A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-π interaction. This resulted in increased cell permeability, suggesting that NH-π interactions may be used in the design of molecular chameleons.

The development of a scalable process for the manufacture of a potent and selective JAK1 inhibitor intended for the inhaled treatment of asthma is described. The initial milligram-scale synthetic protocols were unsuitable for larger-scale synthesis, which led to a systematic evaluation of the reaction conditions to identify the optimized reaction conditions for the Suzuki/ Buchwald−Hartwig coupling, deprotection of the tosyl group, chemoselective nitro-reduction, and developing mild conditions for the amide coupling of a sensitive amino acid. This work also highlights mitigating critical issues associated with the synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzed coupling protocols. The optimized amide coupling conditions using chiral amino acid produced the desired active pharmaceutical ingredient (API) in high overall yield and good high-performance liquid chromatography (HPLC) purity.

A linear 14-step sequence was developed for the synthesis of an oxaspirocyclic cyclopentane-based candidate drug 1 containing four chiral centers. Compared with the first-generation synthesis with an overall yield of 0.7%, which also included several chromatographic purifications, the large-scale approach furnished >800 g of API 1 in 19% overall yield, and chromatography was avoided in all but two steps. The major achievements were the development of a Curtius rearrangement where hazards were minimized, a robust and safer dose-controlled allylzinc addition to a ketone, and a selective monohydrolysis of a diester.

A chemoenzymatic route to (R)-allyl-(3-amino-2-(2-methylbenzyl)­propyl)­carbamate (1-(R)) has been developed on a kilogram scale. The key intermediate, 2-(2-methylbenzyl)­propane-1,3-diamine 4, was isolated as a tartrate salt in a three-step sequence starting from 2-methylbenzyl chloride. The subsequent lipase-catalyzed desymmetrization was optimized, and 1-(R) was isolated as the d-tartrate salt.