Synthesis of a Novel Nucleoside Based on a Spiroacetal Framework

Abstract

The first synthesis of a nucleoside analogue 1 is reported wherein the nucleobase 5-fluorocytosine is attached to a 1,6-dioxaspiro[5.5]undecane spiroacetal ring system. The spiroacetal system acts as a substitute for the sugar unit of natural nucleosides and provides a conformationally restricted framework upon which to append nucleobases in a well defined geometry. Trimethylsilyl triflate promoted Vorbrüggen-type coupling of bis(trimethylsilyl)-5-fluorocytosine 3 with spiroacetal acetate 2 provided spiroacetal nucleoside 1 in which the nucleobase occupied an equatorial position together with the ring opened (Z)-alkene 10. Spiroacetal acetate 2 serves as the spiroacetal donor and was prepared from the readily available starting materials δ-valerolactone and but-3-yn-1-ol 4.

(±)-1-{8′-(tert-Butyldiphenylsilyloxymethyl)-1′,7′-dioxaspiro[5.5]undecan-2′-yl}uridine

“…The title uridine was prepared as a part of study to elaborate 6,6-spiroacetal scaffolds to incorporate a nucleobase at the anomeric position, thus generating a collection of novel hybrid structures. Similar syntheses of 6,6-spiroacetal based molecules in the presence of a Lewis acid and persilylated nucleophile have been reported by Mead & Zemribo (1996) and Brimble et al (1998Brimble et al ( , 2004. (Table 1).…”

Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds

“…Under Vorbr üggen conditions, a persilylated heterobase is added to an oxonium ion generated from a spiroacetal bearing a leaving group at the anomeric position in the presence of a Lewis acid. 24, 25 TMSOTf was the initial choice of Lewis acid due to its proven ability to effect successful oxonium ion generation in a model study, 22,26 and its use by others for structurally related spiroacetals. 27, 28 Nucleosidation of ethoxy-spiroacetal 12 was first attempted because acetal 12 was obtained in higher yield in one less synthetic step than acetoxy-spiroacetal 10.…”

Unified, Radical-Based Approach for the Synthesis of Spiroketals

“…Spiroketals bearing an oxygen substituent at the 2-position were recently employed by Brimble et al for the synthesis of a number of nucleoside analogues, displaying interesting antiviral activity . Our method could easily be extended to the synthesis of such bisspiroketals, by using protected acrolein 14 as a radical trap (entry i).…”