COMMUNICATIONS Angew. Chem. Int. Ed. 1998, 37 , No. 1/2  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998 1433-7851/98/3701-0185 $ 17.50+.50/0 185 A Convergent Route for the Total Synthesis of the Eleuthesides** Xiao-Tao Chen, Clare E. Gutteridge, Samit K. Bhattacharya, Bishan Zhou, Thomas R. R. Pettus, Tony Hascall, and Samuel J. Danishefsky* The marine environment is taking its place beside plant sources and fermentation in providing access to biologically active substances. [1] From the standpoint of organic chemistry, the aquatic biomass warrants particularly close attention, due to the richly varied structures provided therein. Moreover, the reliability of marine feedstocks as a bulk source of natural products is often less than the case with their plant and microbially derived counterparts. Hence, marine-derived natural products may well furnish excellent opportunities for the subspecialty of synthesis. Such an opportunity is presented by a group of structurally related natural products, which we loosely group under the term ªeleuthesidesº (e.g. eleutherobin (1), [2] sarcodictyin (2), [3] and valdivone (3) [4] ). These are each isolated from different marine sources. Interest in the family was consid- erably heightened by the recent report by Fenical et al. [2] that eleutherobin displays excellent potency in a variety of tumor cell lines and that the mechanism of its cytotoxicity involves inhibition of microtubule disassembly. Thus, at least eleuthe- robin (1), manifests a taxolÐepothiloneÐdiscodermolide mode of action. [5] In light of the very interesting structures of these closely related compounds, the high potency of 1, and the difficult availability of all of the eleuthesides from their natural habitats, this family presents a challenging opportu- nity for creative chemistry. Given the discussion above, we defined the criteria for success in our synthetic venture as going beyond the completion of a ceremonial level route to the natural products. Rather, the substantive goal is that of providing significant quantities of end products for thorough biological scrutiny in the context of a detailed SAR (structure ± activity relationship) investigation. An account of the attainment of a flexible and convergent synthesis of the eleuthesides is provided herein. The underlying logic of our scheme, in qualitative terms, is implicit in Scheme 1. Reference to this scheme will identify the stages of the synthesis subsequently documented in Scheme 2 (vide infra). The chiral matrix material selected for elaboration is the readily available R-()-a-phellandrene (4). [6] This compound undergoes cycloaddition with a ketene derivative (dichloroketene). A C1 fragment is then appended to the modified cyclobutanone cycloadduct, and the ring is fragmented to produce a system of the type 5 with differ- entiated arms for subsequent elaboration. A furanoid building block (2,5-dibromofuran (6) [7] ) pro- vides system 7 as a nucleophile. The remaining furyl ± bromine bond constitutes a latent form of carbon nucleophilicity, to be exploited later (vide infra). In the first coupling event, system 7 is delivered to the aldehyde function of 5. Next, the ªarmº extending from the C1 ester linkage is expanded by one carbon through a cyanation reaction. An eventual acetalde- hyde appendage is coupled to the ªbromofurylº carbon (C4), producing a compound of type 8, a highly strained 2,5- furano[6]phane. In this construction, the two benzylic oxygen functions at C8 and C3 in 8, are presented in differentiated forms. The free hydroxyl group at C8 (R  H) accelerates oxidation of the proximal furan. Following bond reorganiza- tion (9 !10), ring formation between the hydroxyl and appropriate keto group leads to a pyranose of the type 11. In this system, the C7 keto group, destined for nucleophilic methylation, has been uniquely identified. Moreover, in 11, the setting for entry of the methyl group in the desired stereochemical sense has been established, since reaction would be directed anti to the more sterically demanding five- membered carbon bridge. Following suitable manipulations, the pyranose ring in 11 is rearranged to a furanose, thereby exposing the two oxygen atoms projecting from C3 and C8 of the skeleton in differentiated form (see compound 12). The actual steps employed for building the eleutheside are summarized in Scheme 2. To be noted here is the regio- specificity of the cycloaddition of dichloroketene to 4 (the stereoselectivity is 9 :1 in favor of the shown isomer 13). [8] The product (14) resulting from the dechlorination of the initial cycloadduct (13) is subjected to a Bredereck-type trans- [*] Prof. S. J. Danishefsky, [] X.-T. Chen, Dr. C. E. Gutteridge, Dr. S. K. Bhattacharya, B. Zhou, Dr. T. R. R. Pettus, T. Hascall Department of Chemistry, Columbia University Havemeyer Hall, New York, NY 10027 (USA) [  ] Other address: Laboratory for Bioorganic Chemistry Sloan-Kettering Institute for Cancer Research 1275 York Avenue, New York, NY 10021 (USA) Fax: Int. code  (1) 212 772-8691 e-mail: c-kandell@ski.mskcc.org [**] This work was supported by the National Institutes of Health (grant HL 25848). Graduate Fellowships are gratefully acknowledged by X.T.C. (Kanagawa Academy of Science and Technology) and B.Z. (Pharmacia-Upjohn) and Postdoctoral Fellowships by C.E.G. (The Royal Commission for the Exhibition of 1851) and T.R.R.P. (The National Science Foundation). We are grateful to Vinka Parmakovich and Barbara Sporer of the Columbia University Mass Spectral Facility, and we thank Prof. G. Parkin for supervising Mr. T. Hascall in expeditiously solving the X-ray crystal structure.