No abstract

Replacement of the butyrolactone unit of the natural products with a quinone subunit has resulted in the synthesis of natural‐product hybrids of quinone–mucocin (1). These compounds, which are combined from partial structures of annonaceous acetogenins and ubiquinone, are very potent inhibitors of complex I (an NADH ubiquinone oxidoreductase) from mitochondrial membranes.

Asymmetric allylation reactions of stannyl‐derived allyldiazaborolanes, a stereoselective cationic cyclization reaction for the formation of the fully substituted C22–C26 tetrahydropyran, and the use of a Julia olefination for the incorporation of the sensitive C37–C46 dienyl system are key features of a highly convergent, stereocontrolled total synthesis of phorboxazole A (see structure).

A highly convergent total synthesis of the potent anticancer agent (؉)-phorboxazole A (1) is accomplished. Four components (3-6) are assembled with considerations for control of absolute and relative stereochemistry. Iterative asymmetric allylation methodology addresses key stereochemical features in the preparation of the 2,6-cisand 2,6-trans-tetrahydropyranyl rings of the C3-C19 component (3). The stereocontrolled asymmetric allylation process is also used for development of the C28 -C41 fragment (4). Novel Barbier coupling reactions of ␣-iodomethyl oxazoles and related thiazoles are described with samarium iodide. The convergent assembly of components 4 and 5 features formation of the fully substituted C22-C26 pyran by intramolecular capture of an allyl cation intermediate with high facial selectivity, and further efforts lead to E-C19͞C20 olefination. The synthesis culminates with use of a modified Julia olefination for attachment of the C42-C46 segment and subsequent late-stage macrocyclization by installation of the (Z)-C2͞C3 ␣,␤-unsaturated lactone. P horboxazoles A (1) and B (2) are natural product diastereoisomers from extracts of the rare Indian Ocean sponge Phorbas sp., which is found near Muiron Island off the coast of Western Australia (1). These unique macrolides exhibit an unusual array of structural features, including a 21-membered macrocyclic lactone that accommodates four adjoining smaller rings along its perimeter. This feature includes a 2,4-disubstituted oxazole, the pentasubstituted tetrahydropyran containing the C22-C26 segment, and the 2,6-cis-and 2,6-trans-disubstituted pyranyl rings installed along the C5 to C15 backbone. A highly unsaturated side chain (C27-C46) comprises nearly one-half of the total carbon atoms of the molecular architecture. This portion of the structure displays a conjugated oxazole and the tetrahydropyranyl ketal terminating with an Ealkenyl bromide. The relative stereochemistry within the macrolide of 1 and 2 was assigned by extensive 2D NMR spectroscopy (1, 2), and the absolute configuration of the macrocycle and the C33-C38 stereochemistry was reported subsequently (3). Finally, the elusive C43 stereochemistry was determined by degradation studies completing the structural elucidation of these novel natural products (4, 5).Phorboxazoles display unprecedented cytostatic activity against all 60 cell lines of the National Cancer Institute human cancer test panel with a mean GI 50 of 1.58 nM. Thus, these compounds rank among the most potent cytostatic agents discovered to date. . Although a mechanism to account for the biological action of these agents is currently uncharted, phorboxazole A does not inhibit microtubulin polymerization or affect microtubule stabilization. Moreover, phorboxazole A has been shown to arrest the cell cycle of Burkitt lymphoma CA46 cultures in S phase (4). Thus, the extraordinary anticancer activity of these metabolites suggests unique opportunities and insights for the discovery of new chemotherapeutic agents. Materials and MethodsA des...

A stereoselective synthesis of the C(28)-C(46) fragment (3) of phorboxazole A is described. Key advances include an enantioselective allylation to establish the stereochemistry of the tetrahydropyran unit and a useful SmI(2)-mediated modification of the Barbier reaction of iodomethyloxazole 15 with aldehyde 14.