The direct amination of aliphatic C—H bonds represents a most valuable transformation in organic chemistry. While a number of transition metal-based catalysts have been developed and investigated for this purpose, the possibility to execute this transformation with biological catalysts has remained largely unexplored. Here, we report that cytochrome P450 enzymes can serve as efficient catalysts for mediating intramolecular benzylic C—H amination reactions in a variety of arylsulfonyl azide compouds. Under optimized conditions, the P450 catalysts were found to support up to 390 total turnovers leading to the formation of the desired sultam products with excellent regioselectivity. In addition, the chiral environment provided by the enzyme active site allowed for the reaction to proceed in a stereo- and enantioselective manner. The C—H amination activity, substrate profile, and enantio/stereoselectivity of these catalysts could be modulated by utilizing enzyme variants with engineered active sites.

Cytochrome P450 enzymes can effectively promote the activation and cyclization of carbonazidate substrates to yield oxazolidinones via an intramolecular nitrene C–H insertion reaction. Investigation of the substrate scope shows that while benzylic/allylic C–H bonds are most readily aminated by these biocatalysts, stronger, secondary C–H bonds are also accessible to functionalization. Leveraging this “non-native” reactivity and assisted by fingerprint-based predictions, improved active-site variants of the bacterial P450 CYP102A1 could be identified to mediate the aminofunctionalization of two terpene natural products with high regio- and stereoselectivity. Mechanistic studies and KIE experiments show that the C–H activation step in these reactions is rate-limiting and proceeds in a stepwise manner, namely, via hydrogen atom abstraction followed by radical recombination. This study expands the reactivity scope of P450-based catalysts in the context of nitrene transfer transformations and provides first-time insights into the mechanism of P450-catalyzed C–H amination reactions.

The direct conversion of aliphatic C—H bonds into C—N bonds provides an attractive approach to the introduction of nitrogen-containing functionalities in organic molecules. Following our recent discovery that cytochrome P450 enzymes can catalyze the cyclization of arylsulfonyl azide compounds via an intramolecular C(sp3)—H amination reaction, we have explored here the C—H amination reactivity of other hemoproteins. Various heme-containing proteins, and in particular myoglobin and horseradish peroxidase, were found to be capable of catalyzing this transformation. Based on this finding, a series of engineered and artificial myoglobin variants containing active site mutations and non-native Mn- and Co-protoporphyrin IX cofactors, respectively, were preparedWmvestigate the effect of these structural changes on the catalytic activity and selectivity of to these catalysts. Our studies showed that metallo-substituted myoglobins constitute viable C—H amination catalysts, revealing a distinctive reactivity trend as compared to synthetic metalloporphyrin counterparts. On the other hand, amino acid substitutions at the level of the heme pocket were found to be beneficial toward improving the stereo- and enantioselectivity of these Mb-catalyzed reactions. Mechanistic studies involving kinetic isotope effect experiments indicate that C—H bond cleavage is implicated in the rate-limiting step of myoglobin-catalyzed amination of arylsulfonyl azides. Altogether, these studies indicate that myoglobin constitutes a promising scaffold for the design and development of C— H amination catalysts.

There is growing interest in developing bio-based products and innovative process technologies that can reduce the dependence on fossil fuel and move to a sustainable materials basis. Biodegradable bio-based nanocomposites are the next generation of materials for the future. Renewable resource-based biodegradable polymers including cellulosic plastic (plastic made from wood), corn-derived plastics, and polyhydroxyalkanoates (plastics made from bacterial sources) are some of the potential biopolymers which, in combination with nanoclay reinforcement, can produce nanocomposites for a variety of applications. Nanocomposites of this category are expected to possess improved strength and stiffness with little sacrifice of toughness, reduced gas/water vapor permeability, a lower coefficient of thermal expansion, and an increased heat deflection temperature, opening an opportunity for the use of new, high performance, lightweight green nanocomposite materials to replace conventional petroleum-based composites. The present review addresses this green material, including its technical difficulties and their solutions.

Direct C−H bond functionalization to form C−N bonds via nitrenoid insertion is one of the most effective strategies to construct N-functionalized molecules of importance. In this context, metalloporphyrins have established themselves as effective catalytic systems for such transformation, following an outer-sphere pathway. In the past few years C(sp 3 )−H bond amination has progressed in leaps and bounds, tackling the chemo-/regioselectivity issue not only in small molecules but also in complex molecules through late-stage functionalization, furnishing valuable N-scaffolds. It is only very recently that the biocatalytic approach with metalloporphyrin-based enzymes has emerged as a promising research area demonstrating very good regio-and stereoselectivity toward the development of environmentally benign C−H amination processes. Importantly, the progress in aromatic C−H bond amination has also gained prominence lately under metalloporphyrin catalysis. This review covers development achieved to date in metalloporphyrin-catalyzed C−H amination, including the very nascent biocatalytic C−H bond nitrenoid insertion, in addition to providing an insight on the mechanistic aspects as well.