Abstract
The assignment of absolute configuration (AC) is a crucial step in the structural characterization of natural products, especially for those subjected to biological assays. Methods such as X-ray crystallography, stereocontrolled organic synthesis, nuclear magnetic resonance (NMR), and chiroptical spectroscopies are commonly used to determine the AC of chiral natural compounds. Even with these well-established techniques, however, unambiguous stereochemical assignments of natural products remain a challenge, resulting in an increasing number of structural misassignments being reported every year. Herein, we will present the main techniques that have been used in AC reassignments of natural products over the last 10 years, along with some selected examples. Special attention will be paid to the strengths and weaknesses of each approach. With this, we expect to provide the readers with critical information to help them to choose the appropriate methods for correct AC determinations.
Highlights
Natural products and/or natural product structural scaffolds have played a significant role in the drug discovery and development processes over the years due to their wide range of biological activities.[1]
Organic synthesis associated with nuclear magnetic resonance (NMR), X-ray crystallography and/or chiroptical methods has been by far the most widely used approach for the stereochemical reassignment of natural products (Table 1)
A careful analysis of the articles dealing with the revision of the absolute configuration (AC) of chiral natural products covered by the present review revealed some approaches that can commonly lead to misassignments
Summary
Natural products and/or natural product structural scaffolds have played a significant role in the drug discovery and development processes over the years due to their wide range of biological activities.[1]. NMR spectroscopy is the main technique used for small molecule structural elucidation, as it is normally used in isotropic media, it is intrinsically insensitive to chirality To that end, it requires the use of chiral auxiliaries, chiral solvents and related methods.[10] Stereocontrolled organic synthesis is dependent on the correct AC of both starting materials and products, besides being expensive, laborious, and time-consuming.[11] Chiroptical methods, which include OR (optical rotation), ORD (optical rotatory dispersion), ECD (electronic circular dichroism), VCD (vibrational circular dichroism), and ROA (Raman optical activity), are naturally sensitive to chirality, yet have limitations. We want to highlight the importance of the proper choice of either individual or combined methods to determine unequivocally the AC of natural products
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