Studies of stereocontrolled allylation reactions for the total synthesis of phorboxazole A

Abstract

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...

Studies for the enantiocontrolled preparation of substituted tetrahydropyrans: applications for the synthesis of leucascandrolide A macrolactone

“…10 These efforts have notably led to total syntheses of hennoxazole A, 11 amphidinolide K 12 and phorboxazole A. 13 To apply this approach toward the synthesis of C 1 –C 9 aldehyde 14 , we first prepared the allylic stannane 16 (Scheme 2), commencing with the alkylation of 2-lithio-1,3-dithiane with ( R )-epichlorohydrin. 14 Effectively, this reaction proceeds with net inversion via initial opening of the oxirane and subsequent internal displacement of chloride to give 19 (86%).…”

Iterative Asymmetric Allylic Substitutions: syn‐ and anti‐1,2‐Diols through Catalyst Control

“…The iterative introduction of multiple contiguous stereocenters of any possible configuration remains a challenging aspect of catalytic asymmetric chemistry because of chiral substrate/chiral catalyst mismatch 1. Though outstanding examples of catalytic iterative syntheses of 1,3‐ and 1,5‐ dialkyl compounds and diols are known,2 an iterative method that gives vicinal optically active polyols remains elusive because of the proximity of the chiral centers 3.…”

Total Synthesis of (−)‐Virginiamycin M2

“…The addition of acetylacetone was used to help prevent further enolization of the ketone product. [26] Final removal of the C11 TBDPS ether using pyridine buffered HF gave virginiamycin M 2 in 70 % yield. The spectral data and analytical data ( 1 H and 13 C NMR, IR, HRMS, optical rotation) were identical with the published data.…”