10.1021/ol301305p r 2012 American Chemical Society Published on Web 06/27/2012 ORGANIC LETTERS 2012 Vol. 14, No. 14 3600–3603 Biomimetic Asymmetric Synthesis of (R)-GTRI-02 and (3S,4R)-3,4-Dihydroxy- 3,4-dihydronaphthalen-1(2H)-ones Syed Masood Husain, † Michael A. Sch € atzle, † Caroline R € ohr, ‡ Steffen L € udeke, † and Michael M € uller* ,† Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany, and Institute for Inorganic and Analytical Chemistry, Albert-Ludwigs-University of Freiburg, Albertstrasse 21, 79104 Freiburg, Germany michael.mueller@pharmazie.uni-freiburg.de Received May 11, 2012 ABSTRACT The NADPH-dependent tetrahydroxynaphthalene reductase (T 4 HNR) from Magnaporthe grisea was used for the biomimetic synthesis of (R)-GTRI- 02 by stereoselective reduction of 1-(3,6,8-trihydroxy-1-methylnaphthalen-2-yl)ethanone. This also led to the isolation of a (3S,4R)-cis-ketodiol formed by T 4 HNR-catalyzed reduction of the corresponding hydroxynaphthoquinone. Flaviolin and lawsone also reduced to corresponding cis- ketodiols in good yields. Naphthol reductases belong to the large family of short- chain dehydrogenases/reductases (SDR) and show a unique ability to catalyze asymmetric NADPH-dependent reduction of polyhydroxynaphthalenes. 1 Although the use of naphthol reductases as biocatalysts in synthesis looks promising, so far their application has remained limited to the reduction of only a few physiological substrates. 1À4 Tetrahydroxynaphthalene reductase (T 4 HNR) from Magna- porthe grisea has been used by us and others to catalyze the reduction of 1,3,6,8-tetrahydroxynaphthalene (T 4 HN, 1) to (R)-scytalone (2) in 33% yield (Scheme 1, A). 1,4,5 T 4 HNR is one of the two naphthol reductases involved in the bio- synthesis of dihydroxynaphthalene melanin. 2À4 For naph- tholic substrates to be reduced by T 4 HNR, the 1,3-dihydroxy substitution pattern represents the essential structural motif. 1 Herein, we report the chemoenzymatic synthe- sis of the natural product GTRI-02 (3) using T 4 HNR as well as the unexpected recognition of hydroxynaph- thoquinones as substrates which are reduced by T 4 HNR to cis-ketodiols. The putatively polyketidic GTRI-02 (3), isolated from soil actinomycetes Micromonospora sp., 6 has been shown to possess antioxidant properties. More recently, it has also been extracted from Streptomyces strain GW4184 and Streptomyces sp. ANK313. 7,8 We proposed that 3 is biosynthesized via an enzymatic reduction. † Institute for Pharmaceutical Sciences. ‡ Institute for Inorganic and Analytical Chemistry. (1) Sch€ atzle, M. A.; Flemming, S.; Husain, S. M.; Richter, M.; G€ unther, S.; M€ uller, M. Angew. Chem., Int. Ed. 2012, 51, 2643–2646. (2) Vidal-Cros, A.; Viviani, F.; Labesse, G.; Boccara, M.; Gaudry, M. Eur. J. Biochem. 1994, 219, 985–992. (3) Liao, D.-I.; Thompson, J. E.; Fahnestock, S.; Valent, B.; Jordan, D. B. Biochemistry 2001, 40, 8696–8704. (4) Simpson, T. J.; Weerasooriya, M. K. B. J. Chem. Soc., Perkin Trans. 1 2000, 2771–2775. (5) Thompson, J. E.; Fahnestock, S.; Farrall, L.; Liao, D.-I.; Valent, B.; Jordan, D. B. J. Biol. Chem. 2000, 275, 34867–34872. (6) Yeo, W. H.; Yun, B. S.; Kim, S. S.; Park, E. K.; Kim, Y. H.; Yoo, I. D.; Yu, S. H. J. Antibiot. 1998, 51, 952–953. (7) Maskey, R. P.; Fotso, S.; Lessmann, H.; Gr€ un-Wollny, I.; Lackner, H.; Laatsch, H. Z. Naturforsch., B 2005, 60, 183–188. (8) Abdalla, M. A.; Win, H. Y.; Islam, M. T.; Tiedemann, A. V.; Sch€ uffler, A.; Laatsch, H. J. Antibiot. 2011, 64, 655–659.