The stereoselective preparation of a novel 4’-spirocyclopropyl nucleoside analogue has been described using a semi-benzilic Favorskii rearrangement of a 4’-(2-chloro-3-oxocyclobutyl)spirofuranose as a key step. We demonstrated that the latter chiral spirocyclic intermediates, readily obtained on multigram scale from chiral pool starting materials, are highly suitable precursors to obtain full stereoselectivity in the reduction-ring contraction sequence. The downstream nucleobase introduction via Vorbrüggen glycosylation successfully resulted in the formation of the corresponding novel 4’-spirocyclic nucleoside analogue in a stereospecific manner.

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.

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Metrics & MoreArticle RecommendationsT he corrected version of Figure 1 is shown here. In the original version, the structures of 2 and 3 were incorrect (typo). Figure 1. Examples of SAM analogues.