This journal is © The Royal Society of Chemistry 2017 Chem. Commun., 2017, 53, 6641--6644 | 6641 Cite this: Chem. Commun., 2017, 53, 6641 Lewis acid catalyzed cascade annulation of alkynols with a-ketoesters: a facile access to c-spiroketal-c-lactones† Digambar A. Kambale, ab Sagar S. Thorat, ab Madhukar S. Pratapure, ab Rajesh G. Gonnade bc and Ravindar Kontham * ab A novel Lewis acid catalyzed intermolecular cascade annulation of alkynols with a-ketoesters has been developed. This simple and efficient cascade annulation proceeds through a 5-exo-dig cyclization of alkynols followed by annulation with a-ketoester to provide a wide variety of unsaturated c-spiroketal-c-lactones (1,6-dioxaspiro[4.4]non- 3-en-2-ones) related to many natural products. Spiroketals and oxa-spirolactones are frequently found structural units in biologically potent natural products. 1,2 In addition, it has been shown that simplified spiroacetals derived from natural products retain their biological properties. Hence, these scaffolds essentially contribute to pharmacological activities and represent privileged pharmacophores in drug discovery. 3 In the recent years, several bioactive natural products with unsaturated g-spiroketal- g- lactone (1,6-dioxaspiro[4.4]non-3-en-2-one) appendage were isolated and have become an important sub-group of spiroketals, which include tuberostemonamide, 4 massarinoline A, 5 aphagrandinoid A, 6 pyrenolide D, 7 crassalactone D, 8 levantenolide, 9 papyracillic acid C, 9 acutissimatriterpene A and many others (Fig. 1). 8,10 Despite their potential properties, only a few synthetic methods have been documented in the literature, for instance, Mitsunobu’s protocol of photo-oxidation of unprotected pre- functionalized furyl-alkanols, which was further developed by Vassilikogiannakis et al. 11 and others. 12 Kitching et al. reported a strategy starting from 3-butyn-1-ol via saturated oxa-spirolactone in a total number of 8 steps. 13 In 2006, Shi and co-workers reported SnCl 4 (stoichiometric amount, 40 1C) mediated annula- tion of cyclopropyl-alkyl ketones and a-ketoesters. 14 Few other miscellaneous reports also present in the literature. 15 All of these approaches have limitations such as the use of prefunctionalized starting materials, the protection and deprotection sequence, stoichiometric amounts of Lewis acids and multiple steps. Thus, the development of a new intermolecular approach to unsaturated g-spiroketal-g-lactones from easily available fragments is of considerable importance from the point of view of diversity- oriented synthesis. 15 Inspired by the emerging importance of cascade/domino reactions 16 involving alkynols 17,18 and as part of our research interest in Lewis acid-promoted cascade reactions involving alkynols, 19 we herein report a protocol for the construction of unsaturated g-spiroketal-g-lactones comprising Bi(OTf) 3 catalyzed cascade annulation of alkynols (4-pentyn-1-ol derivatives) and a-ketoesters, where hydroalkoxylation of alkynol 1 and/or 4 furnishes the exocyclic enol ether 5 via the 5-exo-dig mode of cyclization, which in the proximal presence of an activated a-ketoester 2 would undergo an annulation reaction to furnish the desired product 3 and/or 6 in a cascade manner (Scheme 1). To explore the feasibility of this proposed strategy, the reaction between known alkynol 1a (1.0 eq.) and ethylpyruvate (2a, 1.0 eq.) with commercially available Bi(OTf) 3 (99%, 20 mol%) in anhydrous CH 2 Cl 2 at room temperature was performed (Table 1). Gratifyingly, both starting materials were completely consumed in 12 h at room temperature and gave the desired unsaturated g-spiroketal-g-lactone 3aa in 80% yield (entry 1). The reaction in other solvents such as toluene, acetonitrile and tetrahydrofuran did not result in any improvement in the yield (entries 2–4). Notably, various Lewis (entries 5–15) and Fig. 1 Unsaturated g-spiroketal-g-lactone containing bioactive natural products. a Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008, India. E-mail: k.ravindar@ncl.res.in; Tel: +91 20 2590 2301 b Academy of Scientific and Innovative Research (AcSIR), New Delhi, India c Centre for Materials Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008, India † Electronic supplementary information (ESI) available. CCDC 1510251–1510255. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc03668j Received 11th May 2017, Accepted 30th May 2017 DOI: 10.1039/c7cc03668j rsc.li/chemcomm ChemComm COMMUNICATION Published on 30 May 2017. Downloaded by University of California - San Diego on 17/06/2017 19:58:52. View Article Online View Journal | View Issue