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  • University of Groningen

    Phosphoramidite ligands and artificial metalloenzymes in enantioselective rhodium-catalysis Panella, Lavinia

    IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

    Document Version Publisher's PDF, also known as Version of record

    Publication date: 2006

    Link to publication in University of Groningen/UMCG research database

    Citation for published version (APA): Panella, L. (2006). Phosphoramidite ligands and artificial metalloenzymes in enantioselective rhodium- catalysis: old challenges and new frontiers. s.n.

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    Download date: 10-11-2020

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  • Chapter 5 Merging Homogeneous Catalysis with Biocatalysis: Papain as Hydrogenation Catalyst

    Papain, modified at Cys-25 with a monodentate phosphite ligand and complexed with Rh(COD)2BF4, is an active catalyst in the hydrogenation of methyl 2- acetamidoacrylate.

    […] the pace, at which ‘new’ enzymes for selective biotransformations are appearing, is astonishingly modest. The reasons for this are probably manifold: first, the conservatism of academic and industrial researchers avoiding high-risk projects; second, lack of interdisciplinarity among chemists and biologists; […].

    Faber, K.; Kroutil, W. Curr. Opin. Chem. Biol. 2005, 9, 181.

    Part of this Chapter has been published: Panella, L.; Broos, J.; Jin, J.; Fraaije, M. W.; Janssen, D. B.; Jeronimus-Stratingh, M.; Feringa, B. L.; Minnaard, A. J.; de Vries, J. G. Chem. Commun. 2005, 5656.

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    Chapter 5

    5.1 Introduction There are three main routes for the preparation of enantiomerically pure compounds: (1) separation of racemates; (2) transformation of a precursor provided by natural sources from fermentation or agriculture; (3) asymmetric synthesis from prochiral substrates using both catalytic and stoichiometric methods (Figure 5.1).

    Fermentation Agriculture

    Enantiomerically Pure Compounds

    RacematesProchiral Substrates

    Synthesis Resolution

    Kinetic Crystallization

    Enzymatic Chemical

    Asymmetric Synthesis

    Chemo-catalysis Biocatalysis

    Stoichiometric

    Fermentation Agriculture

    Enantiomerically Pure Compounds

    RacematesProchiral Substrates

    Synthesis Resolution

    Kinetic Crystallization

    Enzymatic Chemical

    Asymmetric Synthesis

    Chemo-catalysis Biocatalysis

    Stoichiometric

    Figure 5.1 Routes to enantiopure compounds

    The most convenient and attractive of these methodologies, in terms of atom efficiency and mildness of reaction conditions, are enantioselective chemo- catalysis and biocatalysis.

    Enantioselective metal-catalyzed transformations have developed enormously in the last decades, providing fundamental contributions to the establishment of modern organic chemistry.1 Nevertheless, although homogeneous asymmetric catalysis has reached an advanced stage in the laboratory, the method of choice to obtain enantiopure intermediates, in the production of pharmaceuticals, is still the resolution by crystallization of diastereomeric salts.2 One of the main reasons for this is the strong time-to-market pressure related to their production. Fortunately, high throughput experimentation can be used increasingly for the rapid identification of a chiral catalyst.3 The availability of large libraries of chiral catalysts and in particular of the corresponding ligands can be, however, a serious bottleneck.4 Phosphorus based chiral ligands are arguably the most versatile ligands for asymmetric catalysis. However, the availability of chiral bidentate phosphorus-based ligands is often associated with cumbersome and lengthy synthesis. Recently, there has been a revival of the use of monodentate chiral phosphorus ligands and excellent results have been achieved in different fields of asymmetric catalysis.5 Moreover, monodentate phosphoramidites, developed in

  • 169

    Merging Homogeneous Catalysis with Biocatalysis: Papain as Hydrogenation Catalyst

    our laboratories, and monodentate phosphite ligands have the advantage of a simple modular design which allows the versatile synthesis of a large diversity of structures (Scheme 5.1).6 These ligands can be synthesized in an automated manner, opening the doors to large libraries and truly combinatorial approaches.7

    P N O

    O

    R1

    R2 P O

    O

    O R3

    PCl3 OH

    OH +

    R3OHHN R1

    R2

    Scheme 5.1 Modular structure of phosphoramidites and phosphites

    Biocatalysis is also increasingly applied in organic chemistry for a variety of transformations, emerging as a valuable alternative for the preparation of enantiopure compounds.8 Characteristics such as chemo-, regio- and stereoselectivity manifested by biocatalysts are among the most appealing features connected with their use. Nevertheless, also in this field, despite the continuous efforts, a limited amount of industrial applications has been established.2b,9 Some of the reasons attributed to the limited implementation of biocatalysis into production seem to be: (1) the commercial availability of the biocatalysts; (2) their limited substrate scope; (3) their operational stability; (4) the reluctance of the chemical community to fully explore their potential.10

    Inevitably, chemocatalysis and biocatalysis have fundamental differences in their positive and negative features (some of which are listed in Table 5.1) that make them rather complementary.

    Table 5.1 Characteristics of homogeneous and enzymatic catalysis11

    homogeneous catalysis enzymatic catalysis

    Enantiomers both accessible generally one enantiomer

    Reaction diversity large small

    Substrate scope large small

    Solvent preference mostly organic mostly aqueous

    Optimization chemical genetic

    Second coordination sphere less defined more defined

    Turnover numbers smaller larger

    As summarized in Figure 5.2, although operating in apparently parallel universes, asymmetric homogeneous catalysis and biocatalysis have the preparation of

  • 170

    Chapter 5

    enantiomerically pure compounds as a common goal. On one side, new routes using metal-catalyzed approaches to target chiral molecules are continuously explored; on the other side, there is a continuous search for enzymes with novel catalytic properties. Similarly, once a hit has been found, improvements of the performance of the catalyst are achieved by its iterative redesign or modification.

    Asymmetric Reaction

    Enantiomerically Pure Compounds

    Chemo-Catalysts Biocatalysts

    Design

    Re-design

    Asymmetric ReactionAsymmetric Reaction

    Enantiomerically Pure CompoundsEnantiomerically Pure Compounds

    Chemo-Catalysts Biocatalysts

    Design

    Re-design

    Design

    Re-design

    Figure 5.2 Chemistry and biochemistry: different approaches, similar goal

    Moreover, the idea of cooperation (for example in cascade reactions) between the two fields starts to emerge as an appealing opportunity to expand the toolbox of modern organic chemistry and the implementation of catalysis in the preparation of chiral molecules.12

    5.2 Scope of this study An even more intriguing development, going beyond their simple cooperation, would be the fusion of these two approaches by the insertion of non-chiral metal catalysts into the active site of an enzyme. In this way, the enzyme will provide the chiral environment and the chemo-catalyst will allow the enzyme to perform new types of catalysis, thereby broadening the scope of both fields (Figure 5.3). Once the methodology has been established, this approach would also allow to take advantage of the tremendous advances in molecular biology techniques, such as gene manipulation and functional selection methodologies, for the preparation of large libraries of proteins, expanding even further the combinatorial approach for the identification of suitable catalysts for all kinds of transformations.13,14

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    Merging Homogeneous Catalysis with Biocatalysis: Papain as Hydrogenation Catalyst

    Site-directed mutagenesis Evolution

    Genetic shuffle Screening o