A Continuous Flow Process for LSN647712 via Double Organometallic Additions to Dimethylcarbamyl Chloride.

The ketone intermediate LSN647712 is a key synthetic intermediate for the drug substance lasmiditan manufacturing process. A three-step connected continuous flow process utilizing a Turbo Grignard reagent, -methylpiperidin-4-ylmagnesium chloride, and lithiated 2,6-dibromopyridine sequentially added to double electrophile (O═C(++) synthon dimethylcarbamyl chloride (DMCC) was developed to deliver the ketone intermediate in a high chemical yield (>85%). This highly productive (>100 g/h lab system) and intensified process (τ ∼ 3 min) yields the product in high purity upon batch reactive crystallization to form a corresponding hydrobromide salt.

Axial shielding of Pd(II) complexes enables perfect stereoretention in Suzuki-Miyaura cross-coupling of Csp boronic acids.

Stereocontrolled Csp cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp boronic acids with perfect stereoretention.

Unified Approach to Substituted Allenoates via Pd-Catalyzed β-Hydride Elimination of (E)-Enol Triflates.

A robust synthesis of allenoates via a Pd-catalyzed β-hydride elimination of (E)-enol triflates is presented. Salient features of this method include low catalyst loadings, mild reaction conditions, and the ability to access all four patterns of substituted allenoates from a single substrate class.

Pd-catalyzed asymmetric β-hydride elimination en route to chiral allenes.

We wish to report our preliminary results on the discovery and development of a catalytic, asymmetric β-hydride elimination from vinyl Pd(II)-complexes derived from enol triflates to access chiral allenes. To achieve this, we developed a class of chiral phosphite ligands that demonstrate high enantioselectivity, allow access of either allene enantiomer, and are readily synthesized. The methodology is demonstrated on over 20 substrates, and application to the formal asymmetric total synthesis of the natural product, (+)-epibatidine, is also provided.