Computationally Assisted Stereochemical Elucidation of Intermediates Encountered En Route to Pyrrole-Imidazole Natural Products: NMR Chemical Shift Calculations Utilizing CREST/DP4+ Applied to Oxidative Spirocyclizations of Tetrahydrobenzimidazoles

Herein, we investigate the use of Boltzmann-weighted NMR chemical shift calculations as a tool for elucidating the stereochemical outcomes of oxidative rearrangement reactions not easily determined by standard NMR experiments. Included is a modular set of scripts for a streamlined workflow integrating xTB/CREST, Gaussian, and DP4+ probability analysis. The use of CREST for this application is assessed by generating conformer ensembles of varying quality through the adjustment of CREST's main parameters. Results support Boltzmann-weighted NMR chemical shift calculations as a viable method for distinguishing diastereomeric spirocyclic compounds and validate CREST as a free alternative to other proprietary software for the generation of relevant conformation ensembles.