Year: 2010
Type: editorial
Abstract: Synthesis of PPARpan Agonist GW693085Recently, selective PPAR agonists were dosed in combination to show that there could be synergy in lowering glucose and triglycerides.GW693085 is a PPARpan agonist, combining the activity of the three known subtypes of the PPAR agonists into a single molecule.As a drug candidate for type 2 diabetes, a supply of multikilogram quantities for preclinical and clinical investigation was required.Xie and co-workers at GSK describe process development of this compound (J.Org.Chem.2010, 75, 3904-3907).Following a study of how to most efficiently prepare the central tertiary amine, a unique buffering effect of various bases (i-Pr 2 NEt and CaCO 3 ) in particular, was observed for the acid-catalyzed chloro displacement of 2-chloro-5ethylpyrimidine with a 2-methyl-2-phenylpropanamine.The use of the carefully chosen bases was essential for the progression of the chloro displacement as well as the stability of the product because of the formation of HCl.Research work leading to an efficient synthesis of PPARpan agonist GW693085 is described, featuring highly selective sequential N-and O-alkylations. Catalyst-Controlled Regioselective Suzuki Couplings at Both Positions of Dihaloimidazoles, Dihalooxazoles, and DihalothiazolesAlthough diaryl-imidazoles, -oxazoles, and -thiazoles are common subunits in pharmaceutical and natural products, these compounds are not always easily accessed in modular fashion.Now Strotman, Chobanian, and coworkers at Merck report that various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling (J.Org.Chem.2010, 75, 1733-1739).By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond.These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion. Ester-Directed Regioselective Borylation of HeteroarenesCatalytic C-H borylation of arenes allows direct access to various borylated arenes, often with regiochemical control that is otherwise difficult to achieve.Application of this reaction to heterocylic substrates broadens the scope of this process with respect to the synthesis of pharmaceutical products.Now Sawamura and co-workers report on an ester-directed regioselective borylation of aromatic heterocycles (J.Org.Chem.2010, 75, 3866-3858).This borylation is catalyzed by a silicasupported monophosphine-Ir complex, which displays broad substrate scope, including thiophene, pyrrole, furan, benzothiophene, benzofuran, indole, and carbazole derivatives.The regioselectivity is complementary to the selectivities observed in the heteroarene C-H borylation with the dtbpy-Ir catalyst system. Ambient-Temperature Cobalt-Catalyzed Cycloaddition Strategies to Aromatic Boronic EstersIn a separate report concerning the synthesis of arylboronic esters, Harrity, Hilt and co-workers describe an interesting alternative approach to these widely used synthetic intermediates (J.
DOI: 10.1021/op100166w
Authors: Mark McLaughlin, Silvina García Rubio, Ian Wilson, Wenyi Zhao, Trevor Laird, Andrei Zlota
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W4244954253