Asymmetric Synthesis DOI: 10.1002/ange.200705816 Highly Diastereoselective Synthesis of Orthoquinone Monoketals through l 3 -Iodane-Mediated Oxidative Dearomatization of Phenols** Laurent PouysØgu, Stefan Chassaing, Delphine Dejugnac, Anne-Marie Lamidey, Karinne Miqueu, Jean-Marc Sotiropoulos, and StØphane Quideau* Orthoquinone monoketals A and orthoquinols B are cyclo- hexa-2,4-dienone derivatives with valuable reactivity features for the construction of complex molecular architectures. [1] Their conjugated dienone unit and the vicinal positioning of their oxygenated functionalities constitute a unique structural arrangement that can be transformed rapidly into various kinds of polyoxygenated (poly)cyclic systems (Scheme 1). [1] This chemical versatility has often been demonstrated over the last fifty years, and these benzoquinonoid cyclohexa- dienones have been used as key intermediates in several syntheses of natural products. [1,2] However, their potential in synthesis has by no means been fully exploited. It still remains to take advantage of their tetrahedral C6 center in asym- metric synthesis. This development has not yet taken place as a result of the lack of efficient methods available for preparing chiral derivatives of A and/or B in nonracemic form. [1c,3] Access to these chiral entities would render possible the enantioselective synthesis of many natural products (e.g., calicheamicinone, [2a] trichodimerol, [2b,c] aquaticol, [2d] and scyphostatin [2e] via transformations I–IV , respectively, Scheme 1), as stated by Pettus and co-workers, [1c] who reported an enantioselective route to paraquinols through diastereoselective phenol dearomatization. [4a] In related con- current investigations, our initial efforts toward the prepara- tion of orthoquinonoid derivatives relied on the dearomati- zation of chiral aryl methyl ethers by anodic oxidation. [4b] This approach did furnish orthoquinone monoketals of type A as single enantiomers, but only in poor yields, for it required monohydrolysis of bisketal intermediates and could not be applied directly to phenolic substrates. Herein, we report a convenient, high-yielding, and highly diastereoselective route to new monoketals of type A through the dearomatization of phenols mediated by hypervalent iodine. The starting phenols 1 contained a chiral ethanol unit O-tethered to the ortho position of the phenolic ring (Table 1). These constructs were thus designed to permit their dearomatization into spiroketals of type A. A substitu- ent was placed at the para position to prevent or at least retard the self-dimerization of the dearomatized species through [4+2] cycloaddition events. [5] The substrates were prepared by a Williamson reaction between 5-substituted 2-benzyloxyphenols and enantiomerically enriched terminal epoxides generated by using the Jacobsen method (see the Supporting Information). After extensive screening of the reaction conditions, [6] we found the use of the l 3 -iodane (diacetoxyiodo)benzene (DIB, 1.0 equiv) in 2,2,2-trifluoro- ethanol (CF 3 CH 2 OH, TFE) at 35 8C, followed by quenching of the released acetic acid with powdered NaHCO 3 at the same temperature without addition of water, to be optimal in furnishing the desired compounds. All eight phenolic alcohols 1a–h were converted into the desired spiroketals 2 and 3, which were isolated in a quantitative combined yield with an excellent level of purity through a simple filtration–evaporation procedure (Table 1). Although the further purification of these products was not necessary before their use in subsequent reactions, they were separated by column chromatography for the characteriza- tion of each diastereomer. Their stereochemistry was estab- lished unambiguously by NOESY experiments (see the Scheme 1. Selected synthetically useful transformations of orthoqui- none monoketals A and orthoquinols B. [*] Dr. L. PouysØgu, Dr. S. Chassaing, Dr. D. Dejugnac, A.-M. Lamidey, Prof. S. Quideau UniversitØ de Bordeaux Institut des Sciences MolØculaires (CNRS-UMR 5255) and Institut EuropØen de Chimie et Biologie 2 rue Robert Escarpit, 33607 Pessac Cedex (France) Fax: (+ 33)5-4000-2215 E-mail: s.quideau@iecb.u-bordeaux.fr Dr. K. Miqueu, Dr. J.-M. Sotiropoulos IPREM (CNRS-UMR 5254) UniversitØ de Pau et des Pays de l’Adour HØlioparc, 2 Avenue Pierre Angot, 64053 Pau Cedex 09 (France) [**] We thank the Institut Universitaire de France, the CNRS (“Jeunes Chercheurs” ATIP grant 2005-2007), and the Ministre de la Recherche for financial support, and IDRIS for the use of computational facilities. Supporting information for this article, including experimental and theoretical details, and characterization data for all new com- pounds, is available on the WWW under http://www.angewand- te.org or from the author. Zuschriften 3608 # 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2008, 120, 3608 –3611