Chasing Molecules That Were Never There: Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Elucidation

Abstract

Over the course of the past half century, the structural elucidation of unknown natural products has undergone a tremendous revolution. Before World War II, a chemist would have relied almost exclusively on the art of chemical synthesis, primarily in the form of degradation and derivatization reactions, to develop and test structural hypotheses in a process that often took years to complete when grams of material were available. Today, a battery of advanced spectroscopic methods, such as multidimensional NMR spectroscopy and high-resolution mass spectrometry, not to mention X-ray crystallography, exist for the expeditious assignment of structures to highly complex molecules isolated from nature in milligram or sub-milligram quantities. In fact, it could be argued that the characterization of natural products has become a routine task, one which no longer even requires a reaction flask! This Review makes the case that imaginative detective work and chemical synthesis still have important roles to play in the process of solving nature's most intriguing molecular puzzles.

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

“…In these instances, researchers determining the structure rely to an increasing extent on extensive batteries of NMR data, including those from multidimensional measurements. Consequently and especially in view of the ever-increasing average level of structural complexity of newly isolated compounds, there is a growing frequency of incorrectly assigned structures 7 . Most often, this takes the form of improperly deduced relative configurations.…”

“…Because the synthetic chemist typically knows the structure of each substrate or reactant, the question of structure assignment for each new product more often involves correctly deducing the relative configuration of newly introduced stereocenters in the product rather than its constitution. In contrast, because there is less structural history to inform the analysis of newly isolated natural products, issues of constitution are more often important for the natural product isolation chemist 7 .…”

Natural occurrence, biological activities and synthesis of eight-, nine-, and eleven-membered ring lactones

“…Topsentolides A 1 , A 2 , B 1 , B 2 , B 3 , C 1 , and C 2 (86)(87)(88)(89)(90)(91)(92) are oxylipins isolated in 2006 from the marine sponge Topsentia sp. 60 These lactones exhibit moderate citotoxicity against human solid tumor cell lines.…”

“…Concerning the structural misassignments presented above, we would like to reproduce some paragraphs of the fascinating work of Nicolaou and Snyder, 87 …”

Experimental and Density Functional Theory Study of a New Dimer with Tetrasubstituted Cyclobutane Ring System Isolated from Psoralea plicata Seeds

“…Thus, the disclosure of the relative configuration has a great impact on the full understanding of their chemical behaviors. Different approaches to determine the exact structure and/or configuration of organic products have been devised (Seco et al, 2004;Nicolaou et al, 2005;Bifulco et al, 2007). Stereochemical information on organic compounds is usually derived from vicinal H, H coupling constants.…”