We report the highly enantioselective addition of photogenerated α-amino radicals to Michael acceptors. This method features a dual-catalyst protocol that combines transition metal photoredox catalysis with chiral Lewis acid catalysis. The combination of these two powerful modes of catalysis provides an effective, general strategy to generate and control the reactivity of photogenerated reactive intermediates.

Photocatalytic reactions of enones using metal polypyridyl complexes proceed by very different reaction manifolds in the presence of either Lewis or Brønsted acid additives. Previous work from our lab demonstrated that photocatalytic [2+2] cycloadditions of enones required the presence of a Lewis acidic co-catalyst, presumably to activate the enone and stabilize the key radical anion intermediate. On the other hand, Brønsted acid activators alter this reactivity and instead promote reductive cyclization reactions of a variety of aryl and aliphatic enones via a neutral radical intermediate. These two distinct reactive intermediates give rise to transformations differing in the connectivity, stereochemistry, and oxidation state of their products. In addition, this reductive coupling method introduces a novel approach to the tin-free generation of β-ketoradicals that react with high diastereoselectivity and with the high functional group compatibility typical of radical cyclization reactions.

In marked contrast to the variety of strategies available for oxidation and nucleophilic functionalization of methylene groups adjacent to amines, relatively few approaches for modification of this position with electrophilic reaction partners have been reported. In the course of an investigation of the reactions of photogenerated α-amino radicals with electrophiles, we made the surprising observation that the efficiency of radical photoredox functionalization of N-aryl tetrahydroisoquinolines is dramatically increased in the presence of a Brønsted acid co-catalyst. Optimized conditions provide high yields and efficient conversion to radical addition products for a range of structurally modified tetrahydroisoquinolines and enones using convenient household light sources and commercially available Ru(bpy)3Cl2 as a photocatalyst. Our investigations into the origins of this unexpected additive effect have demonstrated that the carbon–carbon bond-forming step is accelerated by TFA and is a rare example of Brønsted acid catalysis in radical addition reactions. Moreover, a significant conclusion arising from these studies is the finding that product formation is dominated by radical chain processes and not by photocatalyst turnover. Together, these findings have important implications for the future design and mechanistic evaluation of photocatalytic radical processses.

Enantioselective Conjugate Additions of -Amino Radicals via CooperativePhotoredox and Lewis Acid Catalysis. -The first highly enantioselective intermolecular addition of photogenerated -amino radicals to Michael acceptors is reported. This new method features a dual-catalyst protocol that combines transition metal photoredox catalysis with chiral Lewis acid catalysis which provides an effective, general strategy to generate and control the reactivity of photogenerated reactive intermediates. Efficient removal of the pyrazolidinone auxiliary is cleanly achieved upon reaction with ethanethiolate, providing thioester (V) in nearly quantitative yield and without erosion of enantioselectivity. Auxiliary cleavage can also be induced in an intramolecular fashion by a sufficiently nucleophilic moiety in the product. Under similar conditions, secondary aniline (X) undergoes spontaneously intramolecular transacylation after the addition reaction to afford pyrrolidinone (XI) in high yield and excellent enantioselectivity. -(RUIZ ESPELT, L.; MCPHERSON, I. S.; WIENSCH, E. M.; YOON*, T. P.; J. Am. Chem. Soc. 137 (2015) 7, 2452-2455, http://dx.doi.org/10.1021/ja512746q ; Dep. Chem., Univ. Wis., Madison, WI 53706, USA; Eng.) -S. Adam 25-085