Asymmetric and Geometry‐Selective α‐Alkenylation of α‐Amino Acids

Both E‐ and Z‐N′‐alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α‐amino acids. Generation of their enolate derivatives in the presence of K⁺ and [18]crown‐6 induces intramolecular migration of the alkenyl group from N′ to Cα with retention of double bond geometry. DFT calculations indicate a partially concerted substitution mechanism. Hydrolysis of the enantiopure products under acid conditions reveals quaternary α‐alkenyl amino acids with stereodivergent control of both absolute configuration and double bond geometry.     

Controlling the Helix Handedness of ααβ‐Peptide Foldamers through Sequence Shifting

Peptide foldamers containing both cis ‐β‐aminocyclopentanecarboxylic acid and α‐amino acid residues combined in various sequence patterns (ααβ, αααβ, αβααβ, and ααβαααβ) were screened using CD and NMR spectroscopy for the tendency to form helices. ααβ‐Peptides were found to fold into an unprecedented and well‐defined 16/17/15/18/14/17‐helix. By extending the length of the sequence or shifting a fragment of the sequence from one terminus to another in ααβ‐peptides, the balance between left‐handed and right‐handed helix populations present in the solution can be controlled. Engineering of the peptide sequence could lead to compounds with either a strong propensity for the selected helix sense or a mixture of helical conformations of opposite senses.     

Access to Cyclic β‐Amino Acids by Amine‐Catalyzed Enantioselective Addition of the γ‐Carbon Atoms of α,β‐Unsaturated Imines to Enals

Disclosed herein is a new catalytic approach for an efficient access to cyclic β‐amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ‐carbon atoms of α,β‐unsaturated imines to enals by iminium organic catalysis. This highly chemo‐ and stereo‐selective reaction affords cyclic β‐amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.     

A Metallaphotoredox Strategy for the Cross‐Electrophile Coupling of α‐Chloro Carbonyls with Aryl Halides

Here, we demonstrate that a metallaphotoredox‐catalyzed cross‐electrophile coupling mechanism provides a unified method for the α‐arylation of diverse activated alkyl chlorides, including α‐chloroketones, α‐chloroesters, α‐chloroamides, α‐chlorocarboxylic acids, and benzylic chlorides. This strategy, which is effective for a wide variety of aryl bromide coupling partners, is predicated upon a halogen atom abstraction/nickel radical‐capture mechanism that is generically successful across an extensive range of carbonyl substrates. The construction and use of arylacetic acid products have further enabled two‐step protocols for the delivery of valuable building blocks for medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs.     

Detection and Chiral Recognition of α‐Hydroxyl Acid through 1H and CEST NMR Spectroscopy Using a Ytterbium Macrocyclic Complex

Chiral α‐hydroxyl acids are of great importance in chemical synthesis. Current methods for recognizing their chirality by ¹H NMR are limited by their small chemical shift differences and intrinsic solubility problem in organic solvents. Herein, we developed three YbDO3A(ala)₃ derivatives to recognize four different commercially available chiral α‐hydroxyl acids in aqueous solution through ¹H NMR and chemical exchange saturation transfer (CEST) spectroscopy. The shift difference between chiral α‐hydroxyl acid observed by proton and CEST NMR ranged from 15–40 and 20–40 ppm, respectively. Our work demonstrates for first time, that even one chiral center on the side‐arm chain of cyclen could set the stage for rotation of the other two non‐chiral side chains into a preferred position. This is ascribed to the lower energy state of the structure. The results show that chiral YbDO3A‐like complexes can be used to discriminate chiral α‐hydroxyl acids with a distinct signal difference.     

Light‐Driven Kinetic Resolution of α‐Functionalized Carboxylic Acids Enabled by an Engineered Fatty Acid Photodecarboxylase

Chiral α‐functionalized carboxylic acids are valuable precursors for a variety of medicines and natural products. Herein, we described an engineered fatty acid photodecarboxylase (CvFAP)‐catalyzed kinetic resolution of α‐amino acids and α‐hydroxy acids, which provides the unreacted R‐configured substrates with high yields and excellent stereoselectivity (ee up to 99 %). This efficient light‐driven process requires neither NADPH recycling nor prior preparation of esters, which were required in previous biocatalytic approaches. The structure‐guided engineering strategy is based on the scanning of large amino acids at hotspots to narrow the substrate binding tunnel. To the best of our knowledge, this is the first example of asymmetric catalysis by an engineered CvFAP.