Concise and efficient synthesis of 3′-O-triphosphates of 2′-deoxyadenosine and 2′-deoxycytidine

We describe concise and efficient synthesis of 2′-deoxyadenosine-3′-O-triphosphate (2′-d-3′-ATP) and 2′-deoxycytidine-3′-O-triphosphate (2′-d-3′-CTP) which are well known for their various biological applications. One-pot synthetic methodology was used to convert N⁶-Benzoyl-5′-O-levulinoyl-2′-deoxyadenosine into N⁶-Benzoyl-5′-O-levulinoyl-2′-deoxyadenosine-3′-O-triphosphate in 72% yield. One-step concurrent deprotection of N⁶-Benzoyl and 5′-O-levulinoyl groups using concentrated aqueous ammonia resulted in 2′-d-3′-ATP in 75% yield. The same synthetic strategy was successfully employed to convert N⁴-Benzoyl-5′-O-levulinoyl-2′-deoxycytidine into 2′-d-3′-CTP in 66% yield.     

Fluorous-assisted synthesis of (E)-5-[3-Aminoallyl]-uridine-5′-triphosphate

We describe an efficient method for the synthesis of (E)-5-[3-Aminoallyl]-uridine-5′-triphosphate, AA-UTP that combines the advantage of one-pot triphosphate formation and fluorous solid-phase extraction.     

3′-Selective modification of a 4′,5′-didehydro-5′-deoxy-2′,3′-epoxyuridine using nucleophiles

1-(2,3-Anhydro-5-deoxy-4,5-didehydro-α-l-erythro-pent-4-enofuranosyl)uracil 4 was obtained by the treatment of 5′-iodo-2′,3′-epoxyuridine 5 with LiHMDS in excellent yield. The pyrimidine nucleoside 4 possesses quite unique vinyl epoxide moiety within the molecules. The reactions of 4 with a variety of nucleophiles gave 3′-substituted pyrimidine nucleosides without the formation of the corresponding 2′-substituted isomers. In the case of NaN₃ or PhSH, the corresponding 5′-adduct was obtained as a minor product together with the expected 3′-adduct.     

Syntheses of 5′-amino-2′,5′-dideoxy-2′,2′-difluorocytidine derivatives as novel anticancer nucleoside analogs

A novel class of 5′-amino-2′,5′-dideoxy-2′,2′-difluorocytidine derivatives has been synthesized in order to identify anticancer nucleoside analogs. Several synthetic routes were devised and implemented which relied upon either S_N2 displacement or reductive amination to provide the desired derivatives.     

New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides

A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.     

3′-Amino-5′-carboxymethyl-3′,5′-dideoxy nucleosides for the synthesis of fully amide-linked RNA mimics

A convenient protocol is developed for the synthesis of 3′-[N-(fluorenylmethoxycarbonyl)-amino]-5′-carboxymethyl derivatives of all four natural ribonucleosides from cheap chiral pool compound glucose. Synthesis of fully amide-linked RNA analogues of small oligonucleotides containing, for the first time, all four nucleoside amino acids using standard solid phase Fmoc-chemistry is described.     

Study on disulfur-backboned nucleic acids: Part IV.Efficient synthesis of 3′,5′-dithio-2′-deoxyguanosine

An efficient and novel method for synthesizing 3′,5′-dithio-2′-deoxyguanosine was described. In this method normal guanosine was used as the strating materials. A very efficient procedure was used to synthesize 2´-O-tosylguanosine 1, which used 0.1eq DBTO instead of 2eq. 1 was treated with LTBH to give 9-(2-deoxy-β-D-threo-pentofuranosyl)guanine 2. 2 could be easily truned to the target compound.     

A facile and effective synthesis of lamivudine 5′-diphosphate

We report on the first solution synthesis of lamivudine 5′-diphosphate in both high yield and purity. Efficient synthesis of lamivudine 5′-monophosphate was obtained through lamivudine H-phosphonate oxidation by (−)-(8,8-dichlorocamphorylsulfonyl)oxaziridine.Diphosphorylation was performed by nucleophilic substitution of the phosphorimidazolate derivative of lamivudine. HPLC coupled with UV or MS detection was found to be an invaluable tool for the follow-up of phosphorylation reactions.     

Chemoenzymatic synthesis of novel adenosine carbanucleoside analogues containing a locked 3′-methyl-2′,3′-β-oxirane-fused system

Starting from a readily available enantiopure building block, a straightforward enantioselective approach to 3′-methyl-2′,3′-β-oxirane-fused carbanucleosides bearing adenosine analogues is detailed. The key steps in the syntheses involved a lipase-catalyzed regioselective monoacylation of a diol to obtain the key intermediate and direct coupling of this key intermediate with diversely substituted purine nucleobases under Mitsunobu reaction conditions providing only the N⁹ target molecules.     

General method for the synthesis of 2′-O-carboranyl-nucleosides

The carboranyl cage is a new modifying entity for nucleosides, DNA oligonucleotides, and other biomolecules. Herein, the first reliable method for the synthesis of nucleosides modified with a carborane cluster at the 2′-position is described.     

