11 research outputs found
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<sub>N</sub>2 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<sub>N</sub>2 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<sub>N</sub>2 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<sub>N</sub>2 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]Âpyrrole-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 EC<sub>50</sub> = 0.34 nM)
and selective (N/C interaction EC<sub>50</sub> = 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]Âpyrrole-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 EC<sub>50</sub> = 0.34 nM)
and selective (N/C interaction EC<sub>50</sub> = 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