Abstract
Modified nucleosides are useful therapeutic agents being currently used as antitumor, antiviral, and antibiotic agents. Despite the fact that a significant variety of modified nucleosides display potent and selective action against cancer, viral and microbial diseases, the challenge still attracts full attention since most of them do not discriminate between normal and tumor cell and in viral infections resistant strains usually appear during the course of the treatment.
Access provided by Autonomous University of Puebla. Download chapter PDF
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Modified nucleosides are useful therapeutic agents being currently used as antitumor, antiviral, and antibiotic agents. Despite the fact that a significant variety of modified nucleosides display potent and selective action against cancer, viral and microbial diseases, the challenge still attracts full attention since most of them do not discriminate between normal and tumor cell and in viral infections resistant strains usually appear during the course of the treatment.
Synthetic acyclic and carbocyclic C-nucleosides and modified N-nucleosides have shown remarkable action against AIDS, Hepatitis, and herpes infections among others. Some of the nucleosides used as approved drugs are: acyclovir, carbovir being the treatment of choice against herpes, AZT, ddI, ddC, ddG, abacavir, which in combination with protease inhibitors are indicated in the treatment against HIV, and C-nucleoside ribavirin in the treatment against hepatitis [1, 2].
Representative examples of chemotherapeutic agents modified at the heterocyclic base, the sugar fragment, l and C-nucleosides, carbocyclic and acyclic nucleosides are depicted in Scheme 4.1.
Representative synthetically modified nucleosides
A significant number of synthetically modified nucleosides have been designed as antiretroviral drugs in the therapy of human immunodeficiency virus (HIV) infection. During retroviral infection, the viral RNA is used as template for proviral DNA synthesis, a process mediated by viral DNA polymerase better known as reverse transcriptase. Thus, the process involves the initial formation of a RNA–DNA hybrid which is then degraded by an RNAse to release the DNA strand that will be the template for the synthesis of the double stranded viral DNA, a process also catalyzed by reverse transcriptase [3].
The proposed mechanism of action of modified agents such as AZT during viral infection involves the interruption of the viral replication process that occurs between the virus and host, particularly the replication inhibition inside T cells, monocytes, and macrophages.
When the modified nucleoside is introduced into the cell, a sequential 5′-phosphorylation process mediated by kinases occurs on the furanoside ring which is subsequently incorporated into the DNA as triphosphate (Scheme 4.2).
Phosphorylation of AZT
An important collection of active nucleosides mimetics has been synthesized and classified for better understanding as follows: [4]
-
Modified N-nucleosides
-
l-nucleosides (d-isomers)
-
C-nucleosides
-
Carbocyclic nucleosides
-
Acyclic nucleosides
-
Thionucleosides
4.1 Modified N-nucleosides
A broad number of modified N-nucleosides have been developed and tested on clinical trials, some of them being highly promising. The chemical manipulations have been made at the heterocyclic base, the sugar of both. Some representative examples of chemical modifications leading to key intermediates or active nucleosides are:
4.1.1 Heterocycle Modifications
4.1.1.1 C-5 Substituted Pyrimidines
Several nucleoside analogs bearing modifications at the 5-position have been found to be active as antiviral and anticancer drugs. Examples of this are BVDU, IDU, and FIAU (Scheme 4.3) [5].
Active C-5 substituted pyrimidines
Palladium mediated transformations are a suitable strategy for introducing substituents at C-5. Some of the reactions implemented for this purpose are the Sonogashira [6, 7], Stille [8, 9], Heck [10, 136], and Hiyama [11] (Scheme 4.4).
Palladium mediated substitutions at C-5 pyrimidine position
4.1.1.2 C-6 Substituted Pyrimidines
By following palladium-mediated substitutions , a more limited number of C-6 substituted pyrimidines have been described in comparison with C-5. For instance, by applying the Stille reaction it has been possible to prepare C-6 substituted aryl, vinyl, alkynyl derivatives (Scheme 4.5) [12].
Palladium-mediated substitution of 6-C substituted pyrimidines
4.1.1.3 Purine Formation
The conventional methods of preparation of C-C purines are based on heterocyclization [13, 14]. The classical procedures involve:
-
(a)
2-C-C-purines cyclization of 4-aminoimidazole-5-carboxamides or nitriles with carboxylic acid equivalents.
-
(b)
8-C-C-purines from 5,6-diaminopyrimidines and carboxylic acid derivatives; and for 6-C-C-purines from 4-alkyl or 4-aryl-substituted 5,6-diaminopyrimidines (Scheme 4.6) [15].
Scheme 4.6 
Conventional methods of preparation of C-C purines
Other explored methods involve radical [16, 17] or nucleophilic substitution [18], sulfur extrusion [19], and Wittig type reactions [20, 21]. Despite their usefulness, other methods based on the use of organometallic complex are getting particular significance especially in the synthesis of substituted purines (Scheme 4.7) [15].
General scheme between purines and organometallic compounds
Usually the cross-coupling reactions involving organometallic compounds includes organolithium [22], magnesium [23], aluminum [24], cuprates [25], zinc [26], stannanes [27], and boron [28] reagents, in the presence of palladium catalyst and the purine base bearing a good leaving group usually halides or tosyl (Scheme 4.8).
Cross-coupling reactions for purine modification
Deazapurines are pyrrolo[2,3]pyrimidines of natural or synthetic source with significant antitumor, antiviral and antibacterial activities. Some compounds included in this class are tubercidin, toyocamycin, sangivamycin, and the hypermodified nucleoside queuosine. A flexible route for the preparation of pyrrolo[2,3]pyrimidines (7-deazapurines) has been developed, consisting in the condensation of protected uracil with ethyl N-(p-nitrophenethyl)glycinate and subsequent treatment with acetic anhydride and amine base with heating to provide 5-(acetyloxy)pyrrolo[2,3-d]-pyrimidine-2,4-dione in 74 % yield (Scheme 4.9) [29].
Synthesis of 7-deazapurine analogs
4.1.2 Sugar Modifications
4.1.2.1 2′-3′-dideo xysugars
A significant number of saturated and unsaturated dideoxysugars have been synthesized and tested as antiviral or anticancer drugs. Remarkably, ddI and ddC are approved drugs for the treatment of AIDS [3], and others such as d4T being currently under clinical studies (Scheme 4.10) [30, 31].
Anti-AIDS 2′3′-dideoxy nucleosides
A method for preparing ddC was described involving bromoacetylation with HBr in acetic acid of N4-acetylcytidine followed by reductive elimination with zinc–cooper couple in acetic acid to provide the corresponding 2′3′-unsaturated derivative. Final hydrogenation over 10 % palladium on charcoal gave ddC in 95 %.accompanied by some N-C cleavage in 5 % (Scheme 4.11) [32]. Similar reaction conditions were used for preparing 2′3′-dideoxyadenosine in 81 % yield from adenosine [33].
Synthesis of anti-AIDS ddC
The design and synthesis of potent inhibitors for human hepatitis B Virus (HBV) 2′,3′-dideoxy-2′3′-didehydro-β-l-cytidine (β-l-d4C) and 2′,3′-dideoxy-2′3′-didehydro-β-l-5-fluorocytidine (β-l-Fd4C) nucleosides was carried out according to the pathway shown in Scheme 4.12 [34]. The key starting material 3′,5′-dibenzoyl-2′-deoxy-β-l-uridine was submitted to transglycosilation reaction with silylated 5-fluorouracil using TMSOTf as catalyst, providing an anomeric mixture separated by chromatography. After benzoyl deprotection, the anomeric nucleosides were treated with mesyl chloride followed by base to form cyclic ethers. Further transformation at the pyrimidine ring was followed by potassium tert-butoxide treatment to furnish β-l-d4C and β-l-Fd4C.
Synthesis of anti-hepatitis B virus β-l-d4C and β-l-Fd4C
Other methods designed for the preparation of 2′3′-unsaturated and saturated deoxyfuranosides are based on: (a) Corey–Winter reaction involving cyclic thionocarbonate; [35–37], (b) Eastwood olefination process in which a five-membered cyclic orthoformate suffer a fragmentation to give in the presence of acetic anhydride the desired olefin (successfully applied in the preparation of ddU) [38, 39], and (c) Barton deoxygenation involving the cyclic thionocarbonate or the bisxanthate, and then treated with tributyltin hydride [40, 41], or alternatively diphenylsilane [42] (Scheme 4.13).
Alternative procedures for preparing 2′3′-unsaturated nucleosides
The synthesis of modified nucleosides from natural nucleosides is another useful alternative for preparing pharmaceutically active dideoxy nucleosides. The potent antiviral inhibitors ddC, ddG, d4C, and d4G have been obtained from the corresponding protected natural nucleosides, as shown in Scheme 4.14 [43].
