Synthesis of the C22−C26 Tetrahydropyran Segment of Phorboxazole by a Stereoselective Prins Cyclization

Rychnovsky, S. D.; Thomas, Christian R.

doi:10.1021/ol005646a

Cited by 120 publications

(27 citation statements)

References 44 publications

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“…The Prins reaction has been brought to bear successfully on the challenge of the synthesis of three of the four THP rings in the natural products phorboxazole A and B. Rychnovsky has employed his α‐acetoxy ether Prins methodology to the synthesis of the penta‐substituted THP ring4 and the bis‐THP unit embedded in the structure 5. The 2‐oxonia Cope–Prins cyclisation cascade was employed in the asymmetric synthesis of the C18–C25 segment of Lasonolide A.…”

Section: Cyclisations Onto Oxocarbenium Ionsmentioning

confidence: 99%

Strategies for the Formation of Tetrahydropyran Rings in the Synthesis of Natural Products

2006

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This microreview surveys the literature over the last five years with regard to construction of functionalised tetrahydropyran (THP) rings in the context of the synthesis of natural products. The overview given is intended to provide a working knowledge of the area for those who are unfamiliar, and to refresh and remind those who do work in the area of the exciting developments in the field. While the construction of the THP rings in a number of natural products has been reviewed, we have attempted to highlight the different strategies by focusing on two natural products, namely phorboxazole and centrolobine as case studies. Over the last five years, these natural products have become a test bed for new methods for the construction of THP rings. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Section: Cyclisations Onto Oxocarbenium Ionsmentioning

confidence: 99%

Strategies for the Formation of Tetrahydropyran Rings in the Synthesis of Natural Products

2006

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“…Since the supply of material from natural sources is severely limited, a significant effort toward the preparation of phorboxazoles has been launched within the international organic synthesis community. The unprecedented structural features have provided the impetus for several exploratory studies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Recent total syntheses of phorboxazole A (23-27) and phorboxazole B (28,29) have been reported.…”

Section: Resultsmentioning

confidence: 99%

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

Williams

Kir'yanov

Emde

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…Thus, the C20-C26 segment of phorboxazole A 312 was obtained by cyclization of the -acetoxy ether 313 with 10 mol% of boron trifluoride in the presence of acetic acid [147]. Thus, the C20-C26 segment of phorboxazole A 312 was obtained by cyclization of the -acetoxy ether 313 with 10 mol% of boron trifluoride in the presence of acetic acid [147].…”

Section: Prins Cyclization In Synthesismentioning

confidence: 99%

The Prins Reaction: Advances and Applications

Pastor¹,

Yus

2007

COC

197

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The acid-catalyzed alkene-aldehyde condensation, known as the Prins reaction, is reviewed. Lewis acids, organic acids and supported catalysts have been reported to assist both the Prins acyclic reaction and the Prins cyclization. Acetals and oxocarbenium ions (generated from aldehydes and alcohols) have been described as reacting systems in the Prins reaction. Prins cyclizations have been used to form mainly five-and six-membered rings, albeit formation of seven to nine rings have been described. The Prins reaction (and cyclization) has been developed as a key strategic element in the total synthesis of different natural products. R O O 20 (55%): R = Cl 21 (35%): R = NHAc 14 (95%): R = H 15 (97%): R = Me 16 (88%): R = Cl 17 (65%): R = OMe 18 (99%): R = OAc 19 (56%): R = NHAc O O Cl 22 (81%) 24 (67%) 23 (80%)

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Synthesis of the C22−C26 Tetrahydropyran Segment of Phorboxazole by a Stereoselective Prins Cyclization

Cited by 120 publications

References 44 publications

Strategies for the Formation of Tetrahydropyran Rings in the Synthesis of Natural Products

Strategies for the Formation of Tetrahydropyran Rings in the Synthesis of Natural Products

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

The Prins Reaction: Advances and Applications

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