Large-Scale Manufacturing of All Four 2′-Deoxynucleosides via Novel Strategies Including a Chemo-Enzymatic Process

Abstract

A chemical synthesis of 2-deoxyribose-1-phosphate 2 and its enzymatic conversion into purine 2'-deoxynucleosides (dNus) are shown. Besides the chemo-enzymatic process for purine dNus, a modified process for practical dC preparation is also established. Consequently, a series of practical manufacturing processes of all four dNus have been realized via novel strategies.

New Trends in Nucleoside Biotechnology

“…First of all, they have developed “crystallization–induced asymmetric transformation” for the stereoselective synthesis of 2–deoxy– α – D –ribofuranose–1–phosphate ( 48 ) and its β – D –anomer [125, 126]. Both anomers have been isolated as pure stable bis(cyclohexylammonium) salts.…”

“…A group of researchers from Mitsui Chemicals is also investigating the synthesis of nucleosides via condensation of α – D –pentofuranose–1–phosphates with heterobases using nucleoside phosphorylases [ 125 – 127 ]. First of all, they have developed “crystallization–induced asymmetric transformation” for the stereoselective synthesis of 2–deoxy– α – D –ribofuranose–1–phosphate ( 48 ) and its β – D –anomer [ 125 , 126 ]. Both anomers have been isolated as pure stable bis(cyclohexylammonium) salts.…”

“…A survey of the chemical methods for the production of pento(hexo)–furanose–1–phosphates [ 125 – 132 , 137 – 147 ] and the methods of anomeric carbon atom activation (see [ 139 ] for a review) shows that most of these methods are laborious and low–yielding of the desired phosphates. As can be expected, most of the procedures yield mixtures of anomers, and it seems that only the “crystallization–induced asymmetrical transformation” preferably yields the desired 2–deoxy– α – D –pentofuranose–1–phosphates [ 85 ].…”

Synthesis of 2′‐Deoxynucleosides by Transglycosylation with New Immobilized and Stabilized Uridine Phosphorylase and Purine Nucleoside Phosphorylase

“…[1,2] Nucleosides are largely synthesized by multi-step chemical procedures which, however, are plagued by low yields and the formation of undesired by-products. [3] Alternatively, nucleosides can be prepared by a biosynthetic process through a transglycosylation reaction between a pyrimidine nucleoside and a purine base in aqueous solution catalyzed by nucleoside phosphorylases or microorganisms which produce them.…”

First Stereoselective Synthesis of 2-Deoxy-α-d-ribosyl-1-phosphate: Novel Application of Crystallization-Induced Asymmetric Transformation

“…Large-scale production of 2‘-deoxynucleosides is the focus of growing attention for the development of DNA-relating drugs due to the increased demand of the starting raw materials. Since the known synthetic methods of 2‘-deoxynucleosides are not satisfactory in yield and show low stereoselectivity at the anomeric position, particularly the synthetic methods for purine 2‘-deoxynucleosides, the enzymatic conversion of 1 into 2‘-deoxynucleoside should be the most expedient strategy for its practical manufacture . Even though several methodologies in pyranosyl-1-phosphate or furanosyl-1-phosphate chemistry have been reported during the past decades, to our knowledge, no application to the synthesis of 1 has been demonstrated.…”