Taming secondary benzylic cations in catalytic asymmetric S_N1 reactions

Abstract

Benzylic stereogenic centers are ubiquitous in natural products and pharmaceuticals. A potentially general, though challenging, approach toward their selective creation would be asymmetric unimolecular nucleophilic substitution (S N 1) reactions that proceed through highly reactive benzylic cations. We now report a broadly applicable solution to this problem by identifying chiral counteranions that pair with secondary benzylic cations to engage in catalytic asymmetric C−C, C−O, and C−N bond-forming reactions with excellent enantioselectivity. The critical cationic intermediate can be accessed from different precursors via Lewis- or Brønsted acid catalysis. Key to our strategy is the use of only weakly basic, confined counteranions that are posited to prolong the lifetime of the carbocation, thereby avoiding nonproductive deprotonation pathways to the corresponding styrene.

Rh-Catalyzed Enantioselective Single-Carbon Insertion of Alkenes

“…The key to this process was the generation of enantioenriched allyl cations, which formed a contact ion pair with the nucleophile and evolved to valuable allylic electrophiles with excellent regioselectivity and enantiocontrol. This work represents a complementary addition to the repertoire of enantioselective methodologies developed over the last two decades in nucleophilic substitution with carbocation species, − which had overcome a major difficulty in biasing nucleophilic attack on one of the two prochiral faces of the planar structure of the carbocation.…”

Asymmetric Fluorocyclization of Difluoroalkenes with Concomitant Formation of a Trifluoromethyl Group

“…When these results are taken together with literature precedent revealing the involvement of fluorocarbocation intermediates, ,, the formation of such species even in the case of difluoroalkene substrates seems plausible. In addition to the lower reactivity of the difluoroalkenes, our target transformation was anticipated to be challenging because controlled enantioselectivity is less common in S N 1-type reactions . However, we considered that enantioselectivity might be achieved, as our catalyst 1 would define the position of the substrate by a hydrogen bonding interaction .…”