Rhodaoxetane: synthesis, structure, and theoretical evaluation

Galvão, Adelino M.; Ünaleroğlu, Canan; Zlota, Andrei; Frolow, Felix; Milstein, David

doi:10.1021/om00032a062

Cited by 49 publications

(34 citation statements)

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“…The possibility that the ferraoxetane 6 is a reaction intermediate is intriguing because many metallaoxatanes are known as stable species (14,15), and in the case of Fe interacting with oxirane itself, the 1,2-ferraoxetane has been observed using matrix isolation (16). This species is more stable than is Feþ oxirane (17), and on warming, the ferraoxetane undergoes a ½2 þ 2 dissociation to ethylene and FeO (16).…”

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Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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We report the results of a series of chemical, EPR, ENDOR, and HYSCORE spectroscopic investigations of the mechanism of action (and inhibition) of GcpE, E-1-hydroxy-2-methyl-but-2-enyl-4-diphosphate (HMBPP) synthase, also known as IspG, an Fe 4 S 4 cluster-containing protein. We find that the epoxide of HMBPP when reduced by GcpE generates the same transient EPR species as observed on addition of the substrate, 2-C-methyl-D-erythritol-2, 4-cyclo-diphosphate. ENDOR and HYSCORE spectra of these transient species (using 2 H, 13 C and 17 O labeled samples) indicate formation of an Fe-C-H containing organometallic intermediate, most likely a ferraoxetane. This is then rapidly reduced to a ferracyclopropane in which the HMBPP product forms an η 2 -alkenyl π-(or π∕σ) complex with the 4th Fe in the Fe 4 S 4 cluster, and a similar "metallacycle" also forms between isopentenyl diphosphate (IPP) and GcpE. Based on this metallacycle concept, we show that an alkyne (propargyl) diphosphate is a good (K i ∼ 300 nM) GcpE inhibitor, and supported again by EPR and ENDOR results (a 13 C hyperfine coupling of ∼7 MHz), as well as literature precedent, we propose that the alkyne forms another π∕σ metallacycle, an η 2 -alkynyl, or ferracyclopropene. Overall, the results are of broad general interest because they provide new mechanistic insights into GcpE catalysis and inhibition, with organometallic bond formation playing, in both cases, a key role.4Fe-4S protein | GcpE (IspG) | metallacycle

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confidence: 99%

Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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“…This proposal is in agreement with recent studies on the stoichiometric reaction of aryl boronic acids with a rhodaoxetane complex. [16] Observation of a-substituted alcohols as the major products in these reactions can be explained by initial oxidative addition to access metallaoxetane 1 [17,18] or its ring-opened form, followed by b-hydride elimination and reinsertion to afford h 2 -oxanickellacycle 2 (Scheme 1). [19] Kulasegaram and Kulawiec [20a,b] have disclosed studies on palladium-catalyzed epoxide isomerization that lend support to this proposal.…”

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Nickel‐Catalyzed Cross‐Coupling of Styrenyl Epoxides with Boronic Acids

2011

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Let's get multicatalytic! A Ni0 catalyst complexed with a biaryldialkyl monophosphine ligand facilitates CC bond formation between styrenyl epoxides and aryl boronic acids (see scheme). X‐ray analysis of a catalytically active nickel/ligand complex supports a redox pathway involving C sp 3O bond activation. A variety of α‐substituted alcohols were generated with good reaction efficiency by a multicatalytic sequence.

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“…Isotopenaustausch von 6 (isotopenmarkiertes 3) katalysiert durch oxidierte IspG. [76,77] Zudem wurde im Fall einer Interaktion von Eisen mit Oxiran mittels Matrixisolation das 1,2-Ferraoxetan beobachtet, [78] und beim Erwärmen geht das Ferraoxetan eine [2+2]-Dissoziation zu Ethen und FeO ein. [78] Die Ergebnisse der 31 [31] In jedem Fall weisen die sehr geringen Hyperfeinkopplungen darauf hin, dass die Diphosphatgruppe nicht an den Eisen-Schwefel-Cluster bindet.…”

Section: Die Katalytischen Mechanismen Für Ispgunclassified

Biometallorganische Chemie mit IspG und IspH: Struktur, Funktion und Hemmung der an der Isoprenoid‐Biosynthese beteiligten [Fe₄S₄]‐Proteine

Wang

Oldfield

2014

Angewandte Chemie

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Enzyme des Methylerythritolphosphat‐Weges sind eine attraktive Angriffsstelle für Antiinfektiva. Die letzten beiden Enzyme dieses Biosyntheseweges, IspG und IspH, sind [Fe4S4]‐Proteine, die über neuartige Mechanismen 2 H+/2 e−‐Reduktionen katalysieren und vom Menschen nicht gebildet werden. In diesem Aufsatz fassen wir aktuelle Fortschritte der strukturellen, mechanistischen und inhibitorischen Studien zu diesen beiden Enzymen zusammen. Insbesondere werden mechanistische Vorschläge mit biometallorganischen Zwischenstufen vorgestellt und mit anderen mechanistischen Möglichkeiten verglichen. Auf Substratanaloga basierende Inhibitoren, die durch rationale Überlegungen und das Screening von Substanzbibliotheken entwickelt wurden, werden diskutiert. Die präsentierten Ergebnisse untermauern die biometallorganischen Katalysemechanismen für IspG und IspH und eröffnen Perspektiven für die Entwicklung von Inhibitoren, die auf [Fe4S4]‐Cluster in Proteinen zielen.

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Rhodaoxetane: synthesis, structure, and theoretical evaluation

Cited by 49 publications

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Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)

Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)

Nickel‐Catalyzed Cross‐Coupling of Styrenyl Epoxides with Boronic Acids

Biometallorganische Chemie mit IspG und IspH: Struktur, Funktion und Hemmung der an der Isoprenoid‐Biosynthese beteiligten [Fe₄S₄]‐Proteine

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Rhodaoxetane: synthesis, structure, and theoretical evaluation

Cited by 49 publications

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Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)

Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)

Nickel‐Catalyzed Cross‐Coupling of Styrenyl Epoxides with Boronic Acids

Biometallorganische Chemie mit IspG und IspH: Struktur, Funktion und Hemmung der an der Isoprenoid‐Biosynthese beteiligten [Fe4S4]‐Proteine

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Biometallorganische Chemie mit IspG und IspH: Struktur, Funktion und Hemmung der an der Isoprenoid‐Biosynthese beteiligten [Fe₄S₄]‐Proteine