Recent Synthesis of Nucleoside Phosphonate Analogs Using Olefin Cross-metathesis.

Nucleotide analogs known as acyclic and cyclic nucleoside phosphonates (ANPs and CNPs, respectively) have a variety of biological properties, including antibacterial, antiviral, antiparasitic, antineoplastic, and immunomodulatory. A strong reaction that has emerged in the last several decades has fundamentally changed our knowledge of the chemistry of nucleoside phosphonates. In particular, Olefin cross-metathesis (CM) has been a potent and practical synthesis route to produce functionalized olefins from essential alkene precursors. This review describes recent synthesis examples of ANPs and CNPs analogs using the Ru-catalyzed olefin cross-metathesis reactions. Olefin cross-metathesis reactions are performed in the olefinic parts of nucleoside and phosphonate produced by Grubbs, Hoveyda-Grubbs, and Nolan. This review presents a synthetic overview of a few chosen nucleosides with biological significance. Their biological activity results are briefly discussed.

Recent advances in the synthesis of 4'-truncated nucleoside phosphonic acid analogues.

The synthesis of five series of 4'-truncated nucleoside phosphonic acid analogues is discussed in this review: (1) 4'-truncated furanose nucleoside phosphonic acid analogues; (2) 4'-truncated pyrrolidine nucleoside phosphonic acid analogues; (3) 4'-truncated carbocyclic nucleoside phosphonic acid analogues; (4) 4'-truncated isoxazole nucleoside phosphonic acid analogues; (5) 4'-truncated miscellaneous nucleoside phosphonic acid analogues. Five different ways are used to make the phosphonate moiety: (i) Michaelis-Arbuzov reaction of RX (X = Br, I, OTf) with trialkyl phosphate; (ii) Lewis acid catalyzed Michaelis-Arbuzov reaction of glycoside with trialkyl phosphite; (iii) nucleophilic addition of a dialkyl phosphite to a carbonyl group; (iv) direct coupling reaction with amino alkyl phosphonate; (v) de novo synthesis of phosphonated-isoxazole and 1,3-dioxolane heterocycles from phosphonated starting materials. Their biological activity results are briefly discussed.

Recent Advances in the Synthesis of 5'-deoxynucleoside Phosphonate Analogs.

The present review focuses on the synthesis of cyclic 5'-deoxynucleoside phosphonate analogs. The formation of various phosphonate alkyl moieties is accomplished through (i) Wittig (or HWE) type condensation to the nucleoside aldehyde moiety; (ii) nucleophilic displacement reaction using phosphonate anion or Lewis acid; (iii) Arbuzov reaction; (iv) olefin cross-metathesis between vinyl phosphonates and vinylated nucleosides; and (v) radical reaction and Pd catalyzed alkyne. For the coupling of nucleobases with cyclic moieties, the Mitsunobu reaction and Sonogashira-type cross-coupling are usually applied. For the coupling of furanose moieties with nucleobases, Vorbrüggentype condensation is generally applied. Addition reactions mediated by selenium ions are mainly applied for the coupling of carbocyclic moieties. Their biological activity results have been summarized.

Chemical Synthesis of Acyclic Nucleoside Phosphonate Analogs Linked with Cyclic Systems between the Phosphonate and the Base Moieties.

The syntheses of acyclic nucleoside phosphonate (ANP) analogs linked with cyclic systems are described in the present review. The purpose of the review is to report the methodology of ANP analogs and to give an idea on the synthesis of a therapeutic structural feature of such analogs. The cyclopropane systems were mainly prepared by diazomethane cyclopropanation catalyzed by Pd(OAc)2, intramolecular alkylation, Kulinkovich cyclopropanation, and use of difluorocyclopropane, and so forth. The preparation of methylenecyclopropane system was made by diazoacetate cyclopropanation catalyzed by Rhodium followed by addition-elimination reactions. For the preparation of a variety of tethered 1,2,3-triazole systems, 1,3-dipolar cycloaddition between azidealkylphosphonates and propargylated nucleobases was mainly applied. The formation of various phosphonate moieties was achieved via phosphonylation of alkoxide, cross-coupling between BrZnCF2P (O)(OEt)2 with iodoalkens catalyzed by CuBr, Michaelis-Arbuzov reaction with phosphite, and Rh(II)-catalyzed O-H insertion, and so forth.

Recent advances in the synthesis of cyclic 5'-nornucleoside phosphonate analogues.

Nucleoside phosphonates are isosteric, isopolar, and isoelectronic with phosphates. Nucleoside phosphonates can undergo enzymatic phosphorylation for conversion into the corresponding diphosphoryl phosphonates, which are naturally occurring nucleoside triphosphate analogues. The biological activity, which is mostly antiviral and antitumor but sometimes is as specific enzyme inhibitor, is briefly presented to help discover compounds with increased activity over natural nucleosides to provide structure-activity data. This review focuses on the synthesis of three types of cyclic 5'-nucleoside phosphonate analogues: (1) furanose 5'-nornucleoside phosphonates, (2) carbocyclic 5'-nornucleoside phosphonates, and (3) apiose 5'-nornucleoside phosphonates.

Synthesis and Antiviral Activity Evaluation of 2',5',5'-Trifluoro-Apiosyl Nucleoside Phosphonic Acid Analogs.

Racemic synthesis of novel 2',5',5'-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity.

Synthesis and Potent Anti-HCMV Activity of 2',5',5'-trifluoro-3'-hydroxy-apiosyl Nucleoside Phosphonic Acid Analogues.

As antiviral nucleosides containing a fluorine atom at 2'-position are endowed with increased stabilization of glycosyl bond, it was of interest to investigate the influence of three fluorine atoms at 2'- and 5'-positions of apiosyl nucleoside phosphonate analogues. Various pyrimidine and purine 2',5',5'-trifluoro-3'-hydroxy-apiose nucleoside phosphonic acid analogues were synthesized from 1,3-dihydroxyacetone. Electrophilic fluorination of lactone was performed using N-fluorodibenzenesulfonimide. Difluorophosphonation was performed by direct displacement of triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield nucleoside phosphonate analogues. Deprotection of diethyl phosphonates provided the final phosphonic acid sodium salts. The synthesized nucleoside analogues were subjected to antiviral screening against various viruses.

Synthesis and Biological Evaluation of 9-Deazaadenine 5'-Deoxy-6',6'-Difluoro-Carbocyclic C-Nucleoside Phosphonic Acid Derivatives.

The first synthetic route to 5'-deoxy-6',6'-difluoro-carbocyclic C-nucleoside [9-deazaadenosine, (pyrrolo[3,2-d]pyrimidine)] phosphonic acids from commercially available epichlorohydrin 5 was described. The key C-C bond formation from cyclopentanone to base precursor was performed using the Knoevenagel-type condensation. Synthesized C-nucleoside phosphonic acids were tested for anti-HIV and anti-leukemic activities. They showed moderate cytotoxicity-derived anti-HIV and anti-leukemic activities.

Synthesis of Novel 4'-Trifluoromethyl-5'-Norcarbocyclic C-Nucleoside Phosphonic Acids as Potent Anti-Leukemic Agents.

The syntheses of novel C-nucleoside phosphonic acids as potential antiviral agents are described. The sugar moiety that served as the nucleoside skeleton was produced starting from commercially available 1,3-dihydroxy cyclopentane. The key C-C bond formation from sugar to base precursor was performed using the Knoevenagel-type condensation. The synthesized compounds exhibited anti-HIV activity and cytotoxicity. Also, the synthesized compounds were screened in vitro for tumor growth inhibitory activity against mouse leukemia cell lines (L-1210, P-815).

Synthesis and potent anti-leukemic activity of novel 5'-deoxycarbocyclic C-nucleoside phosphonic acids.