Antiviral modified nucleosides from natural sources
The chemoenzymatic approach has been also explored for the synthesis of 2′,3′ dideoxynucleosides. Such is the case of the antiviral 2′,3′-dideoxyguanosine which was synthesized from guanosine in 40 % overall yield using as a key step the commercially available mammalian adenosine deaminase (ADA) (Scheme 4.15) [44].
Chemoenzymatic synthesis of 2′,3′-dideoxyguanosine
An strategy for preparing d- and l-2′-fluoro-2′3′-unsaturated nucleosides has been described and their anti-HIV activity evaluated. This approach requires 1-acetyl-5-O-benzoyl-2,3-dideoxy-3,3-difluoro-d-ribofuranose as key starting material which was condensed under Vörbruggen’s conditions with purines and pyrimidines to provide the corresponding nucleosides. The resulting nucleosides were subjected to β-elimination to generate the fluoro unsaturated nucleosides (Scheme 4.16) [45].
Preparation of d- and l-2′-fluoro-2′3′-unsaturated nucleosides
4.1.2.2 2′-deoxynucleosides
The Barton deoxygenation provides another useful method for preparing 2′- and 3′-deoxynucleosides (obtained as a mixture), and involves as a key step the hydride reduction of the cyclic thionocarbonate with tributyltin hydride [42]. On the other hand, 2′-monotosylate nucleoside when treated with excess of lithium triethylborohydride produces the 2′-deoxy-3′β-hydroxy nucleoside in high yield (Scheme 4.17) [46].
The Barton deoxygenation for preparing 2′-deoxynucleosides
2′-deoxynucleosides have been obtained from starting materials of different composition such as α,β-unsaturated aldehydes [47] chiral epoxy alcohols [48], butenolides [49, 50] and polyfunctionalized acetals among others [51].
The remarkable 2′-deoxynucleoside AZT widely prescribed as anti-AIDS drug was originally prepared from thymidine by Horwitz and coworkers [52], and since then, several other synthesis have been developed, some of them starting with either a nucleoside, or a sugar derivative [53–56], and others relaying on the use of noncarbohydrate starting materials [56, 57].
The procedure developed by Chu et al. [50] consisted in the use of mannitol as staring material which was subsequently transformed to provide the protected key intermediate 3′-azide-2′-deoxyribofuranose. The next step involved the coupling reaction with silylated thymine under Vörbruggen’s conditions to produce an anomeric mixture of nucleosides in 66 %. Final desilylation and separation by chromatography column provided AZT in overall yield of 25 % from the furanoside intermediate (Scheme 4.18).
Synthesis of AZT from mannitol
Another possibility was described by Hager and Liotta involving the coupling reaction between the azido diol intermediate and silylated thymine under Vörbruggen conditions to yield a diastereomeric mixture of azido diol nucleoside . Finally when exposed to concentrated acidic conditions the open form is converted into the β-anomer of AZT in 67 % yield (Scheme 4.19) [57].
Synthesis of AZT from azido diol intermediate
Transglycosidic reaction mediated by a deoxyribosyl transferase obtained from E. coli has been used in the synthesis of 3′-azido-2′,3′-dideoxyguanosine. The enzymatic reaction occurs between AZT which acts as glycosyl donor and substituted 2-amino-6-purines to generate the desired purine nucleoside and thymine as by-product (Scheme 4.20) [58].
Enzymatic synthesis of 3′-azido-2′,3′-dideoxyguanosine
4.1.2.3 3′-deoxynucleosides
These deoxynucleosides may be readily pre pared from 3′-O-tosylate via a [1,2]-hydride shift from C3′ to C2′ position with accompanying inversion of the C2′ center providing a 3′-ketone which was stereoselectively reduced by the hydride to produce 3′-deoxynucleoside (Scheme 4.21) [2, 46].
Method for preparation of 3′-deoxynucleoside
Also 3′-deoxyguanosine was synthesized by an enzymatic transglycosylation of 2,6-diaminopurine using 3′-deoxycytidine as a donor of the sugar moiety. The diaminopurine nucleoside was transformed to 3′-deoxyguanosine by the action of adenosine deaminase (Scheme 4.22) [59].
Enzymatic synthesis of 3′-deoxyguanoside
Lodenosine [9-(2,3-dideoxy-2-fluoro-β-d-threo-pentofuranosyl)] adenine (FddA) is a reverse transcriptase inhibitor with activity against HIV. This purine analog was evaluated as one of the most selective inhibitors in a series of 2′3′-dideoxyadenosines, although less active than ddA. An efficient method was developed starting from chloropurine riboside which was tritylated and selectively benzoylated at 3′-position. Before fluorination the 2′-hydroxyl group was converted to imidazolesulfonate or trifluoromethanesulfonate. Fluorination proceeds smoothly with 6 equiv. of Et3N.3HF at reflux in 88 % yield. Simultaneous 6-amination and 3′-debenzoylation was done with ammonia in high yield. Elimination of the 3′-hydroxy group was carried out under the Barton-McCombie procedure involving the formation of the 3′-O-thiocarbonyl followed by silane treatment. Final removal of trityl group provided FddA (Scheme 4.23) [60].
Preparation of antiviral 2′3′-fluoro dideoxyadenosine FddA
4.1.2.4 4′-substituted Nucleosides
4′-substituted nucleosides have attracted much attention because of the discovery of potent anti-HIV agents 4′-azido- and 4′-cyano thymidine (Scheme 4.24).
Structure of potent anti-HIV 4′-substituted nucleosides
One procedure involves the epoxidation of the exoglycal with dimethyldioxirane and ring opening of the resulting 4′,5′-epoxynucleosides to produce with high stereoselectivity the 4′-C-branched nucleosides (Scheme 4.25) [61].
Ring opening of 4′,5′-epoxynucleosides
Likewise, others 4′-substituted nucleosides such as 4′-C-Ethynyl-β-d-arabino- and 4′-C-Ethynyl-2′-deoxy-β-d-ribopentofuranosyl pyrimidines have been reported by a different approach outlined in Scheme 4.26 [62].
Synthesis of 4′-C-Ethynyl-β-d-arabino- and 4′-C-Ethynyl-2′-deoxy-β-d-ribopentofuranosyl pyrimidines
4.1.3 Complex Nucleosides
The hypermodified Q base Queuine found in tRNA of plants and animals has been strongly associated with tumor growth inhibition. Three different approaches for preparing queuine have been described [63–65], the more recent in 11 steps from ribose. Completion of the synthesis involved the condensation of bromo aldehyde intermediate with 2,3-diamino-6-hydroxypyrimidine to give the desired heterocyclic product in 45 %. Final removal of protecting groups provided Q base (Scheme 4.27).
Synthesis of hypermodified base Queuine
Capuramycin is a complex nucleoside antibiotic isolated from Streptomyces griseus 446-S3, which exhibit antibacterial activity against Streptococcus pneumoniae and Mycobacterium smegmatis ATCC 607. The total synthesis was reported by Knapp and Nandan [66] consisting in the glycosylation reaction between the key thioglycoside donor and silylated pyrimidine to produce the corresponding l-talo-uridine. The next glycosidic coupling reaction was carried out with l-talo-uridine and imidate glycosyl donor under TMS-OTf conditions to provide the disaccharide nucleoside. Further transformations lead to the target molecule (Scheme 4.28).
Synthesis of Capuramycin
Due its promising role as anti-tuberculosis drug, further efforts for preparing capuramycin and other analogs have been deployed as described in a more recent concise total synthesis [67].
Moreover, capuramycin has been also chemically transformed in an attempt to extend the antibacterial spectrum. Thus, radical oxygenation gave unexpected lactone in moderate yield via an intramolecular radical Ar-C glycosylation-lactonization reaction (Scheme 4.29) [68].
Chemical transformations of capuramycin
Synthestic studies of unique class tunicamycin antibiotics leading to the preparation of (+)-tunicaminyluracil, (+)-tunicamycin-V, and 5′-epi-tunicamacyn-V were described by Myers et al. [69] The key features are the development and application of a silicon-mediated reductive coupling of aldehydes, the allylic alcohols to construct the undecose core of the natural product, and the development of an efficient procedure for the synthesis of the trehalose glycosidic bond within the antibiotic (Scheme 4.30).
Key step for the synthesis of Tunicamycin antibiotic
An alternative approach for the synthesis of tunicamycins is reported in a stereoselective approach, the key reactions being the Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O- and N-glycosylation, and final N-acylation (Scheme 4.31) [70].
Synthesis of tunicamycins mediated by gold complex catalysis
4.1.3.1 Fused Heterocyclic Nucleosides
Selective and potent anti-Varicella Zoster Virus (VZV) bicyclic furanopyrimidine deoxynucleosides were synthesized. The bicyclic formation was performed by palladium-catalyzed coupling of aryl acetylenes with 5-iodo-2′-deoxyridine providing the desired fused furan nucleoside (Scheme 4.32) [71].
