Probing α‐Amino Aldehydes as Weakly Acidic Pronucleophiles: Direct Access to Quaternary α‐Amino Aldehydes by an Enantioselective Michael Addition Catalyzed by Brønsted Bases

Abstract

The high tendency of α‐amino aldehydes to undergo 1,2‐additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α‐amino aldehydes. Herein, it is demonstrated that the chemistry of α‐amino aldehydes may be expanded beyond these limits by documenting the first direct α‐alkylation of α‐branched α‐amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo‐ and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α‐amino aldehyde is key for reaction stereocontrol.

Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II—Design, Synthesis, and Evaluation

“…Detailed procedures and characterization of the synthesized compounds together with copies of the NMR spectra are available in the Supplementary Materials related to this manuscript. Analytical data of compounds 14 [52], 23a [53], 23b [52], 23c [54], 23d [54], 23e [54], 23f [55], 15 [56], 18a [57], 18b [40], 22 [58], 24b [59] and 42a [60] were in agreement with those previously reported.…”

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

“…In another recent example, Palomo laboratory has reported C88 as efficient catalyst for the addition reaction of N ‐acyl α‐aminoaldehydes 197 to nitroolefins to yield the corresponding quaternary α‐amino aldehydes 198 with very good enantio‐ and diastereoselectivity (Scheme 62c) [114] . As shown in TS34 DFT calculations predict a strong intramolecular H‐bonding interaction between the amide NH and the squaramide carbonyl in the catalyst which probably enhances the H‐bonding capability of the squaramide.…”

“…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] …”

Construction of Thioamide Peptide via Sulfur-Involved Amino Acids/Amino Aldehydes Coupling

“…α-Amino aldehydes (1a-v, 1d'-1j') were known compounds. [3][4][5][6][7] Benzyl (S)- (1-((2-hydroxyethyl)amino)-1oxopropan-2-yl)carbamate was a known compound. 8 II.…”