A short approach to the tetrahydrofuran fragment of amphidinolides X and Y has been developed through the combination of iterative Sharpless asymmetric epoxidations, Pd-catalyzed regioselective hydrogenolysis of a 4,5-epoxy-2-alkenoate and the disfavored 5-endo-tet ring closure of a b-hydroxy epoxide promoted by a double bond adjacent to the epoxide function.Amphidinolides are a large family of unique cytotoxic macrolides isolated from the marine dinoflagellates Amphidium sp., living in symbiosis with the Okinawan flatworm Amphiscolops spp. 1 Even though the members of this family display a wide array of structural variation in ring size and carbon skeleton, most of them have an odd-numbered macrocyclic skeleton associated with at least one exo-methylene group. Amphidinolide X (1) does not possess the structural features of its congeners, and moreover, it is the only naturally occurring macrodiolide consisting of polyketide-derived diacid and diol units rather than two hydroxyl fatty acids. 2,3 More recently, amphidinolide Y (2), a 17-membered macrolide, was obtained from the same strain as 1 and is considered to be a biogenetic precursor of amphidinolide X. 4The scarcity of 1 and 2 (0.004% and 0.0007% wet cell weights, respectively) which allowed only limited biological studies, and their unique and challenging structures render them attractive targets for total synthesis. Herein, we describe a stereoselective synthesis of the tetrahydrofuran fragment and its epimer at C2 of these amphidinolides. During the course of our studies, Fürstner and coworkers reported the first total synthesis of amphidinolides X and Y. 5Our retrosynthesis for 1 and 2, which has common features with that of Fürstner, 5 let us envisage that C13-C14 and C12-C13 bonds of 1 and 2, respectively, can be formed via a B-alkyl Suzuki-Miyaura cross-coupling reaction. Subsequent disconnection of the ester linkage of the secondary alcohol of the tetrahydrofuran moiety led to the common building block 3 (Scheme 1). Inspired by the study of Borhan and co-workers concerning the regiocontrol in the cyclization of b-hydroxy epoxides directed by a double bond in the a position of the epoxide function, which stabilized the incipient carbocation, 6,7 we envisaged that the five-membered ring oxygen of 3 could be obtained by the acid-catalyzed cyclization of hydroxy vinyl oxirane 4. During the course of the synthesis of 3, a paper dealing with its synthesis using a 5-endo-tet cyclization strategy appeared in the literature, validating our hypothesis. 8 Other features of our synthetic plan for 3 involved the use of Pd-catalyzed hydrogenolysis of alkenyl oxirane 5, developed by Shimizu and Tsuji,9,10 in order to convert C3 of our target compound into its correct oxidation state and the installation of the tetrasubstituted chiral center at C2 by Sharpless asymmetric epoxidation of allylic alcohol 6.
Scheme 1 Retrosynthetic analysisSynthesis of the tetrahydrofuran derivative 3, shown in Scheme 2, began by the preparation of the trisubstituted alcohol 6, readily...