Abstract
Conformationally restricted diastereomeric homoarabinofuranosylpyrimidines (AZT analogue), i.e., (5′R)-3′-azido-3′-deoxy-2′-O,5′-C-bridged-β-ᴅ-homoarabinofuranosylthymine and -uracil had been synthesized starting from diacetone ᴅ-glucofuranose following chemoenzymatic and chemical routes in 34–35% and 24–25% overall yields, respectively. The quantitative and diastereoselective acetylation of primary hydroxy over two secondary hydroxy groups present in the key nucleoside precursor was mediated with Lipozyme® TL IM in 2-methyltetrahydrofuran following a chemoenzymatic pathway. Whereas, the protection of the primary hydroxy over the lone secondary hydroxy group in the key azido sugar precursor was achieved using bulky tert-butyldiphenylsilyl chloride (TBDPS-Cl) in pyridine in 92% yield following a chemical synthetic pathway. The chemoenzymatic method was found to be superior over the chemical method in respect of the number of synthetic steps and overall yield of the final product.
Highlights
In the last few decades, modification of nucleoside/nucleotide analogues has been a field of keen interest to researchers due to their therapeutic properties for treatment of cancer, viral and microbial infections [1-9]
It was envisioned to synthesize targeted bridged homoarabinofuranosyl nucleosides starting from diacetone-ᴅ-glucofuranose following chemoenzymatic and chemical pathways (Scheme 1)
Azidofuranoside 11 on acetolysis with acetic acid/ acetic anhydride/sulfuric acid (100:10:0.1) at room temperature afforded an anomeric mixture of 1,2,5,6-tetra-O-acetyl-3-azido3-deoxy-α,β-ᴅ-allofuranose (12a,b), which on Vorbrüggen base coupling [29] with thymine and uracil in the presence of N,Obis(trimethylsilyl)acetamide (BSA) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) afforded nucleosides 13a,b
Summary
In the last few decades, modification of nucleoside/nucleotide analogues has been a field of keen interest to researchers due to their therapeutic properties for treatment of cancer, viral and microbial infections [1-9]. We report an efficient chemo-enzymatic and chemical route to synthesize two novel conformationally restricted azido-homoarabino nucleosides 9a,b in excellent overall yields (Figure 1). It was envisioned to synthesize targeted bridged homoarabinofuranosyl nucleosides starting from diacetone-ᴅ-glucofuranose following chemoenzymatic and chemical pathways (Scheme 1).
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