Reassigning the Structures of Natural Products Using NMR Chemical Shifts Computed with Quantum Mechanics: A Laboratory Exercise

Abstract

An applied computational chemistry laboratory exercise is described in which students use modern quantum chemical calculations of chemical shifts to assign the structure of a recently isolated natural product. A pre/post assessment was used to measure student learning gains and verify that students demonstrated proficiency of key learning objectives. ■ INTRODUCTIONThe elucidation of the structures (connectivity, relative stereochemistry, and configuration) of complex natural products is a challenging endeavor despite huge leaps in spectroscopic technology over the past century. Among the most useful tools for structure elucidation is nuclear magnetic resonance (NMR) spectroscopy. Recently, Breton and Reynolds presented an excellent review of the various tools natural products chemists utilize in assigning structures, with an emphasis on how the use of NMR spectroscopy has evolved over the years. 1 Previous work has demonstrated the utility of NMR computations, in conjunction with traditional analyses, in the assignment and reassignment of natural product structures. 2 Upper-division undergraduate chemistry courses generally do not expose students to this important aspect of NMR spectroscopy. Herein, a computer-based laboratory experiment is described that highlights this application of NMR spectroscopy, as well as the utility of quantum chemical calculations, through a brief project that models a state-of-the-art research project in the field of structural elucidation. This exercise is appropriate for students who have been introduced to the basic concepts of NMR spectroscopy and quantum mechanics; advanced knowledge of neither is required. Consequently, this lab exercise could be adapted for an undergraduate or graduate organic, natural products, quantum chemistry, or applied theoretical chemistry course (and perhaps others).Key features of the approach include the following: 1. The exercise described is derived from recent reports on current research problems in the natural products and applied theoretical chemistry fields. 2. The exercise is designed to encourage hypothesis generation and testing, experimental design, discovery, active learning, 3 and data analysis by utilizing many activities and questions that involve higher order cognitive processes. 4 3. The exercise provides a basic framework for applying NMR calculations to structure elucidation that is suitable for a 1−2 h laboratory period, but possible extensions appropriate for different courses, cohorts of students, and instructors are provided in the Supporting Information.

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