Synthesis of bicyclic furano pyrimidine
Triciribine is a tricyclic nucleoside with antineoplastic and antiviral properties, synthesized in an improved fashion from 6-bromo-5-cyanopyrrolo [2,3-d] pyrimidin-4-one intermediate. A series of transformations including N-glycoside coupling reaction provided 4-amino-5-cyano-7-[2,3,5-tri-O-benzoyl-β-d-ribofuranosy] pyrrolo [2,3-d] pyrimidine that was then converted to the desired tricyclic nucleoside (Scheme 4.33) [72].
Synthesis of tricyclic nucleoside Triciribine
4.2 C-nucleosides
These modified nucleosides are structurally distinct to their counterparts N-nucleosides because of the presence of a C-C linkage instead of C-N between the furanoside and the heterocyclic aglycon. Their source could be either naturally occurring (pyrazomycin, showdomycin, formycin) or synthetic (thiazofurin), having in either case significant antitumor and antiviral activity. Also, some of them have been found in tRNA codons (pseudouridine) and others (tiazofurin and oxazofurin) designed as competitive inhibitor of cofactor nicotinamide adenine dinucleotide (Scheme 4.34).
Biologically active C-nucleosides
An early approximation for the preparation of C-nucleosides proposed two basic possibilities depending on the nature of the atoms surrounding the C–C bond (Scheme 4.35) [73].
C-nucleosides partial representations, with and without heteroatom attached to the C-glycosidic bond
-
(a)
If there is one heteroatom adjacent to the C-glycosidic bond, for example tiazofurin, formycin, Pyrazomycin.
-
(b)
If there is no heteroatom adjacent to the C-glycosidic bond.
Alternatively other authors consider three general pathways for preparing C-nucleosides depending on the precursor employed as starting material [74].
An early synthesis of modified C-nucleoside from naturally occurring pseudouridine was carried out via ring opening with ozone to generate intermediate which was treated with thiosemicarbazone to provide 6-azathiopseudouridine. Treatment with iodomethane in acid medium produces the desired C-nucleoside as shown in Scheme 4.36 [75].
Preparation of 6-azapseudouridine
The synthesis of the C-nucleoside pseudouridine was reported by Asburn and Binkley [76], involving the condensation between 5-O-acetyl-2,3-O-isopropylidene-d-ribonolactone and 2,4-dibenzyloxypyrimidin-5-il lithium to provide the condensation product which was subjected to hydride reduction and hydrogenolysis to yield pseudouridine (Scheme 4.37).
Preparation of pseudouridine
Antitumor C-nucleoside tiazofurin was synthesized by Robins et al. [77], from 2,3,5-tri-O-benzoyl-β-d-ribofuranosyl cyanide which undergoes ring closure under conditions described in Scheme 4.38.
Synthesis of tiazofurin
A new report for the synthesis of Tiazofurin is described, avoiding the use of H2S gas which is unsafe on large-scale production. The synthesis initiate with the preparation of 1-cyano-2,3-O-isopropylidene-5-O-benzoyl-β-d-ribofuranose which was reacted with cysteine ethyl ester hydrochloride to give thiazoline derivative in 90 %. Further steps including oxidative aromatization under MnO2 in benzene and acetonide deprotection with iodide in methanol produced the desired C-nucleoside (Scheme 4.39) [78].
A new synthetic methodology for tiazofurin
Another biologically important C-nucleoside known as showdomycin was prepared by Trumnlitz and Moffat [79]. The aldehyde used as starting material was converted first to an α-hydroxyacid and then to α-ketoacid. Wittig reaction on this intermediate and Lewis acid catalysis produced ring closure (Scheme 4.40).
Preparation of showdomycin
Pyrazine riboside derivative was synthesized by treatment of glycine riboside with formaldehyde and cyanide (Strecker conditions) to generate cyanide intermediate as a mixture of isomers. Sulfenylation and sodium methoxide treatment produce the C-nucleoside (Scheme 4.41) [80].
Synthesis of C-nucleoside by pyrazine ring formation
Analogs of antiviral C-nucleoside Formycin have been synthesized by using the palladium-mediated glycosidic reaction between the furanoid glycal and the iodinated heterocycle. Similar conditions were used for preparing the pyrimidine analogs (Scheme 4.42) [81].
Palladium-mediated synthesis of C-nucleoside formycin analogs
Radical cyclization of ribo-phenylselenoglycoside tethered with propargyl moieties on C-5 hydroxyl group provided cyclic intermediates potentially useful for the synthesis of C-nucleoside derivatives. Propargyl intermediate was prepared from ribo-phenylselenoglycoside via two-step sequence and then under radical reaction conditions (Bu3SnH/AIBN) transformed to the cyclic intermediates in high yields. Further ring opening produce aldehyde intermediate which was subjected to coupling reaction with 1,2-phenylenediamine to produce the pyrazine C-glycoside (Scheme 4.43) [82].
C-nucleoside derivative formation via radical cyclization
Polyhalogenated quinoline C-nucleosides were synthesized as potential antiviral agents. The key step reaction for quinolin-2-one ring formation consisted in the condensation between 2-aminophenoneallose derivative and keteneylidene(triphenyl)-phosphorane in benzene under reflux to provide the desired 6,7-dichloroquinolin-2-one nucleoside in 50 % yield (Scheme 4.44) [83].
Quinolin-2-one C-nucleoside formation via Wittig reaction
The novel bicyclic C-nucleoside malayamycin A from Streptomyces malaysiensis was elegantly synthesized from d-ribonolactone which was transformed to the target molecule according to the pathway indicated in Scheme 4.45 [84].
Total synthesis of C-nucleoside Malayamycin A
4.3 Carbocyclic Nucleosides
This class of modified nucleosides in which the furanose ring has been replaced by a cycloalkane ring (mainly cyclopentane) has been prepared by chemical or enzymatic methods. Besides their potent antitumor and antiviral activity for some of them, they have also shown high resistance to phosphorylases.
The use of enzymes particularly lipases for protections and deprotections is an important strategy for preparing carbocyclic nucleosides. This approach has been advantageous especially for the resolution of enantiomeric forms, leading to high enantiomeric purity. Constrained three [85] and four [86] member ring carbocyclic nucleosides have been obtained by applying chemoenzymatic methodologies involving lipase for enantiomeric resolution and stereoselective deprotections. In the case of more abundant five member rings the use of lipases for enzymatic resolution and regioselective deprotections have been under intense study. Special attention has been paid to cyclopentenyl diacetates which have been used as building blocks for the preparation of important carbocyclic nucleosides such as Neplanocin and Aristeromycin. To achieve this goal, the hydrolase enzyme acetyl-cholinesterase (EEAC) [86] showed high efficiency for obtaining the desired enantiomer (1R,4S)-4-hydroxy-2-cyclopentenyl derivative in enantiomeric excess (ee) up to 96 % (Scheme 4.46) [87–89].
Enantiomeric resolution of prochiral cyclopentene diacetate
Racemic cyclopentenyl derivatives have been used as starting material in the preparation of the antiviral carbocyclic nucleoside (−)-5′-deoxyaristeromycin. The key step reaction was the enzymatic resolution with Pseudomonas sp. lipase (PSL) of the racemic mixture providing the (+)-enantiomer which was transformed chemically to the desired carbocyclic nucleoside (Scheme 4.47).
Enzymatic resolution of racemic cyclopentene building blocks
The separation of racemic carbocyclic nucleosides by enzymatic means has been reported as an alternative approach. Thus, racemic aristeromycin was treated with adenosine deaminase (ADA) to give (−)-carbocyclic inosine and pure dextrorotatory enantiomer (Scheme 4.48) [90].
Enzymatic resolution of carbocyclic nucleoside
4.3.1 Cyclopropane Carbocyclic Nucleosides
Conformationally constrained cyclopropane nucleosides have been prepared following a chemoenzymatic approach [85]. Thus, the racemic resolution of trans-1-(diethoxyphosphyl)difluoromethyl-2-hydroxymethylcyclopropane followed by acetate hydrolysis was carried out with porcine pancreas lipase (PPL) to yield (+)- and (−)-cyclopropanes in high enantiomeric excess. Further transformation lead to the preparation of the target cyclopropane nucleoside (Scheme 4.49).
Chemoenzymatic syntheses of cyclopropane nucleosides
4.3.2 Cyclobutane Carbocyclic Nucleosides
Lubocavir is a synthetic potent inhibitor of DNA polymerase, active against cytomegalovirus [91] (Scheme 4.50).
Structures of carboxetan carbocyclic nucleoside
The carbocyclic four-membered C-nucleoside cyclobut-A was prepared following the Barton decarboxylation method. The method is based on the reaction between carboxylic acids and heteroaromatic compounds (Scheme 4.51) [92].
The Barton decarboxylation method for the preparation of carbocyclic C-nucleosides
Other carbocyclic oxetanocin analogs have been prepared from oxetanocin A [93] 3,3-diethoxy-1,2-cyclobutanedicarboxylate [94], and enantiomeric cyclobutanone intermediates [95] as starting materials.
4.3.3 Cyclopentane Carbocyclic Nucleosides
The Mitsunobu reaction has become a valuable alternative approach for preparing cyclopentane carbocyclic nucleosides. This has been demonstrated in the preparation of conformationally locked carbocyclic AZT triphosphate analogs under these versatile conditions [96]. The standard procedure usually takes place with diethyl or diisipropylazocarboxylate (DEAD or DIAD) with triphenylphosphine (Ph)3P in THF to yield carbocyclic purines or pyrimidines nucleosides in high yield (Scheme 4.52) [97].
Synthesis of conformationally locked carbocyclic purine and pyrimidines under the Mitsunobu approach
Another example on the applicability of this method was observed in the preparation of the carbocyclic thymidine nucleoside. It is worth mentioning that the desired stereochemistry of the hydroxyl group is obtained also through the Mitsunobu reaction (Scheme 4.53) [98].
The Mitsunobu reaction for preparation of the carbocyclic thymidine nucleoside
4.3.4 Palladium Mediated
Based on the widespread palladium-coupling methodologies , several dideoxy, carbocyclic and C-nucleosides have been efficiently prepared. For instance the antiviral C-nucleosides 2′-deoxyformycin B was prepared by condensation reaction between the heterocycle iodide intermediate and the glycal, under Pd(dba)2 as palladium catalyst in 62 % yield (Scheme 4.54) [99].
Palladium-mediated 2′-deoxyformycin B and 2′,3′-dideoxyformycin B
Solid phase synthesis of carbovir analogs under palladium catalysis was recently reported [100]. The carbocyclic derivative was linked to the Wang resin and then coupled with chloropurines under Pd(0) catalyst (Scheme 4.55).
Solid-phase synthesis of carbocyclic nucleosides under palladium catalysis
The Tsuji-Trost approach was used to prepare (−)-neplanocin A and its analog [101]. This synthesis proceeds via an allylic rearrangement of the hydroxyl group from the (+)-allylic alcohol to the (−)-allylic acetate (Scheme 4.56).
Tsuji-Trost reaction for the preparation of neplanocin A
Carbocyclic nucleoside aristeromycin with antitumor and antiviral activity was prepared by condensation of the carbocyclic diacetate intermediate with the sodium salt of adenosine base under Pd(0) in 75 % yield (Scheme 4.57) [102].
Palladium catalyzed synthesis of aristeromycin
Palladium mediated coupling of purine base with carbocyclic acetates, carbonates or benzoates lead to a mixture of N-7 and N-9 isomers. The regioselectivity of purine alkylations depends on the size and nature of the ligands, the most typical being Ph3P, BINAP, P(OMe)3, P(OiPr)3, P(OPh)3 (Scheme 4.58) [103].
Palladium-catalyzed coupling with purine base
Another straightforward methodology for preparing carbocyclic nucleosides involves the direct condensation of mesylated carbocyclic intermediate with the heterocyclic base in the presence of potassium carbonate and crown ethers as coupling conditions (Scheme 4.59) [104].
Preparation of carbocyclic nucleosides with mesylated carbocyclic intermediates
4.3.5 Enzymatic Synthesis
Likewise, carbocyclic nucleosides aristeromycin and neplanocin A can be biosynthetically prepared by using a mutant strain of S. citricolor as it is observed in Scheme 4.60.
Biosynthetic pathway of neplanocin A and aristeromycin
The cyclopropylamino carbocyclic nucleosides (–)-abacavir is a potent anti-HIV with promising results on clinical trials [105]. An improved synthesis has been described by Crimmins et al. [106], involving the treatment of key carbocyclic 2-amino-6-chloropurine intermediate with cyclopropylamine producing Abacavir along its parent anti-HIV carbocyclic nucleoside (−)-Carbovir (Scheme 4.61).
Synthesis of anti-HIV (−)-abacavir and (−)-carbovir
4.3.5.1 Base Ring Formation
Another useful strategy used for preparing carbocyclic nucleosides involves the use of intermediates in which the amino group is already attached to the sugar moiety and once the coupling reaction is achieved, a ring closure process takes place to generate the expected nucleoside. According to this procedure Roberts et al. [107] prepared the potent antiviral inhibitor (−)-carbovir which posses similar activity than AZT against HIV in MT-4 cells. Thus, the starting material (±)-2-azabiciclo [2.2.1] hept-5-en-3-one was submitted to microbial treatment with Pseudomonas solanacearum to provide enantiomerically pure (−) isomer. The enantiomerically pure carbocyclic amine was then conjugated to 2-amino-4,6-dichloropyrimidine to produce the carbocyclic precursor which was ultimately cyclized to provide the desired (−)-carbovir (Scheme 4.62).
Synthesis of (−)-carbovir
Antileukemia carboxylic nucleoside Neplanocin A has been synthesized by Marquez et al., using the ring closure approach mentioned above. Thus, condensation of pyrimidine intermediate with isopropylideneaminocyclopentenediol furnished an intermediate which was further cyclized to the purine base with triethylorthoformate. Final conversion to adenine ring with ammonia and protecting group removal gave rise to neplanocin A (Scheme 4.63) [108].
Synthesis of neplanocin A
Likewise, this procedure was applied for the preparation of the close related pyrimidine analog by condensation of the previous carbocyclic amine with the unsaturated ether to produce the pyrimidine precursor who was transformed to thiopyrimidine and then to carbocyclic cytosine as it can be observed in Scheme 4.64. This compound has been found to be active against leukemia type L1210 in vivo [109].
Synthesis of carbocyclic pyrimidine nucleoside
An antiviral carbocyclic purine nucleoside was also reported [110] by following a ring closure step for purine formation. Condensation between pyrimidine intermediate and carbocyclic amine provided condensation product which is activated with diazonium salt for amino introduction. Ring closure was achieved with triethyl orthoformate in acid medium (Scheme 4.65).
Ring closure approach for preparation of carbocyclic purine
4.3.6 Carbocyclic C-nucleosides
This class of C-nucleosides in which a methylene group replaces the furan oxygen ring has not shown significant biological activity so far; however, there is an interest to synthesize C-nucleoside with natural heterocycle moieties in a stereocontrolled fashion. A recent stereocontrolled synthesis of carbocyclic C-nucleosides has been proposed involving as key starting material the cyano carbocyclic intermediate which was condensed to 9-deazapurine to produce saturated and unsaturated carbocyclic 9-deazapurine nucleosides (Scheme 4.66) [111].
Stereocontrolled syntheses of carbocyclic 9-deazapurine nucleosides
4.4 Acyclic Nucleosides
Since the discovery of acyclovir as an anti-herpes drug, important efforts have been made toward the synthesis of analogs of acyclovir and other acyclic nucleosides. A comprehensive review made by Chu and Cutler [112] summarizes the major achievements carried out for preparing acyclonucleosides defined as those heterocyclic compounds containing one or more hydroxyl groups on the alkyl side chain.
At least three representative synthesis of acyclovir have been made, the first by Schaeffer et al. [113] involving a condensation reaction of dichloropurine with ether chloride intermediate, and further purine transformation to generate 9-(2-hydroxyethoxymethyl)guanine (acyclovir) (Scheme 4.67).
First synthesis of acyclovir
An improved version introduced by Barrio et al. [114, 115] consists in the initial reaction of 1,3-dioxolane with trimethylsilyl iodide to produce the side chain which was then condensed with the halogenated purine, to yield after hydrolysis and ammonolysis the target acyclovir (Scheme 4.68).
Improved synthesis of acyclovir
Robins and Hatfield [116] employed a chemoenzymatic approach for preparing acyclovir consisting initially in the use of mercury salts and hexamethyldisilane (HMDS) and in the final step an enzymatic conversion. Thus, the procedure involves the condensation between 2,6-dichloropurine and the bromoether, providing regioisomer N-7 shown in Scheme 4.69. Further amination and final transformation to guanine with the enzyme adenosin-deaminase produces the desired antiviral compound.
Acyclovir synthesis
The phosphonate acyclic nucleoside 9-(2-phosphonomethoxyethyl)adenine (PMEA) was found to be a good antiviral analog with prolonged action [117]. A regio-defined synthesis base on the purine ring formation was described involving the initial attachment of the phosphonate amine intermediate by nucleophilic substitution to the 5-amino-4,6-dichloropyrimidine base, and then ring formation followed by amination to produce the desired phosphonate acyclic adenine PMEA (Scheme 4.70) [118].
Synthesis of phosphonate acyclic adenine PMEA
The effectiveness of acyclovir as antiviral drug encouraged different group to synthesize more potent acyclic analogs. As a result of this efforts, the acyclic nucleoside 9-[(1,3-dihydroxy-2-prpoxy)methyl]guanine (DHPG) [119] was prepared and tested as antiviral nucleoside, showing similar potency as acyclovir against simple herpes but stronger against encephalitis and vaginitis herpes.
Various report of DHPG were described, one of them involving the use of hexamethyldisilazane (HMDS) as condensing agent (Scheme 4.71) [112].
Synthesis of antiviral acyclic nucleoside DHPG
An alternative route for preparing DHPG involved the condensation reaction of acetylguanine base and triacetate derivative in the presence of ethanesulfonic acid, at temperatures ranging from 155 to 160 °C. As result two regioisomers were obtained from which one of those was converted to the desired antiviral compound Scheme 4.72 [112].
Alternative synthesis of DHPG
4.5 Thionucleosides
Nucleosides having the sugar ring oxygen replaced by sulfur are known as thionucleosides. The synthesis and therapeutic evaluation mainly as antiviral and anticancer drugs of these nucleoside mimics has been reviewed [120]. A comparative analysis of thionucleosides and nucleosides showed that sulfur replacement in some cases produced equivalent or higher potency [9, 121], and do not undergo enzymatic cleavage of the glycosidic bond, although it has been also observed increased toxicity as in the case of β-4′-thiothymidine [122] Some thionucleosides displaying antiviral and/or anticancer activity are shown in Scheme 4.73.
Some active N-thionucleosides
Based on their structural features N-thionucleosides defined also as thioribosyl sugars are classified into four groups (Scheme 4.74):
Classification of N-thionucleosides
4.5.1 Preparation of Thioribofuranosyl Intermediates
A number of approaches oriented to replace or insert a sulfur atom instead or besides the cyclic oxygen into the ribose ring have been described. One of the earliest methods for preparing thioribosyl acetates was described by Reinst et al. [123, 124] involving as key steps the conversion of the 4-thiobenzoyl pyranoside into the thioribofuranosyl acetate (Scheme 4.75).
Early synthesis of thioribofuranosyl derivatives
Short time later another report introduced the use of sodium in liquid ammonia followed by benzoylation to yield tribenzoylated thioribofuranoside as a mixture of anomers (α:β, 1:3) (Scheme 4.76) [125].
Preparation of benzoylated thioribofuranoside
The thioribosyl derivative benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-d-erythro-pentofuranoside has been prepared and used as glycosyl donor in various thionucleoside synthesis [125–127]. The synthesis started from 2-deoxy ribose which was transformed to the methylbenzyl derivative by following a standard procedure and then treated with benzylmercaptan in acid to produce the dithiobenzylated derivative. Next, was to invert the hydroxyl group at 4-position by using the Mitsunobu protocol to generate the intermediate with the desired stereochemistry. Final tosyl protection and NaI-BaCO3 treatment provided the desired thiosugar (Scheme 4.77) [126].
Synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-d-erythro-pentofuranoside
4.5.2 Glycosidic Bond Formation
The general methods for preparing N-thionucleosides are similar as for N-nucleosides; however, variations from slight to significant can be found specially in the preparation of four ring thietanocin or thiolane analogs [127, 128] Thus, according to a comprehensive review [120], the earliest reports for N-thionucleoside formation used chloromercury salt of purine and chlorine or benzoyl thioriboside as glycosyl donor, while more recently the silyl approach has been preferred (Scheme 4.78).
4.5.2.1 Chloromercuration Promoted Coupling Reactions
Ref. [123].
Ref. [129].
Ref. [130].
4.5.2.2 Silyl-Mediated Coupling Reactions
The preparation of potential anti-HIV N-isothionucleosides was described starting from glucose. The key coupling reaction proceeds in low yield between the pyrimidine base and the mesyl tetrahydrothiophene derivative under potassium conditions (Scheme 4.79) [133].
Preparation of N-isothionucleoside
N-thioxonucleosides are another class of N-thionucleosides tested as anti-HIV agents. The conditions employed for performing the coupling reaction were TMSOTf as Lewis acid catalyst, providing a mixture of anomers (α:β, 1:2) in 64 % (Scheme 4.80) [134].
Preparation of N-thioxonucleosides
Thietane nucleoside was synthesized starting from the benzoyl thietane derivative which prior to the coupling reaction was treated with peroxide to produce the sulfoxide derivative. Then under Lewis acid conditions a Pummerer rearrangement process takes place to produce in the presence of thymine the expected thietane nucleoside (Scheme 4.81) [128].
Synthesis of thymidine thietane nucleoside
More recently the stereoselective synthesis of β-4′-thionucleosides based on electrophilic glycosilation of 4-thiofuranoid glycals has been described. Thus, the condensation of TBDMS-4-thioglycal with silylated uracil in the presence of PhSeCl as electrophile furnished thionucleosides in 88 % as a mixture of anomers (α:β; 1:4) (Scheme 4.82) [135].
Synthesis β-4′-thionucleosides based on electrophilic glycosidation of 4-thiofuranoid glycols
The thio analog of antiviral DHPG with comparable activity to DHPG against HSV-1 and human cytomegalovirus was synthesized according to the scheme shown below (Scheme 4.83) [112].
Synthesis of thio analog of DHPG
References
Mitsuya H, Yarchoan R, Broder S (1990) Molecular targets for AIDS therapy. Science 249:1533–1544
Huryn DM, Okabe M (1992) AIDS-driven nucleoside chemistry. Chem Rev 92:1745–1768
Mitsuya H, Broder S (1986) Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides. Proc Natl Acad Sci U S A 83:1911–1915
Simons C (2001) Nucleoside mimetics: their chemistry and biological properties. Gordon and Breach Science Publishers, Amsterdam
Agrofolio LA, Guillaizeau I, Saito Y (2003) Palladium-assisted routes to nucleosides. Chem Rev 103:1875–1916
Crisp G, Flynn BL (1993) Palladium-catalyzed coupling of terminal alkynes with 5-(trifluoromethanesulfonyloxy) pyrimidine nucleosides. J Org Chem 58:6614–6619
Mansur TS, Evans CA, Charron M, Korba BE (1997) Discovery of imidazol[1,2-c]pyrimidin-5(6h)-one heterosubstituted nucleoside analogs with potent activity against human hepatitis-b virus in-vitro. Bioorg Med Chem Lett 7:303–308
Farina V, Hauck SI (1991) Palladium-catalyzed approach to 5-substituted uracil and uridine derivatives. Synlett 1991:157–159
Rahim SG, Trivedi N, Bogunovic-Batchelor MV, Hardy GW, Mills G, Selway JW, Snowden W, Littler E, Coe PL, Basnak I, Whale RF, Walker RT (1996) Synthesis and anti-herpes virus activity of 2′-deoxy-4′-thiopyrimidine nucleosides. J Med Chem 39:789–795
Heck RF (1968) Acylation, methylation, and carboxyalkylation of olefins by Group VIII metal derivatives. J Am Chem Soc 90:5518–5526
Hanamoto T, Kobayashi T, Kondo M (2001) Fluoride ion-assisted cross-coupling reactions of (alpha-fluorovinyl)diphenylmethylsilane with aryl iodides catalyzed by Pd(0)/Cu(I) systems. Synlett 2001:281–283
Palmisano G, Santagostino M (1993) Base-modified pyrimidine nucleosides. Efficient entry to 6-derivatized uridines by sn-pd transmetallation-coupling process. Tetrahedron 49:2533–2542
Lister JH (1971) Fused pyrimidines. Part II Purines. In: Weissberger A, Taylor EC (eds) The chemistry of heterocyclic compounds, vol 24. New York, NY, Wiley Interscience
Shaw G (1984) Purines. In: Comprehensive heterocycle chemistry, vol 5. Pergamon, Oxford, pp 499–605
