been efficiently synthesized. A protected (3'-C-vinyl-beta-D-allofuranosyl)thymine derivative 28 was easily prepared from diacetone-D-glucose and the thymine moiety was protected with a BOM-group. After the introduction of a leaving group in the 2'-position, the subsequent nucleoside 31 was used as the substrate for a stereoselective dihydroxylation and a regioselective oxetane ring-formation to give after deprotection the bicyclic nucleoside 34. The surprisingly efficient formation of an oxetane was first discovered by serendipity on a corresponding methylfuranoside derivative. The allo-configured bicyclic nucleoside 34 was easily shortened to a ribo-configured analogue 35 by a diol-cleaving reaction and subsequent reduction. Both 34 and 35 are conformationally restricted in the important intermediate 04'-endo conformation.     

A comparative picosecond transient infrared study of 1-methylcytosine and 5'-dCMP that sheds further light on the excited states of cytosine derivatives

The role of N1-substitution in controlling the deactivation processes in photoexcited cytosine derivatives has been explored using picosecond time-resolved IR spectroscopy. The simplest N1-substituted derivative, 1-methylcytosine, exhibits relaxation dynamics similar to the cytosine nucleobase and distinct from the biologically relevant nucleotide and nucleoside analogues, which have longer-lived excited-state intermediates. It is suggested that this is the case because the sugar group either facilitates access to the long-lived (1)n(O)π* state or retards its crossover to the ground state.     

Improved synthesis of oligonucleotides with an allylic backbone. Oligonucleotides containing acyclic, achiral nucleoside analogues: N-1 or N-9-[3-hydroxy-2-(hydroxymethyl)prop-1-enyl]nucleobases

An improved phosphoramidite method is described to prepare oligonucleotides modified with the acyclic, achiral monomers 1. Examination of dimers, prepared on solid support or in solution, showed that phosphortriester dimers containing the allylic unit 1 were unstable towards bases, whereas phosphordiester dimers were stable. Phosphordiester dimers were obtained by replacing cyanoethyl phosphoramidites 2 with phosphoramidites 3, which gave phosphordiesters directly upon oxidation. The phosphordiester dimers were found to be stable towards capping and oxidation, but were somewhat labile towards acids. By reducing the contact time to acids during detritylation it was possible to prepare oligonucleotides containing 4 or 8 modified A, G or T units. The modified oligonucleotides hybridized to complementary DNA and RNA, although with reduced affinity (DeltaT(m) per modification -1 to -5 degrees C).     

(R)-9-[2-(Hydroxyphosphinylmethoxy)propyl]adenine as the precursor molecule for antivirals

The biological importance and practical significance of phosphonates have been a major driving force for antiviral research in the past two decades. We describe in this Letter the potential of the H-phosphinate derivative (R)-9-[2-(hydroxyphosphinylmethoxy)propyl]adenine as the versatile synthetic intermediate in the preparation of N-alkylphosphonamidate and alkylphosphonate series.     

Nucleosides. CXXXV. Synthesis of some 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purines and their biological activities

Seven purine nucleosides containing the 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl moiety were synthesized and tested for their antitumor activity. Direct condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (1) with N6-benzoyladenine in CH2Cl2 followed by saponification of the product afforded the adenine nucleoside (I, 2'-F-ara-A). Deamination of I with NaNO2 in HOAc gave the hypoxanthine analogue (II, 2'-F-ara-H). The 6-thiopurine nucleoside (III, 2'-F-ara-6MP) was prepared by condensation of 1 with 6-chloropurine by the mercury procedure followed by thiourea treatment and saponification of the product. Methylation of III gave the 6-SCH3 analogue (IV). Raney Ni desulfurization of III afforded the unsubstituted purine nucleoside (V, 2'-F-ara-P). Condensation of 1 with 2-acetamido-6-chloropurine by the silyl procedure afforded the protected 2-acetamido-6-chloropurine nucleoside which served as the precursor for both the guanine and 6-thioguanine nucleosides (VI, 2'-F-ara-G and VII, 2'-F-ara-TG, respectively). Thus, alkaline hydrolysis of the precursor gave VI. Thiourea treatment prior to alkaline hydrolysis gave VII. The new nucleoside, 2'-F-ara-G (VI) is found to be selectively toxic to human T-cell leukemia CCRF-CEM.     

Methoxymethyl (MOM) group nitrogen protection of pyrimidines bearing C-6 acyclic side-chains

Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).     

Synthesis of 3-O-aryl esters of (R,S)-9-(2,3-dihydoxypropyl)adenine and its pyrimidine analogs as new potential inhibitors ofS-adenosyl-L-homocysteine hydrolase

With the aim of searching for new antiviral agents of the acyclonucleoside type, 3-O-arly esters of (R,S)-9-(2,3-dihydroxypropyl)adenine adenine and its pyrimidine analogs have been synthesized. Alkylation of adenine and cytosine by aryl glycidyl ethers in the presence of potassium carbonate affords 46–76% yields of the corresponding N⁹- and N¹-substituted derivatives. The interaction of aryl glycidyl ethers with trimethylsilyl derivatives of uracil and thymine also results in 41–57% yields of N¹-monosubstituted products with identical acyclic chain structure.Scientific-Research Institute of Pharmacology at the Volgograd Medical Academy, Volgograd 400066, Russia.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 82–86, January, 1999.     

