ABSTRACT
The synthesis of the γ-secretase modulator MK-8428 (1) is described. The synthesis is highlighted by an enzyme-catalyzed reaction to access 3,4,5-trifluoro-(S)-phenylglycine, a 1-pot activation/displacement/deprotection sequence to introduce the aminooxy functionality and a dehydrative intramolecular cyclization under mild conditions to form the oxadiazine heterocycle of 1. In situ reaction monitoring was employed to understand the deleterious role of water during the formation of a methanesulfonate ester in the 1-pot activation/displacement/deprotection sequence.
Subject(s)
Acrylates/chemical synthesis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Oxazines/chemical synthesis , Acrylates/pharmacology , Carbon-13 Magnetic Resonance Spectroscopy , Catalysis , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Oxazines/pharmacologyABSTRACT
Using hydrostatic pressure to induce protein conformational changes can be a powerful tool for altering the availability of protein reactive sites and for changing the selectivity of enzymatic reactions. Using a pressure apparatus, it has been demonstrated that hydrostatic pressure can be used to modulate the reactivity of lysine residues of the protein ubiquitin with a water-soluble amine-specific homobifunctional coupling agent. Fewer reactive lysine residues were observed when the reaction was carried out under elevated pressure of 3 kbar, consistent with a pressure-induced conformational change of ubiquitin that results in fewer exposed lysine residues. Additionally, modulation of the stereoselectivity of an enzymatic transamination reaction was observed at elevated hydrostatic pressure. In one case, the minor diasteromeric product formed at atmospheric pressure became the major product at elevated pressure. Such pressure-induced alterations of protein reactivity may provide an important new tool for enzymatic reactions and the chemical modification of proteins.
Subject(s)
Enzymes/chemistry , Enzymes/metabolism , Proteins/chemistry , Proteins/metabolism , Amines/chemistry , Animals , Hydrostatic Pressure , Protein Binding , Solubility , Substrate Specificity , Water/chemistryABSTRACT
Aryl imidazolylsulfonates participate as electrophilic coupling partners in palladium-mediated cross-coupling reactions. The aryl imidazolylsulfonates display good stability while maintaining good reactivity in a variety of palladium-catalyzed coupling reactions. Imidazolylsulfonates are a practical and economic alternative to triflates.
