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

• Published in: Tetrahedron Vol. 67; no. 52; pp. 10119 - 10128
• Main Authors: Paterson, Ian, Steadman neé Doughty, Victoria A., McLeod, Malcolm D., Trieselmann, Thomas
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 30.12.2011; Elsevier
• Subjects: Aldehydes; Aldol reaction; Chemistry; Chemistry, Organic; Derivatives; Enzyme inhibitor; Ethers; Exact sciences and technology; Fragments; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Inhibitors; Iodides; Ketones; Macrolactonisation; Macrolide; Organic chemistry; Organometalloidal and organometallic compounds; Physical Sciences; Preparations and properties; Protecting groups; Science & Technology; Si derivatives; Stille coupling; Synthesis (chemistry); Enzyme inhibitor; Stille coupling; Macrolactonisation; Aldol reaction; Macrolide; Protecting groups; PI-FACE SELECTIVITY; V-ATPASES; NATURAL-PRODUCTS; CONCANAMYCIN-A; MACROLIDE SYNTHESIS; SWINHOLIDE-A; CROSS-COUPLING REACTIONS; POLYPROPIONATE SYNTHESIS; H+-ATPASE; STEREOSELECTIVE-SYNTHESIS; Ketol; Deprotection; Organic siloxane; Palladium complex; p-Toluenesulfonic acid derivative; Chiral compound; Oxygen heterocycle; Aldol condensation; Macrocycle; Aldol; Stereoselectivity; Organic iodine compounds; Asymmetric synthesis; Yamaguchi esterification; Vinylic compound; Cross reaction; Enol ether; Protection; Organic stannane; Intramolecular reaction; Protecting group; Ether; Enzyme; Organic silylene; Adenosinetriphosphatase; Organic boron compounds; Organic silane; Hemiacetal; Aldehyde; Dienic compound; Ketone; Diastereoselectivity; Total synthesis; Chemical coupling; Side chain; Cyclization; Cyclic compound; Hydrolases; Macrolactonization
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2011.09.012

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 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 (12 E,14 E)-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 (12 E,14 E)-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. [Display omitted]