Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones.

The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. 1 H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.

One-Pot Catalytic Enantioselective Synthesis of 2-Pyrazolines.

A scalable, one-pot, enantioselective catalytic synthesis of 2-pyrazolines from beta-substituted enones and hydrazines is described. Pivoting on a two-stage catalytic Michael addition/condensation strategy, the use of an aldehyde to generate a suitable hydrazone derivative of the hydrazine was found to be key for curtailing background reactivity and tuning the catalyst-controlled enantioselectivity. The new synthetic method is easy to perform, uses a new and readily prepared cinchona-derived bifunctional catalyst, is broad in scope, and tolerates a range of functionalities with high enantioselectivity (up to >99:1 e.r.). The significant scalability of this methodology was demonstrated with the synthesis of more than 80 grams of a pyrazoline product with 89 % catalyst recovery.

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,ß-unsaturated esters.

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,ß-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

Fluorinated cyclopropanes: synthesis and chemistry of the aryl α,ß,ß-trifluorocyclopropane motif.

A general route to aryl α,ß,ß-trifluorocyclopropanes is reported and aryl oxidation gave the corresponding α,ß,ß-trifluorocyclopropane carboxylic acid. Reactions of the corresponding amides with phenol/thiophenol resulted in HF elimination and then conjugate addition. The partially fluorinated cyclopropane has a similar lipophilicity to -CF3 despite three carbon atoms, and it emerges as a novel motif for drug discovery.