10 research outputs found
Lewis Base/Bronsted Acid Dual-Catalytic C–H Sulfenylation of Aromatics
A Lewis
base/Bronsted acid catalyzed aromatic sulfenylation is
reported. These studies demonstrated that the incorporation of electron-rich
sulfenyl groups proceeded in the absence of a Lewis base, with kinetic
studies indicating an autocatalytic mechanism. The incorporation of
electron-poor sulfenyl groups demonstrated little autocatalysis necessitating
the use of a Lewis base. This method proved amenable to diverse arenes
and heterocycles and was effective in the context of the late-stage
functionalization of biologically active small molecules
Enantioselective Synthesis of Pyrrolopyrimidine Scaffolds through Cation-Directed Nucleophilic Aromatic Substitution
The
catalytic enantioselective synthesis of 3-aryl-substituted
pyrrolopyrimidines (PPYs), a common motif in drug discovery, is achieved
through a kinetic resolution via quaternary ammonium salt-catalyzed
nucleophilic aromatic substitution (S<sub>N</sub>Ar). Both enantioenriched
products and starting materials can be functionalized with no observed
racemization to give enantiodivergent access to diverse chiral analogues
of an important class of kinase inhibitor. One of the compounds was
found to be a potent and selective inhibitor of breast tumor kinase
A Practical Lewis Base Catalyzed Electrophilic Chlorination of Arenes and Heterocycles
A mild
phosphine sulfide catalyzed electrophilic halogenation of
arenes and heterocycles that utilizes inexpensive and readily available <i>N</i>-halosuccinimides is disclosed. This methodology is shown
to efficiently chlorinate diverse aromatics, including simple arenes
such as anthracene, and heterocycles such as indoles, pyrrolopyrimidines,
and imidazoles. Arenes with Lewis acidic moieties also proved amenable,
underscoring the mild nature of this chemistry. Lewis base catalysis
was also found to improve several diverse aromatic brominations and
iodinations
The Catalyst-Controlled Regiodivergent Chlorination of Phenols
Different
catalysts are demonstrated to overcome or augment a substrate’s
innate regioselectivity. Nagasawa’s bis-thiourea catalyst was
found to overcome the innate <i>para</i>-selectivity of
electrophilic phenol chlorination, yielding <i>ortho</i>-chlorinated phenols that are not readily obtainable via canonical
electrophilic chlorinations. Conversely, a phosphine sulfide derived
from 2,2′-BisÂ(diphenylÂphosphino)-1,1′-binaphthyl
(BINAP) was found to enhance the innate <i>para</i>-preference
of phenol chlorination
Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation
Proteolysis
targeting chimera (PROTAC) technology, the recruitment
of E3 ubiquitin ligases to induce the degradation of a protein target,
is rapidly impacting chemical biology, as well as modern drug development.
Here, we explore the universality of this approach by evaluating different
E3 ubiquitin ligases, engineered in their substrate binding domains
to accept a recruiting ligand. Five out of six E3 ligases were found
to be amenable to recruitment for target degradation. Taking advantage
of the tight spatiotemporal control of inducing ubiquitination on
a preselected target in living cells, we focused on two of the engineered
E3 ligases, βTRCP and parkin, to unravel their ubiquitination
characteristics in comparison with the PROTAC-recruited endogenous
E3 ligases VHL and cereblon
Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones
We report a cinchona alkaloid catalyzed
addition of thiophenol
into rapidly interconverting aryl-naphthoquinones, resulting in stable
biaryl atropisomers upon reductive methylation. An array of thiophenols
and naphthoquinone substrates were evaluated, and we observed selectivities
up to 98.5:1.5 e.r. Control of the quinone redox properties allowed
us to study the stereochemical stabilities of each oxidation state
of the substrates. The resulting enantioenriched products can also
be moved on via an S<sub>N</sub>Ar-like reaction sequence to arrive
at stable derivatives with excellent enantioretention
Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones
We report a cinchona alkaloid catalyzed
addition of thiophenol
into rapidly interconverting aryl-naphthoquinones, resulting in stable
biaryl atropisomers upon reductive methylation. An array of thiophenols
and naphthoquinone substrates were evaluated, and we observed selectivities
up to 98.5:1.5 e.r. Control of the quinone redox properties allowed
us to study the stereochemical stabilities of each oxidation state
of the substrates. The resulting enantioenriched products can also
be moved on via an S<sub>N</sub>Ar-like reaction sequence to arrive
at stable derivatives with excellent enantioretention
Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones
We report a cinchona alkaloid catalyzed
addition of thiophenol
into rapidly interconverting aryl-naphthoquinones, resulting in stable
biaryl atropisomers upon reductive methylation. An array of thiophenols
and naphthoquinone substrates were evaluated, and we observed selectivities
up to 98.5:1.5 e.r. Control of the quinone redox properties allowed
us to study the stereochemical stabilities of each oxidation state
of the substrates. The resulting enantioenriched products can also
be moved on via an S<sub>N</sub>Ar-like reaction sequence to arrive
at stable derivatives with excellent enantioretention
Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones
We report a cinchona alkaloid catalyzed
addition of thiophenol
into rapidly interconverting aryl-naphthoquinones, resulting in stable
biaryl atropisomers upon reductive methylation. An array of thiophenols
and naphthoquinone substrates were evaluated, and we observed selectivities
up to 98.5:1.5 e.r. Control of the quinone redox properties allowed
us to study the stereochemical stabilities of each oxidation state
of the substrates. The resulting enantioenriched products can also
be moved on via an S<sub>N</sub>Ar-like reaction sequence to arrive
at stable derivatives with excellent enantioretention
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Small molecule-induced
protein degradation is an attractive strategy
for the development of chemical probes. One method for inducing targeted
protein degradation involves the use of PROTACs, heterobifunctional
molecules that can recruit specific E3 ligases to a desired protein
of interest. PROTACs have been successfully used to degrade numerous
proteins in cells, but the peptidic E3 ligase ligands used in previous
PROTACs have hindered their development into more mature chemical
probes or therapeutics. We report the design of a novel class of PROTACs
that incorporate small molecule VHL ligands to successfully degrade
HaloTag7 fusion proteins. These HaloPROTACs will inspire the development
of future PROTACs with more drug-like properties. Additionally, these
HaloPROTACs are useful chemical genetic tools, due to their ability
to chemically knock down widely used HaloTag7 fusion proteins in a
general fashion