Synthesis of racemic and optically active forms of novel antimalarial agents, spirocyclopentanone–anthracene adducts, via tandem Michael addition–Dieckmann condensation reactions as the key steps Ruangrat Choommongkol a , Rattana Jongkol a , Samran Prabpai c , Palangpon Kongsaeree c,d , Puttinan Meepowpan a,b,⇑ a Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand b Material Science Research Center, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand c Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand d Center for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand article info Article history: Received 2 February 2012 Accepted 5 March 2012 Available online 11 April 2012 abstract Spirocyclopentanone–anthracene adducts, novel antimalarial agents, have been synthesized by employ- ing the racemic and the optically active dimethyl itaconate–anthracene adducts in a reaction with piper- ine via tandem Michael addition–Dieckmann condensation reactions as the key steps. All adducts exhibited antimalarial activity with IC 50 values of 3.4–4.7 lg/mL, and importantly displayed non-cytotox- icity to vero cells. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. 1. Introduction Malaria is a serious problem that is spreading in tropical and subtropical areas of the world. 1 Approximately 3.3 billion people were at risk of malaria in 2010. 2 Malaria is an infectious disease caused by the protozoa parasite of the genus Plasmodium and is carried from person to person by the anopheles mosquitoes. The parasites are of many types, but only five species of the genus Plas- modium cause malaria in humans. 2 The parasites that cause malar- ia in humans are Plasmodium falciparum (malaria tropica); Plasmodium vivax (malaria tertiana); Plasmodium ovale (malaria quartana); Plasmodium malariae (malaria tertiana) and Plasmodium knowlesi. 2 The first two species (P. falciparum and P. vivax) cause the most infections worldwide. 2 P. falciparum is the agent of severe and potentially fatal malaria because of antimalarial drug resis- tance. 3 Thus, the research and development of antimalarial drugs is especially important in order to eradicate this infectious disease. Piperine 1 (Fig. 1) is a major alkaloid compound in Piper ni- grum. 4 It displays a variety of pharmacological and other bioactiv- ities such as antifungal, 5 antidiarrheal, 6 antiinflammatory, 7 insecticidal, 8 nematocidal activity, 4a inhibition of life metabolism, 9 immunomodulatory 10 , and antitumor activities. 10 Recently, piper- ine dimers such as chabamide 11 (antiplasmodial) and dipiperamide A, B, C 12 (CYP3A4 inhibitor) were discovered. Previously, the use of the dimethyl itaconate–anthracene ad- duct 13 (±)-2 (Fig. 1) in racemic form has been reported as a building block in the syntheses of biologically active natural products, including methylenomycin B, 14 sarkomycin, 15 deepoxy-4,5-dide- hydromethylenomycin A, 16 methylenomycin A methyl esters, 16 diospyrol, 17 a-methylene-c-butyrolactones 18a,b such as methyle- nolactocin, nephrosterinic acid, and protolichesterinic acid, and a-methylene bis-c-butyrolactones 18 such as cannadensolide, spo- rothriolide, and xylobovide. Moreover, optically active methylene lactones, 19 such as methylenolactocin, nephrosterinic acid and pro- tolichesterinic acid, can be prepared by employing tandem aldol– lactonization reactions of the enantiomerically pure forms (+)-2 and ()-2. Herein we report the synthesis of the racemic and optically ac- tive forms of a spirocyclopentanone–anthracene adduct via tan- dem Michael addition–Dieckmann condensation reactions as the key steps. The racemic and optically active forms of dimethyl itac- onate–anthracene adducts 2 react with piperine 1 as a precursor 0957-4166/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.03.006 ⇑ Corresponding author. Tel.: +66 53 94 3341 5x317; fax: +66 53 89 227. E-mail addresses: pmeepowpan@gmail.com, puttinan@chiangmai.ac.th (P. Mee- powpan). COOMe 2 MeOOC N O O O 1 Figure 1. Structures of piperine 1 and dimethyl itaconate–anthracene adduct 2. Tetrahedron: Asymmetry 23 (2012) 357–363 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy