Hirsutellones and beyond: figuring out the biological and synthetic logics toward chemical complexity in fungal PKS-NRPS compounds

Abstract

Covering: up to early 2013. Fungal polyketides and their hybrid non ribosomal peptide derivatives are characterized by often striking structural features and biological activities. Their diversity and their complexity arise from highly organized and programmable biosynthetic pathways and have been challenged by many synthetic chemists. This review will conceptually illustrate how complexity can be generated, starting from a general biosynthetic purpose (the fundaments of PKS-NRPS assembly lines) and finally showing how the particular class of hirsutellone compounds has emerged from such processes in relation to post-elongation and secondary tailoring events. Synthetic efforts to produce these natural products will be described with a special emphasis on complexity-generating strategies and steps. Thus, the biosynthetic and synthetic works will be analyzed in a continuous flow, focusing on both the logic of Nature and organic chemists.

Collaborative Biosynthesis of Maleimide- and Succinimide-Containing Natural Products by Fungal Polyketide Megasynthases

“…The most abundant compounds oxaleimides A ( 1 ) , B ( 2 ) and C ( 3 ) all contain an unusual disubstituted succinimide moiety. 10 At the 3 position of the succinimide ring in 1 and 2 (or C18 in Figure 1), both compounds contain a branched aliphatic chain that has a terminal olefin (oct-1-en-3-yl). 1 contains a substituted trans- decalin ring that is carboxylated at C7.…”

Bio‐Inspired Formal Synthesis of Hirsutellones A–C Featuring an Electrophilic Cyclization Triggered by Remote Lewis Acid‐Activation

“…This work, in addition to providing a bio‐inspired formal synthesis of hirsutellone B ( 2 ), also gives clues to the alternative biosynthetic pathway suggested by Oikawa for the biosynthesis of GKK1032s8 and adapted to hirsutellones in Scheme (pathway b) 9. It shows that from a linear biosynthetic precursor like 4 , an oxidation at the terminal position of the acyl chain is conceivable to trigger the cyclization.…”

“…This work, in addition to providing a bio-inspired formal synthesis of hirsutellone B (2), also gives clues to the alternative biosynthetic pathway suggested by Oikawa for the biosynthesis of GKK1032s [8] and adapted to hirsutellones in Scheme 1 (pathway b). [9] It shows that from a linear biosynthetic precursor like 4, an oxidation at the terminal position of the acyl chain is conceivable to trigger the cyclization. Moreover, during the stereoselective sequence from the chiral intermediate 9 to the tricyclic compound 8, we were able to control the formation of seven new stereocenters, which originate from the stereochemistry of the methyl substituent in 9.…”

“…Oikawa’s study allowed us to predict the biosynthetic origin of hirsutellones (Scheme ). The most intriguing biosynthetic event is the conversion of a linear tyrosine‐nonaketide precursor ( 4 ) into the skeleton 7 , which is supposed to take place in an auxiliary enzyme active site after an oxidative activation, following two mechanistic hypotheses (Scheme , pathways a and b) 9…”

“…The most intriguing biosynthetic event is the conversion of a linear tyrosine-nonaketide precursor (4) into the skeleton 7, which is supposed to take place in an auxiliary enzyme active site after an oxidative activation, following two mechanistic hypotheses (Scheme 1, pathways a and b). [9] Considering these biosynthetic hypotheses, we imagined a biomimetic strategy towards the total synthesis of hirsutellones. Not only would such a strategy bring clues to the biosynthetic pathways, but also would give a straightforward access to the natural product and potential antitubercular analogues.…”