Studies of Stereocontrolled Allylation Reactions for the Total Synthesis of Phorboxazole A
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 i...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (33), p.12058-12063 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Williams, David R. Kiryanov, Andre A. Emde, Ulrich Clark, Michael P. Berliner, Martin A. Reeves, Jonathan T. Nicolaou, Kyriacos C. |
| description | 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-cis- and 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 α-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-C19/C20 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-C2/C3 α,β-unsaturated lactone. |
| doi_str_mv | 10.1073/pnas.0402477101 |
| format | Article |
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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-cis- and 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 α-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-C19/C20 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-C2/C3 α,β-unsaturated lactone.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0402477101</identifier><identifier>PMID: 15277662</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Alcohols ; Aldehydes ; Alkenes ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Biological Products - chemical synthesis ; Biological Products - chemistry ; Cancer ; Chemical reactions ; Chemical synthesis ; Chemistry ; Chemistry, Organic - methods ; Condensation ; Ethers ; Heterocyclic Compounds, 4 or More Rings - chemical synthesis ; Heterocyclic Compounds, 4 or More Rings - chemistry ; Molecular Structure ; Natural Product Synthesis Special Feature ; Oxazoles ; Oxazoles - chemical synthesis ; Oxazoles - chemistry ; Oxidation ; Physical Sciences ; Porifera - chemistry ; Salts ; Stereochemistry ; Stereoisomerism ; Studies ; Tetrahedrons</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2004-08, Vol.101 (33), p.12058-12063</ispartof><rights>Copyright 1993/2004 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 17, 2004</rights><rights>Copyright © 2004, The National Academy of Sciences 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c495t-cce09ed6ec74758115bb674d9ccf6a918705abbb0898b65b9645d5d1b09cb0fd3</citedby><cites>FETCH-LOGICAL-c495t-cce09ed6ec74758115bb674d9ccf6a918705abbb0898b65b9645d5d1b09cb0fd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/101/33.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3373089$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3373089$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15277662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Williams, David R.</creatorcontrib><creatorcontrib>Kiryanov, Andre A.</creatorcontrib><creatorcontrib>Emde, Ulrich</creatorcontrib><creatorcontrib>Clark, Michael P.</creatorcontrib><creatorcontrib>Berliner, Martin A.</creatorcontrib><creatorcontrib>Reeves, Jonathan T.</creatorcontrib><creatorcontrib>Nicolaou, Kyriacos C.</creatorcontrib><title>Studies of Stereocontrolled Allylation Reactions for the Total Synthesis of Phorboxazole A</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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-cis- and 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 α-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-C19/C20 olefination. 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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-C2/C3 α,β-unsaturated lactone.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>15277662</pmid><doi>10.1073/pnas.0402477101</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alcohols Aldehydes Alkenes Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Biological Products - chemical synthesis Biological Products - chemistry Cancer Chemical reactions Chemical synthesis Chemistry Chemistry, Organic - methods Condensation Ethers Heterocyclic Compounds, 4 or More Rings - chemical synthesis Heterocyclic Compounds, 4 or More Rings - chemistry Molecular Structure Natural Product Synthesis Special Feature Oxazoles Oxazoles - chemical synthesis Oxazoles - chemistry Oxidation Physical Sciences Porifera - chemistry Salts Stereochemistry Stereoisomerism Studies Tetrahedrons |
| title | Studies of Stereocontrolled Allylation Reactions for the Total Synthesis of Phorboxazole A |
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