Direct Generation of Triketide Stereopolyads via Merged Redox-Construction Events: Total Synthesis of (+)-Zincophorin Methyl Ester

Kasun, Zachary A.; Gao, Xiaohui; Lipiński, Radosław; Krische, Michael J.

doi:10.1021/jacs.5b05296

Cited by 45 publications

(35 citation statements)

References 79 publications

(61 reference statements)

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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

“…Verglichen mit den wegweisenden Arbeiten von Danishefsky [42,43] ergab Kocienskis Modifikation der Julia-Olefinierung basierend auf Te trazol-abgeleiteten Alkylsulfon-Spezies 13 eine exzellente E-Selektivität in einem vereinfachten Eintopf-Protokoll. 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. [47] Neue und robuste stereoselektive C-C-Bindungsknüpfungsreaktionen verschaffen mehr Mçglichkeiten fürs trate- gische Trennungen in der Syntheseplanung,u nd solche Methoden sind auch in jüngsten Routen zu Zincophorin zu finden.…”

Section: Zincophorinunclassified

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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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Section: Zincophorinunclassified

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

Liu¹,

Lin²,

Jacobsen³

et al. 2019

Angewandte Chemie

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“…By contrast, and uniquely among the reported total syntheses, the Krische disconnection did result in two fragments ( 7 and 8 ) of similar complexity that were prepared in highly efficient eight and ten step sequences, respectively, and which were converted into zincophorin methyl ester in just three additional steps (Figure 2b). 18 One of the major benefits of this convergent strategy was a vastly simplified protecting group strategy as well as more direct access to the functionalities (iodide, aldehyde) necessary to execute the fragment coupling strategy by aldehyde alkylation. Unfortunately, this three-step fragment coupling and end game sequence proved inefficient and less than readily practicable, and as this sequence comes at the end of the synthesis with valuable late-stage intermediates, the overall efficiency of the synthesis is significantly diminished.…”

Section: Strategic Considerationsmentioning

confidence: 99%

Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester

2017

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Due both to their synthetically challenging and stereochemically complex structures and their wide range of often clinically relevant biological activities, non-aromatic polyketide natural products have for decades attracted an enormous amount of attention from synthetic chemists and played an important role in the development of modern asymmetric synthesis. Often, such compounds are not available in quantity from natural sources, rendering analog synthesis and drug development efforts extremely resource-intensive and time-consuming. In this arena, the quest for ever more step-economical and efficient methods and strategies – useful and important goals in their own right – takes on added importance and the most useful syntheses will combine high levels of step-economy with efficiency and scalability. The non-aromatic polyketide natural product zincophorin methyl ester has attracted significant attention from synthetic chemists due primarily to the historically synthetically challenging C(8)–C(12) all-anti stereopentad. While great progress has been made in the development of new methodologies to more directly address this problem and as a result in the development of more highly step-economical syntheses, a synthesis that combines high levels of step economy with high levels of efficiency and scalability has remained elusive. To address this problem, we have devised a new synthesis of zincophorin methyl ester that proceeds in just nine steps in the longest linear sequence and proceeds in 10% overall yield. Additionally, the scalability and practicability of the route have been demonstrated by performing all of the steps on a meaningful scale. This synthesis thus represents by a significant margin the most step-economical, efficient, and practicable synthesis of this stereochemically complex natural product reported to date, and is well suited to facilitate the synthesis of analogs and medicinal chemistry development efforts in a time- and resource-efficient manner.

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“…The key building block was prepared through hydrogen borrowing catalysis (Scheme 19). [22] Using the simple, cheap, achiral starting material 67 , the authors were able to use an ( S )-Ir-SEGPHOS complex to catalyze a double anti -crotylation with 3-butenyl-2-acetate to give 68 . From that point, an iodoetherification allowed a diastereotopic discrimination between the two terminal alkenes to provide 69a in high yield and stereoselectivity, forming a “propionate based triketide motif”.…”

Section: Diastereotopic Group Selection and Configurational Definimentioning

confidence: 99%

“…From that point, an iodoetherification allowed a diastereotopic discrimination between the two terminal alkenes to provide 69a in high yield and stereoselectivity, forming a “propionate based triketide motif”. [22] Using an analysis of the conformer equilibrium between 70a and 70b , we can understand that prohibitively strong 1,3-diaxial interactions arise when the 1-buten-3-yl group is placed in the axial position, which results in the observed diastereomer (Scheme 20). This reaction sequence installed six contiguous stereocenters in only two synthetic operations.…”

Section: Diastereotopic Group Selection and Configurational Definimentioning

confidence: 99%

Local Desymmetrization through Diastereotopic Group Selection: An Enabling Strategy for Natural Product Synthesis

Horwitz

Johnson

2017

Eur J Org Chem

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The application of desymmetrization strategies in chemical synthesis has allowed fundamentally new synthetic sequences that efficiently create dense and polyfunctional stereochemical arrays. Enantiotopic group discrimination has become a well-established method of global desymmetrization, while the conceptually unique strategy of local desymmetrization by diastereotopic group discrimination has its own advantages. This microreview focuses on the application of local desymmetrization in natural product synthesis and places a particular emphasis on the efficiency engendered by diastereotopic group discrimination. Local desymmetrization is subdivided into three distinct manifolds; examples under each paradigm are presented and compared.

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Direct Generation of Triketide Stereopolyads via Merged Redox-Construction Events: Total Synthesis of (+)-Zincophorin Methyl Ester

Cited by 45 publications

References 79 publications

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

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

Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester

Local Desymmetrization through Diastereotopic Group Selection: An Enabling Strategy for Natural Product Synthesis

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