Methods of Nucleoside Bond Formation

Nucleotides are the phosphate esters of nucleoside and are the building blocks of DNA and RNA. All nucleotides have three components: a nitrogen-containing heterocyclic base, a pentose sugar, and a phosphate group. The most effective antiviral drugs used in clinics are nucleoside analogs, such as AZT, ddI, ddC for HIV, and cytarabine for herpes virus. Therefore, nucleoside synthesis has attracted increasing attention, and many bioactive nucleoside analogs are synthesized every year. In nucleosides, purine or pyrimidine bases are connected to the C-1 position of the sugar through the nitrogen on the ring, forming various nucleosides and their derivatives. This is a valuable method for synthesizing nucleoside analogs. Below are some strategies for constructing nucleoside bonds:

1. Base Heavy Metal Salt Condensation

Koenings and Knorr used protected C-1 halogenated sugars catalyzed by purine heavy metal salts (initially Ag salts) to prepare purine nucleosides. Later, Dovoll and Lowy improved the reaction by applying Hg salts, which increased the yield. This method is still used today and can be used to react halogenated sugar derivatives with base salts with different protective groups to obtain a series of nucleosides. Its main advantage is that the sugar substitution position and the end-group configuration on C-1′ can be accurately determined. The main disadvantage is that the poor solubility of mercury salts results in a heterogeneous reaction. In addition, the low stability of halogenated sugar derivatives leads to low yields.

2. Fusion Synthesis

Sugar is acetylated with an appropriate base under vacuum and melted under mild acid-catalysis conditions such as ZnCl₂, AlCl₃, or p-toluenesulfonic acid to obtain nucleosides with high yields. For example, 2,6,8-trichloropurine or 3-bromo-5-nitro-1,2,4-triazole is melted with 1,2,3,5-tetra-O-acetyl-D-furanose to obtain the corresponding acetylated nucleosides. This method is particularly suitable for synthesizing low-melting-point weakly basic heterocyclic nucleosides and is generally more suitable for purine bases, as pyrimidine bases are less likely to be melted.

3. Quaternary Ammonium Ionization

This method, also known as the Hillbert-Johnson method, allows direct nucleophilic substitution of substituted pyrimidines with halogenated sugars without electrophilic catalysts. For example, 2-alkoxy pyrimidines can undergo alkylation reactions with halogenated sugars to produce quaternary ammonium salts. The intermediate is eliminated under higher temperatures, then chemical modifications are performed on the substituents on the pyrimidine ring to obtain various naturally or artificially modified nucleosides. The advantage of this method is that the reactive C-4 position of the intermediate can undergo nucleophilic substitutions or be converted into corresponding uracil nucleosides. The disadvantage is that α- and β-end groups are obtained as isomeric mixtures, where the addition of HgBr₂ results in a larger proportion of β-isomer. This method is general for preparing pyrimidine nucleosides.

4. Base Trimethylsilyl Derivative

This method has three advantages:

(1) It is easy to prepare and the yield is relatively high;

(2) It can undergo homogeneous reactions with sugar;

(3) The intermediate can be easily transformed into various modified bases.

Early mercury oxide catalysts are replaced by Lewis acid catalysts (SnCl₄ or Hg(OAc)₂), then replaced by strong acid trimethylsilyl esters, such as trifluoromethanesulfonic acid trimethylsilyl ester and perchloric acid trimethylsilyl ester. This reaction is carried out in a polar solvent such as acetonitrile or 1,2-dichloroethane, depending on the reactivity of the reactants; the reaction temperature ranges from -20°C to 50°C. However, this method lacks precise regional and stereoselectivity, which is due to the SN₁ reaction characteristics, which are determined by the negative nitrogen in the base capturing the sugar ring C-1 carbon cationic.

5. Glycosyl Transfer

It can easily convert standard nucleosides, especially 2′-deoxythymidine, into modified nucleosides such as 3′-azido-2′,3′-dideoxythymidine (AZT). However, it is difficult to convert 2′-deoxyadenosine into AZdA. In this case, the sugar ring can be transferred from one base to another by glycosyl transfer. This reaction is particularly suitable for transferring the sugar ring (including very complex sugar rings) from the pyrimidine electron-deficient ring to the more basic purine electron-rich ring.