The nonadrides. Part VI. Dimerisation of the C9 unit in vivo and in vitro

Abstract

But-I -enyl(methyl)maleic anhydride (4) has been synthesised and shown to act as an efficient (55% incorporation) precursor of the cyclononadienes, glauconic and glaucanic acids, in Penicillium purpurogenum. Base-catalysed dimerisation of compound (4) yields 5% of an epimer of glaucanic acid.IN Part V evidence, based on feeding of labelled acetate, succinate, glucose, and n-butyl(methy1)maleic anhydride, was presented supporting the hypothesis that a key step in the biosynthesis of glaucanic acid (1) was the dimerisation of a C, unit and that glaucanic acid was further oxidised to glauconic acid (2). The anhydride (4) appeared to be the most likely C, unit which dimerises to (1) since it is of the correct oxidation level and functionality.The synthesis of the anhydride (4) was based on our findings that a-keto-esters condense with cc-phosphonato-ester anions in a Wadsworth-Emmons reaction4 to give high yields of maleic esters with little or none of the corresponding fumarates. The required keto-ester (5) was synthesised from ethyl 2-oxohexanoate, which, was first converted into the enol acetate

Elucidation of the Biosynthetic Pathway Leading to the Complex Nonadride Phomoidride B

“…11 Later, a biomimetic synthesis of 12-epi-glaucanic acid was achieved by Sutherland via treatment of a DMF solution of anhydride 5 with triethylamine to afford 8. [12][13][14] Although the dimerization product 8 was obtained in only a 4% yield, the outcome nonetheless provided further evidence supporting a dimerization biosynthetic pathway for the nonadrides.…”

Structural and synthetic studies on maleic anhydride and related diacid natural products

“…Recreation of this dimerisation step in vitro is an attractive strategy for the total synthesis of nonadrides. Early work by Sutherland showed that treatment of 12 with Et3N in DMF could promote cyclisation giving iso-glaucanic acid 13 in 4% isolated yield, 27 and this work was further developed by Baldwin using Et3N and MgCl2 in DMSO which gave 13 along with further products. 28 Sulikowski tethered the two methylmaleic anhydride moieties together to enhance the efficiency of ring formation.…”

“…This may be attributed, in part, to an early report from Sutherland which indicated that such compounds are unstable. 27 Pursuing an interest in the biosynthesis of maleidride natural products with fungicidal activities, herein we describe recent studies on the total syntheses of fungal dienoic acids tricladic acids A, B and C as well as the reported structure of waquafranone B isolated from Wicklowia aquatica and analogues of the exo-diene monomer 10 required for dimerisation studies. 31,32…”

“…This was in accord with Sutherland who had reported that such anhydrides are unstable. 27 The 1 H-NMR spectrum (CDCl3) of anhydride 34 displayed alkenic signals at  7.24, 6.59 and 6.13 whereas for waquafranone B these were reported to resonate at  6.97, 6.45 and 5.62. The 1 H-NMR spectrum of diacid 33 was found to be pH dependent and in CDCl3 + 1 equivalent of DABCO gave alkenic signals at  6.96, 6.43 and 5.56 which correlated well with the natural product.…”

Novel nonadride, heptadride and maleic acid metabolites from the byssochlamic acid producer Byssochlamys fulva IMI 40021 – an insight into the biosynthesis of maleidrides

“…All three metabolites, 1 , 3 and 4 , were hypothesised to be biosynthesised via alternative dimerisation modes of a C 9 /C 10 -maleic acid precursor 5 and/or 6 , and evidence for this was obtained by feeding studies with radiolabelled 6 . 9 Many more nonadride metabolites have since been reported, e.g. heveadride 7 , 10 an isomer of 1 , and others which are expected to be biosynthesised through dimerisation of differently substituted maleic anhydride units, including scytalidin 8 , 11 and castaneolide 9 .…”