The first synthetic route to 5'-deoxycarbocyclic C-nucleoside [9-deazaadenosine, (pyrrolo[3,2-d]pyrimidine)] phosphonic acids from commercially available 1,4-dihydroxy-2-butene was described. The key C-C bond formation from cyclopentanone to base precursor was performed using Knoevenagel-type condensation. Synthesized C-nucleoside phosphonic acids were tested for anti-HIV activity as well as anti-leukemic activity. They showed moderate cytotoxicity derived anti-HIV activity and anti-leukemic activity.

Synthesis and Anti-HIV Activity of Novel 2'-Deoxy-2'-ß-Fluoro-Threosyl Nucleoside Phosphonic Acid Analogues.

Novel 2'-deoxy-2'-ß-fluoro-threose purine phosphonic acid analogues were designed and racemically synthesized from 2-propanone-1,3-diacetate. Condensation successfully proceeded from a glycosyl donor 9 under Vorbrüggen conditions. Cross-metathesis of vinyl analogues 13 and 23 with diethyl vinylphosphonate yielded the desired nucleoside phosphonate analogues 14 and 24, respectively. Ammonolysis and hydrolysis of phosphonates yielded the nucleoside phosphonic acid analogues 16, 19, 26, and 29. The synthesized nucleoside analogues were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Adenine analogue 18 exhibited weak in vitro activities against human immunodeficiency virus (HIV)-1.

Synthesis and Anti-HIV Activity of Novel 4'-Trifluoromethylated 5'-Deoxycarbocyclic Nucleoside Phosphonic Acids.

Efficient synthetic route to novel 4'-trifluoromethylated 5'-deoxycarbocyclic nucleoside phosphonic acids was described from α-trifluoromethyl-α,ß-unsaturated ester. Coupling of purine nucleosidic bases with cyclopentanol using a Mitsunobu reaction gave the nucleoside intermediates which were further phosphonated and hydrolyzed to reach desired nucleoside analogs. Synthesized nucleoside analogs were tested for anti-HIV activity as well as cytotoxicity. Adenine analog 22 shows significant anti-HIV activity (EC50 = 8.3 µM) up to 100 µM.

The first synthesis of 4'-branched 5'-deoxycarbocyclic 9-deazaadenosine and phosphonic acids as antiviral agents.

The first synthetic route to 4'-trifluoromethylated 5'-deoxycarbocyclic-9-deazaadenosine analog and its phosphonic acid derivatives was described from α-trifluoromethyl-α,ß-unsaturated ester. The C-C bond connection between cyclopentane and base moiety was accomplished using Knoevenagel type condensation from ketone derivative 11. Synthesized nucleoside and phosphonic acid analogs were tested for anti-HIV activity as well as cytotoxicity.

Synthesis of novel 4'α-trifluoromethyl-2'ß-C-methyl-carbodine analogs as anti-hepatitis C virus agents.

Novel 4 'α-trifluoromethyl-2 'ß-methyl carbocyclic nucleoside analogs have been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell cultures. Construction of cyclopentene intermediate 10a was achieved via sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis starting from the α-trifluoromethyl-α,ß-unsaturated ester 5. Stereoselective dihydroxylation and desilylation yielded the target carbodine analogs. The synthesized nucleoside analogs mentioned above (18 and 19) were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line (LucNeo#2). However, the synthesized nucleosides showed neither significant antiviral activity nor toxicity up to 50 µM.

Synthesis of novel 2',3'-difluorinated 5'-deoxythreosyl phosphonic acid nucleosides as antiviral agents.

A novel route for the synthesis of 2',3'-difluorinated 5'-deoxythreosyl phosphonic acid nucleosides from glyceraldehyde using the Horner-Emmons reaction in the presence of triethyl α-fluorophosphonoacetate is described. The second fluorination at the 2'-position was an electrophilic reaction performed using N-fluorodibenzenesulfonimide. Glycosylation reactions between the nucleosidic bases and glycosyl donor 9 generated nucleosides that were further phosphonated and hydrolyzed to produce the desired nucleoside analogues. The synthesized nucleoside analogues 13, 16, 20, and 23 were tested for anti- human immunodeficiency virus (HIV) activity as well as cytotoxicity. Adenine derivative 16 showed significant anti-HIV activity up to 100 µM.

