Daniel R. Fandrick

Assessing atropisomer axial chirality in drug discovery and development.

Assessing Atropisomer Axial Chirality in Drug Discovery and Development Steven R. LaPlante,* Lee D. Fader, Keith R. Fandrick, Daniel R. Fandrick, Oliver Hucke, Ray Kemper, Stephen P. F. Miller, and Paul J. Edwards* Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada Chemical Development, Non-Clinical Drug Safety, Boehringer Ingelheim Pharmaceutical Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States Office of New Drug Quality Assessment, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 1446, Silver Spring, Maryland 20993, United States

Copper Catalyzed Asymmetric Propargylation of Aldehydes

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

Room Temperature Palladium-Catalyzed Cross Coupling of Aryltrimethylammonium Triflates with Aryl Grignard Reagents

Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe(3)OTf relative to PhCl, PhBr, PhI, and PhOTf.

Copper-catalyzed annulation of 2-formylazoles with o-aminoiodoarenes.

In the presence of catalytic CuI and sparteine, 2-formylpyrroles can be annulated with o-aminoiodoarenes to give substituted pyrrolo[1,2-a]quinoxalines and related heterocycles. The reaction also works for annulation of 2-formylindoles, 2-formylimidazole, 2-formylbenzimidazole, and a 3-formylpyrazole.

N-Heterocyclic Carbene-Catalyzed Silyl Enol Ether Formation†

N-Heterocyclic carbenes (NHCs) were found to catalyze the silyl transfer from trialkylsilyl ketene acetals to ketones. In the presence of a catalytic amount of NHC 3 (IAd, 0.1 to 5 mol %), a series of enolizable ketones as well as cyclohexanecarboxaldehyde were efficiently converted into the corresponding silyl enol ethers at 23 degrees C in THF.

A general copper-BINAP-catalyzed asymmetric propargylation of ketones with propargyl boronates.

An operationally simple copper-BINAP-catalyzed, highly enantioselective propargylation of ketones is presented. The methodology was developed as an enantioselective process for methyl ethyl ketone and shown to be applicable to a wide variety of prochiral ketones. The resulting homopropargyl adducts are versatile latent carbonyls from which γ-butyrolactones, β-hydroxy methyl ketones, and β-hydroxycarboxylates are readily obtained.

Zinc catalyzed and mediated propargylations with propargyl boronates.

The utility of allenyl and propargyl boronates for the propargylation of aldehydes and ketones mediated by zinc is presented. The reaction is catalytic in zinc with allenyl or propargyl borolanes. The propargylation with crystalline and air-stable propargyl diethanolamine boronates was also achieved. A catalytic cycle is proposed, and preliminary mechanistic studies are discussed.

Zinc Catalyzed and Mediated Asymmetric Propargylation of Trifluoromethyl Ketones with a Propargyl Boronate

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.

Highly Diastereoselective Zinc-Catalyzed Propargylation of tert-Butanesulfinyl Imines

A zinc-catalyzed diastereoselective propargylation of t-butanesulfinyl imines is presented. The methodology provided both aliphatic and aryl homopropargylic amines in up to 98:2 and 99.8:0.2 dr, respectively. The utility of the homopropargylic amines was demonstrated by the application to the synthesis of a cis-substituted pyrido-indole through a diastereoselective Pictet-Spengler cyclization.

Zinc-catalyzed allenylations of aldehydes and ketones.

The general zinc-catalyzed allenylation of aldehydes and ketones with an allenyl boronate is presented. Preliminary mechanistic studies support a kinetically controlled process wherein, after a site-selective B/Zn exchange to generate a propargyl zinc intermediate, the addition to the electrophile effectively competes with propargyl-allenyl zinc equilibration. The utility of the methodology was demonstrated by application to a rhodium-catalyzed [4+2] cycloaddition.