Asymmetric Malonic and Acetoacetic Acid Syntheses – A Century of Enantioselective Decarboxylative Protonations

Blanchet, Jérôme; Baudoux, Jérôme; Amere, Mukkanti; Lasne, Marie‐Claire; Rouden, Jacques

doi:10.1002/ejoc.200800759

Cited by 85 publications

(36 citation statements)

References 67 publications

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“…Dazu wurden verschiedene metallkatalysierte und organokatalytische enantioselektive decarboxylierende Protonierungsreaktionen (EDP) beschrieben, bislang blieben jedoch die jeweiligen Stereoselektivitä-ten moderat. [94] Demgegenüber erwies sich Enzymkatalyse auf der Basis der Arylmalonat-Decarboxylase (AMDase) aus Bordetella bronchiseptica in einigen Fällen als hoch enantioselektiv.…”

Section: Erweiterung Der Substratbreite Und Erhöhung Derunclassified

Gerichtete Evolution stereoselektiver Enzyme: Eine ergiebige Katalysator‐Quelle für asymmetrische Reaktionen

Reetz

2010

Angewandte Chemie

130

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Asymmetrische Katalyse spielt eine Schlüsselrolle in der modernen synthetischen organischen Chemie, wobei künstliche Katalysatoren und Enzyme die zwei wichtigsten Optionen darstellen. Die Verwendung von Enzymen in der organischen Chemie und Biotechnologie hat in der zweiten Hälfte des vergangenen Jahrhunderts stark zugenommen, oft blieb jedoch der Anwendungsbereich aus mehreren Gründen eingeschränkt. Dazu gehören begrenzte Substratakzeptanz, geringe oder fehlende Stereoselektivität, unzureichende Stabilität und manchmal Produktinhibierung. Während der vergangenen 15 Jahre wurde die genetische Technik der gerichteten Evolution so weit entwickelt und verfeinert, dass all diese Probleme angegangen und in der Regel gelöst werden können. Sie basiert auf wiederholende Zyklen von Genmutagenese, Expression und Screening (oder Selektion). Der vorliegende Aufsatz fokussiert auf gerichtete Evolution stereoselektiver Enzyme, ein fundamental neuer Ansatz zur asymmetrischen Katalyse. Der Schwerpunkt liegt auf Methodenentwicklung in dem Bestreben, diese Art der Katalysator‐Optimierung einfacher, schneller und effizienter als in der Vergangenheit zu gestalten. Die neueren Methoden bescheren dem Chemiker und dem Biotechnologen robuste und selektive Katalysatoren für eine Vielzahl von nützlichen Anwendungen.

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Section: Erweiterung Der Substratbreite Und Erhöhung Derunclassified

Gerichtete Evolution stereoselektiver Enzyme: Eine ergiebige Katalysator‐Quelle für asymmetrische Reaktionen

Reetz

2010

Angewandte Chemie

130

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“…Various metal-catalysed and organocatalytic methods have been explored for related enantioselective decarboxylative protonation (EDP) reactions. [1] However, the synthetic EDP methods can only deliver chiral carboxylic acids or esters with moderate enantioselectivities (ee). [1] On the other hand, enzymatic decarboxylation offers a cleaner, more sustainable and more efficient approach to deliver carboxylic acids of very high ee.…”

mentioning

confidence: 99%

“…[1] However, the synthetic EDP methods can only deliver chiral carboxylic acids or esters with moderate enantioselectivities (ee). [1] On the other hand, enzymatic decarboxylation offers a cleaner, more sustainable and more efficient approach to deliver carboxylic acids of very high ee. Notably, the arylmalonate decarboxylase (AMDase) isolated from Bordetella bronchiseptica [2] has been shown to be highly effective in the decarboxylation of a-arylmalonates to give enantiomerically pure a-arylcarboxylic acids (Scheme 1).…”

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confidence: 99%

Structure‐Guided Directed Evolution of Alkenyl and Arylmalonate Decarboxylases

et al. 2009

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The asymmetric decarboxylation of prochiral a-disubstituted malonic acids is an attractive route to produce homochiral asubstituted carboxylic acids. Various metal-catalysed and organocatalytic methods have been explored for related enantioselective decarboxylative protonation (EDP) reactions.[1] However, the synthetic EDP methods can only deliver chiral carboxylic acids or esters with moderate enantioselectivities (ee).[1] On the other hand, enzymatic decarboxylation offers a cleaner, more sustainable and more efficient approach to deliver carboxylic acids of very high ee. Notably, the arylmalonate decarboxylase (AMDase) isolated from Bordetella bronchiseptica [2] has been shown to be highly effective in the decarboxylation of a-arylmalonates to give enantiomerically pure a-arylcarboxylic acids (Scheme 1). [3, 4] The fact that the AMDase is highly robust and does not require co-factors further increases the potential of this enzyme for biocatalysis. Despite this, the pool of substrates accepted by the enzyme is limited to malonates that possess aaryl substituents. Indeed a number of other bacterial AMDases have been discovered from sequence similarity searches, [5] or selective enrichment experiments.[6] While all these enzymes could catalyse the decarboxylation of aarylmalonates, none have so far been demonstrated to decarboxylate malonates which do not possess a-aryl substituents.In order to rationalise this, and guide the development of new enzymes which could catalyse a wider range of reactions, we solved the X-ray crystal structure of the B. bronchiseptica AMDase.[5] Our first high-resolution structure [7] reveals a "dioxyanion hole" motif, which can donate six hydrogen bonds to potentially stabilize a putative high-energy enediolate intermediate, along with a small hydrophobic cavity likely favouring the formation of the neutral CO 2 . From this we were able to suggest a mechanism for the AMDase (Scheme 1). From comparison of the AMDase structure [5] with structures of Asp/Glu racemases, [8] we proposed that conserved dioxyanion hole motifs could have evolved to stabilise common enediolate intermediates in these mechanistically related enzymes. Indeed, up until our structure of the AMDase, there was no evidence to suggest how the AMDase or Asp/Glu racemases stabilised common putative high-energy enediolate intermediates.[5] However, our proposal was based on a structure which only possessed phosphate as an active-site ligand.[5] To lend further support to our proposal, we here present a second B. bronchiseptica AMDase structure with a mechanism-based inhibitor that more closely resembles the enediolate intermediate bound to the active site of the enzyme. This allowed us to rationalise the mechanism of this simple yet intriguing enzyme and design new and effective malonate substrates for the AMDase. Also, the new structure guided directed evolution of new AMDase mutants with significantly enhanced catalytic efficiency with a range of substrates. Scheme 1. Proposed mechanism of the AMDase.[5] Preferred ma...

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“…This closely related reaction to the malonic acid synthesis has been recently reviewed [21]. The first example of this reaction in its enantioselective version, reported by Marckwald in 1904, is also probably the first example of an asymmetric reaction in the chemical history [22].…”

Section: Enantioselective Decarboxylative Protonationmentioning

confidence: 99%