Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

Abstract

The paraherquamides constitute an unusual family of prenylated indole alkaloids that are secondary metabolites produced by Penicillium sp. and Aspergillus sp. fungi. This review will cover both the biosynthesis as well as the chemical synthesis of this family of natural products. Particular emphasis will be placed on the provocative hypothesis that the core bicyclo[2.2.2]diazaoctan ring system, which is common to this entire family, is formed by a biological DielsAlder reaction.Despite its widespread use in synthetic organic chemistry, the Diels-Alder cycloaddition reaction does not occur frequently in nature. 1,2) There are just a few reports in the literature claiming the identification of an enzyme that catalyzes this most ubiquitous synthetic ring-forming reaction. [3][4][5][6] A possible explanation for this is that, enzymes generally catalyze reactions by stabilizing the structure and charge of the developing transition state. For most reactions subject to this stratagem of catalysis, both the starting substrate and the product differ significantly with respect to structure from the transition state; it is this fundamental difference that allows for turnover; i.e., both the product and the starting substrate must bind to the enzyme less tightly than the transition state structure. In the Diels-Alder reaction, the transition state is highly ordered and closely resembles the structure of the product (see Fig. 1, below). In other words, an enzyme that was designed to stabilize the transition state structure for this reaction would be expected to be inhibited by the product (via tight binding) and turnover (thus catalysis) would be precluded. It is from within the excitement of this fundamental question, that this review will hold as a guiding light.The only examples of protein-catalyzed Diels-Alder reactions are those of catalytic antibodies that have recently been shown to catalyze the intermolecular [4ϩ2] cycloaddition reaction.7-9) In these cases, the initial Diels-Alder adducts were high-energy substances that significantly change their structure or conformation after the initial cyclocondensation and were subsequently released from the antibody CDR (allowing for turnover). In addition, ribozymes have been reported to catalyze the Diels-Alder reaction and findings in this area have been reviewed. 10) The Penicillium sp. that produces the brevianamides/paraherquamides may be a rare, but vitally important example of the existence of DielsAlderases. It is further significant to note in the context of the catalytic antibody stratagem that, the brevianamide DielsAlder adducts (which are proposed to be the brevianamides themselves) are very rigid substances; therefore, a significant change in conformation or structure is either impossible or highly unlikely. Elucidation of the mechanism for turnover in the purported paraherquamide and brevianamide [4ϩ2] cycloaddition reaction should be an extremely interesting and significant finding.In order to do proper justice to the history of the biosynthetic Diels-Alder p...

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