Development of a Safe and Economical Synthesis of Methyl 6‑Chloro-5-(trifluoromethyl)nicotinate: Trifluoromethylation on Kilogram Scale

Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)­nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emphasis on the development work which led to this effective process

An Enantioselective Synthesis of an 11-β-HSD‑1 Inhibitor via an Asymmetric Methallylation Catalyzed by (<i>S</i>)‑3,3′‑F₂‑BINOL

An efficient asymmetric synthesis of 11-β-HSD inhibitor <b>1</b> has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (<i>S</i>)-3,3′-F₂-BINOL under solvent-free and metal-free conditions

Addressing the Configuration Stability of Lithiated Secondary Benzylic Carbamates for the Development of a Noncryogenic Stereospecific Boronate Rearrangement

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of <i>sec</i>-BuLi combined with an <i>in situ</i> trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale

Asymmetric Methallylation of Ketones Catalyzed by a Highly Active Organocatalyst 3,3′‑F₂‑BINOL

(<i>S</i>)-3,3′-F₂-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The catalyst (<i>S</i>)-3,3′-F₂-BINOL could be easily recovered and reused

Early Development Scale-Up of a Structurally-Challenging 5‑Lipoxygenase Activating Protein (FLAP) Inhibitor

A practical and efficient synthesis of the FLAP inhibitor <b>1</b> was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of <b>1</b>: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling

Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor

Development of a Scalable, Chromatography-Free Synthesis of <i>t</i>‑Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF₃‑Alcohol Derivative with High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine <i>t</i>-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%)