Synthetic studies towards phorboxazole A. A convergent synthesis of the C31C46 polyene oxane-hemiacetal side chain

Pattenden, Gerald; Plowright, Alleyn T.; Tornos, James A.; Ye, Tao

doi:10.1016/s0040-4039(98)01258-1

Cited by 56 publications

(21 citation statements)

References 17 publications

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“…Already three total syntheses of the phorboxazoles have been reported,2–4 and the results of several structure–activity studies are beginning to emerge 5. In previous publications we described synthetic routes to the key fragments 3 ,6 4 ,7 and 5 a 8 in phorboxazole A 9. We now show how we have brought these fragments together, leading to a new and convergent total synthesis of the natural product itself.…”

Section: Methodsmentioning

confidence: 70%

“…Thus, the lactone 8 was first elaborated from the known aldehyde 6 6 and the sulfone 7 11 in four relatively straightforward steps, and the oxane–oxazole 11 was prepared through an E ‐selective Wadsworth–Emmons olefination between the oxane methyl ketone 9 , derived from 4 ,7 and the oxazole phosphonate ester 10 ,12 as highlighted in Scheme . To our satisfaction, when the oxane‐substituted 2‐methyloxazole 11 was deprotonated with lithium diethylamide generated in situ at −78 °C, and treated with the lactone 8 , the desired cyclic hemiketal 12 a was obtained in high yield and was immediately protected as its corresponding triethylsilyl ketal 12 b in 66 % overall yield (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

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A Convergent Total Synthesis of Phorboxazole A

González

Pattenden

2003

Angew Chem Int Ed

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The potent cytostatic marine metabolite phorboxazole A (see structure) was prepared from three key fragments. Following attachment of a major portion of the side chain through C32C33 and an intermolecular E‐selective olefination reaction to form the C19C20 double bond, the C2C3 double bond was put in place through an intramolecular Z‐selective olefination reaction, with formation of the macrolide.

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Section: Methodsmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

A Convergent Total Synthesis of Phorboxazole A

González

Pattenden

2003

Angew Chem Int Ed

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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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“…Initially, both the primary and secondary hydroxy groups in compound 8 were protected with TBDMSCl (2.4 mol) and imidazole in N,N-dimethylformamide (DMF) to furnish compound 16. Selective deprotection of the primary O-TBDMS group with camphorsulfonic acid (CSA) [14] in methanol afforded alcohol 17. Deprotection of the carbamate group by catalytic hydrogenation gave amino alcohol 7 in four steps with an overall yield of 92%.…”

Section: Introductionmentioning

confidence: 99%

Syntheses of 1,2-Amino Alcohols and Their Applications for Oxazaborolidine Catalyzed Enantioselective Reduction of Aromatic Ketones

2007

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Six new chiral 1,2-amino alcohol derivatives have been synthesized starting from (1R,2R)-2-amino-1-phenylpropane-1,3-diol. Asymmetric reduction of aryl ketones with in-situ generated oxazaborolidine from these amino alcohol derivatives and BH 3 ·Me 2 S afforded secondary alcohols with good yield and moderate to high enantiomeric excess. Results and DiscussionCommercially available [12] and inexpensive chiral amino alcohol (1R,2R)-2-amino-1-phenylpropane-1,3-diol 1, a precursor for the preparation of chloramphenicol, has been used by us for the synthesis of all six new chiral auxiliaries. The amino alcohols

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Synthetic studies towards phorboxazole A. A convergent synthesis of the C31C46 polyene oxane-hemiacetal side chain

Cited by 56 publications

References 17 publications

A Convergent Total Synthesis of Phorboxazole A

A Convergent Total Synthesis of Phorboxazole A

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

Syntheses of 1,2-Amino Alcohols and Their Applications for Oxazaborolidine Catalyzed Enantioselective Reduction of Aromatic Ketones

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