We demonstrate that incorporation of MnSalen into a protein scaffold enhances the chemoselectivity in sulfoxidation of thioanisole and found that both the polarity and hydrogen bonding of the protein scaffold play an important role in tuning the chemoselectivity.Metalloenzymes have set a golden standard for carrying out reactions with high reactivity and selectivity. Understanding how proteins confer such reactivity and selectivity is important not only to providing deeper insight in biological functions, but also to its application in chemical transformations. [1][2][3][4][5][6][7][8][9][10][11] Toward this goal, much work has focused on the study of native metalloenzymes, such as cytochrome P-450s, a metalloenzyme with high chemoselectivity in the oxidation of C-H bonds. [12][13][14] These studies indicate that the protein scaffold is capable of creating the proper environment to modulate the reactive pathways of active intermediates so as to inhibit side reactions such as over oxidization. In contrast to the tremendous progress made in biochemical and biophysical studies of native metalloenzymes and their variants, much less has been reported regarding the application of the insight gained from such studies for designing artificial enzymes. In addition to testing our knowledge of metalloenzymes, designing artificial enzymes can provide new information that otherwise may be difficult to obtain from studying native enzymes. 1-8, 12, 15 By carefully choosing protein scaffolds that are small, stable and easy to produce, such artificial enzymes may find interesting applications in chemical transformations to generate fine chemical intermediates. An emerging area in artificial enzyme design is the incorporation of non-native metal catalysts into proteins to expand the reactivity and functionality of metalloenzymes, thus transforming achiral and water-insoluble metal catalysts into asymmetric aqueous solution catalysts for reactions such as sulfoxidation, hydrogenation, and cycloaddition (Diels-Alder reaction). 7,8,[16][17][18][19][20][21][22][23][24] A notable bonus to such an approach is the opportunity to compare how the selectivity of the metal catalyst can be fine-tuned using biological and chemical approaches. 7 Understanding how such systems control catalysis can enrich our knowledge of catalyst design, generating more selective catalysts. The majority of artificial metalloenzyme design studies have been devoted to exploring the use of the protein scaffold to tune enantioselectivity. 7,8,[16][17][18][19] However, learning to control chemoselectivity in these artificial biocatalysts, especially in catalytic oxidation, is equally important. To demonstrate the ability of the protein scaffold to tune the oxidative reactivity of metal catalysts and to discover factors involved in tuning such chemoslectivity, we report here that introducing manganese salen (salen=N,N′-bissalicylidene-1,2-ethanediamino anion, MnSalen, 1) as a non-native metal cofactor into apo
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