A simple procedure for the preparation of protected 2′-O-methyl or 2′-O-ethyl ribonucleoside-3′-O-phosphoramidites (original) (raw)

High yield protection of purine ribonucleosides for phosphoramidite RNA synthesis

Tetrahedron Letters, 1999

We report high yield procedures for protection of purine ribonocleosides based on a reaction which allows concomitant highly regiospecific 2'-silylation and 3'-phosphitylation. Subsequent cleavage of the H-phosphonate monoester moiety without silyl migration provides intermediates ready for phosphitylation by standard methods to give fully protected phosphoramidites.

Streamlined Process for the Chemical Synthesis of RNA Using 2′- O -Thionocarbamate-Protected Nucleoside Phosphoramidites in the Solid Phase

Journal of the American Chemical Society, 2011

An improved method for the chemical synthesis of RNA was developed utilizing a streamlined method for the preparation of phosphoramidite monomers and a single-step deprotection of the resulting oligoribonucleotide product using 1,2-diamines under anhydrous conditions. The process is compatible with most standard heterobase protection and employs a 2 0-O-(1,1-dioxo-1λ 6-thiomorpholine-4-carbothioate) as a unique 2 0-hydroxyl protective group. Using this approach, it was demonstrated that the chemical synthesis of RNA can be as simple and robust as the chemical synthesis of DNA.

The 4-( N -Dichloroacetyl- N -methylamino)benzyloxymethyl Group for 2‘Hydroxyl Protection of Ribonucleosides in the SolidPhase Synthesis of Oligoribonucleotides

Journal of Organic Chemistry, 2008

Emerging RNA-based technologies for controlling gene expression have triggered a high demand for synthetic oligoribonucleotides and have motivated the development of ribonucleoside phosphoramidites that would exhibit coupling kinetics and coupling efficiencies comparable to those of deoxyribonucleoside phosphoramidites. To fulfill these needs, the novel 4-(N-dichloroacetyl-N-methylamino)benzyloxymethyl group for 2′-hydroxyl protection of ribonucleoside phosphoramidites 9a-d has been implemented (Schemes 1 and 2). The solid-phase synthesis of AUCCGUAGCUAACGUCAUGG was then carried out employing 9a-d as 0.2 M solutions in dry MeCN and 5-benzylthio-1H-tetrazole as an activator. The coupling efficiency of 9a-d averaged 99% within a coupling time of 180 s. Following removal of all basesensitive protecting groups, cleavage of the remaining 2′-[4-(N-methylamino)benzyl] acetals from the RNA oligonucleotide was effected in buffered 0.1 M AcOH (pH 3.8) within 30 min at 90°C. RP-HPLC and PAGE analyses of the fully deprotected AUCCGUAGCUAACGUCAUGG were comparable to those of a commercial RNA oligonucleotide sharing an identical sequence. Enzymatic digestion of the RNA oligomer catalyzed by bovine spleen phosphodiesterase and bacterial alkaline phosphatase revealed no significant amounts of RNA fragments containing (2′f5′)-internucleotidic phosphodiester linkages or noteworthy nucleobase modifications.

Studies on Synthesis and Structure of O-β-D-Ribofuranosyl(1″→2′)-ribonucleosides and Oligonucleotides

Nucleosides Nucleotides & Nucleic Acids, 1998

Minor nucleosides found in several eukaryotic initiator tRNAsiMet, 0-p-Dribofiuanosyl( 1"+2')adenosine and -guanosine (Ar and Gr), as well as their pyrimidine analogues, were obtained from N-protected 3'3 '-O-( 1,1,3,3-tetraisopropyldisiloxane-1,3-diy1)ribonucleosides and 1 -0-acetyl-2,3,5-tri-O-benzoyl-~-D-ribofuranose in the presence of tin tetrachloride in 1,2-dichloroethane. A crystal structure has been solved for 2'-0ribosyluridine. The 3'-phosphoramidites of protected 2'-O-ribosylribonucleosides were prepared as the reagents for 2'-O-ribo~anosyloligonucleotides synthesis. 0-p-D-Ribofuranosyl( 1"+2')adenylyl(3 '+5')guanosine (ArpG) was obtained and its structure was analysed by NMR spectroscopy.

