A central goal of modern organic chemistry is to develop novel catalytic enantioselective carbon-carbon bond-forming strategies for forging quaternary stereogenic centres. While considerable advances have been achieved in the realm of polar reactivity 1 , radical transformations have found very limited application 2 . This is despite the fact that open-shell intermediates are intrinsically primed for connecting structurally congested carbons, as their reactivity is only marginally affected by steric factors 3 . Herein we demonstrate how the combination of photoredox 4 and asymmetric organic catalysis 5 enables enantioselective radical conjugate additions to β,β-disubstituted cyclic enones to set quaternary carbon stereocentres with high fidelity. Key to our success was the design of a chiral organic catalyst, purposely adorned with a redox-active carbazole moiety, which drives the stereoselective interception of photochemically-generated carbon-centred radicals by means of an electron-relay mechanism. We demonstrate the generality of this organocatalytic radical-trapping strategy with two sets of open-shell intermediates, formed through unrelated light-triggered pathways from readily available substrates and photoredox catalysts. To the best of our knowledge, this method represents the first application of iminium ion activation 6 (a successful catalytic strategy for enantioselective polar chemistry) within the realm of radical reactivity.Organic chemists generally rely on polar reactivity to address the challenge of forging quaternary carbon stereocentres in a catalytic enantioselective fashion 1 . Of the synthetic methods available, metal-catalysed conjugate additions of organometallic nucleophilic species to trisubstituted unsaturated carbonyl substrates have recently emerged as a powerful technology [7][8][9][10][11] (Fig. 1a). These are reliable and stereoselective processes, but they generally require controlled reaction conditions and preformed organometallic reagents 7-10 . In contrast, there has been limited success in developing analogous transformations with nucleophilic carbon-centred radicals. While a few examples of metal-catalysed enantioselective radical conjugate additions have been reported [12][13][14][15] , none of these approaches provide for the formation of sterically demanding quaternary carbons. Our herein-reported work was prompted by the desire to address this gap in catalytic enantioselective methodology.Our initial motivation stems from the notion that, due to the long incipient carbon-carbon bond in the early transition state 16 , additions of radicals to electron-deficient olefins are rather insensitive to steric hindrance 3 . This makes radical reactivity particularly suited to connecting structurally complex carbon fragments while forging quaternary carbons, as testified to by literature synthesis of a natural product facilitated by radical conjugate additions 17 .

Equilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in . By comparing the exchange reactions between pairs (enamine A þ carbonyl B f carbonyl A þ enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1, 3-dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one) show a greater tendency to afford enamines than many R-substituted aldehydes.The renaissance of enamine chemistry 1 over the past 10 years, as secondary amine-catalyzed direct reactions of carbonyl compounds with electrophiles (enamine catalysis), has already given rise to around 1300 reports and 110 reviews.2 Due to our interest in Michael reactions, 3 including organocatalytic reactions involving nitroalkenes, 3cÀf and in the conversion of the nitro groups into carbonyl compounds by procedures mild enough to be applicable to complex polyfunctional fragments, 4 we focused on very recent, outstanding studies by Seebach et al.,5a Gschwind et al., 5b and List et al. 5c in which special examples of stable enamines were characterized.5 These papers prompted us to report the results that we obtained with O-tertbutyldiphenylsilyl-(S)-prolinol, 1, the catalytic performance of which was first examined by Peng et al. 6 We chose this catalyst because the bulky substituent (TBDPS group) is away from the R position of the pyrrolidine ring, which permits the attack of its amine not only on aldehydes but also on much less reactive ketones (with which catalysts such as those of MacMillan and JørgensenÀHayashi, more hindered sterically, do not form detectable amounts of enamines). In this context, we disclose here which enolizable carbonyl compounds show a higher tendency to form enamines with pyrrolidine derivative 1 (Scheme 1).When standard enolizable aldehydes, such as benzeneacetaldehye (phenylethanal), isovaleraldehyde (3-methylbutanal), cyclohexanecarboxaldehyde, or isobutyraldehyde (2-methylpropanal), were mixed with equimolar amounts of 1 in anhydrous DMSO-d 6 and the NMR spectra were

The enantioselective direct vinylogous aldol reaction of 3-methyl 2-cyclohexen-1-one with α-keto esters has been developed. The key to success was the design of a bifunctional primary amine-thiourea catalyst that can combine H-bond-directing activation and dienamine catalysis. The simultaneous dual activation of the two reacting partners results in high reactivity while securing high levels of stereocontrol.

We report a triple vinylogous cascade reaction, yielding valuable spiro‐oxindolic cyclohexane derivatives. The three‐component domino process proceeds by way of a catalyzed Michael/1,6‐addition/vinylogous aldol sequence affording the products with six stereogenic centers and very high control over the stereochemistry. The chemistry is based on a rare example of asymmetric 1,6‐addition to linear 2,4‐dienals proceeding with complete δ‐site selectivity. Key to the reaction development was a directing group positioned at the β‐dienal position, which was essential for achieving highly predictable reaction outcomes.magnified image