Organic & Biomolecular Chemistry PAPER Cite this: Org. Biomol. Chem., 2013, 11, 905 Received 11th July 2012, Accepted 3rd October 2012 DOI: 10.1039/c2ob26329g www.rsc.org/obc First total synthesis of Debilisone C† Bishwajit Saikia, Thongam Joymati Devi and Nabin C. Barua* Total synthesis of Debilisone C, a lactone containing conjugated endiyne has been achieved. The adopted strategy involves the stereoselective construction of the five membered lactone ring and the C20 endiyne chain followed by regioselective coupling of both the parts. The lactone was obtained from the oxidative cleavage of the hydroxy olefin which was derived from the benzyl protected S-epichlorohydrine by regioselective epoxide opening with allyl trimethyl silane in presence of a Lewis acid at -78 °C. Takai olefination, Pd 0 /Ag 1 catalyzed cross-coupling reaction and selective substitution of trimethylsilyl groups were successfully utilized to establish the C20 polyyne chain. The final coupling of both the parts have been carried out by alkyl coupling using LDA in THF–DMPU (1 : 1) Introduction Natural products have been the source of new structural enti- ties having potential pharmacological activity. Terrestrial plants of traditional origin have been one among the most promising sources of natural products as a result of their wide ranging biological activity profile. Recently, S. Kanokmedhakul and co-workers reported isolation of six new linear polyacetyle- nic C25 and C27 acetogenins, named as Debilisone A–F, from the methanol extract of the roots of Polyalthia debilis, 1 a Thai herbal plant growing widely in the northeastern part of Thai- land. It is known as “Kon Krok” in Thai and water decoctions of its roots are used as a traditional medicine for treatment of abdominal pain. Polyacetylenes are characteristic natural pro- ducts which are abundant in nature and have attracted much attention due to their interesting biological activity. 2,3 Debili- sone C 1, containing two consecutive triple and a trans double bond with a five membered lactone ring display antimyco- bacterial activity against Mycobacterium tuberculosis 1 with a minimum inhibitory concentration (MIC) of 12.5 μg mL -1 . The structural complexity and intriguing biological activities of γ-lactone 4 containing polyyne natural products 6 continue to attract the attention of chemists and biologists. Due to the interesting antimycobacterial activity coupled with our own interest in novel anti tubercular drug discovery 7 prompted us to take-up the total synthesis of this molecule. To the best of our knowledge, total synthesis of this molecule has not been reported to date. The main challenge associated with the synthesis of Debilisone C was the construction of the long 20-membered carbon chain 8 containing two consecutive triple bonds and a trans double bond. Herein, we report a total synthesis of Debilisone C 1, where the key steps involved in our synthetic plan were Takai iodoolefination and the Pd 0 /Ag 1 catalyzed cross-coupling reaction. Retrosynthetic analysis of Debilisone C is depicted in Scheme 1. We envisioned completion of the synthesis of Debili- sone C occurring through coupling between lactone 2 and C-20 endiyne chain. A Takai-Iodo olefination 9 between penta- nal and iodoform would create the C 17 –C 18 trans-double bond. Construction of C 12 –C 13 and C 16 –C 17 single bonds of the C-20 endiyne chain relies on alkylation and Pd 0 /Ag 1 catalyzed cross-coupling reaction with commercially available 1,4-bis- (trimethylsilyl)-1,3-butadiyne. Synthesis of the lactone part 2 could be achieved from cheap commercially available Scheme 1 Retrosynthetic approach for the synthesis of Debilisone C. † Electronic supplementary information (ESI) available: 1 H and 13 C NMR spectra of all pure compounds prepared. See DOI: 10.1039/c2ob26329g Natural Products Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat-785006, Assam, India. E-mail: ncbarua2000@yahoo.co.in; Fax: +91-376-2370011; Tel: +91-376-2371283 This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 905–913 | 905 Downloaded by Regional Research Laboratory (RRL-Jorhat) on 19 January 2013 Published on 03 October 2012 on http://pubs.rsc.org | doi:10.1039/C2OB26329G View Article Online View Journal | View Issue