Efficient metathesis route to the B-ring of eleutherobin and other medium-sized cyclic ethers Krishna P. Kaliappan * and Nirmal Kumar Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India Dedicated to Professor K. K. Balasubramanian on the occasion of his 65th birthday Abstract—A short and efficient RCM route is reported for the synthesis of the B-ring of eleutherobin and other medium-sized cyclic ethers from readily available 1,2,5,6-diisopropylidene-D-glucose. This strategy is successfully extended to the synthesis of a few bicyclic ethers, which may find applications in the synthesis of novel bicyclic nucleosides. 1. Introduction The success of the anti-cancer drug taxol w (paclitaxel) has stimulated an intensive search for other drugs that operate by the same mode of action. 1 Successful examples, isolated from natural sources, include discodermolide, 2 the epo- thilones, 3 laulimalide 4 and eleutherobin. 5 Among them, the latest discovery, eleutherobin 1 6 was isolated from a marine soft-coral found in the Indian ocean and found to be closely related to sarcodictyins 4, 5, 7 valdivone 6 8 and eleuthesides (Fig. 1). 9 Later, several related congeners of eleutherobin were isolated 10 from the Caribbean soft coral Erythropo- dium caribaeorum. Eleutherobin has been shown to possess potent cytotoxicity with an IC 50 of 10.7 nM, which is comparable to taxol. As eleutherobin was only available in scarce amounts from natural sources, chemical syntheses have become important to study its biological properties further. These prompted synthetic chemists to develop new strategies 11 to synthesize eleutherobin and their sustained efforts have culminated in two total syntheses. 12–14 In continuation of our interest in the development of simple and efficient routes to the syntheses of tubulin binding anti- cancer agents, we became interested in the synthesis of eleutherobin and its congeners. 15 2. Results and discussion A strategy for the synthesis of eleutherobin was designed based on the retrosynthetic analysis involving metathesis reaction as the key step and is shown in Scheme 1. With the discovery of air stable Grubbs’ first 16 and second generation catalysts, 17 the last decade has witnessed a meteoric rise in the utility of the ring closing metathesis reaction (RCM) 18 in the formation of several types of alkenes, carbo- and heterocycles. The reaction tolerates a wide range of functional groups and with these reliable and practical catalysts, the RCM reaction has been widely used in the synthesis of a number of cyclic natural and unnatural products. However, construction of medium-size rings by ring closing metathesis has often been hampered by entropic and thermodynamic instability factors. 19 Nevertheless, there are quite a few successful reports of constructing medium size rings by ring closing metathesis reaction. 20 Encouraged by these reports, we envisaged that a RCM reaction would be an ideal key reaction to construct these natural product skeletons. Eleutherobin possesses three double bonds, which could be formed as a result of a RCM reaction. However, only disconnection of the B-ring double bond will simplify the target molecule leading to precursor C, which then can be further disconnected to the bicyclic enone 8 and the epoxide 9 (Scheme 1). From this retrosynthetic modus operandi, it is clear that the success of our synthetic route to eleutherobin depends on the construction of the B-ring with the strategically placed double bond. Furthermore, there are several natural products, which have nine-membered cyclic ethers as their Keywords: Eleutherobin; Cyclic ethers; Ring closing metathesis; Grubbs’ catalyst; Bicyclic nucleosides.