Hocek M (2003) Syntheses of purines bearing carbon substituents in positions 2, 6 or 8 by metal- or organometal-mediated C–C bond-forming reactions. Eur J Org Chem 2003:245–254
Nair V, Chamberlain SD (1985) Novel photoinduced carbon-carbon bond formation in purines. J Am Chem Soc 107:2183–2185
Nair V, Young D (1984) Synthetic transformations of transient purinyl radicals: formation of mono- and diarylated and heteroarylated nucleosides. J Org Chem 49:4340–4344
Tanji K, Higashino T (1990) Purines. IX. Reaction of 9-phenyl-9H-purine-2-carbonitriles with grignard reagents. Heterocycles 30:435–440
Vorbrügen H, Krolikiewicz K (1976) C-substitution of nucleosides with the aid of the eschenmoser sulfide contraction. Angew Chem Int Ed 15:689–690
Taylor EC, Martin SF (1974) A general method of alkylation and alkenylation heterocycles. J Am Chem Soc 96:8095–8102
Mornet R, Leonard NJ, Theiler M, Doree M (1984) Specificity of the 1-methyladenine receptors in starfish oocytes: synthesis and properties of some 1,8-disubstituted adenines, 1,6-dimethyl-1H-purine, and of the 1-(azidobenzyl)adenines. J Chem Soc Perkin 1 879-885
McKenzie TC, Glass D (1987) The reaction of 6-halopurines with phenyl metal complexes. J Heterocycl Chem 24:1551–1553
Nguyen CD, Beaucourt L, Pichat L (1979) Modification de la position 8 des purines nucleosides et de l’adenosine monophosphate cyclique-3′,5′. Reactions de couplage catalytique des organo-magnesiens avec les bromo-8 purines ribosides et bromo-8 adenosine monophosphate cyclique-3′,5′ silyles en presence de dichloro-bis-triphenylphosphine palladium. Tetrahedron Lett 20:3159–3162
Hirota K, Kitade Y, Kanbe Y, Maki Y (1992) Convenient method for the synthesis of C-alkylated purine nucleosides(palladium-catalyzed cross-coupling reaction of halogenopurine nucleosides with trialkylaluminums). J Org Chem 57:5268–5270
Dvořáková H, Dvořák D, Holý A (1996) Coupling of 6-chloropurines with organocuprates derived from grignard-reagents - a convenient route to sec and tert 6-alkylpurines. Tetrahedron Lett 37:1285–1288
Gundersen LL, Bakkestuen AK, Aasen AJ, Øveras H, Rise F (1994) 6-Halopurines in palladium-catalyzed coupling with organotin and organozinc reagents. Tetrahedron 50:9743–9756
Van Aerschot AA, Mamos P, Weyns NJ, Ikeda S, Clercq E, Herdewijn P (1993) Antiviral activity of C-alkylated purine nucleosides obtained by cross-coupling with tetraalkyltin reagents. J Med Chem 36:2938–2942
Vottori S, Camaioni E, Di Francesco E, Volpini R, Monopoli A, Dionisotti S, Ongini E, Cristalli G (1996) 2-alkenyl and 2-alkyl derivatives of adenosine and adenosine-5′-N-ethyluronamide: different affinity and selectivity of E- and Z-diastereomers at A2A adenosine receptors. J Med Chem 39:4211–4217
Edstrom E, Wei Y (1995) A new synthetic route to beta-2′-deoxyribosyl-5-substituted pyrrolo[2,3-d]pyrimidines. Synthesis of 2′-deoxycadeguomycin. J Org Chem 60:5069–5076
Balzarini J, Kang GJ, Dalal M, Herdeweijn P, De Clercq E, Broder S, Johns DG (1987) The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2′,3′-didehydro-2′,3′-dideoxyribonucleosides: a comparison with their parental 2′,3′-dideoxyribonucleosides. Mol Pharmacol 32:162–167
Hamamoto Y, Nakashima H, Matsui T, Matsuda A, Ueda T, Yamamoto N (1997) Inhibitory effect of 2′,3′-didehydro-2′,3′-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus. Antimicrob Agents Chemother 31:907–910
Manchand PS, Belica PS, Holman MJ, Huang TN, Maehr H, Tam SYK, Yang T (1992) Syntheses of the anti-AIDS drug 2′,3′-dideoxycytidine from cytidine. J Org Chem 57:3473–3478
Robins MJ, Hansske F, Low NW, Park JI (1984) A mild conversion of vicinal diols to alkenes. Efficient transformation of ribonucleosides into 2′-ene and 2′,3′-dideoxynucleosides. Tetrahedron Lett 25:367–370
Lin T-S, Luo MZ, Liu M-C, Zhu Y-L, Gullen E, Dutschman EG, Cheng Y-C (1996) Design and synthesis of 2′,3′-dideoxy-2′,3′-didehydro-beta-L-cytidine (beta-L-d4C) and 2′,3′-dideoxy 2′,3′-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV) in vitro. J Med Chem 39:1757–1759
Corey EJ, Winter RAE (1963) A new, stereospecific olefin synthesis from 1,2-diols. J Am Chem Soc 85:2677–2678
Dudycz LW (1989) Synthesis of 2′,3′-dideoxyuridine via the Corey-Winter reaction. Nucleosides Nucleotides 8:35–41
Corey EJ, Hopkins PB (1982) A mild procedure for the conversion of 1,2-diols to olefins. Tetrahedron Lett 23:1979–1982
Mansuri MM, Starrett JE, Wos JA, Tortolani DR, Brodfuerhrer PR, Howell HG, Martin JC (1989) Preparation of 1-(2,3-dideoxy-.beta.-D-glycero-pent-2-enofuranosyl)thymine (d4T) and 2′,3′-dideoxyadenosine (ddA): general methods for the synthesis of 2′,3′-olefinic and 2′,3′-dideoxy nucleoside analogs active against HIV. J Org Chem 54:4780–4785
Shiragami H, Irie Y, Yokozeki H, Yasuda N (1988) Synthesis of 2′,3′-dideoxyuridine via deoxygenation of 2′,3′-O-(methoxymethylene)uridine. J Org Chem 53:5170–5173
Rosowsky A, Solan VC, Sodroski JG, Ruprecht RM (1989) Synthesis of the 2-chloro analogs of 3′-deoxyadenosine, 2′,3′-dideoxyadenosine, and 2′,3′-didehydro-2′,3′-dideoxyadenosine as potential antiviral agents. J Med Chem 32:1135–1140
Kim CH, Marquez VE, Broder S, Mitsuya H, Driscoll JS (1987) Potential anti-AIDS drugs. 2′,3′-dideoxycytidine analogs. J Med Chem 30:862–866
Barton DHR, Jang DO, Jaszberenyi JC (1991) Towards dideoxynucleosides: the silicon approach. Tetrahedron Lett 32:2569–2572
Chu C, Bhadti UT, Doboszowski B, Gu ZP, Kosugi Y, Pullaiah KC, Van Roey P (1989) General syntheses of 2′,3′-dideoxynucleosides and 2′,3′-didehydro-2′,3′-dideoxynucleosides. J Org Chem 54:2217–2225
Fleet GWJ, Son JC, Derome AE (1988) Tetrahedron, Methyl 5-0-tert-butyldiphenylsilyl-2-deoxy-α β -d-threo-pentofuranoside as a divergent intermediate for the synthesis of 3′-substituted-2′,3′-dideoxynucleosides: synthesis of 3′-azido-3′-deoxythymidine, 3′-deoxy-3′-fluorothymidine and 3′-cyano-3′-deoxythymidine. Tetrahedron 44:625–636
Zhou W, Gumina G, Chong Y, Wang J, Schinazi RF, Chu CK (2004) Synthesis, structure–activity relationships, and drug resistance of β-d-3′-Fluoro-2′,3′-unsaturated nucleosides as anti-HIV agents. J Med Chem 47:3399–3408
Hansske F, Robins MJ (1983) Nucleic acid related compounds. 45. A deoxygenative [1,2]-hydride shift rearrangement converting cyclic cis-diol monotosylates to inverted secondary alcohols. J Am Chem Soc 105:6736–6737
Motawia MS, Wendel J, Abdel-Megid AES, Pedersen EB (1989) A convenient route to 3′-amino-3′-deoxythymidine. Synthesis 1989:384–387
Svansson L, Kvarnström I, Classon B, Samuelson B (1991) Synthesis of 2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides as potential inhibitors of HIV. J Org Chem 56:2993–2997
Okabe M, Sun RC, Tam SYK, Todaro LJ, Coffen DL (1988) Synthesis of the dideoxynucleosides “ddC” and “CNT” from glutamic acid, ribonolactone, and pyrimidine bases. J Org Chem 53:4780–4786
Chu CK, Beach JW, Ullas GV, Kosugi Y (1988) An efficient total synthesis of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZDDU, CS-87) from D-mannitol. Tetrahedron Lett 29:5349–5352
Lavallée JF, Just G (1991) Asymmetric synthesis of 3′-carbomethoxymethyl 3′-deoxythymidine via radical cyclization. Tetrahedron Lett 32:3469–3472
Horwitz JP, Chua J, Noel M (1964) Nucleosides. V. The monomesylates of 1-(2′-deoxy-β-D-lyxofuranosyl)thymine. J Org Chem 29:2076–2078
Rideout JL, Barry DW, Lehman SN, St. Clair MH, Furman PA, Freeman GA (1987) E.P. 3,608,606; Chem Abst 106: P38480b
Zaitseva VE, Dyatkina NB, Krayavskii AA, Skaptsova NV, Turina OV, Gnuchev NV, Gottikh BP, Azhaev AV (1984) Aminonucleosides and their derivatives. Bioorg Khim 10:670–680
Wilson JD, Almond MR, Rideout JL (1989) E.P. 295,090; Chem Abst 111: P23914a
Jung ME, Gardiner JM (1991) Synthetic approaches to 3′-azido-3′-deoxythymidine and other modified nucleosides. J Org Chem 113:2614–2615
Hager MW, Liotta DC (1991) Cyclization protocols for controlling the glycosidic stereochemistry of nucleosides. Application to the synthesis of the antiviral agent 3′-azido-3′-deoxythymidine (AZT). J Am Chem Soc 113:5117–5119
Freeman GA, Shauer SR, Rideout JL, Short SA (1995) 2-amino-9-(3-azido-2,3-dideoxy-β-d-erythro-pentofuranosyl)-6-substituted-9H-purines: synthesis and anti-HIV activity. Bioorg Med Chem 3:447–458
Barai VN, Zinchenko AI, Eroshevskaya LA, Zhernosek EV, Balzarini J, De Clercq E, Mikhailopulo IA (2003) Chemo-enzymatic synthesis of 3-deoxy-β-D-ribofuranosyl purines and study of their biological properties. Nucleosides Nucleotides Nucleic Acids 22:751–753
Izawa K, Takamatsu S, Katayama S, Hirose N, Kosai S, Maruyama T (2003) An industrial process for synthesizing lodenosine (FddA). Nucleosides Nucleotides Nucleic Acids 22:507–517
Haraguchi K, Takeda S, Tanaka H (2003) Ring opening of 4′,5′-epoxynucleosides: a novel stereoselective entry to 4′-C-branched nucleosides. Org Lett 5:1399–1402
Ohrui H, Kohgo S, Kitano K, Sakata S, Kodama E, Yoshimura K, Matsuoka M, Shigeta S, Mitsuya H (2000) Syntheses of 4′-C-ethynyl-β-d-arabino- and 4′-C-ethynyl-2′-deoxy-β-d-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity. J Med Chem 43:4516–4525
Kondo T, Ohgi T, Goto T (1983) Synthesis of q base (queuine). Chem Lett 419–422
Akimoto H, Imamiya E, Hitaka T, Nomura H (1988) Synthesis of queuine, the base of naturally occurring hypermodified nucleoside (queuosine), and its analogues. J Chem Soc Perkin 1 1637–1644
Barnett CJ, Grubb LM (2000) Total synthesis of Q base (Queuine). Tetrahedron 56:9221–9225
Knapp S, Nandan SR (1994) Synthesis of capuramycin. J Org Chem 59:281–283
Kurosu M, Li K, Crick DC (2009) Concise synthesis of capuramycin. Org Lett 11:2393–2396
Hotoda H, Daigo M, Takatsu T, Muramatsu A, Kaneko M (2000) Novel intramolecular radical Ar-C glycosylation-lactonization reaction in the transformation of capuramycin. Heterocycles 52:133–136
Myers AG, Gin DY, Rogers DH (1994) Synthetic studies of the tunicamycin antibiotics. Preparation of (+)-tunicaminyluracil, (+)-tunicamycin-V, and 5′-epi-tunicamycin-V. J Am Chem Soc 116:4697–4718
Li J, Yu B (2015) A modular approach to the total synthesis of tunicamycins. Angew Chem Int Ed 54:6618–6621
McGwigan C, Barucki H, Blewett S, Caragio A, Erichsen G, Andrei G, Snoock R, De Clercq E, Balzarini J (2000) Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain. J Med Chem 43:4993–4997
Porcari AR, Towsend LB (2004) An improved total synthesis of triciribine: a tricyclic nucleoside with antineoplastic and antiviral properties. Nucleosides Nucleotides Nucleic Acids 23:31–39
Hannesian S, Pernet AG (1976) Synthesis of naturally occurring C-nucleosides, their analogs, and functionalized C-glycosyl precursors. Adv Carbohydr Chem Biochem 33:111–188
De las Heras F, Tam SY, Klein RS, Fox JJ (1976) Nucleosides. XCIV. Synthesis of some C-nucleosides by 1,3-dipolar cycloadditions to 3-(ribofuranosyl) propiolates. J Org Chem 41:84–90
Bobek M, Farkas J, Sorm F (1969) Nucleic acid components and their analogues. CXXIV. Synthesis of 5-β-D-ribofuranosyl-6-azauracil (6-azapseudouridine). Collect Czech Chem Commun 34:1690–1695
Asbun WA, Binkley SB (1968) Synthesis of 5-substituted pyrimidines. II. J Org Chem 33:140–142
Sriswastava PC, Pickering MV, Allen LB, Streeter DG, Campbell MT, Witkowski JT, Sidwell RW, Robins RK (1977) Synthesis and antiviral activity of certain thiazole C-nucleosides. J Med Chem 20:256–262
Ramasamy KS, Bandaru R, Averett D (2000) A new synthetic methodology for tiazofurin. J Org Chem 65:5849–5851
Trummlitz G, Moffat JG (1973) C-Glycosyl nucleosides. III. Facile synthesis of the nucleoside antibiotic showdomycin. J Org Chem 38:1841–1845
Von Krosigk U, Benner SA (2004) Expanding the genetic alphabet: pyrazine nucleosides that support a donor[bond]donor[bond]acceptor hydrogen-bonding pattern. Helv Chim Acta 87:1299–1324
Zhang HC, Daves GD Jr (1992) Syntheses of 2′-deoxypseudouridine, 2′-deoxyformycin B, and 2′,3′-dideoxyformycin B by palladium-mediated glycal-aglycon coupling. J Org Chem 57:4690–4696
Kim G, Kim HS (2000) C-Glycosylation via radical cyclization: synthetic application to a new C-glycoside. Tetrahedron Lett 41:225–227
Chen JJ, Drach JC, Towsend LB (2003) Convergent synthesis of polyhalogenated quinoline C-nucleosides as potential antiviral agents. J Org Chem 68:4170–4178
Hannessian S, Marcotte S, Machaalani S, Huang G (2003) Total synthesis and structural confirmation of malayamycin A: a novel bicyclic C-nucleoside from streptomyces malaysiensis. Org Lett 5:4277–4280
Yokamatsu T, Salto M, Abe H, Suemune K, Matsumoto K, Kihara T, Soeda S, Shimeno H, Shibuya S (1997) Synthesis of (2′S,3′S)-9-(4′-phosphono-4′,4′-difluoro-2′,3′-methanobutyl)guanine and its enantiomer. Evaluation of the inhibitory activity for purine nucleoside phosphorylase. Tetrahedron 53:11297–11306
Katagiri N, Morishita Y, Yamaguchi M (1998) Highly regio- and enantio-selective deacylation of carbocyclic 3′,5′-di-O-acyloxetanocins by lipases. Tetrahedron Lett 39:2613–2616
Deardorff DR, Mattews AJ, McKeenin DS, Craney CL (1986) A highly enantioselective hydrolysis of cis-3,5-diacetoxycyclopent-1-ene: an enzymatic preparation of 3(R)-acetoxy-5(S)-hydroxycyclopent-1-ene. Tetrahedron Lett 27:1255–1256
Deardorff DR, Shambayati S, Myles DC, Heerding D (1988) Studies on the synthesis of (-)-neplanocin A. Homochiral preparation of a key cyclopentanoid intermediate. J Org Chem 53:3614–3615
Deardorff DR, Savin KA, Justman CJ, Karanjawala ZE, Sheppeck JEII, Hager DC, Aydin N (1996) Conversion of allylic alcohols into allylic nitromethyl compounds via a palladium-catalyzed solvolysis: an enantioselective synthesis of an advanced carbocyclic nucleoside precursor1. J Org Chem 61:3616–3622
Herdewijn P, Balzarini J, De Clercq E, Vanderhaeghe H (1985) Resolution of aristeromycin enantiomers. J Chem Med 28:1385–1386
Tenney DJ, Yamanaka G, Voss SW, Cianci CW, Tuomari AV, Sheaffer AK, Alamn M, Colonno RJ (1997) Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase. Antimicrob Agents Chemother 41:2680–2685
Barton DHR, Ramesh M (1990) Tandem nucleophilic and radical chemistry in the replacement of the hydroxyl group by a carbon-carbon bond. A concise synthesis of showdomycin. J Am Chem Soc 112:891–892
Kitagawa M, Hasegawa S, Saito S, Shimada N, Takita T (1991) Synthesis and antiviral activity of oxetanocin derivatives. Tetrahedron Lett 32:3531–3534
Honjo M, Maruyama T, Sato Y, Horii T (1989) Synthesis of the carbocyclic analogue of oxetanocin A. Chem Pharm Bull 37:1413–1415
Bisacchi GS, Braitman A, Cianci CW, Clark JM, Field AK, Hagen ME, Hockstein DR, Malley MF, Mitt T, Slusarchyk WA, Sundeen JE, Terry BJ, Tuomari AV, Weaver ER, Young MG, Zahler R (1991) Synthesis and antiviral activity of enantiomeric forms of cyclobutyl nucleoside analogs. J Med Chem 34:1415–1421
