Cyclopropane fusion of the only rotatable carbon-carbon bond in furanosyl nucleosides (i.e., exocyclic 4'-5') is a powerful design strategy to arrive at conformationally constrained analogues. Herein, we report a direct stereodivergent route toward the synthesis of the four possible configurations of 4-spirocyclopropane furanoses, which have been transformed into the corresponding 4'-spirocyclic adenosine analogues. The latter showed differential inhibition of the protein methyltransferase PRMT5-MEP50 complex, with one analogue inhibiting more effectively than adenosine itself, demonstrating the utility of rationally probing 4'-5' side chain orientations.

Stereodivergent Synthesis of Biologically Active Spironucleoside Scaffolds via Catalytic Cyclopropanation of 4-exo-Methylene Furanosides.

The synthesis of cyclopropyl pinacol boronic esters from dibromocyclopropanes via Matteson–Pasto rearrangement is reported. The method is readily scalable and shows limited levels of stereoinduction, with a selectivity that is in part complementary to that observed in existing stereoselective borylcyclopropanation strategies. The method can be used to rapidly access borylcyclopropanes as interesting building blocks for diversely functionalized cyclopropanes.

Synthesis of Cyclopropyl Pinacol Boronic Esters from Dibromo­cyclopropanes

Synthesis of Spirocyclic Cyclopropyl Glycosyl-1-phosphate Analogues.

Regio- and Stereoselective Synthesis of C-4' Spirocyclobutyl Ribofuranose Scaffolds and Their Use as Biologically Active Nucleoside Analogues.

In continuation of our efforts of finding novel nucleoside inhibitors for the treatment of viral diseases, we initiated a discovery research program aimed at identifying novel nucleos(t)ide inhibitors for emerging diseases like Dengue and Chikungunya. Based on the previously reported 2'-spiro-oxetane uridine derivatives active against Hepatitis C Virus (HCV), we envisaged its sulfur analogue as an interesting congener both from a synthetic as well as biological point of view. Surprisingly, we found the 2'-spirothietane uridine derivatives not only to be active against HCV and Dengue virus (DENV), viruses belonging to the flavivirus family, but also to demonstrate activity against alphaviruses like Chikungunya virus (CHIKV) and Sindbis virus (SINV).

From Oxetane to Thietane: Extending the Antiviral Spectrum of 2'-Spirocyclic Uridines by Substituting Oxygen with Sulfur.

The stereoselective preparation of a novel 4′-spirocyclopropyl nucleoside analogue has been developed by using a semibenzilic Favorskii rearrangement of a 4′-(2-chloro-3-oxocyclobutyl)spirofuranose as a key step These chiral spirocyclic intermediates, readily obtained on a multigram scale from chiral-pool starting materials, were shown to be highly suitable precursors for achieving full stereoselectivity in the reduction–ring contraction sequence The downstream introduction of a nucleobase through Vorbruggen glycosylation successfully resulted in the formation of the corresponding novel 4′-spirocyclic nucleoside analogue in a stereospecific manner

Wenbin Wang

Papers

Stereodivergent Synthesis of Biologically Active Spironucleoside Scaffolds via Catalytic Cyclopropanation of 4-exo-Methylene Furanosides.

Preparation of Novel 4′-Spirocyclopropyl Nucleoside Analogues

Regio- and Stereoselective Synthesis of C-4' Spirocyclobutyl Ribofuranose Scaffolds and Their Use as Biologically Active Nucleoside Analogues.