The total synthesis of hirsutellones A (1), B (2), and C (3) has been achieved through a bioinspired late-stage sequence starting from advanced intermediate 6. The sequence proceeded via labile intermediate 17,1'-dehydrohirsutellone B (5) and delivered, in addition to the natural products (1-3), hirsutellone analogue 1',2',17-epi-hirsutellone C (1',2',17-epi-3).
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| http://dx.doi.org/10.1021/ol202239u | DOI Listing |
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Biosynthesis of Cyclophane-Containing Hirsutellone Family of Fungal Natural Products.
J Am Chem Soc
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State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, MOE-LSB and MOE-LSC, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Hirsutellones are fungal natural products containing a macrocyclic cyclophane connected to a decahydrofluorene ring system. We have elucidated the biosynthetic pathway for pyrrocidine B () and GKK1032 A (). Two small hypothetical proteins, an oxidoreductase and a lipocalin-like protein, function cooperatively in the oxidative cyclization of the cyclophane, while an additional hypothetical protein in the pyrrocidine pathway catalyzes the specific cycloaddition to form the fused decahydrofluorene.
View Article and Find Full Text PDFBio-inspired formal synthesis of hirsutellones A-C featuring an electrophilic cyclization triggered by remote Lewis acid-activation.
Chemistry
November 2013
Muséum National d'Histoire Naturelle, 57 rue Cuvier (CP 54), 75005 Paris (France); CNRS, UMR 7245, Unité Molécules de Communication et Adaptation des Micro-organismes, Paris (France).
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.
View Article and Find Full Text PDFToward a synthesis of hirsutellone B by the concept of double cyclization.
J Org Chem
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Frick Chemistry Laboratory, Department of Chemistry, Princeton University, Princeton, New Jersey, 08544, United States.
This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring-forming, nucleophilic capture of a transient acylketene and an intramolecular Diels-Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced "double cyclization" cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B.
View Article and Find Full Text PDFHirsutellones and beyond: figuring out the biological and synthetic logics toward chemical complexity in fungal PKS-NRPS compounds.
Nat Prod Rep
June 2013
Muséum National d'Histoire Naturelle, Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.
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.
View Article and Find Full Text PDFTotal synthesis of hirsutellone B via Ullmann-type direct 13-membered macrocyclization.
Org Lett
December 2011
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
Total synthesis of Hirsutellone B has been achieved by a convergent synthetic strategy. This synthesis features direct construction of the highly strained 13-membered macrocycle of Hirsutellone B utilizing the Ullmann-type reaction. To the best of our knowledge, this is the first application of macrocyclization utilizing an intramolecular Ullmann-type reaction between an aliphatic alcohol and aryl halide.
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