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A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig’s procedure.

A scalable process for the preparation of 4,4,5,5-tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane from trimethylsilylpropyne, isopropyl pinacol borate, and n-butyllithium is described. Problems associated with implementing a typical aqueous workup and batch process into production due to borolane “ate” equilibration and protonolysis are presented. To address these issues, a continuous-flow and distillation process was developed which efficiently produced 297 kg of the key propargylation reagent.

A one-pot process for the synthesis of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxy-phenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (3) is described, which was a key intermediate for the preparation of a class of novel glucocorticoid receptor ligands. The chemistry features the preparative-scale synthesis of (R)-p-tolyl methyl sulfoxide [(R)-pTMSO] from (2R,4S,5R)-4-methyl-5-phenyl-3-(tolene-4-sulfonyl)oxathiazolidine-2-oxide (5) and the synthesis of 3 from 5 without isolation of (R)-pTMSO during the process.

We describe the discovery and development of a chiral auxiliary-controlled asymmetric acetate aldol reaction with a trifluoromethyl ketone. Chiral acetate 3d was prepared efficiently from (1S,2R)-1-amino-2-indanol. Reaction of the lithium enolate of 3d with trifluoromethyl ketone 2 afforded aldol adducts in 95% HPLC assay yield (by weight) with a 78:22 dr. The major isomer 5 was obtained via a robust crystallization method in 45% one-crop isolated yield with a >98.7:1.3 dr. Compound 5 was subjected to transesterification to give β-hydroxy ester 1. The cleaved auxiliary 7 was readily recovered by a direct crystallization/filtration method. Process optimization led to better volume efficiencies, improved isolation protocols, and less consumption of organic solvents, all contributing to enhanced throughput, reduced processing labor and time, as well as reduction in chemical wastes.

An unexpected highly exothermic decomposition was observed during routine safety analysis of the magnesium−iodine exchange reaction of 2-iodo-4-fluorotoluene (3) with commercially available i-PrMgCl (2.0 M solution in THF). When the reaction mixture was scanned in an adiabatic calorimeter with the use of a 2 °C/min temperature ramp, a rapid exothermic decomposition with an onset temperature of approximately 80 °C was observed. The system temperature rapidly rose to 210 °C at a peak rate of 200 °C/min. Subsequent testing of three simplified substrates showed the same type of exothermic decomposition for all cases. Control experiments indicated that the decomposition requires both aryl iodide and i-PrMgCl (or arylMgCl and i-PrI). While the onset temperatures for all cases studied were generally well above the typical operating temperature for these reactions (0−10 °C), it is nonetheless important to cautiously evaluate these types of processes and install proper engineering controls for analogous decomposit...