Job/Unit: O50208 /KAP1 Date: 14-04-15 12:59:34 Pages: 9 FULL PAPER DOI: 10.1002/ejoc.201500208 Collective Synthesis of Natural Products Sharing the Dihydro-γ-Ionone Core Alexis Castillo, [a] Lucia Silva, [b] David Briones, [c] José F. Quílez del Moral,* [a] and Alejandro F. Barrero* [a] Keywords: Natural products / Organocatalysis / Molecular diversity / Chiral pool We decided to follow the so-called “collective total synthe- sis” approach to synthesize several structurally different mol- ecules from a common intermediate possessing appropriate stereochemistry and functionalities. As the common precur- sor for the efficient preparation of these bioactive molecules, we chose (+)-3,4-dihydro-γ-ionone (1), a natural compound Introduction Nature provides an almost endless source of impressive structural diversity. However, it is also recognized that the myriad of complex and diverse natural products is ulti- mately derived from a limited number of common precur- sors. Inspired by this concept [1] and to mimic the action of nature, we used natural (+)-3,4-dihydro-γ-ionone (1) as a common precursor [2] for the syntheses of 2–8 (Figure 1). [3–8] The significant decrease in the total number of steps is one of the main advantages of this methodology. Siccanin (8) is a mold metabolite isolated from the cul- tured broth of the pathogenic plant fungus Helminthospos- ium siccans , a parasitic organism of rye grass. [8a] Siccanin possesses remarkable antifungal activity against some pathogenic fungi of the genera Trichophyton (the cause of the skin infection trichophytosis), Epidermophyton, and Microsporum. [8b] Thus, clinical tests showed that siccanin was effective against superficial fungal infections, [8c] includ- ing those of the opportunistic fungus Candida albicans . [8d] It has been reported recently by Mogi that siccanin is a species-selective succinate dehydrogenase (SDH) inhibi- tor. [8e] These studies have renewed interest in this molecule. Siccanin inhibits bacterial SDH from Pseudomonas aerugi- nosa (one of the leading causes of hospital-acquired infec- [a] Department of Organic Chemistry, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain E-mail: jfquilez@ugr.es, afbarre@ugr.es http://www.ugr.es/~sinmobio/ [b] Department of Chemistry, University of Beira Interior, Rua Marquês d’Ávila e Bolama, 6200 Covilhã, Portugal [c] Department of Chemical and Energy Technology, Rey Juan Carlos University, C/ Tulipán s/n, 28933 Móstoles, Spain Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201500208. Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 present in minor quantities in ambergris and in the plant Bellardia trixago. Thus, we report herein the enantioselective synthesis of siccanochromene F (2), metachromins U (3) and V(4), and bicyclic squalene derivative 5 as well as the formal syntheses of ambrein (6), phenazinomycin (7), and (–)-sic- canin (8). tions, mainly owing to innate and acquired resistance to antimicrobial drugs) and P. putida but not SDH from Esch- erichia coli or Corynebacterium glutamicum. Species-selec- tive inhibition is unique among SDH inhibitors, and this makes siccanin a potential lead compound for new chemo- therapeutics. To date, only one enantioselective and two ra- cemic total syntheses of siccanin have been reported. [8f–8i] Together with siccanin, siccanochromenes were also iso- lated from H. siccans . One of these molecules is siccano- chromene F (2). [3] Metachromins U and V (3 and 4) were isolated from the marine sponge Thorecta reticulata. The cytotoxicities of these compounds were assessed against a panel of human tumor cell lines (SF-268, H460, MCF-7, and HT-29) and a mammalian cell line (CHOK1). Both compounds are cytotoxic against all of these cell lines, and metachromin V is the most active [50% growth inhibition (GI 50 ) 2.1–10 μ]. [4] Compound 5 is a bicyclic squalene de- rivative, isolated from an anoxic sulfur-rich sediment in Lake Cadagno, Switzerland. [5] This triterpene possesses a hydrocarbon skeleton not reported in living organisms. Phenazinomycin (7), isolated from Streptomyces sp. WK- 2057, belongs to the group of phenazine antibiotics. [7a] This compound is also active against P 388 leukemia cells and also shows in vivo activity against murine tumors. [7b] Phen- azinomycin also possesses antitrypanosomal activities both in vitro and in vivo. [7c] Ambrein (6) is a major constituent of ambergris, which is a concretion formed by sperm whales that has been highly valued since ancient times and is currently used in the fabrication of expensive perfumes. [6a] Recently, the anti- oxidant and antiinflammatory activities of ambrein were also reported. [6b,6c] The total synthesis of this triterpene was previously achieved, [6d–6f] and this compound was very re- cently obtained enzymatically. [6g]