Ohnishi Y, Ichikawa Y (2002) Stereoselective synthesis of a C-glycoside analogue of N-Fmoc-serine β-N-acetylglucosaminide by Ramberg–Bäcklund rearrangement. Bioorg Med Chem Lett 12:997–999
Russ P, Schelling P, Scapozza L, Folkers G, De Clercq E, Marquez VE (2003) Synthesis and biological evaluation of 5-substituted derivatives of the potent antiherpes agent (north)-methanocarbathymine. J Med Chem 46:5045–5054
Ludek OR, Meier C (2003) Synthesis of carbocyclic analogues of thymidine. Nucleosides Nucleotides Nucleic Acids 22:683–685
Zhang HC, Daves GD Jr (1993) Enantio- and diastereoisomers of 2,4-dimethoxy-5-(2,3-dideoxy-5-O-tritylribofuranosyl)pyrimidine. 2′,3′-dideoxy pyrimidine C-nucleosides by palladium-mediated glycal-aglycon coupling. J Org Chem 58:2557–2560
Crimmins MT, Zuercher WJ (2000) Solid-phase synthesis of carbocyclic nucleosides. Org Lett 2:1065–1067
Obara T, Shuto S, Saito Y, Snoeck R, Andrei G, Balzarini J, De Clercq E, Matsuda A (1996) New neplanocin analogues. 7. Synthesis and antiviral activity of 2-halo derivatives of neplanocin A. J Med Chem 39:3847–3892
Saville-Stones EA, Lindell SD, Jennings NS, Head JC, Ford MJ (1991) Synthesis of (±)-2′,3′-didehydro-2′,3′-dideoxy nucleosides via a modified Prins reaction and palladium(0) catalysed coupling. J Chem Soc Perkin 1 2603–2604
Gundersen LL, Benneche T, Undheim K (1992) Pd(0)-catalyzed allylic alkylation in the synthesis of (±)carbovir. Tetrahedron Lett 33:1085–1088
Jeong LS, Park JG, Choi WJ, Moon HR, Lee KM, Kim HO, Kim HD, Chun MW, Park HY, Kim K, Sheng YY (2003) Synthesis of halogenated 9-(dihydroxycyclopent-4′-enyl) adenines and their inhibitory activities against S-adenosylhomocysteine hydrolase. Nucleosides Nucleotides Nucleic Acids 22:919–921
Foster RH, Faulds D (1998) Abacavir. Drugs 55:729–736
Crimmins MT, King BW (1996) An efficient asymmetric approach to carbocyclic nucleosides: asymmetric synthesis of 1592U89, a potent inhibitor of HIV reverse transcriptase. J Org Chem 61:4192–4193
Taylor SJC, Sutherland AG, Lee C, Wisdom R, Thomas S, Roberts SM, Evans C (1990) Chemoenzymatic synthesis of (–)-carbovir utilizing a whole cell catalysed resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one. J Chem Soc Chem Commun 1120–1121
Lim MI, Marquez VE (1983) Total synthesis of (–)-neplanocin A. Tetrahedron Lett 24:5559–5562
Marquez VE, Lim MI, Treanor SP, Plowman J, Priest MA, Markovac A, Khan MS, Kaskar B, Driscoll JS (1988) Cyclopentenylcytosine. A carbocyclic nucleoside with antitumor and antiviral properties. J Med Chem 31:1687–1694
Shearly YF, O’Dell CA, Amett G (1987) Synthesis and antiviral evaluation of carbocyclic analogs of 2-amino-6-substituted-purine 3′-deoxyribofuranosides. J Med Chem 30:1090–1097
Chun BK, Song GY, Chu CK (2001) Stereocontrolled syntheses of carbocyclic C-nucleosides and related compounds. J Org Chem 66:4852–4858
Chu CK, Cutler S (1986) Chemistry and antiviral activities of acyclonucleosides. J Heterocycl Chem 23:289–319
Schaeffer HJ, Beauchamp L, de Miranda P, de Elion G, Bauer DJ, Collins P (1978) 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 272:583–585
Barrio JR, Bryant JD, Keyser GE (1980) A direct method for the preparation of 2-hydroxyethoxymethyl derivatives of guanine, adenine, and cytosine. J Med Chem 23:572–574
Keyser GE, Bryant JD, Barrio JR (1979) Iodomethylethers from 1,3-dioxolane and 1,3-oxathiolane: preparation of acyclic nucleoside analogs. Tetrahedron Lett 20:3263–3264
Robins MJ, Hatfield PW (1982) Nucleic acid related compounds. 37. Convenient and high-yield syntheses of N-[(2-hydroxyethoxy)methyl] heterocycles as “acyclic nucleoside” analogues. Can J Chem 60:547–553
Naesens L, De Clercq E (1997) Therapeutic potential of HPMPC (Cidofovir), PMEA (Adefovir) and related acyclic nucleoside phosphonate analogues as broad-spectrum antiviral agents. Nucleotides Nucleosides 16:983–992
Dang Q, Liu Y, Erion MD (1998) A new regio-defined synthesis of PMEA. Nucleotides Nucleosides 17:1445–1451
Field AK, Davies ME, de Witt C, Perry HC, Liou R, Germerhausen JL, Karkas JD, Ashton WT, Johnson DB, Tolman RL (1983) 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci U S A 80:4139–4143
Yokohama M (2000) Synthesis and biological activity of thionucleosides. Synthesis 2000:1637–1655
Van Drannen NA, Freeman GA, Short SA, Harvey R, Jansen R, Szczech G, Koszalka GW (1996) Synthesis and antiviral activity of 2′-deoxy-4′-thio purine nucleosides. J Med Chem 39:538–542
Dyson MR, Coe PL, Walker RT (1991) The synthesis and antiviral activity of some 4′-thio-2′-deoxy nucleoside analogs. J Med Chem 34:2782–2786
Reist EJ, Gueffroy DE, Goodman L (1964) Synthesis of 4-Thio-D- and -L-ribofuranose and the corresponding adenine nucleosides. J Am Chem Soc 86:5658–5663
Reist EJ, Fischer LV, Goodman L (1968) Thio sugars. Synthesis of the adenine nucleosides of 4-thio-D-xylose and 4-thio-D-arabinose. J Org Chem 33:189–192
Ritchie RGS, Vyals DM, Szarek WA (1978) Addition of pseudohalogens to unsaturated carbohydrates. VI. Synthesis of 4′ -thiocordycepin. Can J Chem 56:794–802
Haraguchi K, Nishikawa A, Sasakura E, Tanaka H, Nakamura K, Miyasaka T (1998) Electrophilic addition to 4-thio furanoid glycal: a highly stereoselective entry to 2′-deoxy-4′-thio pyrimidine nucleosides. Tetrahedron Lett 39:3713–3716
Naka T, Nishizono N, Minakawa N, Matsuda A (1999) Nucleosides and nucleotides. 189. Investigation of the stereoselective coupling of thymine with meso-thiolane-3,4-diol-1-oxide derivatives via the Pummerer reaction. Tetrahedron Lett 40:6297–6300
Nishikono N, Koike N, Yamagata Y, Fujii S, Matsuda A (1996) Nucleosides and nucleotides. 159. Synthesis of thietane nucleosides via the Pummerer reaction as a key step. Tetrahedron Lett 37:7569–7572
Bobek M, Whistler RL, Bloch A (1970) Preparation and activity of the 4′-thio-derivatives of some 6-substituted purines nucleosides. J Med Chem 13:411–413
George R, Ritchie S, Szarek WA (1973) Synthesis of 4′-thiocordycepin synthesis of 4′-thiocordycepin. J Chem Soc Chem Commun 686–687
Bobek M, Bloch A, Parthasarathy R, Whistler RL (1975) Synthesis and biological activity of 5-fluoro-4′-thiouridine and some related nucleosides. J Med Chem 18:784–787
Secrist JA III, Tiwari KM, Riordan JM, Montgomery JA (1991) Synthesis and biological activity of 2′-deoxy-4′-thio pyrimidine nucleosides. J Med Chem 34:2361–2366
Niedballa U, Vorbrueggen H (1974) Synthesis of nucleosides. 9. General synthesis of N-glycosides. I. Synthesis of pyrimidine nucleosides. J Org Chem 39:3654–3660
Jones MF, Noble SA, Robertson CA, Storer R (1991) Tetrahydrothiophene nucleosides as potential anti-HIV agents. Tetrahedron Lett 32:247–250
Beach JW, Jeong LS, Alves AJ, Pohl D, Kim HO, Chang CN, Doong SL, Schinazi RF, Cheng YC, Chu CK (1992) Synthesis of enantiomerically pure (2′R,5′S)-(-)-1-(2-hydroxymethyloxathiolan-5-yl)cytosine as a potent antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV). J Org Chem 57:2217–2219
Li JJ, Gribble GW (2000) Palladium in heterocyclic chemistry. Pergamon Press, New York, NY
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Brito-Arias, M. (2016). Nucleoside Mimetics. In: Synthesis and Characterization of Glycosides. Springer, Cham. https://doi.org/10.1007/978-3-319-32310-7_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-32310-7_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-32308-4
Online ISBN: 978-3-319-32310-7
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)