Synthesis and crystal structure of 2′-deoxy-2′-fluoro-4′-thioribonucleosides: substrates for the synthesis of novel modified RNAs

We report herein the synthesis of appropriately protected 2′-deoxy-2′-fluoro-4′-thiouridine (5), -thiocytidine (7), and -thioadenosine (35) derivatives, substrates for the synthesis of novel modified RNAs. The synthesis of 5 and 7 was achieved via the reaction of 2,2′-O-anhydro-4′-thiouridine (3) with HF/pyridine in a manner similar to that of its 4′-O-congener whereas the synthesis of 35 from 4′-thioadenosine derivatives was unsuccessful. Accordingly, 35 was synthesized via the glycosylation of the fluorinated 4-thiosugar 25 with 6-chloropurine. The X-ray crystal structural analysis revealed that 2′-deoxy-2′-fluoro-4′-thiocytidine (8) adopted predominately the same C3′-endo conformation as 2′-deoxy-2′-fluorocytidine.     

Syntheses of nucleosides with 2′-spirolactam and 2′-spiropyrrolidine moieties as potential inhibitors of hepatitis C virus NS5B polymerase

To discover novel nucleosides as potential antiviral agents, 2′-spirolactam and 2′-spiropyrrolidine-containing nucleoside analogs were envisioned. Efficient synthetic routes were developed with an epoxide opening as the key step to establish the quaternary center at the 2′ position, leading to the design and synthesis of uridine analogs 8 and 21, prodrugs 13–16, and cytidine analog 11.     

Synthesis of 2′-dealkylmumbaistatin

The sterically congested 1,2,3-substituted 3′-dealkyl mumbaistatin derivatives 16, 20, and 21 were prepared for the first time by base-catalyzed cyclization of the 2,3-bis-substituted naphthoquinone precursor 11 followed by bromine mediated photooxidation and methyl ether cleavage.     

A new, facile, and protection-free one-pot chemical synthesis of 2′-deoxynucleoside-5′-tetraphosphates

A new straight forward, reliable, and an efficient method for the chemical synthesis of 2′-deoxynucleoside-5′-tetraphosphate is reported. The present ‘one-pot, three step’ synthetic strategy involves the monophosphorylation of nucleoside followed by reaction with tris-(tri-n-butylammonium) triphosphate and hydrolysis of the putative cyclic tetrametaphosphate intermediate to provide the corresponding 2′-deoxynucleoside-5′-tetraphosphate in moderate yield with high purity.     

A versatile reagent for the synthesis of 5′-phosphorylated, 5′-thiophosphorylated or 5′-phosphoramidate-conjugated oligonucleotides

We report the synthesis of a new phosphorylating reagent that is easily accessible and allows not only the chemical synthesis of 5′-phosphorylated and 5′-thiophosphorylated oligonucleotides but also the 5′-conjugation through a phosphoramidate linkage. 5′-Amino-linker and 5′-alkyne oligonucleotides were obtained and the latter was conjugated by a 1,3-dipolar cycloaddition (click chemistry) with a galactosylated azide derivative to afford 5′-galactosyl oligonucleotide with high efficiency.     

Synthesis of 8-vinyladenosine 5′-di- and 5′-triphosphate: evaluation of the diphosphate compound on ribonucleotide reductase

The synthesis of 5′-di- and 5′-triphosphate of 8-vinyladenosine to be tested on ribonucleotide reductases requires the modification of known methods. The phosphate group was introduced by treatment with an in situ generated chlorophosphite. Protection of the 2′,3′ diol with acetyl groups suppressed depurination during acid removal of the phosphotriester protecting groups. The di- and triphosphate compounds were obtained by treatment of the activated adenylic acid with phosphate or pyrophosphate anions followed by removal of the acetate protecting groups. Preliminary studies were conducted on Escherichia coli ribonucleotide reductase and have shown that the diphosphate compound is efficiently reduced.     

Heptakis-6-(5-methylene-thioureido-5′-methyl-2,2′-bipyridyl)-β-cyclodextrin: synthesis and metal complexation study

A new heptapode heptakis-6-(5-methylene-thioureido-5′-methyl-2,2′-bipyridyl)-β-cyclodextrin was prepared and its complexation properties towards metal cations were investigated. Substituting the urea functions by the corresponding thioureas promoted the inversion of the metal coordination selectivity. Preliminary results showed the heptapode unable to complex lanthanides but authorise selective complexation of ‘soft’ and ‘borderline’ metal cations.     

Cyclization versus oligomerization of SP- and RP-5′-OH-N-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane)s

The S_P-isomer of 5′-OH-N⁴-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane) undergoes DBU-promoted intramolecular cyclization providing as a sole product S_P-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate. Unexpectedly, the R_P-counterpart yields a mixture of products consisting of R_P-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate and macrocyclic oligo(deoxycytidine phosphorothioate)s. The results of molecular modeling indicate that the dychotomy observed for the R_P substrate may result from remarkably higher energy of the corresponding transition states, caused by the presence of bulky ‘spiro’ pentamethylene substituent at the position C4 in the oxathiaphospholane ring.     

Synthesis of 2′-C-methyl-branched isonucleosides

Novel regioisomers of 2′-methyl-branched nucleosides were designed and synthesized to mimic potent anti-viral drugs like Valopicitabine. The short and efficient synthesis of the targets involves a one-pot tosylation/cyclization step that leads to an activated furan scaffold on which the isonucleosides were built.