syn‐Selective Michael Reaction of α‐Branched Aryl Acetaldehydes with Nitroolefins Promoted by Squaric Amino Acid Derived Bifunctional Brønsted Bases

Abstract

Here we describe a direct access to 2,2,3-trisubstituted syn γnitroaldehydes by addition of α-branched aryl acetaldehydes to nitroolefins promoted by a cinchona based squaric acid-derived amino acid peptide. Different α-methyl arylacetaldehydes react with β-aromatic and β-alkyl nitroolefins to afford the Michael adducts in high enantioselectivity and syn-selectivity. NMR experiments and DFT calculations predict the reaction to occur through the intermediacy of E-enolate. The interaction between the substrates and the catalyst follows Pápai's model, wherein an intramolecular H-bond interaction in the catalyst between the NH group of one of the tert-leucines and the squaramide oxygen seems to be key for discrimination of the corresponding reaction transition states.

Progress in (Thio)urea‐ and Squaramide‐Based Brønsted Base Catalysts with Multiple H‐Bond Donors

“…The alternative Re enolate / Si nitroolefin approach that would lead to minor ent ‐ 198 product lies 3.1 kcal/mol higher in energy, as happens with the Re enolate / Re nitroolefin approach leading to the syn diastereomer of 198 (5.2 kcal/mol higher in energy). As shown in Scheme 62d, the same group also demonstrated that related catalysts C89 and C90 are capable of efficiently promoting the Michael addition of α‐branched aryl acetaldehydes 199 [115] . More specifically α‐methyl arylacetaldehydes react efficiently with β‐(hetero)aromatic and β‐alkyl nitroolefins 2 to provide 1,2,3‐trisubstituted syn γ‐nitroaldehydes 200 in high enantio‐ and syn ‐selectivity.…”

“…As shown in Scheme 62d, the same group also demonstrated that related catalysts C89 and C90 are capable of efficiently promoting the Michael addition of α-branched aryl acetaldehydes 199. [115] More specifically α-methyl arylacetaldehydes react efficiently with β-(hetero)aromatic and β-alkyl nitroolefins 2 to provide 1,2,3-trisubstituted syn γ-nitroaldehydes 200 in high enantio-and syn-selectivity. In this case DFT calculations predict the reaction to occur through the intermediacy of the E-enolate.…”

“…This was attributed [112] b) Zhao, 2019 [113] and c,d) Mielgo and Palomo, 2021. [114,115] to a larger steric congestion between the tert-butyl group of one of the tert-Leucines and the phenyl group of the enolate in TS35'. The calculated energy for the TS affording the minor syn diastereomer of 200 was found to be 6.3 kcal/mol higher in energy.…”

“… Stereoselective reactions promoted by amide‐squaramide BBs C86 ‐ C90 . a) Yan, 2019; [112] b) Zhao, 2019 [113] and c,d) Mielgo and Palomo, 2021 [114,115] …”

Asymmetric decarboxylative [3 + 2] cycloaddition for the diastereo- and enantioselective synthesis of spiro[2.4]heptanes via cyclopropanation

“…On the one hand, nitroolefins have been proven to be excellent Michael acceptors and are used in stereoselective conjugated addition reactions for the construction of numerous structurally essential nitro-functionalized frameworks due to their high reactivity. 10 Meanwhile, hydrogen-bonding catalysts, especially squaramides and urea-tertiary amines, have been introduced in the Michael addition of nitroolefins due to their ability to create a rigid chiral environment through the formation of strong hydrogen bonds with the nitro group. 10 a Besides, the Zhang group recently reported an asymmetric [3 + 2] cycloaddition of vinylethylene carbonates with β-nitroolefins under the cooperative catalysis of a palladium complex and squaramide, providing chiral tetrahydrofurans with good to high yields and stereoselectivities.…”