FULL PAPER DOI: 10.1002/ejoc.201201199 A Concise and Efficient Synthesis of Spiroketals – Application to the Synthesis of SPIKET-P and a Spiroketal from Bactrocera Species Loic Tomas, [a] Benjamin Bourdon, [a] Jean Claude Caille, [b] David Gueyrard,* [a] and Peter G. Goekjian* [a] Keywords: Synthetic methods / Cyclization / Olefination / Spiro compounds / Natural products / Lactones / Enol ethers We report the synthesis of spiroketals by sequence of enol ether synthesis and cyclization. The enol ethers were pre- pared from lactones by a Julia olefination reaction, and the starting chiral lactone was prepared from an industrial inter- Introduction Spiroketals are found in many natural products of bio- logical interest such as marine macrolides, ionophores, and polyether antibiotics [1] (Figure 1). The synthesis of spiroket- als has thus attracted considerable attention over the past decades. [2] Figure 1. Structures of spiroketal-containing natural products. We recently developed a short and convenient route to sugar-derived spiroketals using modified Julia reagents. [3] Starting from lactones, enol ethers were synthesized by treatment with a benzothiazolyl sulfone containing a pro- tected alcohol. At this stage, the use of an acid-labile pro- tecting group allowed us to prepare the spiroketals in a single step in acidic media (Figure 2). [4] We recently ex- [a] Université de Lyon, Laboratoire Chimie Organique 2, ICBMS - UMR 5246, Université Claude Bernard Lyon 1, 43 Bd. du 11 Novembre 1918, 69622 Villeurbanne Cedex, France E-mail: gueyrard@univ-lyon1.fr goekjian@univ-lyon1.fr Homepage: http://www.icbms.fr/user/main.asp?num=150 [b] PPG Sipsy, Z. I. La Croix Cadeau, BP 79, 41012 Avrillé, France Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201201199 Eur. J. Org. Chem. 2013, 915–920 © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 915 mediate. This route is a concise and efficient way to synthe- size naturally occurring and biologically interesting spiroket- als. We used this sequence for the preparation of SPIKET-P and a spiroketal from Bactrocera species. tended this methodology to non-carbohydrate lactones in the synthesis of the spiroketal fragment of bistramide A. [4b] Figure 2. Synthetic route to spiroketals (Btz = benzothiazolyl). In this paper, we describe how we have used this syn- thetic strategy for the preparation of two additional spi- roketals of interest, and so tested the scope of the reaction with minimally substituted lactones. SPIKET-P (Figure 3) was rationally designed as a pharmacophore of spongista- tin, [5] and has shown promising cytotoxicity against human breast cancer. [6] The second target is a component of the cephalic secretions of a cleptoparasitic bee. [7] Figure 3. Structures of the two synthetic targets. Results and Discussion Optically active 2-hydroxymethyl lactones such as 4a and 4b are key intermediates for the synthesis of a large number