title: Harnessing a p-Quinone Methide Intermediate in the Biomimetic Total Synthesis of the Highly Active Antibiotic 20-Deoxy-Elansolid B1.
abstract: The polyketide, 20-deoxy elansolid B1, was prepared by a convergent strategy that relied on a putative biomimetic intramolecular Diels-Alder cycloaddition (IMDA) via a vinylic p-quinone methide intermediate to furnish the key tetrahydroindane unit. The (Z,E,Z)-configured triene unit was constructed by Pd-catalyzed Suzuki-Miyaura and Stille cross-coupling reactions without isomerization of any of the olefinic double bonds. Formation of a p-methide quinone intermediate under basic conditions and subsequent Michael addition by water to this intermediate proceeded with high facial selectivity which terminated this total synthesis. Remarkably, the new elansolid derivative 2 c shows very good inhibitory effect against Bacillus subtilis and Staphylococcus aureus (including MRSA) similarly to the best elansolid derivatives reported so far. Consequently, the hydroxyl group at C20 is not essential for antibacterial activity.
authors.affiliation: Institut für Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.
authors.forename: Liang Liang
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Institut für Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Candito
authors.affiliation: Institut für Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Dräger
authors.affiliation: Helmholtz Zentrum für Infektionsforschung, Helmholtz Institut für Pharmazeutische Forschung Saarland und Pharmazeutische Biotechnologie, Universität des Saarlandes, Campus E 8.1, 66123, Saarbrücken, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: Helmholtz Zentrum für Infektionsforschung, Helmholtz Institut für Pharmazeutische Forschung Saarland und Pharmazeutische Biotechnologie, Universität des Saarlandes, Campus E 8.1, 66123, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institut für Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschning
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D032701:Biomimetics; D002384:Catalysis; D061565:Cycloaddition Reaction; D045563:Indolequinones / Q000138:chemical synthesis* / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D013211:Staphylococcus aureus
chemical_list: D000475:Alkenes; D000900:Anti-Bacterial Agents; D045563:Indolequinones; D018942:Macrolides; C559179:elansolid B1; C068040:quinone methide
keywords: antibiotics; biosynthesis; intramolecular Diels-Alder cycloaddition; polyketides; total synthesis