An asymmetric total synthesis of the trisoxazole marine macrolides mycalolides Aa nd Bi sd escribed. This synthesis involves the convergent assembly of highly functionalized C1-C19 trisoxazole and C20-C35 side-chain segments through the use of olefin metathesis and esterification as well as Julia-Kocienski olefination and enamide formation as key steps.Mycalolides,isolated from the marine sponge Mycale sp., are cytotoxic and antimycotic trisoxazole macrolides.[1] Mycalolides inhibit the enzyme actomyosin Mg 2+ -ATPase [2] and show potent actin-depolymerizing activity by forming a1 :1 complex with the monomeric molecule.[3] Mycalolide B( 1) contains a2 ,3-O-dimethyl-d-glyceryl ester moiety and 13 asymmetric centers as structural features,w hile ac losely related mycalolide A( 2)c ontains ak etone functionality at the C30 position (Scheme 1). Several trisoxazole macrolides that are closely related to mycalolides have been isolated, such as ulapualides, [4] halichondramides, [5] jaspisamides, [6] and kabiramides; [7] all of these exhibit actin-depolymerizing activity and potent cytotoxicity,a nd some induce apoptosis in tumor cells.[8] Thus,t hese agents may be useful for the design and development of novel pharmacological tools for analyzing actin-mediated cell functions,s uch as muscle contraction, cell motility,a nd cytokinesis,a sw ell as those of therapeutic agents. [9] Mycalolides can be divided into two structurally characteristic parts:t he C1-C24 trisoxazole macrolactone and the C25-C35 side chain functionalized by an N-methyl enamide moiety.S tudies on the structure-activity relationships [10] and photolabeling experiments [11] have established that the sidechain component of mycalolides is important for its ability to bind to and depolymerize actin. Additionally,X-ray analyses of the actin-kabiramide C, [12] actin-jaspisamide A, [12] and actin-ulapualide Ac omplexes [13] have revealed that the aliphatic side chains of the macrolides intercalate into the hydrophobic cleft between subdomains 1and 3ofactin. More recently,wesynthesized the 19E-and 19Z-lactone analogues of mycalolides that lack the C25-C35 side chain.[14] These analogues exhibited moderate cytotoxicity against tumor cells (circa 1/100 of 1), but did not show actin-depolymerizing properties or antimycotic activity against pathogenic fungi. [14] Thus,b oth the side-chain and macrolactone moieties were suggested to be essential for the potent biological activities of the parent molecules.As aresult of their extraordinary structures and biological activities,m ycalolides and their congeners have received considerable attention in the synthetic community,a nd several approaches to the construction of conformationally restricted trisoxazole macrolactone structures have been described. [15] To date,t otal syntheses of mycalolide A( 2) [16] and ulapualide A [17] have been accomplished, in which Yamaguchi lactonization, cyclization of the central oxazole ring, or intramolecular Horner-Wadsworth-Emmons olefination were used to construct macr...
