Engineered Myoglobin Catalysts for Asymmetric Intermolecular Cyclopropanation Reactions

Abstract

Optically active cyclopropanes are highly valuable structural motifs in medicinal chemistry, constituting key pharmacophores in several drug molecules such as the antidepressant tranylcypromine and anticoagulant drug ticagrelor. 1 Cyclopropane rings are also present in several biologically active natural products, including the insecticides permethrin and phenothrin. Because of their unique structural and conformational properties along with their established value for the design of bioactive molecules, extensive research has been devoted to the development of catalytic methods for the asymmetric construction of cyclopropane rings. 2 In this context, a direct method for the synthesis of cyclopropanes involves the metal-catalyzed cyclopropanation of olefins in the presence of diazo compounds as carbene donors. 2 These transformations involve the metal-catalyzed decomposition of the diazo compound (or an equivalent carbene donor reagent) to give rise to a reactive metallocarbenoid species, which then mediates the insertion of the carbene moiety into the C=C double bond of the olefin (Fig. 1a). Among others, chiral dirhodium complexes, ruthenium (or copper) bisoxazoline complexes, cobalt-salen complexes, and metalloporphyrins (Fig. 1b), have represented valuable catalytic systems for the realization of asymmetric cyclopropanation reactions. 2 Despite this progress, several outstanding challenges remain in this field in particular as related to achieving high stereoselectivity, catalytic efficiency, and/or overcoming the need for precious and toxic metals in these systems. Complementing chemocatalysis, biocatalysis has covered an increasingly important role in chemical synthesis and manufacturing in both academia and industry. 3 Most attractive features of biocatalysis are the potential for high chemo-, regio-and stereoselectivity offered by enzyme-catalyzed reactions, the application of mild reaction conditions, and its sustainable nature. 3 As a result, biocatalytic processes have been implemented for the synthesis and manufacturing of a growing number of the pharmaceuticals and other high value compounds. 3a, 4 While various enzyme classes has now become integral part of the catalytic toolbox available for asymmetric synthesis, the reaction scope of naturally occurring enzymes is inherently limited compared to that of chemical methods. Biocatalysis has covered an increasingly important role in the synthesis and manufacturing of pharmaceuticals and other high value compounds. In the interest of expanding the range of synthetically useful reactions accessible via biocatalysts, our group has explored the potential and application of engineered myoglobins for ʻabiologicalʼ carbene transfer catalysis. These transformations provide a direct route for the construction of new carbon-carbon and carbon-heteroatom bonds, including the synthesis of cyclopropane rings, which are key motifs and pharmacophores in many drugs and bioactive natural products. In this award article, we survey the progress made by our group toward the development of myoglobin-based catalysts for asymmetric intermolecular cyclopropanation reactions. The high stereoselectivity exhibited by these biocatalysts in these reactions, combined with their broad substrate scope, scalability, and robustness to high substrate loading and organic co-solvents, contribute to make these systems particularly useful for chemical synthesis and biocatalysis at the preparative scale. Extension of the scope of biocatalytic carbene transfer reactions to include different classes of carbene donor reagents has created new opportunities for the asymmetric synthesis of functionalized cyclopropanes. Furthermore, the integration of myoglobin-catalyzed stereoselective cyclopropanations with chemical diversification of the enzymatic products has furnished attractive chemoenzymatic strategies to access a diverse range of optically active cyclopropane scaffolds of high value for drug discovery, medicinal chemistry, and the synthesis of natural products.