6 research outputs found
Hydromethylation of Unactivated Olefins
A solution
to the classic unsolved problem of olefin hydromethylation
is presented. This highly chemoselective method can tolerate labile
and reactive chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted olefins,
are all smoothly hydromethylated. This mild protocol can be used to
simplify the synthesis of a specific target or to directly “edit”
complex natural products and other advanced materials. The method
is also amenable to the simple installation of radioactive and stable
labeled methyl groups
Hydromethylation of Unactivated Olefins
A solution
to the classic unsolved problem of olefin hydromethylation
is presented. This highly chemoselective method can tolerate labile
and reactive chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted olefins,
are all smoothly hydromethylated. This mild protocol can be used to
simplify the synthesis of a specific target or to directly “edit”
complex natural products and other advanced materials. The method
is also amenable to the simple installation of radioactive and stable
labeled methyl groups
Hydromethylation of Unactivated Olefins
A solution
to the classic unsolved problem of olefin hydromethylation
is presented. This highly chemoselective method can tolerate labile
and reactive chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted olefins,
are all smoothly hydromethylated. This mild protocol can be used to
simplify the synthesis of a specific target or to directly “edit”
complex natural products and other advanced materials. The method
is also amenable to the simple installation of radioactive and stable
labeled methyl groups
Hydromethylation of Unactivated Olefins
A solution
to the classic unsolved problem of olefin hydromethylation
is presented. This highly chemoselective method can tolerate labile
and reactive chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted olefins,
are all smoothly hydromethylated. This mild protocol can be used to
simplify the synthesis of a specific target or to directly “edit”
complex natural products and other advanced materials. The method
is also amenable to the simple installation of radioactive and stable
labeled methyl groups
Hydromethylation of Unactivated Olefins
A solution
to the classic unsolved problem of olefin hydromethylation
is presented. This highly chemoselective method can tolerate labile
and reactive chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted olefins,
are all smoothly hydromethylated. This mild protocol can be used to
simplify the synthesis of a specific target or to directly “edit”
complex natural products and other advanced materials. The method
is also amenable to the simple installation of radioactive and stable
labeled methyl groups
Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
A novel series of pyrrolidine-containing
GPR40 agonists is described
as a potential treatment for type 2 diabetes. The initial pyrrolidine
hit was modified by moving the position of the carboxylic acid, a
key pharmacophore for GPR40. Addition of a 4-<i>cis</i>-CF<sub>3</sub> to the pyrrolidine improves the human GPR40 binding <i>K</i><sub>i</sub> and agonist efficacy. After further optimization,
the discovery of a minor enantiomeric impurity with agonist activity
led to the finding that enantiomers <b>(</b><i><b>R,R</b></i><b>)-68</b> and <b>(</b><i><b>S,S</b></i><b>)-68</b> have differential effects on the radioligand
used for the binding assay, with <b>(</b><i><b>R,R</b></i><b>)-68</b> potentiating the radioligand and <b>(</b><i><b>S,S</b></i><b>)-68</b> displacing
the radioligand. Compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> activates both
G<sub>q</sub>-coupled intracellular Ca<sup>2+</sup> flux and G<sub>s</sub>-coupled cAMP accumulation. This signaling bias results in
a dual mechanism of action for compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b>, demonstrating glucose-dependent insulin and GLP-1 secretion in
vitro. In vivo, compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> significantly lowers
plasma glucose levels in mice during an oral glucose challenge, encouraging
further development of the series