Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A

Abstract

Nature synthesizes many strained natural products that have diverse biological activities. Uncovering these biosynthetic pathways may lead to biomimetic strategies for organic synthesis of such compounds. In this work, we elucidated the concise biosynthetic pathway of herquline A, a highly strained and reduced fungal piperazine alkaloid. The pathway builds on a nonribosomal peptide synthetase derived di-tyrosine piperazine intermediate. Following enzymatic reduction of the P450-crosslinked di-cyclohexadienone, N-methylation of the piperazine serves as a trigger that leads to a cascade of stereoselective and nonenzymatic transformations. Computational analysis of key steps in the pathway rationalizes the observed reactivities.

Oxidative Cyclization in Natural Product Biosynthesis

“…94–97 93 has also been shown to inhibit replication of the influenza virus without notable toxicity to humans. 94 In contrast to the DKP core of 82 , 91 contains a reduced piperazine core, likely derived from a multitude of reductions on the L-Tyr-L-Tyr dipeptide.…”

Structure-guided function discovery of an NRPS-like glycine betaine reductase for choline biosynthesis in fungi

“…2 The members of the CAR family are functionally diverse and play indispensable roles in both primary and secondary metabolism, such as the a-aminoadipate reductase Lys2 required for lysine biosynthesis in fungi; 3 and tyrosine reductase HqlA involved in biosynthesis of herquline A ( Figure 1A). 4 CARs also show substantial promise as green biocatalysts for the conversion of aromatic, or aliphatic carboxylic acids into the corresponding aldehydes. Indeed, synthetic applications of CARs have been reported for biocatalytic synthesis of vanillin; 5 preparation of methyl branched aliphatic aldehydes; 6 production of biofuels, [7][8] and other chemical commodities.…”

Bioinspired Syntheses of Herqulines B and C from Cyclodipeptide Mycocyclosin

“…2 The structurally related tetracyclic piperazine herquline B (2) 3 was isolated in 1996 although its absolute configuration could only recently be determined upon the completion of the first synthesis by Wood 4a and Baran 4b . The structure of a third congener, herquline C (3), 5 was isolated in 2016 by Houk and Tang during studies of the herquline biosynthetic pathway and identified as a diastereomer to herquline B (2) by Wood in 2018 4a . All three herqulines are characterized by a highly strained macrocyclic scaffold, a piperazine moiety, and a 2,3-disubstituted 1,4-dicarbonyl subunit (11 and 11a in 1-3) that has historically proven extremely difficult to access synthetically.…”

“…6 Reported synthetic efforts towards the herqulines corroborate these challenges: 7 specifically, intramolecular coupling reactions to form the 1,4-diketone subunit are hampered by the ring strain imparted by the macrocycle, while macrocyclic ring closure to forge the piperazine ring after installation of the 1,4-diketone scaffold has proven to be equally difficult. Our interest in these natural products started with the isolation of mycocyclosin (4), 8,9 a strained diketopiperazine dipeptide derived from cyclodityrosine cYY (5), which was hypothesized to be a biosynthetic precursor for the herqulines 10 (Fig. 1B).…”