Total Synthesis of Zincophorin and Its Methyl Ester

Defosseux, Magali; Blanchard, Nicolas; Meyer, Christophe; Cossy, Janine

doi:10.1021/jo0496042

Cited by 53 publications

(28 citation statements)

References 91 publications

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“…27 Three sequential deprotection steps (oxidative PMB removal, basic carbonate methanolysis, and TBS deprotection) then completed the synthesis of zincophorin methyl ester 2 in 60% overall yield. Full spectral comparison to the data provided by Cossy 8b and Miyashita 9 confirmed the identity of our synthetic material.…”

supporting

confidence: 69%

Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

Harrison

Leighton

2011

J. Am. Chem. Soc.

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A highly efficient and step-economical synthesis of zincophorin methyl ester has been achieved. The unprecedented step-economy of this zincophorin synthesis is principally due to an application of the tandem silylformylation-crotylsilylation/Tamao oxidation-diastereoselective tautomerization reaction that achieves in a single step what would typically require a significant multi-step sequence.Polyketide natural products continue to influence small molecule drug development efforts. Both natural products (e.g. discodermolide 1 ) and designed analogs thereof (e.g. fludelone 2 ) have progressed into clinical trials, and it seems reasonable to anticipate that it might only be a matter of time before approved drugs begin to emerge from such medicinal chemistry programs. It is equally reasonable to anticipate that most such compounds will have to be synthesized (as will, of course, most analogs), as was certainly the case for both discodermolide 3 and fludelone. It is for this reason that, despite decades of beautiful, powerful, and profoundly influential chemistry devoted to the synthesis of such structures, there remains a great need for creative new approaches that achieve significantly greater levels of "ideality." 4 Progress in this regard would be expected to have an impact on every aspect of polyketide natural product-based synthesis and drug development efforts.Zincophorin (1) and its methyl ester (2) 5 have been popular targets for synthetic chemists ever since the groundbreaking synthesis by Danishefsky in 1987 (Figure 1). 6,7 Two additional total syntheses have been reported since then by Meyer and Cossy 8 and by Miyashita 9 (in addition to numerous reports of fragment syntheses 10 ), and, interestingly, all three syntheses (of 2) required ~47/~52 total steps 11 with longest linear sequences of 36, 28, and 37 steps resepectively. As part of a broad program devoted to the development of highly efficient and step-economical syntheses of polyketide structures of this type, 12 we decided to undertake a new synthesis of zincophorin methyl ester. Our primary motivation was to set for ourselves the goal of completing the synthesis in about half the number of total steps as the three previous syntheses, because we felt that achieving this would require a fresh approach and true methodological innovation (i.e. greater ideality). We report here the results of these efforts that have culminated in a 27/31 total step synthesis of 2.The synthesis commenced with an asymmetric epoxidation of alkene 3 13 using Shi's catalyst 14 to provide 4 in 87% yield and 90% ee (Scheme 1). Epoxide opening using Pagenkopf's procedure 15 gave 5 in 43% yield. 16 NaH-catalyzed silane alcoholysis with dicis-crotylsilane 12d then provided 6 in 97% yield and set the stage for an application of the tandem silylformylation-crotylsilylation/Tamao oxidation-diastereoselective tautomerization reaction. 12k Applied to 6, this complex series of chemical events produced 7 in 67% yield Supporting Information Available: Experimental procedures, ...

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supporting

confidence: 69%

Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

Harrison

Leighton

2011

J. Am. Chem. Soc.

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“…[42,43] Basierend auf vorherigen Studien der gleichen Gruppe zur Rekonstruktion von Zincophorin aus Zerfallsprodukten [44] wurde die Julia-Olefinierung gewählt, um die späte Ligation zwischen zwei Hauptfragmenten 6 und 7 an C16ÀC17 durchzuführen. [45][46][47][48][49][50][51] Auch über zahlreiche Synthesestudien von Fragmenten des Moleküls wurde berichtet [52,53] Hier werden wir primära uf die neuesten Synthesen (nach 2010) eingehen, aber auch frühere Studien (vor 2009), [54] diskutieren, um die Evolution der Synthesestrategien zu veranschaulichen. [42,43] Seit 2000 wurden sechs Totalsynthesen von Zincophorin von fünf Forschungsgruppen realisiert.…”

