Phorboxazole Synthetic Studies. 1. Construction of a C(3−19) Subtarget Exploiting an Extension of the Petasis−Ferrier Rearrangement

Smith, Andrew T.; Pr, Verhoest; Kp, Minbiole; Jj, Lim

doi:10.1021/ol990830l

Cited by 73 publications

(24 citation statements)

References 26 publications

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“…In common with the work of Smith, 12 and Donaldson and Greer, 10a,13 2,3-dihydro-c-pyrone 3 was recognised as being a suitable building block around which a synthesis of a C(1-14) fragment could be fashioned (Scheme 1). Its enantioselective synthesis via an HDA reaction between Danishefsky's diene 4 and aldehyde 5 using Jacobsen's HDA catalyst 6a 14 proceeded in 89% yield with an acceptable 90% ee.…”

Section: Synthesis Of a C(1-14) Fragmentmentioning

confidence: 82%

Phorboxazole B synthetic studies: construction of C(1–32) and C(33–46) subtargets

Paterson¹,

Steven²,

Luckhurst³

2004

Org. Biomol. Chem.

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The convergent syntheses of the C(1-32) and C(33-46) domains of phorboxazole B are described. An iterative cyclocondensation strategy exploited the Jacobsen hetero-Diels-Alder (HDA) reaction as a platform for the synthesis of both the C(5-9) and C(11-15) tetrahydropyran rings. The use of 2-silyloxydiene coupling partners bearing an increasing resemblance to the phorboxazole skeleton was found to lead to a reduction in diastereoselectivity, however, in the case of the C(11-15) ring. The coupling of aldehyde and 2-silyloxydiene by this route provided a C(1-32) fragment which was elaborated to the macrolide core of phorboxazole B. The synthesis of the C(33-46) domain involved a Nozaki-Kishi coupling of aldehyde 31 and vinyl iodide 39. The syntheses of 31 and 39 were highly diastereoselective: an Evans [Cu(Ph-pybox)](SbF6)2-catalysed Mukaiyama aldol reaction formed the cornerstone of the synthesis of 31 whilst a Nagao-Fujita acetate aldol reaction provided a convenient means of installing the sole stereogenic centre of 39.

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Section: Synthesis Of a C(1-14) Fragmentmentioning

confidence: 82%

Phorboxazole B synthetic studies: construction of C(1–32) and C(33–46) subtargets

Paterson¹,

Steven²,

Luckhurst³

2004

Org. Biomol. Chem.

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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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“…Only a 4:1 α/β isomeric ratio was observed in this C-glycosidation of an anomeric lactol with an acetaldehyde-derived enol silane. Interestingly, a similar ZnCl 2 -promoted Mukaiyama aldol reaction with acetaldehyde-derived enol silanes was used by Smith et al 47 and Panek et al 48 to construct the 2,6-trans-THP cores 2-2r and 2-2s as single dia-…”

Section: Silyl Enol Ether Addition To Oxocarbenium Ions (Mukaiyama Almentioning

confidence: 99%

Synthetic Approaches to 2,6-trans-Tetrahydropyrans

Tong

2017

Synthesis

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Being different from 2,6-cis-tetrahydropyrans (2,6-cis-THPs), the corresponding 2,6-trans-THPs are thermodynamically less stable and more challenging to construct. The fact that there are many natural products and/or bioactive molecules containing this 2,6-trans-THP subunit has led to the development of many efficient synthetic approaches to access 2,6-trans-THPs. This review summarizes various synthetic methods reported for this structural motif and/or related applications in the total synthesis of natural products.1 Introduction2 Nucleophilic Addition to an Oxocarbenium Ion (Strategy A)3 Intramolecular Oxa-Michael Addition (Strategy B)4 Intermolecular Michael Addition to Dihydropyranones (Strategy A)5 The Heck–Matsuda (Strategy A) Reaction and Oxa-Heck Cyclization (Strategy B)6 Intramolecular SN2 Substitution and Epoxide Opening (Strategy B)7 Miscellaneous Methods8 Conclusion and Outlook

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Phorboxazole Synthetic Studies. 1. Construction of a C(3−19) Subtarget Exploiting an Extension of the Petasis−Ferrier Rearrangement

Cited by 73 publications

References 26 publications

Phorboxazole B synthetic studies: construction of C(1–32) and C(33–46) subtargets

Phorboxazole B synthetic studies: construction of C(1–32) and C(33–46) subtargets

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

Synthetic Approaches to 2,6-trans-Tetrahydropyrans

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