Direct biosynthetic cyclization of a distorted paracyclophane highlighted by double isotopic labelling of l-tyrosine

Abstract

The biosynthesis of pyrrocidines, fungal PK-NRP compounds featuring a strained [9]paracyclophane, was investigated in Acremonium zeae. We used a synthetic L-tyrosine probe, labelled with oxygen 18 as a reporter of phenol reactivity and carbon 13 as a tracer of incorporation of this exogenous precursor. The ((18)O)phenolic oxygen was incorporated, suggesting that phenol behaves as a nucleophile during the formation of the bent aryl ether.

Oxidative Cyclization in Natural Product Biosynthesis

“…161 Recently, Nay and coworkers performed feeding studies of 173 by using doubly labeled 18 O, 13 C-L-tyrosine 176 . 162 The feeding studies confirmed that both of the labeled atoms were incorporated into 173 , suggesting that oxygen atom of cyclophane ether is derived from the nucleophilic phenolic oxygen of tyrosine. Several P450-catalyzed cyclization mechanisms can be proposed for morphing the acyclic PK-NRP product 177 into the paracyclophane as shown in Scheme 30B.…”

“…There are three distinct routes for C-C bond formation: (1) epoxidation, (2) radical coupling with phenolate, (3) an apparent Diels-Alder to create the 6-5-6 tricyclic scaffold element. 162 …”

Didymellanosine, a new decahydrofluorene analogue, and ascolactone C from Didymella sp. IEA-3B.1, an endophyte of Terminalia catappa

“…35,40,43 The complex molecular architecture, consisting of a tricyclic polyketide fused to a 12 or 13-membered macroether ring which contains a g-lactam or a succinimide moiety, combined with their intriguing bioactivities, have triggered tremendous efforts in synthetic and biosynthetic studies as well. [45][46][47] However, decahydrouorenes featuring a tetracyclic core as encountered in compound 1 are rarely reported. To date, only embellicines A and B, possessing cytostatic, cytotoxic and NFkB inhibitory activities, from a fungal endophyte Embellisia eureka, 23 antitubercular phomapyrrolidones A-C from an endophytic Phoma sp.…”

Recent highlights in biosynthesis research using stable isotopes

“…However, a recently investigated example shows, that breaking the aromatic character of a phenyl ring is not necessary for building up a bended aryl ether in a biological scaffold. In this study, 13 C- and 18 O-labeled L-tyrosine was used to elucidate the biosynthesis of pyrrocidines such as pyrrocidine A ( 24 , Scheme 6 ) bearing a [9]paracyclophane moiety in the fungus Acremonium zeae [ 52 ]. Compound 24 is the product of a mixed PKS and NRPS machinery containing nine acetate units, five methyl groups from SAM and one L-tyrosine [ 53 ].…”