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

Abstract

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.

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

“…By systematic protecting group iterations, a further tuning of the steric bias of the exo -methylene furanose building block proved feasible, and we were able to improve the facial selectivity. This approach was already demonstrated to be highly successful in work toward cyclopropanations of such furanose substrates . For instance, with the 4′- exo -methylene α- d -ribofuranose 7b as the starting material, only the β regioisomer 17b was obtained in 75% yield (Scheme ).…”

Synthesis of Cyclopropyl Pinacol Boronic Esters from Dibromo­cyclopropanes

“…1 H NMR (400 MHz, CDCl 3 ):  = 3.89 (d, J = 8.1 Hz, 1 H), 3.78 (dt, J = 10.9, 3.7 Hz, 1 H), 3.35 (ddd, J = 11.8, 11.0, 2. 4 Hz, 1 H), 2.09-1.98 (m, 1 H), 1.94-1.72 (m, 3 H), 1.38 (dddd, J = 13.7, 8.0, 5.4, 2.6 Hz, 1 H) ppm. 13 C NMR (75 MHz, CDCl 3 ):  = 64.…”

“…1 H NMR (400 MHz, CDCl 3 ):  = 7.36-7.10 (m, 10 H), 4.61 (d, J = 12.1 Hz, 1 H), 4.57 (d, J = 12.1 Hz, 1 H), 3.65 (dd, J = 10.5, 5.8 Hz, 1 H), 3.43 (dd, J = 10.5, 6.9 Hz, 1 H), 2.25 (dd, J = 10.5, 5. 4 Hz, 1 H), 2.07-2.01 (m, 1 H), 1.02 (s, 6 H), 0.89 (s, 6 H), 0.41 (dd, J = 10.5, 6.6 Hz, 1 H) ppm. 13 C NMR (175 MHz, CDCl 3 ):  = 140.0, 138.8, 128.9 (2 C), 128.5 (2 C), 127.9 (2 C), 127.7 (2 C), 127.6, 126.0, 83.2 (2 C), 74.1, 72.4, 27.9, 24.9 (m, 10 H), 4.57 (d, J = 11.9 Hz, 1 H), 4.52 (d, J = 11.9 Hz, 1 H), 3.79 (dd, J = 10.2, 6.5 Hz, 1 H), 3.59 (dd, J = 10.2, 8.0 Hz, 1 H), 2.12 (dd, J = 6.0, 5.3 Hz, 1 H), 1.78 (dddd, J = 9.8, 7.9, 6.6, 5.0 Hz, 1 H), 1.24 (s, 6 H), 1.22 (s, 6 H), 0.58 (dd, J = 9.8, 6.4 Hz, 1 H) ppm.…”

“…As part of our investigations towards 4′-spirocyclic nucleoside precursors, 4 8 the present study was initiated with the dibromocyclopropanation of 4- exo -methylene furanoside 1a using a phase-transfer-catalysis procedure 9 and bromoform as a carbene precursor under basic conditions (Scheme 2 , eq. 1).…”

“…2 In the last decade, borylcyclopropanes have gained interest in organic synthesis as valuable building blocks for the functionalization of cyclopropanes. 3 In the course of ongoing synthetic investigations, 4 we developed an interest in the synthesis of cyclopropyl pinacol boronic esters. Generally, cyclopropyl pinacol boronic esters can be synthesized by borylation, 2a 5 borylcyclopropanation, 6 as well as transformation of pinacol boron-containing molecules.…”