FULL PAPER DOI: 10.1002/ejoc.201301763 Naphthoquinone Diels–Alder Reactions: Approaches to the ABC Ring System of Beticolin Carsten S. Kramer, [a] Martin Nieger, [b] and Stefan Bräse* [a,c] Keywords: Synthetic methods / Cycloaddition / Natural products / Quinones / Beticolin The syntheses of highly substituted anthraquinones through Diels–Alder reaction by using naphthoquinones are de- scribed. As an application, the first synthesis of the ABC tri- cycle of beticolin 0 (1) is reported. By using substituted naphthoquinone monoketal dienophiles, the congested quar- Introduction Beticolin 0 (1; Figure 1), is a naturally occurring xan- thone produced by the fungal phytopathogen Cercospora beticola [1,2] Infection of sugar beet plants with this fungus causes leaf spot disease (cercosporiosis), making it the most destructive foliar pathogen of sugar beet worldwide. [3] The structure of 1 was determined in 1996, four years after the structural elucidation of the first member of the beticolin family. Beticolin 0 shares the same polycyclic skeleton with 19 congeners that incorporate chlorinated tetrahydroxan- thone and anthraquinone subunits, which combine to form a unique bicyclo[3.2.2]nonane framework. A similar motif is found in the structurally related acremoxanthones A–D, [4] acremonidins A–C, [5] xanthoquinodins A 1 –A 6 , B 1 –B 5 , [6] and xanthoquinodin-like molecules JBIR-97, -98, and -99. [7] Biological studies have revealed a broad cytotoxic profile for all beticolins. The compounds interact with multiple cellular targets and can even dimerize to form nonspecific ion channels. [8] The above notwithstanding, and despite the fact that many naturally occurring xanthones have attracted significant interest from the synthetic community, [9] little synthetic work has been recorded in the beticolin domain. Studies on the assembly of the bicyclo[3.2.2]nonane system of the natural products by radical cyclization chemistry have been reported; however, beticolins have yet to yield to total synthesis. [a] Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Campus South, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany E-mail: braese@kit.edu http://www.ioc.kit.edu/braese/english/index.php [b] Laboratory of Inorganic Chemistry, Department of Chemistry, P. O. Box 55, 00014 University of Helsinki, Finland [c] Institute of Toxicology and Genetics, KIT, Campus North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201301763. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 2150–2159 2150 ternary center, the alkenyl methyl group and the oxo-substit- uent on the C ring could be established in the desired 1,3- relationship. By switching to a 1,4-naphthoquinone dieno- phile, cycloaddition reaction of sensitive substrates succeed with nearly quantitative yield at moderate temperatures. Figure 1. Structure of beticolin 0 (1) and our retrosynthetic analy- sis. In 1992, the first structure of a beticolin was assigned by X-ray analysis and NMR spectroscopic studies, [10] followed by the isolation and structure elucidation of beticolin 0 (1) in 1996. [2] Although biological effects and structures have been known for decades, no total or partial syntheses were published. [11] In this study we focused our investigations towards the synthesis of the anthraquinone-subunit bearing the quaternary center. Moreover preliminary model studies towards bicyclo[3.2.2]nonane systems were conducted by Duffault by using radical cyclization. [12] Our strategy for the formation of the ABC tricycle 2 in- volved a Diels–Alder reaction of a naphthoquinone monoacetal building block 3 with diene 4 (Scheme 1). In this way, the quaternary center, the alkenyl methyl group and the oxo-substituent should be established in a 1,3-rela- tionship to each other. Our synthesis commenced with a