Recent advances in the chemo-biological characterization of decalin natural products and unraveling of the workings of Diels–Alderases

Abstract

The Diels–Alder (DA) reaction refers to a [4 + 2] cycloaddition reaction that falls under the category of pericyclic reactions. It is a reaction that allows regio- and stereo-selective construction of two carbon–carbon bonds simultaneously in a concerted manner to generate a six-membered ring structure through a six-electron cyclic transition state. The DA reaction is one of the most widely applied reactions in organic synthesis, yet its role in biological systems has been debated intensely over the last four decades. A survey of secondary metabolites produced by microorganisms suggests strongly that many of the compounds possess features that are likely formed through DA reactions, and most of them are considered to be catalyzed by enzymes that are commonly referred to as Diels–Alderases (DAases). In recent years, especially over the past 10 years or so, we have seen an accumulation of a substantial body of work that substantiates the argument that DAases indeed exist and play a critical role in the biosynthesis of complex metabolites. This review will cover the DAases involved in the biosynthesis of decalin moieties, which are found in many of the medicinally important natural products, especially those produced by fungi. In particular, we will focus on a subset of secondary metabolites referred to as pyrrolidine-2-one-bearing decalin compounds and discuss the decalin ring stereochemistry and the biological activities of those compounds. We will also look into the genes and enzymes that drive the biosynthetic construction of those complex natural products, and highlight the recent progress made on the structural and mechanistic understanding of DAases, especially regarding how those enzymes exert stereochemical control over the [4 + 2] cycloaddition reactions they catalyze.