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.
Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4′‐spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]‐cycloaddition of dichloroketene on readily available 4′‐exo‐methylene furanose sugars efficiently results in the diastereoselective formation of novel 4′‐spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non‐synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3′‐position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4′‐spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4′‐spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.
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