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.

Recent Advances in Azlactone Transformations

“…[61] In this context, the Steglich rearrangement is an interesting approach, which involves an O-to C-acyl migration, with formation of a new stereogenic center. [61] In this context, the Steglich rearrangement is an interesting approach, which involves an O-to C-acyl migration, with formation of a new stereogenic center.…”

Applications of Chiral Squaramides: From Asymmetric Organocatalysis to Biologically Active Compounds

“…[33] In 2014, Palomo and coworkers reported that glutamic acid derivative 53 can be obtained through the asymmetric conjugate addition of azlactones using chiral squaramide C2 as the catalyst (Scheme 19). [34] In 2015, Palomo and coworkers demonstrated for the first time that various N-substituted a-amino acid derivatives could be obtained in excellent diastereoselectivities and enantioselectivities through the enantioselective 1,4-addition reaction of imidazolones to nitroolefins (Scheme 20). [35] Scheme 8.…”

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

“…For example in 2013, Palomo and co-workers introduced 5 H -thiazol-4-ones as a new class of sulfur-containing pro-nucleophiles in a highly enantio- and diastereoselective conjugate addition to nitroalkenes, providing α,α-disubstituted α-mercapto carboxylic acids [5]. Since then, several asymmetric variants using 5 H -thiazol-4-ones as nucleophiles have been disclosed; such as amination [6], allylation [7], conjugate addition to enones [8], and γ-addition with allenoates [9]. All these examples focused on nucleophilic addition reactions of the C5 atom of 5 H -thiazol-4-ones.…”