title: Enantioselective construction of tetrasubstituted stereogenic carbons through Brønsted base catalyzed michael reactions: α'-hydroxy enones as key enoate equivalent.
abstract: 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.
authors.affiliation: Departamento de Química Orgánica I, Universidad del País Vasco , Manuel Lardizábal 3, 20018-San Sebastián, Spain.
authors.forename: Eider
authors.initials: E
authors.lastname: Badiola
authors.forename: Béla
authors.initials: B
authors.lastname: Fiser
authors.forename: Enrique
authors.initials: E
authors.lastname: Gómez-Bengoa
authors.forename: Antonia
authors.initials: A
authors.lastname: Mielgo
authors.forename: Iurre
authors.initials: I
authors.lastname: Olaizola
authors.forename: Iñaki
authors.initials: I
authors.lastname: Urruzuno
authors.forename: Jesús M
authors.initials: JM
authors.lastname: García
authors.forename: José M
authors.initials: JM
authors.lastname: Odriozola
authors.forename: Jesús
authors.initials: J
authors.lastname: Razkin
authors.forename: Mikel
authors.initials: M
authors.lastname: Oiarbide
authors.forename: Claudio
authors.initials: C
authors.lastname: Palomo