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A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both β-substituted and β-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.

Listeria monocytogenes is one of the most virulent foodborne pathogens. L. monocytogenes Sortase A (SrtA) enzyme, which catalyzes the cell wall anchoring reaction of the leucine, proline, X, threonine, and glycine proteins (LPXTG, where X is any amino acid), is a target for the development of antilisteriosis drugs. In this study, the structure of the L. monocytogenes SrtA enzyme-substrate complex was obtained using homology modeling, molecular docking and molecular dynamics simulations. Explicit enzyme-substrate interactions in the inactive and active forms of the enzyme were compared, based on 30 ns simulations on each system. The active site arginine (Arg 197) was found to be able change its hydrogen donor interactions from the LP backbone carbonyl groups of the LPXTG substrate in the inactive form, to the TG backbone carbonyls in the active form, which could be of importance for holding the substrate in position for the catalytic process.

Hybrid meta-GGA density functional theory (the MPWB1K functional) was used to study the hydroxylation and ring-opening mechanism of 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase (MHPCO). This enzyme catalyses the conversion of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) to alpha-(N-acetylaminomethylene)succinic acid (AAMS), which is the essential ring-opening step in the bacterial degradation of vitamin B(6). MHPCO belongs to the flavin-containing aromatic hydroxylases family. However, MHPCO is capable of catalysing a subsequent aromatic ring-cleavage reaction to give acyclic products rather than hydroxylated aromatic ones. Our calculations show that the re-aromatisation of the hydroxylated intermediate occurs spontaneously in aqueous solution; this implies that the ring-opening process occurs inside the enzyme's active site, in which limited water is available. The instability of the hydroxylated intermediate of MHPCO is the main reason why acyclic products are formed. Previously proposed mechanisms for the ring-opening step were studied, and were shown to be less likely to occur (DeltaDeltaG(not equal298)35 kcal mol(-1)). Two new pathways with reasonable barrier heights (DeltaDeltaG(not equal 298)15 kcal mol(-1)) are reported herein, which are in accordance with all experimental information present to date.

A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both β-substituted and β-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.