ABSTRACT
Infectious diseases caused by resistant Gram-negative bacteria have become a serious problem, and the development of therapeutic drugs with a novel mechanism of action and that do not exhibit cross-resistance with existing drugs has been earnestly desired. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a drug target that has been studied for a long time. However, no LpxC inhibitors are available on the market at present. In this study, we sought to create a new antibacterial agent without a hydroxamate moiety, which is a common component of the major LpxC inhibitors that have been reported to date and that may cause toxicity. As a result, a development candidate, TP0586532, was created that is effective against carbapenem-resistant Klebsiella pneumoniae and does not pose a cardiovascular risk.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Imidazoles/pharmacology , Klebsiella pneumoniae/drug effects , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Imidazoles/chemical synthesis , Imidazoles/chemistry , Klebsiella pneumoniae/enzymology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
This paper describes catalytic asymmetric Mannich-type reactions of beta-ketoesters and malonates using chiral palladium complexes. Although readily enolizable, carbonyl compounds are attractive substrates, the use of such compounds as nucleophiles in Mannich-type reactions has not been extensively investigated. In the presence of chiral Pd aqua complexes (2.5 mol %), beta-ketoesters reacted with various N-Boc imines (Boc=tert-butoxycarbonyl) to afford the desired beta-aminocarbonyl compounds in good yield with high to excellent stereoselectivity (up to 96:4 d.r., 95-99 % ee in most cases). In these reactions, construction of highly crowded vicinal quaternary and tertiary carbon centers was achieved in one step. A chiral Pd enolate is considered to be the key intermediate. To elucidate the stereoselectivity observed in the reaction, possible transition-state models are discussed, taking into account steric and stereoelectronic effects. Furthermore, this catalytic system was applied to the Mannich-type reaction of malonates with N-Boc imine as well as one-pot classical aminomethylation of beta-ketoesters using benzylamine salt and formalin. The reactions proceeded smoothly, and the corresponding Mannich products were obtained in high yield with moderate to good enantioselectivity.
ABSTRACT
Detailed mechanistic studies on our recently reported asymmetric addition reactions of malonates to dihydroisoquinolines (DHIQs) catalyzed by chiral Pd(II) complexes were carried out. It was found that an N,O-acetal was generated in situ by the reaction of DHIQ with (Boc)2O, and cooperative action of the Pd(II) complex as an acid-base catalyst allowed the formation of a chiral Pd enolate and a reactive iminium ion via alpha-fragmentation. The iminium ion was also accessible via oxidation with DDQ as an oxidant, and a catalytic asymmetric oxidative Mannich-type reaction was achieved with tetrahydroisoquinolines (THIQs) as starting materials. This oxidation protocol was applicable to N-acryloyl-protected THIQs, allowing the efficient synthesis of optically active tetrahydrobenzo[a]quinolizidine derivatives via intramolecular Michael reaction.
Subject(s)
Isoquinolines/chemistry , Amines/chemistry , Catalysis , Crystallography, X-Ray , Esters/chemistry , Imines/chemistry , Ligands , Magnetic Resonance Spectroscopy , Mannich Bases/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Palladium/chemistry , Spectrophotometry, Infrared , Stereoisomerism , TemperatureABSTRACT
We have developed a highly efficient reaction for catalytic asymmetric addition of malonates to dihydroisoquinolines using chiral Pd(II) complexes. In the reactions, substrates with various substitution patterns were available, and the reactions were complete within several hours (<3 h in most cases) under mild reaction conditions, affording various optically active C1-substituted tetrahydroisoquinoline derivatives (up to 98% yield, up to 97% ee). Furthermore, slow addition of DDQ allowed the in situ generation of the reactive intermediate from the corresponding N-Boc-protected amine, and dehydrogenative addition reaction was successfully demonstrated.