DOI: 10.1002/ajoc.201200171 Synthesis of (Æ)-Panduratin A and Related Natural Products Using the High Pressure Diels–Alder Reaction Luke A. Pasfield, Laura de la Cruz, Junming Ho, Michelle L. Coote, Gottfried Otting, and Malcolm D. McLeod* [a] Panduratin A (1) is the prototypical member of a family of related cyclohexenyl natural products and is isolated as a racemic mixture from Boesenbergia rotunda, a perennial herb found in South East Asia (Scheme 1). [1–4] The plant has been used in traditional medicine to treat conditions such as diarrhea, asthma, indigestion, dysentery, and many others. [1–4] More recently, studies have shown that these ex- tracts have anti-HIV, antibacterial, antifungal, and anti- tumor activity. [3–6] Our particular interest in panduratin A and its congeners stems from a report that they competi- tively inhibit the dengue virus NS2B-NS3 protease. [7, 8] Herein, we report the synthesis of panduratin A in six steps including a high pressure Diels–Alder reaction. This diver- gent sequence also allowed the synthesis of the related nat- ural products 4-hydroxypanduratin A (2), panduratin H (3), panduratin I (4), nicolaioidesin B (5), and 2-hydroxyisopan- duratin A (6). [1–9] We investigated the binding of 4-hydroxy- panduratin A (2) to the dengue virus NS2B-NS3 protease by NMR spectroscopy. To date, two syntheses of panduratin A have been report- ed, [10, 11] both of which used a cycloaddition reaction be- tween protected chalcone derivative 7 and (E)-ocimene (8) (Scheme 2). The first reported synthesis by Rahman and co-workers [10] in 2010 was achieved by a thermally promot- ed Diels–Alder reaction between 7 (P = 2-methoxyethoxy- methyl ether, MEM) and (E)-ocimene followed by depro- tection to afford a mixture of panduratin A and its regioiso- mer nicolaioidesin B. No regioisomer ratio was reported for this mixture, nor were the regioisomers separated. In the same year, Porco and co-workers [11] used a silver nanoparti- cle catalyst developed in their laboratory to facilitate the cycloaddition between 7 (P = Ac) and (E)-ocimene. This method afforded the adduct leading to panduratin A with a small amount of the exo isomer, which corresponded to the isomeric natural product nicolaioidesin A. These efforts serve to highlight two key issues encoun- tered in synthetic strategies targeting the panduratin natu- ral product family. Firstly, the requisite chalcones are typi- [a] L. A. Pasfield, L. de la Cruz, Dr. J. Ho, Prof. M. L. Coote, Prof. G. Otting, Assoc. Prof. M. D. McLeod Research School of Chemistry, Australian National University Canberra ACT 0200 (Australia) Fax: (+ 61) 2-6125-8114 E-mail : malcolm.mcleod@anu.edu.au Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ajoc.201200171. Scheme 1. Panduratin A (1) and related natural products. Scheme 2. Rahman [10] and Porco [11] synthetic strategy and retrosynthetic analysis for this work. Asian J. Org. Chem. 2013, 2, 60 – 63  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 60 COMMUNICATION