Synthesis and biological activity of novel N6-substituted and 2,N6-disubstituted adenine ribo- and 3′-C-methyl-ribonucleosides as antitumor agents

European Journal of Medicinal Chemistry, 2011

A series of N 6 -aminopurine-9-b-D-ribonucleosides and ribose-modified 3 0 -C-methyl analogues substituted at N 6 -position with a small group like hydroxy, methoxy or amino group or at C2(N 6 ) position have been synthesized and tested against a panel of human leukemia and carcinoma cell lines. N 6 -Hydrazino-9-b-D-ribofuranosyl-purine (5) displayed the best antiproliferative activity in the low micromolar or submicromolar range against all tested tumor cell lines. The activity of this nucleoside is related in part to ribonucleotide reductase inhibition. C2-modification or 3 0 -C-methylation in N 6substituted adenosine analogues leads to a decrease or loss in activity.

Design and synthesis of phosphonoacetic acid (PPA) ester and amide bioisosters of ribofuranosylnucleoside diphosphates as potential ribonucleotide reductase inhibitors and evaluation of their enzyme inhibitory, cytostatic and antiviral activity

Antiviral chemistry & chemotherapy, 2003

Continuing our investigations on inhibitors of ribonucleotide reductase (RNR), the crucial enzyme that catalyses the reduction of ribonucleotides to deoxyribonucleotides, we have now prepared and evaluated 5'-phosphonoacetic acid, amide and ester analogues of adenosine, uridine and cytidine with the aim to verify both substrate specificity and contribution to biological activity of diphosphate mimic moieties. A molecular modelling study has been conducted on the RNR R1 subunit, in order to verify the possible interaction of the proposed bioisosteric moieties. The study compounds were finally tested on the recombinant murine RNR showing a degree of inhibition that ranged from 350 microM for the UDP analogue 5'-deoxy-5'-N-(phosphon-acetyl)uridine sodium salt (amide) to 600 microM for the CDP analogue 5'-O-[(diethyl-phosphon)acetyl]cytidine (ester). None of the tested compounds displayed noteworthy cytostatic activity at 100-500 microM concentrations, whereas ADP analog...

Synthesis of 6′‐Methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐L‐ ribofuranosyl‐pyrimidine Nucleosides

ChemistrySelect, 2019

Herein, we report the efficient synthesis of (6'R)-and (6'S)-6'methyl-2'-O,4'-C-methylene-α-L-ribofuranosyl-thymine, and (6'R)-and (6'S)-6'-methyl-2'-O,4'-C-methylene-α-L-ribofuranosyluracil starting from diacetone glucofuranose in overall yields of 6.3, 4.7, 5.4 and 4.0%, respectively. The key step in the synthesis of stereochemically defined 6'-Me-bicyclic-nucleosides is the nucleophilic addition of methyl group at methylene carbon of 4-C-CH 2 OH moiety of the 4-C-tert-butyldiphenylsilyloxymethylated sugar precursor. Thus, the methyl group was added on the aldehyde obtained from Dess-Martin periodinane oxidation of the precursor alcohol employing AlMe 3 in hexane. Both (6'R)and (6'S)-stereoisomers of bicyclic nucleosides T and U were successfully synthesized following Vorbrüggen nucleobase coupling of T and U with triacetylated glycosyl donor obtained from acetolysis of (5R)-and (5 S)-4-C-(tert-butyldiphenylsilyloxymethyl)-5-C-methyl-1,2-O-isopropylidene-3-O-(2-naphthylmethyl)-α-D-xylofuranoses and further cyclization and deprotection of the resulted nucleoside. One of the nucleosides, (6'R)-6'-methyl-2'-O,4'-C-methylene-α-L-ribofuranosyl-uracil has been reported earlier in 1.8% yield, while the present methodology yielded the nucleoside in 5.4% yield. All the synthesized 6'-Me-bicyclic-nucleosides showed no significant anti-viral activity against H1 N1 strain of influenza A virus (A/Puerto Rico/ 8/1934). Experimental procedures including materials, reagents and solvents used for the synthesis of compounds 1, 2, 3 a, 3 b, (5R)-4, (5S)-5, (5R)-6, (5S)-7, 8 ad , 9 ad , 10 ad , 11 ad , 12 ad and 13 ad and their characterization data along with their 1 H and 13 C NMR spectra are given in the supplementary information.