The diastereoselective synthesis of anti -γ− oxo-αaminocarboxylates by aminoalkylation of ketones with in situ generated ternary iminium salts from inexpensive starting materials is described. These compounds are easily transformed diastereoselectively into syn,anti-or anti,anti − γ -hydroxy-α -aminocarboxylates by the use of different reducing agents. The configuration of the products has been determined by NMR. The aminoalkylation of enamines and imines is also reported.

Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used 19 F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency.

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Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure–activity relationship enabled efficient potency optimization.

Iminium salts generated in situ from ethyl glyoxylate, secondary amines and 1-H-benzotriazole are demonstrated to be excellent reagents for the regioselective mono-aminoalkylation of indoles, phenols, furans and pyrroles. This method provides a simple and straightforward "one-pot" reaction sequence to a variety of ethyl α-aryl-α-amino acid esters 5 and 8 in high yields.