title: Access to the aeruginosin serine protease inhibitors through the nucleophilic opening of an oxabicyclo[2.2.1]heptane: total synthesis of microcin SF608.
abstract: Serine proteases play key roles in many biological processes and are associated with several human diseases such as thrombosis or cancer. During the search for selective inhibitors of serine proteases, a family of linear peptides named the aeruginosins was discovered in marine cyanobacteria. We herein report an entry route into the synthetically challenging core fragment of these natural products. Starting from the common oxabicyclic building block 11, we accessed the octahydroindole core of the aeruginosins, exemplified by the total synthesis of microcin SF608 (2). Key to the synthetic strategy is a highly efficient nucleophilic opening of an oxabicyclo[2.2.1]heptane producing the hydroindole motif of microcin SF608. Moreover, during the synthetic efforts we have observed an unusual regioselective epoxide reduction. Detailed experimental studies of this reaction led us to propose a mechanistic rationale involving intramolecular hydrogen atom delivery by a carbamate NH group to control the regioselectivity of the homolytic epoxide cleavage.
authors.affiliation: Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland).
authors.forename: Stefan
authors.initials: S
authors.lastname: Diethelm
authors.forename: Corinna S
authors.initials: CS
authors.lastname: Schindler
authors.forename: Erick M
authors.initials: EM
authors.lastname: Carreira
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D001688:Biological Products; D004852:Epoxy Compounds; D007211:Indoles; D010455:Peptides; D015842:Serine Proteinase Inhibitors; C470082:microcin SF608
keywords: aeruginosins; epoxide reduction; hydroindoles; natural products; serine protease inhibitors