Structural and functional insight into human O-GlcNAcase.

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value.

A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors.

Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.

Short chemoenzymatic total synthesis of ent-hydromorphone: an oxidative dearomatization/intramolecular [4+2] cycloaddition/amination sequence.

A short synthesis of ent-hydromorphone has been achieved in twelve steps from ß-bromoethylbenzene. The key transformations involved the enzymatic dihydroxylation of the arene to the corresponding cis-dihydrodiol, Mitsunobu coupling with the ring A fragment, oxidative dearomatization of the C3 phenol, and the subsequent [4+2] cycloaddition to form ring B of the morphinan. The synthesis was completed by intramolecular amination at C9.

NHC-catalysed annulation of enals to tethered dienones: efficient synthesis of bicyclic dienes.

Homoenolates generated from α,ß-unsaturated aldehydes using NHC catalysis underwent facile addition to dibenzylidene cyclohexanone to afford bicyclic cyclopentenes as single diastereomers.

NHC catalyzed transformation of aromatic aldehydes to acids by carbon dioxide: an unexpected reaction.

A facile NHC-mediated reaction of aromatic aldehydes with carbon dioxide leading to carboxylic acids is described. The present protocol is mechanistically important, and it can serve as a tool for the sequestration of carbon dioxide.

A novel pseudo four component reaction involving homoenolate for the synthesis of gamma-aminobutyric acid (GABA) derivatives.

Homoenolate generated from alpha,beta-unsaturated aldehydes by NHC catalysis underwent facile addition to conjugated sulfonimines, generated in situ, and subsequent methanolysis to afford protected GABA derivatives stereoselectively and in high yields, thus constituting a novel pseudo four component reaction.

Novel nucleophilic heterocyclic carbene mediated stereoselective conjugate addition of enals to nitrostyrenes via homoenolate.

A stereoselective Michael addition of homoenolate, generated from enals by nucleophilic heterocyclic carbene (NHC) catalysis, to beta-nitrostyrenes is reported for the first time. The products of this reaction obtained in good yields are of potential value in the synthesis of a variety of acyclic and heterocyclic compounds.

Nucleophilic heterocyclic carbene catalyzed annulation of enals to chalcones in methanol: a stereoselective synthesis of highly functionalized cyclopentanes.

Homoenolates generated from enals by nucleophilic heterocyclic carbene (NHC) catalysis undergo annulation with chalcones in methanol to afford methyl beta-hydroxycyclopentanecarboxylates, stereoselectively. Construction of four contiguous stereocenters in a stereoselective manner is noteworthy.