Nucleosides with Nitrogen-substituted Sugars

When mesylate (40) was treated with azide ion, substitution occurred predominantly with retention via a 2,3 -anhydride if R B H, He, whereas for R - 1, F, direct substitution predom- 

3 -Azido-3 -deoxy analogues of BVDU have been 

Pyrimidine nucleosides of N-acetylneurauninic acid have been prepared, with / -anomers predominating tinder Koenigs-Knorr conditions.  

In work similar to that reported last year (Vol. 19, p. 201), 3,4,6-tri-0 acetyl-2-deoxy 2-nitroso-a-D-galactopyranosyl 

Some bridged adenosine - isocytosine derivatives (43 n - 2-7) have been reported, but without the anticipated anti-bacterial activity. 

2 -Amino-2 -deoxyuridine has been coupled at the amino group with various Fmoc-protected aminoacids the resultant conjugates were incorporated into ribozymes using phosphoramidite methods.  

3 -Amino-3 -deoxyadenosine has been prepared by coupling of the base to a sugar synthon derived from levoglucosenone (see Chapter 9).  

There has been a further report (see Vol.27, p.250) on the formation of 3 -N-alkylamino-3 -deoxythymidines, either by reductive alkylation, or by treabnent of AZT with TPP followed by an alkyl halide. 3 -Amino-3 -deoxythymidine has been converted to various TV-substituted analogues such as 61, which showed some anti-HIV activity.  

A new route to AZT involves bromomesylate 37 reductive removal of the bromine, followed by treatment with sodium azide and lithium carbonate gave 5 -0-benzoyl-AZT, presumably via a 2,3 -anhydronucleoside. 2-Alkylthio- and the 4-methylthio-analogues of AZT have been made by base-sugar condensation, as have 3 -azido-2, 3 -dideoxynucleosides of hydantoins. Some computational work on conformations of AZT is mentioned in Chapter 21. 

A new synthesis of 3 -deoxy-3 -nitrothymidine involves displacement of an up -iodo-substituent by nitrite ion in DMSO in the presence of phloroglucinol. The (hydroxylamino)nucleoside 65 has been made by reduction of a C-3 nitrone with NaBHsCN, and related 0-alkylhydroxylamines were also described, prepared by reduction of O-alkyloximes. Similar O-alkyloximes at both C-2 and C-3 of uridine have been prepared as potential inhibitors of ribonucleoside diphosphate reductase.  

A similar displacement of a 2 -triflate was used in the synthesis of amides such as 60, related to a known inhibitor of trypanosomal glyceraldehyde-3-phosphate dehydrogenase, from ara-A. 2 -Amino-2 -deoxyuridine has been linked through an amide to a coumarin the resultant derivative was incorporated into oligonucleotides to act as a fluorescence energy donor to DNA.  

AZT was used as a precursor to prepare a compound in which fluorescein was linked to the amino group of 3 -amino-3 -deoxythymidine through a thioamide, a link resistant to enzymic degradation, and a spacer. The product was converted to its 5 -triphosphate for use as a chain terminator for DNA dye-terminator sequencing. 3 -Amino-3 -deoxythymidine has been joined in hybrid structures. 

The L-enantiomer of 3 -azido-2, 3 -dideoxyguanosine has been prepared from L-xylose, but no significant antiviral activity was observed.  

Uridine has been converted in seven steps into 5 -amino-3, 5 -dideoxyuridine (66), related to the 4, 5 -unsaturated structure found in the mureidomycin antibiotics. Some 5 -Amino-5 -deoxy-5-iodo-pyrrolopyrimidine nucleosides such as 67 (X = Cl, NH2) have been prepared by sodium salt glycosylation procedures, and shown to be powerful adenosine kinase inhibitors.  

A number of purine 2 -amino-2 -deoxy-8-D-ribonuc1eosides have been prepared by microbial transglycosy1 ation between the purine base and 2 -amino-2 -deoxyuridine. The 3 -azido-3 -deoxy-6- and 3 -azido,2, 3 -dideoxy-a- and 3-D-ribofuranosides of benzimidazole were synthesized conventionally from 3-azido sugar derivatives. 

A range of 3 -0-acyl derivatives of 5 -amino-5 -deoxy thymidine have 

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Phospha sugar nucleosides have not yet been shown to be naturally occurring. Some analogues of phospha sugar nucleosides (e.g., 118) are prepared from 2-bromo-3-hydroxyphospholanes 94 or 103 by nucleophilic substitution reaction with nitrogen nucleophiles (Schemes 35 and 36, and Table 8). However, the nucleophilic substitution reaction (or electrophilic substitution reaction in the presence of catalyst) of 2-bromo-3-hydroxyphospholanes 94... 

Scheme 35 Preparation of phospha sugar nucleoside 118 from 2-bromo-3-hydroxyphos-pholane 103 by nucleophilic substitution reaction with nitrogen nucleophiles...

As with other nitrogen-containing heterocycles, TV-alkylation is a reaction of some interest. This is particularly true when the products are nucleosides. One interesting example of nucleoside formation arises from reaction of a suitable furo[3,4-J]pyrimidine (41) and l-O-acetyl-2,3,5-tribe nzoyl-/ -D-ribose the product formed seems to be solvent dependent. The N-l substituted nucleoside (42 R = tribenzoylribose) is formed in 81 % yield when the heterocycle and the protected sugar are treated with tin(IV) chloride in acetonitrile. However, use of 1,2-dichloroethane as solvent affords only 17% of this product together with 81% of the N-l,N-3 disubstituted product (Equation (10)) <83CPB3074>. 

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