Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals

Abstract

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 .

Toward a mild dehydroformylation using base-metal catalysis

“…While appealing from a synthetic standpoint, we recognized that the dioxolane methylene of substrate 2a served as a competitive site of activation by TBADT as demonstrated by Fagnoni and coworkers, 34 suggesting that the elimination of this group would increase the reaction efficiency. To our delight, subjecting phenyl dimethyl propanal 3a to the same conditions afforded two alkenes in a combined yield of 73%, and a higher selectivity of 6.3 : 1 (Table 2).…”

Photoredox Catalysis in Organic Chemistry

“…Elegant work from the Yoon and Melchiorre groups has subsequently demonstrated that by using a chiral Lewis acid or organocatalyst respectively, these transformations can be rendered asymmetric (vide infra). 33,34 …”

“…Recently, Melchiorre and co-workers were able to elegantly leverage the long-established LUMO lowering strategy of iminium catalysis to develop asymmetric conjugate additions of α-amino radicals, derived from N -arylamines, to α,β-unsaturated ketones (Scheme 9). 34 A key challenge in the development of radical conjugate additions to iminium ions is the propensity for the radical cation intermediates (such as 18) to undergo β-scission to regenerate the iminium species (i.e., 17 ). 48 To overcome this issue, chiral primary amine catalyst 20 was employed wherein rapid intramolecular electron transfer between the electron-rich carbazole and the α-iminyl radical cation functionality of 18 occurs, thereby delivering the corresponding enamine and precluding an undesirable β-scission event.…”

Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

“…Their construction has long been recognized as an important challenge to the field of chemical synthesis, and several distinct catalytic, enantioselective approaches have been developed in response. 1,2,3,4 Notable examples include cycloadditions, 5 α and β-alkylation and arylation of carbonyls, 6–8 3,3′-additions, 9 S N 2′ reactions, 10 and Heck-type cross-couplings. 11 Each of these very powerful methods relies on enantiofacial addition across a prochiral substrate (Figure 1a) and therefore requires the preparation of stereochemically well-defined starting materials (such as trisubstituted olefins), and subsequent enantioselective bond formation.…”