Small Change, Big Impact: Reversal of Diastereoselection in Cuprate Conjugate Additions to α,β-Unsaturated Lactams and Identification of a Competing Mechanism

A seemingly minor change to a reactant is shown to cause a change in reaction mechanisms. Conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Aminals derived from aldehydes give anti addition; those from ketones give syn addition. Divergence in diastereoselection occurs because the substrates react by different mechanisms, ultimately due to a small but significant difference in pyramidalization of the aminal nitrogen

Aminocarbonylation of Aryl Tosylates to Carboxamides

The palladium - catalyzed aminocarbonylation of aryl tosylates with amines is reported. Suitable conditions were identified by high throughput reaction screening and then further optimized. The substrate scope of the reaction with respect to the aryl tosylate component and the amine component are reported. Competitive aminolysis of the aryl tosylates to afford the amine toluenesulfonamides and the phenol was not observed

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Reversal of Diastereoselection in the Conjugate Addition of Cuprates to Unsaturated Lactams

We report that the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Bicyclic α,β-unsaturated lactams in which the aminal is derived from a ketone have been found to afford products of <i>syn</i> conjugate addition. By contrast, bicyclic α,β-unsaturated lactams in which the aminal is derived from an aldehyde afford products of <i>anti</i> conjugate addition. These remarkably different results obtained from very similar starting materials are unexpected

Covalent Enzyme Inhibition through Fluorosulfate Modification of a Noncatalytic Serine Residue

Irreversible enzyme inhibitors and covalent chemical biology probes often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (<i>e.g.</i>, acrylamide) on the ligand template. However, cysteine residues are not always available for site-specific protein labeling, and therefore new approaches are needed to expand the toolkit of appropriate electrophiles (“warheads”) that target alternative amino acids. We previously described the rational targeting of tyrosine residues in the active site of a protein (the mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with a sulfonyl fluoride electrophile. These inhibitors subsequently enabled the development of clickable probe technology to measure drug-target occupancy in live cells. Here we describe a fluorosulfate-containing inhibitor (aryl fluorosulfate probe (FS-p1)) with excellent chemical and metabolic stability that reacts selectively with a noncatalytic serine residue in the same active site of DcpS as confirmed by peptide mapping experiments. Our results suggest that noncatalytic serine targeting using fluorosulfate electrophilic warheads could be a suitable strategy for the development of covalent inhibitor drugs and chemical probes

Structure-Based Approach To Identify 5‑[4-Hydroxyphenyl]­pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators

In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound <b>7</b>, a potent AR (ARE EC₅₀ = 0.34 nM) and selective (N/C interaction EC₅₀ = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of <b>7</b>, and further insights from modeling studies of ligand receptor interactions are also presented

Structure-Based Approach To Identify 5‑[4-Hydroxyphenyl]­pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators

In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound <b>7</b>, a potent AR (ARE EC₅₀ = 0.34 nM) and selective (N/C interaction EC₅₀ = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of <b>7</b>, and further insights from modeling studies of ligand receptor interactions are also presented