Section: Zincophorinunclassified

“…[55] In Miyashitas 2004 publizierter Synthese wurde die C15-C16-Bindung über eine Palladium-katalysierte sp 2 -sp 3 -Suzuki-Kupplung zwischen Alkenyliodid 16 und Alkylboran 15 gebildet (Schema 2). In einer Synthese von Cossy,welche 2003 publiziert wurde, [45,46] wurde die C12-C13-Bindung über eine Ti IV -vermittelte Aldol-Reaktion des vom Keton 19 abgeleiteten Z-Enolats in exzellenter syn-Selektivitätr ealisiert (Schema 2 < xschr2). In der von Krische publizierten Synthese von 2015 [51] wurde die äquivalente finale Fragmentkupplung an der C13-C14-Bindung über eine stereoselektive Alkyllithium-Aldehyd-Addition durchgeführt.…”

Section: Zincophorinunclassified

“…Alternativ liefern Crotylierung und verwandte Reaktionen in einer Stufe und in stereodivergenter Weise die minimale chirale C 3 -Einheit des Polypropionat-Motivs,u nd das Olefin im Produkt kann einfach in eine Aldehydgrupppe überführt werden, was anschließende Tr ansformationen erleichtert. In einer Synthese von Cossy [45,46] ergab die asymmetrische Addition chiraler Allenylzink-Reagenzien an Aldehyde (von Marshall [59] entwickelt) die beste anti-Selektivitäti mR ahmen dieser Studie.D as (P)A llenylzink-Reagenz 36,d as aus dem (R)-Alkoholmesylat 35 hergestellt wurde,r eagiert mit dem C1-C9-Aldehyd 37 zu dem C9-C10-anti-Addukt 38 als einzelnes Diastereomer. In den Synthesen von Zincophorin wurden zahlreiche Crotylierungen und verwandte Reaktionen fürd en Polypropionat-Teil eingesetzt (Schema 5).…”

Section: Kurzaufsätzeunclassified

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Chemische Synthesen und chemische Biologie von Carboxylpolyether‐Ionophoren: Aktuelle Entwicklungen

Liu¹,

Lin²,

Jacobsen³

et al. 2019

Angewandte Chemie

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Ein zentrales Ziel der chemischen Biologie ist die Entwicklung von molekularen Sonden, die grundlegende Untersuchungen zellulärer Systeme ermöglichen. In der Hierarchie bioaktiver Moleküle nehmen die sogenannten Ionophore eine unspektakuläre Position ein, wobei typische Charakterisierungen “unspezifisch” und “toxisch” sind. Tatsächlich führt die bloße Möglichkeit, dass ein Kandidatenmolekül “Ionophoraktivität” besitzt, dazu, dass es aus weiteren Studien entfernt wird; Ionophore sind, aus einer chemobiologischen Perspektive betrachtet, “molekulare Gesetzlose”. Im Widerspruch zu diesem insgesamt schlechten Ruf der Ionophore verdankt die synthetische Chemie einige ihrer erstaunlichsten Erfolge den Untersuchungen von Ionophor‐Naturstoffen, insbesondere den Carboxylpolyethern, die für ihre komplizierten molekularen Strukturen bekannt sind. Diese Verbindunge waren jahrzehntelang akademische Spielwiesen, um neue Synthesemethoden zu testen und retrosynthetische Taktiken zu perfektionieren. Hier betrachten wir die aufregendsten jüngsten Fortschritte bei der Synthese von Carboxylpolyether‐Ionophoren (CPI) und diskutieren darüber hinaus das aufkeimende Feld der chemischen Biologie von CPIs.

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“…The synthetic three-contiguous-propionate framework (hexad) present in aflastatin fragment 4 was also checked, as were those in sekothrixide (6) [9] and zincophorin methyl ester (7) synthesized by Cossy [10] (Scheme 4). Each example was carefully chosen in order to explore a wide range of possibilities that can be encountered in the structural elucidation of polypropionate natural compounds.…”

Section: Introductionmentioning

confidence: 99%

Advances in the Universal NMR Database: Toward the Determination of the Relative Configurations of Large Polypropionates

et al. 2009

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The relative stereochemical determination of naturally occurring large polyketides has proved to be critical, especially when the polyketides are available only in small quantities. Difficulties are often circumvented by the tedious synthesis either of adapted compound libraries (databases) or of all the presumed structures, because both methods allow efficient NMR comparison. To predict the stereochemistries of these frameworks, we have developed a straightforward method requiring neither the derivatisation of the natural product nor the synthesis of a new database of model stereoisomers. With the aid of 13 C NMR spectroscopy, the relative configurations

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Total Synthesis of Zincophorin and Its Methyl Ester

Cited by 53 publications

References 91 publications

Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

Chemische Synthesen und chemische Biologie von Carboxylpolyether‐Ionophoren: Aktuelle Entwicklungen

Advances in the Universal NMR Database: Toward the Determination of the Relative Configurations of Large Polypropionates

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