Catalytic 2-Ethylhexanoic Acid Promotes Mild Miyaura Borylations.

The Miyaura borylation of aryl and heteroaryl chlorides and bromides using a combination of potassium carbonate and 5 mol % 2-ethylhexanoic acid at 25 °C is reported. The generation of a catalytic amount of potassium 2-ethylhexanoate under these conditions avoids the need for special handling of stoichiometric quantities of hygroscopic potassium 2-ethylhexanoate during the reaction setup as well as difficulties in removing the resulting carboxylic acid during product isolation.

Electrochemical Nickel-Catalyzed C(sp)-C(sp) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp)-C(sp) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates.

Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment.

We demonstrate that arylchlorodiazirines serve as photo-activated halocarbene precursors for the selective one-carbon ring expansion of N-substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N-substituted pyrazoles to pyrimidinium salts. The N-substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co-product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations.

Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor.

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over β-arrestin recruitment.

Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.

Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36).

Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent.

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer and the unwanted enantiomer (,)- during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A.

Asymmetric synthesis of (+)-vertine and (+)-lythrine.

The total syntheses of the Lythracea alkaloids (+)-vertine and (+)-lythrine are described. Enantioenriched pelletierine is used as a chiral building block and engaged into a two step pelletierine condensation leading to two quinolizidin-2-one diastereomers in a 8 : 1 ratio. The major product is used in the synthesis of (+)-vertine via aryl-aryl coupling and ring closing metathesis to provide a Z-alkene α to the lactone carbonyl function.

Total synthesis of (+/-)-vertine with Z-selective RCM as a key step.

A concise total synthesis of the strained pentacyclic alkaloid (+/-)-Vertine has been achieved in eleven steps with the key steps being pelletierine condensation, Suzuki-Miyaura coupling, and ring-closing metathesis.

Asymmetric catalytic hydrogenolysis of aryl-halide bonds in fused arene chromium and ruthenium complexes.

Access to highly enantioenriched planar chiral [Cr(5-bromonaphthalene)(CO)(3)] (6), [Ru(eta(5)-C(5)R(5))(5-bromonaphthalene)][PF(6)] (42) and [Ru(eta(5)-C(5)R(5))(4-bromoindene)] (44) was sought using asymmetric hydrogenolysis of [Cr(5,8-dibromonaphthalene)(CO)(3)] (5), [Ru(eta(5)-C(5)R(5))(5,8-dibromonaphthalene)] (39) and [Ru(eta(5)-C(5)R(5))(4,7-dibromoindene)] (40), respectively. Initial efforts focused on the chromium complex 5. Pd(0) catalysts with dimethoxyethane as the solvent and LiBH(4) or NaBH(3)CN as a hydride source worked best.

Highly enantiomerically enriched planar chiral naphthalene tricarbonylchromium complexes.

Lithiation/electrophile trapping reactions were carried out with the highly enantiomerically enriched complex [Cr(5-bromonaphthalene)(CO)3]. Electrophile quenching with ClPPh2, PhCHO, and (Me3SiO)2 afforded the enantiomerically enriched (>97% ee) planar chiral 5-substituted naphthalene complexes with PPh2, CH(Ph)OH, and OH substituents, respectively. Very mild Pd-catalyzed Suzuki-Miyaura cross-coupling reactions were developed and applied to the highly labile [Cr(5-bromonaphthalene)(CO)3] to give nine new planar chiral aryl-, heteroaryl-, alkynyl-, and alkenylnaphthalene chromium complexes with high enantiomeric purity.

Aminative rearrangement of 2-alkoxy-3,4-dihydro-2H-pyrans: a novel stereocontrolled route to substituted pyrrolidines.

Aziridination of 2-alkoxy-3,4-dihydro-2H-pyrans leads to rearrangement and stereocontrolled formation of 5-alkoxypyrrolidines which may be reduced to pyrrolidines or allylated stereoselectively.