Biomimetic Synthesis Enables the Structural Revision of Natural Products

Abstract

Chemists have managed to isolate and catalogue innumerable chemical compounds synthesized by nature. The diversity, complexity, and therapeutic potential present in some of these natural products often make them alluring targets for total synthesis. Yet, despite the evolution of analytical techniques it is still commonplace for novel molecules to be mischaracterized. The scarcity, purity, and intricate structures of some chemical compounds all contribute to the challenges an isolation chemist faces when characterizing newly discovered natural products. A biomimetic synthesis takes into account the target molecule’s biosynthetic origins and attempts to replicate chemical reactions of the compound’s known or proposed biosynthesis within a laboratory setting. Recently, total synthesis, and by extension biomimetic synthesis, has been expertly employed in the structural revisions of many natural products. This thesis will describe in detail the first biomimetic synthesis of several meroterpenoid natural products. Every compound’s total synthesis features the same key step: a hetero-Diels–Alder reaction between a common ortho-quinone methide intermediate and caryophyllene or humulene. Furthermore, structural revisions are proposed for three of these compounds: littordial E, littordial F and drychampone B. These revisions are proposed on the basis of our biosynthetic speculation and the final structural reassignments of these compounds were carried out by means of 2D NMR spectroscopy with supporting computational studies. This work addresses a long-standing and still present problem in natural product chemistry: the erroneous assignment of newly isolated compounds. There are many avenues leading to mischaracterization of novel natural products and this work exemplifies how total synthesis in conjunction with insightful biosynthetic speculation can be used alongside modern sprectoscopic tools to correct such misassignments.