Development of an α′-hydroxy enone for the aminocatalytic asymmetric formal conjugate addition of aldehydes to acrylates, vinyl ketones and acrolein

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C-C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α'-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl-vinyl ketones and acrylates, respectively.Support has been provided by the Basque Government (GV grant IT‐1583‐22), and Ministerio de Ciencia e Innovación (grant PID2019‐109633GB/AEI/10.13039/501100011033), Spain. A predoctoral grant to B. L. from Navarra Government is acknowledged

Organocatalytic Michael Addition of Unactivated α-Branched Nitroalkanes to Afford Optically Active Tertiary Nitrocompounds

The direct, asymmetric conjugate addition of unactivated α-branched nitroalkanes is developed based on the combined use of chiral amine/ureidoaminal bifunctional catalysts and a tunable acrylate template to provide tertiary nitrocompounds in 55–80% isolated yields and high enantioselectivity (e.r. up to 96:4). Elaboration of the ketol moiety in thus obtained adducts allows a fast entry to not only carboxylic and aldehyde derivatives but also nitrile compounds and enantioenriched 5,5-disubstituted γ-lactams.We thank the Basque Government (EJ, grant IT1583-22) and Agencia Estatal de Investigación (grants PID2019-109633GB and PID2022-137153NB-C21/AEI/10.13039/501100011033) for financial support. A.G.-U. thanks EJ; B.L. thanks the Navarra Government, and M.E.-V. thanks UPNA (PJUPNA18-2022). Authors also thank SGIker (UPV/EHU/ERDF, EU) for providing NMR, HRMS, and X-ray resources

Development of an α’-hydroxy enone for the aminocatalytic asymmetric formal conjugate addition of aldehydes to acrylates, vinyl ketones and acrolein

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C–C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α′-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl–vinyl ketones and acrylates, respectively.Support has been provided by the Basque Government (GV grant IT1583-22), and Ministerio de Ciencia e Innovación (grant PID2019-109633GB/AEI/10.13039/501100011033), Spain.A predoctoral grant to B. L. from Navarra Government (34E/ 2020) is acknowledge

Enantioselective Construction of Tetrasubstituted Stereogenic Carbons through Brønsted Base Catalyzed Michael Reactions: α´-Hydroxy Enones as Key Enoate Equivalent

Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C–C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Brønsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.Financial support was provided by the University of the Basque Country UPV/EHU (UFI 11/22), Basque Government (Grant No IT-628-13 and Saiotek 2014), and Ministerio de Economía y Competitividad (Grant CTQ2013-47925-C2), Spain. E.B. and I.O. thank Ministerio de Educación y Ciencia, and I.U. thanks Gobierno Vasco for Fellowships. B.F. thanks the European Commission (FP7-3163792012-ITN). We also thank SGIker (UPV/EHU) for providing NMR, HRMS, X-ray, and computational resources