Synthesis of Pyranonucleoside‐6′‐triphosphates through the cycloSal‐Method

Abstract

The high yielding synthesis of pyranonucleoside‐6′‐triphosphates by using the cycloSal‐method is described. Synthesis of the activated cycloSal‐pyranonucleoside‐6′‐phosphate triesters was achieved by applying a synthetic route that had been developed for the synthesis of cycloSal‐(glycopyranosyl‐6)‐phosphates by us. The route involved regioselective 6′‐tert‐butyldimethylsilyl protection and exchange of the silyl protecting group by the fluorenylmethyloxycarbonyl (Fmoc) group. The 6′‐Fmoc‐protected derivatives were selectively converted into the cycloSal‐triester. These were then very efficiently converted into triphosphates by a “titration‐like” reaction with pyrophosphate. Simple purification by first ion exchange followed by reversed phase (RP) column chromatography afforded the triphosphates in very good yields.

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

“…Here, we report the synthesis of C8‐ N ‐acetyl‐ and C8‐ N H‐arylamine‐modified 2′‐deoxyguanosine‐5′‐triphosphates. The triphosphorylated adducts were synthesized by using cyclo Sal technology, which has been used successfully for the synthesis of various phosphorylated biomolecules . Conformation data on the C8‐ N ‐arylamine‐modified 2′‐deoxyguanosine‐5′‐triphosphates were collected by NOE spectroscopy and compared with DFT data.…”

The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

“…The first 2,6-difluorinated glucose derivative, nucleoside analogue 349 , was reported in 1978 by Etzold et al The synthesis started from 1-glucosyl thymine 343 (Scheme ), which can be obtained from glucose peracetate 155 in two steps. , Tosylation was only moderately selective at the 6-position, and the mixture was acetylated to then separate the 2,6-ditosylated byproduct. This gave 344 in 61% yield .…”

Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates

“…Other strategies such as the ProTide (aryloxyphosphoramidate) approach developed by McGuigan, − utilized in the prodrug Sofosbuvir (Figure ), and the related bisamidate prodrugs, which release innocuous amino acids as byproducts, were also attractive targets. The highly lipophilic alkoxyalkyl prodrugs [e.g., hexadecyloxypropyl (HDP)] pioneered by Hostetler were also considered as potential protecting groups for the phosphonate moiety of the α-CNPs. − Additionally, the cyclic, salicyl alcohol-derived “CycloSal” prodrugs described by Meier were of particular interest given that the CycloSal moiety undergoes a pH-dependent chemical hydrolysis to unmask the phosphonate rather than enzymatic hydrolysis; the stability of the CycloSal prodrugs can be altered by modification of substituents on the aromatic ring. − A further prodrug moiety of interest, also developed by Meier, was the acyloxybenzyl phosphonate. Acyloxybenzyl prodrugs have been used with nucleoside phosphates, diphosphates, , and triphosphates, and also with phosphonates. , In this case, the deprotection of the phosphonate function is triggered by enzymatic hydrolysis of the acyl group, which is remote from the carboxyphosphonate, followed by spontaneous loss of the resulting hydroxybenzyl groups to reveal the free phosphonate.…”