Absolute Configuration Reassignment of Natural Products: An Overview of the Last Decade

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.

A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases

“…However, an open matter remained the AC at the C7 carbon atom. Considerable mobility of the substituents on this carbon, most likely resulting in a diversity of near-energy conformers and rotamers, hindered the computing-supported CD analysis, including VCD as we have explicated just above and very recently by Batista et al [ 63 ]. On the other hand, transforming the tert/tert 1,2-diol subunit present in 10 into an ECD-active cottonogenic derivative is not straightforward.…”

Combined application of DP4+ and ANN‐PRA to determine the relative configuration of natural products: The alpha‐bisabol case study

“…[1,4] For years, our research group has been dedicated to applying and developing new tools for the structural elucidation of complex natural products by means of quantum chemical calculations of NMR parameters. [2,[14][15][16][17][18][19][20][21][22][23] The chemical shifts (δ) linear scaling factors developed in our group are widely accessible to nonspecialists and have been successfully applied to structural characterization and revision of different natural products. [2,14] Therefore, following our continuous interest in the field, in this article, we discuss a case study focusing on the analysis of the stereostructure of the sesquiterpene (À)-α-bisabolol (αBis) (Figure 1).…”

Vibrational Circular Dichroism for the Assignment of Absolute Configuration of Natural Products in Brazil

“…Even with the use of accurate and wellestablished analytical and theoretical protocols, however, errors in the determination of structures commonly occur (Polavarapu and Santoro 2020). As a result, a considerable number of natural product structural misassignments are reported every year (Nicolaou and Snyder 2005;Suyama et al 2011;Marcarino et al 2020;Batista et al 2021;). These errors are based mainly on misinterpretations of experimental and/or theoretical data from NMR (especially NOE and/or HMBC data), circular dichroism (CD), and/or optical rotation (OR), including empirical comparisons, structural derivatization results, biosynthetic considerations, and computational modeling, as well as by the presence of contaminations, artifacts, etc.…”

“…the leading causes of errors in the determinations of their absolute configuration (Batista et al 2021). Therefore, it is extremely important to consider the limitations of each method used and apply a combination of methodologies whenever possible to achieve a complete and reliable structural characterization (Polavarapu 2008;Batista et al 2021).…”

“…the leading causes of errors in the determinations of their absolute configuration (Batista et al 2021). Therefore, it is extremely important to consider the limitations of each method used and apply a combination of methodologies whenever possible to achieve a complete and reliable structural characterization (Polavarapu 2008;Batista et al 2021). As the enantiomers of a chiral compound have distinct pharmacological and toxicological profiles in chiral biological environments, the unambiguous determination of the absolute configuration of bioactive natural products is also an essential step in this context.…”