ChemoselectiveN-Deacetylation of Protected Nucleosides and Nucleotides Promoted by Schwartz's Reagent

Abstract

Protection and deprotection strategies involving the N-acetyl group are widely utilized in nucleoside and nucleotide chemistry. Herein, we present a mild and selective N-deacetylation methodology, applicable to purine and pyrimidine nucleosides, by means of Schwartz's reagent, compatible with most of the common protecting groups used in nucleoside chemistry.

Hydrozirconation of C=X Functionalities with Schwartz's Reagent

“…[26,27] Twenty years later, Bhat and co-workers [44] reported a general study on N-deacylation of various N-acetamides with [Cp 2 Zr(H)Cl]. Ferrari and co-workers [45] applied Bhat's approach in the N-deacetylation of a series of functionalized nucleosides and nucleotides. in THF at room temp., followed by water addition, either N-acetylated anilines or aliphatic amines were readily transformed into free amines in high yields in 2-5 min (Scheme 36).…”

“…Even heteroaromatic N-Ac amines could be depro- Scheme 35. [45] tected efficiently without any problems.…”

“…Additionally, Bhat and coworkers [44] demonstrated that the described hydrozirconation/ hydrolysis sequence can be applied successfully for chemoselective N-deacetylation of protected amino acids without any racemization (Scheme 37). Ferrari and co-workers [45] applied Bhat's approach in the N-deacetylation of a series of functionalized nucleosides and nucleotides. Unfortunately, the deprotection of N-Ac purine and pyrimidine nucleosides by treatment with [Cp 2 Zr(H)Cl] ( , along with the recovery of the starting material.…”

“…The same authors demonstrated that Schwartz's reagent is compatible with the phosphoramide moiety, frequently present in nucleoside-based phosphoramide prodrugs, such as sofosbuvir (hepatitis C treatment), [46] which gives an opportunity to develop this protocol as the method of choice for late-stage modification of such class of bioactive compounds (Scheme 39). [45] Scheme 39. The synthesis and deacetylation of N-acetyl-2′,3′-O-isopropylidene-cytidine-5′-O-[naphthyl(cyclohexyl-L-alanyl)] phosphate promoted by Schwartz's reagent.…”

Synthetic Approaches for the Preparation of Phosphoramidate Prodrugs of 2′‐Deoxypseudoisocytidine

“…[27] Acidic deprotection of 20 a-f afforded after preparative HPLC purification compounds 21 a-f in moderate yields (Scheme2and Table 1). Attempts to removet he acetyl protec-tion from 21 a with Schwartz's reagent as described by Ferrari et al, [28] failed due to the ring openingo ft he base. The difficultiese ncountered in removing the N-acetyl group from 21 af using mild conditions, and the fact that the labile PÀOb ond of the ProTide would not tolerate other harsh de-acetylating agentss uch as methanolic ammonia,p romptedu st oa bandon our attempts toward modification of 21 a-f.W et herefore continued our effort to conceiveamore efficient route that would allow the preparation of the N-deacetylated analogues.…”