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Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

Paterson, Ian; Doughty, Victoria A; McLeod, Malcolm; Trieselmann, Thomas

Description

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving...[Show more]

dc.contributor.authorPaterson, Ian
dc.contributor.authorDoughty, Victoria A
dc.contributor.authorMcLeod, Malcolm
dc.contributor.authorTrieselmann, Thomas
dc.date.accessioned2015-12-10T22:57:10Z
dc.identifier.issn0040-4020
dc.identifier.urihttp://hdl.handle.net/1885/60536
dc.description.abstractA highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.
dc.publisherElsevier
dc.sourceTetrahedron
dc.subjectKeywords: 3 hydroxyketone; acetone; aldehyde; boron; concanamycin A; concanamycin b; concanamycin c; concanamycin D; concanamycin E; concanamycin F; hydroxyl group; ketol; ketone derivative; macrocyclic compound; macrolide; palladium; silane derivative; silylene de Aldol reaction; Enzyme inhibitor; Macrolactonisation; Macrolide; Protecting groups; Stille coupling
dc.titleStereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume67
dc.date.issued2011
local.identifier.absfor030503 - Organic Chemical Synthesis
local.identifier.ariespublicationu4005981xPUB546
local.type.statusPublished Version
local.contributor.affiliationPaterson, Ian, University of Cambridge
local.contributor.affiliationDoughty, Victoria A, University of Cambridge
local.contributor.affiliationMcLeod, Malcolm, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationTrieselmann, Thomas, University of Cambridge
local.description.embargo2037-12-31
local.bibliographicCitation.issue52
local.bibliographicCitation.startpage10119
local.bibliographicCitation.lastpage10128
local.identifier.doi10.1016/j.tet.2011.09.012
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
dc.date.updated2016-02-24T10:24:40Z
local.identifier.scopusID2-s2.0-82255179407
local.identifier.thomsonID000298274600007
CollectionsANU Research Publications

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