Structural elucidation of the antitubercular benzothiazinone BTZ043: A combined X-ray, variable temperature NMR and DFT study

A structural study of (S)-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one (BTZ043), a promising antitubercular drug candidate, is reported. The chiral compound crystallizes in the triclinic system (space group P1) with two molecules in the asymmetric unit (Z' = 2), which are related by pseudo inversion symmetry. The two crystallographically distinct molecules represent diastereomeric conformers, which can be transformed to one another by an approximate 180 degrees rotation about the C2(BTZ)-N-piperidine bond connecting the (S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane side chain to C2 of the benzothiazinone (BTZ) scaffold. Variable temperature C-13 NMR measurements of BTZ043 in CDCl3 in the range 248-333 K indicate a rotational barrier of E-a = 17.1 +/- 1 kcal mol(-1) and Delta G' = 14.6 +/- 1 kcal mol(-1). DFT calculations reveal two barriers to rotation about the C2(BTZ)-N-piperidine bond, one larger than the other by 4.1 kcal mol(-1). (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The study reports the crystal structure of a chiral compound BTZ043, which is a potential antitubercular drug candidate, and analyzes its molecular conformation and rotational barrier. The results show that the rotation of this compound is influenced by two barriers.