An Efficient Method for the Preparation of 1′α-Branched-Chain Sugar Pyrimidine Ribonucleosides from Uridine: The First Conversion of a Natural Nucleoside into 1′-Substituted Ribonucleosides

Abstract

The 1'alpha-phenylselenouridine derivative 13 was successfully synthesized by enolization of the 3',5'-O-TIPDS-2'-ketouridine 8, and was subjected to a radical reaction with a vinylsilyl tether--an efficient procedure for preparing 1'alpha-branched-chain sugar pyrimidine nucleosides. Successive treatment of 8 with LiHMDS and PhSeCl in THF at < -70 degrees C gave the desired 1'-phenylseleno products in 85% yield as an anomeric mixture of the 1'alpha-product 11 and the 1'beta-product 12 (11/12= 2.5:1). Highly stereoselective reduction at the 2'-carbonyl of the 1'alpha-product 11 occurred from the beta-face by using NaBH4/CeCl3 in MeOH, and subsequent introduction of a dimethylvinylsilyl tether at the 2'-hydroxyl gave the radical reaction substrate 14. The photochemical radical atom-transfer reaction of 14 by using a high-pressure mercury lamp proceeded effectively in benzene to give the exo-cyclized PhSe-transferred product 18, in which (PhSe)2 proved to be essential as an additive for radical atom-transfer cyclization reactions. Subsequent phenylseleno-group elimination of 18 gave the sugar-protected 1'alpha-vinyluridine. With this procedure, 1'alpha-vinyluridine (22) and -cytidine (25), designed to be potential antitumor agents, were successfully synthesized. This study is the first example of functionalization at the anomeric 1'-position of a nucleoside by starting from a natural nucleoside to produce a ribo-type 1'-modified nucleoside.

A Highly Stereoselective Samarium Diiodide-Promoted Aldol Reaction with 1‘-Phenylseleno-2‘-keto Nucleosides. Synthesis of 1‘α-Branched Uridine Derivatives

“…Our synthetic plan, using the 1‘-phenylseleno-2‘-ketouridine derivative IV as the precursor for the 1‘-enolate, is summarized in Scheme . We previously reported that a phenylseleno group could be introduced stereoselectively at the 1‘α-position of 2‘-ketouridine derivatives, which readily provides the substrate IV for the SmI 2 -promoted aldol reaction. We speculated that if the phenylseleno group at the 1‘-position of VI was reductively cleaved by SmI 2 like the anomeric phenylthio group of the ulose I , the samarium enolate V would be formed.…”

“…Using this method, they prepared the antitumor 1‘-cyano cytosine nucleoside 4 7b. Most recently, we stereoselectively synthesized 1‘-vinyl pyrimidine ribonucleosides starting from uridine, via a novel intramolecular radical cyclization reaction with a silyl tether as the key step . These are the only two practical examples reported so far that provide 1‘-branched nucleosides in rather good overall yield because they use natural nucleosides as the synthon thereby shortening the reaction steps.…”

From the Chemistry of Epoxy-Sugar Nucleosides to the Discovery of Anti-HIV Agent 4&apos;-ethynylstavudine-Festinavir

“…The method shown in Scheme 4 is intermolecular radical reaction of 1′-phenylsulfanyldeoxyuridine 9 with allyltributyltin to give 1′-allyl-2′-deoxynucleoside ( 10 ) [13]. The other method depicted in Scheme 5 is intramolecular radical cyclization of 11 (Scheme 5) [14]. The cyclized product 12 could be transformed into 1′-vinyluridine ( 13 ) by means of fluoride ion-mediated E2-elimination.…”

Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis

“…These methods are not very practical and have drawbacks: (1) the preparation of the 1Ј-branched sugars requires many reaction steps and the overall yields are low and (2) the stereoselective introduction or construction of the nucleobase is tedious. [93][94][95][96] We thought that the SmI 2 -promoted aldol reaction could be applicable to the synthesis of 1Ј-branched nucleosides. Namely, 1Ј-phenylseleno-2Ј-ketouridine derivative 54 or 55 95,96) was chosen as a precursor to the SmI 2 -promoted aldol reaction.…”

“…[93][94][95][96] We thought that the SmI 2 -promoted aldol reaction could be applicable to the synthesis of 1Ј-branched nucleosides. Namely, 1Ј-phenylseleno-2Ј-ketouridine derivative 54 or 55 95,96) was chosen as a precursor to the SmI 2 -promoted aldol reaction. First, the SmI 2 -promoted generation of the 1Ј-enolate was examined (Chart 8).…”