Ni-Catalyzed Regioselective Dicarbofunctionalization of Unactivated Olefins by Tandem Cyclization/Cross-Coupling and Application to the Concise Synthesis of Lignan Natural Products

Abstract

We disclose a (terpy)NiBr₂-catalyzed reaction protocol that regioselectively difunctionalizes unactivated olefins with tethered alkyl halides and arylzinc reagents. The reaction shows an excellent functional group tolerance (such as ketones, esters, nitriles, and halides) and a moderate to good level of diastereoselectivity. The current cyclization/cross-coupling also tolerates molecules containing base-sensitive racemizable stereocenters, which are preserved without racemization during the reaction. This cyclization/cross-coupling provides a rapid access to (arylmethyl)carbo- and heterocyclic scaffolds, which occur widely as structural cores in various natural products and bioactive molecules. In order to show synthetic utility and generality, we have applied this new method in gram-scale quantities to the concise synthesis of six lignan natural products containing three different structural frameworks. We further conducted mechanistic investigations with radical probes and selectivity studies, which indicated that the current reaction proceeds via a single electron transfer (SET) process.