Progress towards the total synthesis of 2,3-dihydroxytrinervitanes Jhillu Singh Yadav * , Swapan Kumar Biswas, Sandip Sengupta Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India article info Article history: Received 17 December 2009 Revised 13 March 2010 Accepted 17 March 2010 Available online 9 April 2010 Keywords: Trinervitanes Intramolecular Diels–Alder reaction Julia–Kocienski olefination Evan’s asymmetric alkylation abstract Intramolecular Diels–Alder approach to construct the fused AB ring of trinervitane has been demon- strated efficiently. The key intermediate for the Diels–Alder cyclization has been achieved following highly stereoselective Julia–Kocienski olefination, Sharpless epoxidation and Evan’s asymmetric alkyl- ation as the key reactions. Ó 2010 Elsevier Ltd. All rights reserved. Diterpenoid compounds play a key role in chemical communi- cations and defense of nasute termite soldiers by squirting at potential predators. More than two decades ago, characterization of 2,3-dihydroxytrinervitanes 1a and 1b (Fig. 1) was reported as the typical defensive substances from several species of termite soldiers inhabiting the tropics. 1 Recently, trinervitanes 1a and 1b have entered into phase I clinical trials though they are ten times less potent than any clinically practiced antibiotic and the potency can be improved by structural optimization. 2 To the best of our knowledge there are only a few reports of its biogenetic-type syn- thesis but no chemical synthesis has been known so far. 3 Because of its unique structural features and interesting biological activity, an effort towards the total synthesis of 2,3-dihydroxytrinervitanes (1a) was considered attractive. The key compound 3 was prepared following standard protocol starting from geraniol 2 (Scheme 1). 4 Chlorination of hydroxyl group of 3 with triphenylphosphine (TPP) and catalytic amount of NaHCO 3 in CCl 4 at reflux temperature afforded the epoxychloro compound 4 in 90% yield. Double elimination reaction of epoxy-chloride 4 to secondary propargylic alcohol 5 was achieved with Li/liq.NH 3 and catalytic amount of ferric nitrate at 78 °C. 5 The hydroxyl group was pro- tected as its tert-butyl diphenylsilyl (TBDPS) ether, and formylation with formaldehyde in the presence of n-butyllithium (n-BuLi) fol- lowed by its methoxyethoxymethyl (MEM) ether formation with MEM-Cl and N,N-diisopropylethylamine (DIPEA) in dichlorometh- ane afforded 6 in 72% yield over three steps. 6 Selective deprotec- tion of the TBDPS group on primary hydroxyl functionality was achieved with (±)-10-camphorsulfonic acid (CSA) (0.1 equiv) in MeOH and CH 2 Cl 2 (1:1). 7 The free hydroxyl group was then OH HO H H 1a OH HO H H 1b Figure 1. Typical trinervitanes from termites. Geraniol (2) ref. 3 OH O TBDPSO Cl O TBDPSO TBDPSO OH TBDPSO OTBDPS OMEM S OTBDPS OMEM O O N N N N Ph a b c, d, e f, g, h 3 4 5 6 7 OH Scheme 1. Reagents and conditions: (a) TPP, NaHCO 3 , CCl 4 , 90%; (b) LiNH 2 , cat. Fe(NO 3 ) 3 78 °C, 95%; (c) TBDPS-Cl, imidazole, CH 2 Cl 2 , 90%; (d) n-BuLi, THF, 78 °C to rt, CH 2 O, 0 °C to rt, 89%; (e) MEM-Cl, DIPEA, CH 2 Cl 2 ,0 °C to rt, 90%; (f) CSA, MeOH/ CH 2 Cl 2 (1:1), 12 h, 90%; (g) DEAD, TPP, tetrazole, THF, 80%; (h) (NH 4 ) 2 MoO 4 ,H 2 O 2 , EtOH, 0 °C to rt 70%. 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.03.065 * Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160387. E-mail addresses: yadav@iict.res.in, yadavpub@iict.res.in (J.S. Yadav). Tetrahedron Letters 51 (2010) 4014–4016 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet