The Chemoenzymatic Synthesis of 2-Chloro- and 2-Fluorocordycepins

Abstract

Two approaches to the chemoenzymatic synthesis of 2-fluorocordycepin and 2-chlorocordycepin were studied: (i) the use of 3′-deoxyadenosine (cordycepin) and 3′-deoxyinosine (3′dIno) as donors of 3-deoxy-d-ribofuranose in the transglycosylation of 2-fluoro- (2FAde) and 2-chloroadenine (2ClAde) catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP), and (ii) the use of 2-fluoroadenosine and 3′-deoxyinosine as substrates of the cross-glycosylation and PNP as a biocatalyst. An efficient method for 3′-deoxyinosine synthesis starting from inosine was developed. However, the very poor solubility of 2ClAde and 2FAde is the limiting factor of the first approach. The second approach enables this problem to be overcome and it appears to be advantageous over the former approach from the viewpoint of practical synthesis of the title nucleosides. The 3-deoxy-α-d-ribofuranose-1-phosphate intermediary formed in the 3′dIno phosphorolysis by PNP was found to be the weak and marginal substrate of E. coli thymidine (TP) and uridine (UP) phosphorylases, respectively. Finally, one-pot cascade transformation of 3-deoxy-d-ribose in cordycepin in the presence of adenine and E. coli ribokinase, phosphopentomutase, and PNP was tested and cordycepin formation in ca. 3.4% yield was proved.

A deamination-driven biocatalytic cascade for the synthesis of ribose-1-phosphate

“…Pentose-1-phosphates (P1Ps), such as ribose-1-phosphate (Rib1P), are central molecules in the nucleoside salvage pathway. As substrates for nucleoside phosphorylases (NPs), they additionally serve as valuable starting points for the enzymatic synthesis of nucleoside analogues, [1][2][3][4][5][6][7] one of the most successful classes of small-molecule drugs to treat viral infections 8,9 or cancer, 10,11 and which recently attracted interest as precursors of mRNA vaccines 12,13 and antibacterial agents. 14,15 Employing P1Ps for the synthesis of nucleoside analogues is especially advantageous when product yields are low due to thermodynamic constraints [16][17][18][19] or when suitable donor nucleosides are not readily available.…”