Synthesis and antiretroviral activity of novel 4'-fluoro-5'-deoxyphosphonic acid carbocyclic nucleoside analogs.

Novel 5'-deoxycarbocyclic purine phosphonic acid analogs with the 4'-electropositive moiety, fluorine were designed, and synthesized from glyceraldehyde. The cyclopentenol intermediate, 9, was successfully synthesized by the ring-closing metathesis of divinyl 8. The condensation reaction of cyclopentanol 15 with purine bases under Mitsunobu conditions successfully afforded the desired phosphonate analogs. The synthesized nucleoside phosphonic acid analogs, 19, 22, 26, and 29, were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Guanine phosphonic acid analog 29 showed significant anti-HIV activity (EC50 = 10.3 µM).

Synthesis and antiviral evaluation of novel 2',2'-difluoro 5'-norcarbocyclic phosphonic acid nucleosides as antiviral agents.

A very efficient synthetic route to novel 2',2'-difluoro 5'-norcarbocyclic phosphonic acid nucleosides from but-3-en-1-ol 5 is described. The discovery of 2'-fluorinated furanose nucleoside 1 as a potent anti-HIV-1 agent has led to the synthesis and biological evaluation of 2'-modified 5'-norversions of the carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 18, 19, 23a, 23b, and 24 were tested for anti-HIV activity as well as cytotoxicity. Adenine analogue 19 shows significant anti-HIV-1 activity (EC(50) = 13 µM).

Synthesis of novel 2'-fluoro-3'-hydroxymethyl-5'-deoxythreosyl phosphonic acid nucleoside analogues as antiviral agents.

A series of purine 5'-deoxyphosphonate analogues were designed and synthesized to mimic naturally occurring purine monophosphate from 1,3-dihydroxyacetone as starting material. The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 µM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 2',3'-modified 5'-deoxyversions of the threosyl phosphonate nucleosides. The synthesized 2'-fluoro-3'-hydroxymethyl 5'-deoxythreosyl phosphonic acid nucleoside analogues 14, 18, 23, and 27 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 18 exhibits weak in vitro anti-HIV-1 activity (EC50 = 19.2 µM).

Efficient electrophilic fluorination for the synthesis of novel 2'-fluoro-3'-methyl-5'-deoxyphosphonic acid apiosyl nucleoside analogues.

Novel 5'-deoxyapiosyl purine phosphonic acid analogues with a 2'-electropositive moiety, such as, a fluorine atom were designed and synthesized from commercially available hydroxylacetone. Condensation of a glycosyl donor 10 with purines under Vorbruggen conditions and cross-metathesis give the desired nucleoside phosphonic acid analogues 14, 17, 21, and 24. The synthesized nucleoside analogues were subjected to antiviral screening against HIV-1, and the adenine analogue 17 exhibited weak in vitro anti-HIV-1 activity (EC50=26.6 µM).

Synthesis and evaluation of novel 6',6'-difluoro 5'-deoxycarbocyclic phosphonic acid nucleosides as antiviral agents.

The authors describe highly efficient synthetic routes for the preparation of novel 6',6'-difluoro 5'-deoxycarbocyclic phosphonic acid nucleosides from 1,4-dihydroxy-2-butene. The discovery that the 6'-fluorinated carbocyclic nucleoside (2, EC50 = 0.16 µM) is a potent anti-HSV-1 agent led to the syntheses and biological evaluations of 6'-modified 5'-deoxyversions of carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 15, 18, 22, and 25 were tested for anti-HIV activity and for cytotoxicity. However, none of them showed significant anti-HIV-1 activity or cytotoxicity at concentrations up to 100 µM.