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Total Synthesis of Laulimalide: Synthesis of the Northern and Southern Fragments

Identifieur interne : 000228 ( Ncbi/Curation ); précédent : 000227; suivant : 000229

Total Synthesis of Laulimalide: Synthesis of the Northern and Southern Fragments

Auteurs : Barry M. Trost ; W. Michael Seganish ; Cheol K. Chung ; Dominique Amans

Source :

Chemistry (Weinheim an der Bergstrasse, Germany) [ 0947-6539 ] ; 2012.

RBID : PMC:3517066

Abstract

The first stage of the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C₁₉ hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru-Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, however, the inability to effect a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn:anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517066

DOI: 10.1002/chem.201102898
PubMed: 22307837
PubMed Central: 3517066

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Barry M. Trost

<affiliation><nlm:aff id="A1">Department of Chemistry, Stanford University, Stanford, California, 94305-5080, Ph: 650-723-3385, Fax: 650-725-0002</nlm:aff>
<wicri:noCountry code="subfield">Fax: 650-725-0002</wicri:noCountry>
</affiliation>

W. Michael Seganish

<affiliation><nlm:aff id="A1">Department of Chemistry, Stanford University, Stanford, California, 94305-5080, Ph: 650-723-3385, Fax: 650-725-0002</nlm:aff>
<wicri:noCountry code="subfield">Fax: 650-725-0002</wicri:noCountry>
</affiliation>

Cheol K. Chung

<affiliation><nlm:aff id="A1">Department of Chemistry, Stanford University, Stanford, California, 94305-5080, Ph: 650-723-3385, Fax: 650-725-0002</nlm:aff>
<wicri:noCountry code="subfield">Fax: 650-725-0002</wicri:noCountry>
</affiliation>

Dominique Amans

<affiliation><nlm:aff id="A1">Department of Chemistry, Stanford University, Stanford, California, 94305-5080, Ph: 650-723-3385, Fax: 650-725-0002</nlm:aff>
<wicri:noCountry code="subfield">Fax: 650-725-0002</wicri:noCountry>
</affiliation>

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<front><div type="abstract" xml:lang="en"><p id="P1">The first stage of the development of a synthetic route for the total synthesis of laulimalide (<bold>1</bold>
) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C<sub>19</sub>
 hydroxyl group, joining together two equally sized synthons, the northern fragment <bold>7</bold>
 and the southern fragment <bold>8</bold>
. Our first generation approach to the northern fragment entailed a key sequential Ru-Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, however, the inability to effect a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct <bold>66</bold>
 with excellent <italic>syn:anti</italic>
 selectivity (10:1), and allowed for the successful completion of the northern fragment <bold>7</bold>
. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.</p>
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Total Synthesis of Laulimalide: Synthesis of the Northern and Southern Fragments

Total Synthesis of Laulimalide: Synthesis of the Northern and Southern Fragments

Source :

Abstract

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