Progress on PPAPs cyclization: Guttiferone A as a case study Pauline Menelle a , Kévin Cottet a,⇑ , Yann Fromentin a , Thomas Gaslonde a , François-Hugues Porée a , Didier Buisson b , Marie-Christine Lallemand a a Laboratoire de Pharmacognosie, Faculté de Pharmacie de Paris, UMR CNRS 8638 COMETE, Université Paris Descartes Sorbonne Paris Cité, 4 Avenue de l’Observatoire, 75006 Paris, France b Laboratoire Molécules de Communication et Adaptation des Microorganismes (MCAM), UMR 7245 CNRS-MNHN, Muséum national d 1 Histoire naturelle, CNRS, Sorbonne Universités, CP 54, 57 rue Cuvier, 75005 Paris, France article info Article history: Received 2 September 2017 Revised 9 November 2017 Accepted 17 November 2017 Available online xxxx Keywords: Symphonia globulifera Plant metabolites PPAPs Guttiferone A xanthones Phenolic oxidation abstract Guttiferone A and cyclized analogs are naturally occurring polycyclic polyprenylated acyl phloroglucinols possessing antiparasitic activities. Naturally occurring xanthones possess increased activity, but are either rare or difficult to synthesize. In this paper, three optimized methodologies to access natural, hydroxylated and non-natural xanthonic skeletons from guttiferone A are described. These compounds will serve as starting materials for further SAR studies. Ó 2017 Published by Elsevier Ltd. Introduction Symphonia globulifera is a widespread tropical tree used in Afri- can and American traditional medicine. 1 Several phytochemical investigations have been carried out, leading to the isolation of approximately 40 secondary metabolites, including a dozen poly- cyclic polyprenylated acyl phloroglucinols (PPAPs). PPAPs repre- sent a structurally fascinating and synthetically challenging class of natural products possessing a highly oxygenated acylphloroglu- cinol-derived core densely decorated with prenyl or geranyl sub- stituents. Additionally, these compounds have been shown to exhibit a broad range of biological activities, including antioxidant, antiviral, or anticancer properties. 2 Guttiferone A (1), one of the most representative compounds of this series, demonstrated promising activities against the pathogen agent Plasmodium falciparum in the micromolar range and can be efficiently accessed on the multigram scale using centrifugal partition chromatography (Fig. 1). 3 The availability of 1 combined with its biological potential prompted us to initiate a series of structure activity investigations. In the first study, we demonstrated the importance of the catechol moiety for the antiparasitic activity. 4 A library of twenty com- pounds possessing modified catechol moieties was synthesized and its potency evaluated toward Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani. Despite a moderate impact concerning the antiparasitic activity, this pharmacomodu- lation clearly decreased the non-specific toxicity which resulted in an enhancement of the selectivity index. Moreover, naturally occurring 3,16- (2) and 1,16-oxy-guttifer- one A (3) have shown greater antiparasitic activities, thus high- lighting the interest in xanthone-type PPAPs. Recently, our team reported a yeast mediated 5 and electrochemical 6 xanthone synthe- sis from guttiferone A (1). It is important to note that this particu- lar phenolic coupling could theoretically produce four possible compounds which could be related to the xanthone series (2–5, Fig. 2). Herein, we report new and convenient methodologies to synthesize four oxy-guttiferone A skeletons by phenolic coupling. This methodology may be particularly interesting regarding com- pounds 4 and 5, which are not yet known as naturally occurring. Results and discussion Previous results obtained via biotransformations 5 or electro- chemistry 6 permitted access to naturally occurring 3,16- (2) and 1,16-oxy-guttiferone A (3) from guttiferone A (1). PPAPs are an excellent inspiration for the development of new ring-forming reactions in organic synthesis. 7–9 Lewis and co-workers 10 and Jef- ferson 11 independently documented the xanthone cyclization route, using the model compound maclurin which was also https://doi.org/10.1016/j.tetlet.2017.11.041 0040-4039/Ó 2017 Published by Elsevier Ltd. ⇑ Corresponding author. E-mail address: kevin.cottet@hotmail.fr (K. Cottet). Tetrahedron Letters xxx (2017) xxx–xxx Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Please cite this article in press as: Menelle P., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.11.041