Conformational Restriction of Nucleosides by Spirocyclic Annulation at C4‘ Including Synthesis of the Complementary Dideoxy and Didehydrodideoxy Analogues

Abstract

The concept of spirocyclic restriction, when generically applied to nucleoside mimics, allows for the preparation of diastereomeric pairs carrying either a syn- or anti-oriented hydroxyl at C-5'. Reported herein are convenient synthetic routes to enantiomerically pure 1-oxaspiro[4.4]nonanes featuring fully dihydroxylated end products as well as congeners having dideoxy and didehydrodideoxy substitution patterns. Notable use is made of the capacity for introducing unsaturation in the furanose sector via phenylsulfenylation and the incorporation of uracil and thymine by way of their silylated derivatives under catalysis with stannic chloride.

Synthesis of chiral tetrahydrofuran derivatives

“…43 These results lead us to search more suitable methods for reducing spirodilactone 2g. A similar over reduction problem was also observed in the synthesis of conformationally restricted spirocyclic nucleosides by Paquette et al 44 and they solved the problem by using a low DIBALH concentration in the presence of an excess of Lewis acid (4.5 eq Me 3 SiCl). We applied that method to spirodilactone 2g and obtained lactol 9 together with bicyclic acetal 12 as a single diastereomer (up to 45% yield; Scheme 5).…”

Stereoselective Reactions in Preparation of Chiral α-Hetera­spiro[m.n]alkanes

“…28 The 3-sulfenyl derivative 81a is a substrate for nucleoside synthesis (Scheme 18). 28,29 Diisobutylaluminum hydride reduction of 81a and ester formation using acetic anhydride afford a mixture of the two anomeric acetates 83. The acetates 83 are glycosylated with a 2,4-bis(trimethylsiloxy)pyrimidine (trimethylsilyl-protected uracil or thymine), promoted by tin(IV) chloride to give uracil-derived product 84 in a 9:1 mixture in favor of the β-anomer.…”

Efficient Synthesis of Spirocyclic Nucleosides via Michael Addition-Initiated Intermolecular Cyclopropanation Reaction

“…[7] Moreover, spirocyclic nucleoside V had also demonstrated strong inhibitory effect against human coronavirus. [8] Traditional routes to construct spirocyclic nucleoside have been based on either a linear approach or a convergent synthesis that requires multiple steps from an equivalent starting material. [9] Hence, development of efficient methods to synthetize various spirocyclic nucleoside is Figure 1 Examples of biologically active spirocyclic nucleoside analogs highly desirable.…”