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 in situ 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(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp3)-C(sp3) 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(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)-C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.

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. This latter point is illustrated by subjecting the quinolinium salts to four complementary partial reductions, which provide concise access to ring-expanded products with different degrees of increased C(sp3 ) character. Thermal analysis of the diazirines by differential scanning calorimetry (DSC) provides detailed insight into their energetic properties, and highlights the safety benefits of photolyzing-rather than thermolyzing-these reagents.

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)NH2 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)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over ß-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.

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). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric Gs. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.

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 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al(iBu)3] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.

The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

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. The same procedure was used for (+)-lythrine after base induced epimerization of the main quinolizidin-2-one diastereomer. Alternative classical ring closure strategies like macrolactonisation or aryl-aryl coupling failed.

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. Nineteen chiral bidentate phosphorus ligands were screened in this reaction. Asymmetric induction was low to modest with product ee's in the range of 4 to 52% and yields of 6 of up to 70%. Chiral phosphoramidite ligands proved superior and a bulky ligand derived from a Whitesell amine and 3,3'-diphenyl-binaphtol afforded 6 with an ee of 97%. The high enantioselectivity is largely due to the initial desymmetrization reaction though kinetic resolution also plays an important role as shown by the determination of a selectivity factor s=8.5 at -10 degrees C. Initially high ligand loadings (4 equiv/Pd) were necessary to achieve good asymmetric induction. This could be traced to the trapping of the chiral ligand by borane formed in the reaction. Addition of 1,4-diazabicyclo[2.2.2]octane (DABCO) suppressed this, and its addition led to the use of Pd and chiral ligand in a 1:1.2 ratio. Asymmetric hydrogenolysis of cationic dibromonaphthalene and neutral dibromoindenyl complexes of Ru cyclopentadienyl complexes was investigated and afforded the following results: [RuCp(5-bromonaphthalene)][PF(6)] (39a; 75%, 90% ee), [RuCp*(5-bromonaphthalene)] [PF(6)] (39b; 88%, 99% ee), [RuCp(4-bromoindenyl)] (44a; 72%, 96% ee), and [RuCp*(4-bromoindenyl)] (44b; 62%, 68% ee).

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. The efficient ambient-temperature coupling reactions with borinates prepared in situ were also applied to a number of chlorobenzene complexes and to aryl and vinyl halides.

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.