title: Stereoselective Synthesis of Isochromanones by an Asymmetric Ortho-Lithiation Strategy: Synthetic Access to the Isochromanone Core of the Ajudazols.
abstract: Full details on the design, development, and application of a highly stereoselective strategy for the synthesis of isochromanones are reported. The method is based on an asymmetric ortho lithiation with aldehyde electrophiles and utilizes the chiral memory of a preoriented atropisomeric amide axis for stereocontrol. For direct transformation of sterically hindered amides to isochromanones, efficient and mild one-pot protocols involving either O-alkylation or acidic microwave activation were developed. The procedures may be applied also to highly functionalized as well as stereochemically complex and sensitive substrates and demonstrate a high protective group tolerance. Furthermore, asymmetric crotylborations of axially chiral amides were studied in detail. These methodologies enable a general access to all possible stereoisomers of hydroxyl-isochromanones with up to three contiguous stereocenters. The true applicability of our approach was finally demonstrated by synthesis of the authentic anti,anti-configured isochromanone core of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain from myxobacteria.
authors.affiliation: Institut für Organische Chemie, Ruprecht-Karls Universität Heidelberg , Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Essig
authors.affiliation: Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn , Gerhard-Domagk-Straße 1, 53121 Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000478:Alkylation; D000577:Amides / Q000737:chemistry*; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D008094:Lithium / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D000577:Amides; D002867:Chromones; D003374:Coumarins; C485090:ajudazol A; D008094:Lithium