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.
Subject(s)
Isotope Labeling , Piperidines/chemistry , Polycyclic Compounds/chemistry , Tyrosine/metabolism , Acremonium/metabolism , Biosynthetic Pathways , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Cyclization , Heterocyclic Compounds, 4 or More Rings/chemistry , Mass Spectrometry , Pyrrolidinones/chemistry , Stereoisomerism , Tyrosine/chemical synthesis , Tyrosine/chemistryABSTRACT
A bio-inspired strategy was used to complete the formal synthesis of the antitubercular hirsutellone B and congeners A and C, through construction of its decahydrofluorene core from a linear polyene strand activated at both ends by a silyl enol ether and an allyl acetate. Our synthesis features a key electrophilic cyclization, starting with the remote activation (by [Yb(OTf)3] or BF3·OEt2) of the allyl acetate and stereoselectively affording the C ring. This was followed by an intramolecular Diels-Alder reaction to get the tricyclic core of the natural product. The stereoselective reduction of the resulting ketone towards the formal intermediate was critical to the success of this strategy.
Subject(s)
Antitubercular Agents/chemical synthesis , Biological Products/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Lewis Acids/chemistry , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Cyclization , Cycloaddition Reaction , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Hypocreales/chemistry , Ketones/chemistry , Molecular StructureABSTRACT
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.
