Calcium-Controlled Regiodivergent Alkylation: Overriding Olefin Geometry Bias for the Synthesis of Cyclopropylated Nucleosides

Abstract

Cyclopropylated nucleoside derivatives as adenosine receptor ligands were designed and synthesized using an olefin geometry-independent intramolecular SN2′ enolate alkylation as a key step. Notably, (Z)-olefin, which has been reported to favor conventional SN2 reactivity over SN2′, afforded efficient SN2′ cyclopropanation with a markedly improved regioselectivity when calcium bases were employed. Our computational analysis suggests that the calcium cation complex, involving a bulkier cationic species with weaker Lewis acidity, enhances selectivity toward the SN2′ pathway. In the regiodivergent TSs leading to SN2 and SN2′ reactions, where two activated substrate molecules coordinate to Ca2+, we found that the SN2′ pathway was favored energetically.