Synthesis of 1,4-disubstituted mono and bis-triazolocarbo-acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine by Cu(I)-catalyzed click azide-alkyne cycloaddition

A series of novel mono-1,2,3-triazole and bis-1,2,3-triazole acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine was prepared via copper(I)-catalyzed 1,3-dipolar cycloaddition of N-9 propargylpurine, N-1-propargylpyrimidines/as-triazine with the azido-pseudo-sugar 4-azidobutylacetate under solvent-free microwave conditions, followed by treatment with K(2)CO(3)/MeOH, or NH(3)/MeOH. All compounds studied in this work were screened for their antiviral activities [against human rhinovirus (HRV) and hepatitis C virus (HCV)] and antibacterial activities against a series of Gram positive and negative bacteria.     

Synthesis of [2-(vinyloxy)ethyl]uracil and [2-(allyloxy)ethyl]uracil

A synthesis is reported for N¹-mono- and N¹,N³-disubstituted uracil derivatives containing a terminal carbon-carbon double bond in the side-chain. Alkylation of vinyl 2-chloroethyl ether by uracil potassium salts leads to a mixture of 1-[2-(vinyloxy)ethyl] and 1,3-di[2-(vinyloxy)ethyl] derivatives while treatment of 2,4-bis(trimethylsilyloxy)pyrimidines by vinyl 2-chloroethyl ether leads exclusively to N¹-monosubstituted products. Alkylation of cytosine by this chloroether gave 1-[2-(vinyloxy)ethyl]cytosine. The synthesis of 1-[2-(allyloxy)ethyl]uracil derivatives was carried out by treatment of uracil potassium salts by 1-(allyloxy)-2-(p-toluenesulfonyloxy)ethane.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 393–397, March, 1993.     

Efficient N-arylation and N-alkenylation of the five DNA/RNA nucleobases

A general approach to N-arylation and N-alkenylation of all five DNA/RNA nucleobases at the nitrogen atom normally attached to the sugar moiety in DNA or RNA has been developed. Various protected or masked nucleobases engaged readily in the copper-mediated Chan-Lam-Evans-modified Ullmann condensation with a range of different boronic acids at room temperature and were subsequently converted to the corresponding deprotected or unmasked adducts. Different N(3)-protecting groups were examined in the case of thymine, where the benzoyl group afforded the highest yields. A 4-alkylthio-substituted pyrimidin-2(1H)-one served as both a cytosine and a uracil precursor and was N-arylated and N-alkenylated in high yields. Adenine was efficiently and selectively N-arylated and N-alkenylated at the N(9) position by employing a bis-Boc-protected adenine derivative, while a bis-Boc-protected 2-amino-6-chloropurine served as guanine precursor and could also be selectively N(9)-arylated and N(9)-alkenylated.     

Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l-lyxopyranosyl]thymine

Previously different types of nucleosides with a six-membered carbohydrate moiety have been evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with a 1,4-substitution pattern like 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this nucleoside would show the (4)C(1) conformation in contrast to anhydrohexitol nucleosides (1) whose most stable conformation is (1)C(4). The key to the synthesis of 4 involves the stereoselective introduction of the hydroxymethyl group onto the C-4 carbon of the pyranose sugar. Attempts to achieve this via hydroboration/oxidation of a C-4'-exocyclic vinylic intermediate selectively yielded the undesired alpha-directed hydroxymethyl group. Therefore, we envisaged another approach in which the C-4 substituent was introduced upon treatment of 2,3-O-isopropylidene-1-O-methyl-4-O-phenoxythiocarbonyl-alpha-l-lyxopyranose with beta-tributylstannyl styrene. This allowed stereoselective beta-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/reduction (OsO(4), NaIO(4)/NaBH(4)) into the desired 4-hydroxymethyl group (20). The resulting 1-O-methyl-2,3,6-tri-O-acetyl-protected sugar was coupled with silylated thymine, using SnCl(2) as Lewis acid (22). After suitable protection, Barton deoxygenation of the 2'-hydroxyl function of the obtained ribo-nucleoside yielded the desired 2'-deoxynucleoside 4, indeed showing the expected equatorial orientation of the thymine ring ((4)C(1)).     

Syntheses,structures and properties of isonicotinamidium,thionicotinamidium, 2- and 3-(hydroxymethyl)pyridinium nitrates

New salts containing cations of selected pyridine derivatives of the composition [pyH]NO₃, where py is 2-pyridylmethanol (2-(hydroxymethyl)pyridine, 2pm), 3-pyridylmethanol (3-(hydroxymethyl) pyridine, 3pm), isonicotinamide (4-(aminocarbonyl)-pyridine, inia) and thionicotinamide (4-(aminothiocarbonyl)pyridine, tnia) were synthesised using two methods. By the first method, the above salts were obtained from reaction mixtures prepared from Fe(NO₃)₃ · 9H₂O and the appropriate pyridine derivative py in ethanol without the addition of acids. The protons required for protonation of the given pyridine derivatives are formed by the protolytic reaction of [Fe(H₂O)₆]³⁺, which acts as a cationic Brønstedt acid. These cations are present in the solid state of Fe(NO₃)₃ · 9H₂O as well as in its solutions. Under the second procedure, the salts were prepared by a direct reaction of the selected pyridine derivative py with a diluted solution of HNO₃. The first method affords crystals with lower yields but the second method produces microcrystals with higher yields. All the compounds were characterised by elemental analysis, infrared and NMR spectroscopic analyses and [3pmH]NO₃ and [2pmH]NO₃ by X-ray structure analysis also. [3pmH]NO₃ crystallises in the monoclinic and [2pmH]NO₃ in the triclinic system.