Catalyst Design in Oxidation Chemistry; from KMnO4 to Artificial MetalloenzymesReview
Bioorg. Med. Chem. 2014, 22, 5657-5677, 10.1016/j.bmc.2014.07.002
Oxidation reactions are an important part of the synthetic organic chemist’s toolkit and continued advancements have, in many cases, resulted in high yields and selectivities. This review aims to give an overview of the current state-of-the-art in oxygenation reactions using both chemical and enzymatic processes, the design principles applied to date and a possible future in the direction of hybrid catalysts combining the best of chemical and natural design.
Intramolecular C(sp3)-H Amination of Arylsulfonyl Azides with Engineered and Artificial Myoglobin-Based Catalysts
Bioorg. Med. Chem. 2014, 22, 5697-5704, 10.1016/j.bmc.2014.05.015
The direct conversion of aliphatic CH bonds into CN bonds provides an attractive approach to the introduction of nitrogen-containing functionalities in organic molecules. Following the 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 CH 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 prepared to investigate the effect of these structural changes on the catalytic activity and selectivity of these catalysts. Our studies showed that metallo-substituted myoglobins constitute viable CH 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 CH 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 CH amination catalysts.
Metal: MnLigand type: Amino acid; PorphyrinHost protein: Myoglobin (Mb)Anchoring strategy: Metal substitutionOptimization: Chemical & geneticReaction: C-H activationMax TON: 142ee: ---PDB: ---Notes: ---
Neocarzinostatin-Based Hybrid Biocatalysts with a RNase like Activity
Bioorg. Med. Chem. 2014, 22, 5678-5686, 10.1016/j.bmc.2014.05.063
A new zinc(II)-cofactor coupled to a testosterone anchor, zinc(II)-N,N-bis(2-pyridylmethyl)-1,3-diamino-propa-2-ol-N′(17′-succinimidyltestosterone) (Zn-Testo-BisPyPol) 1-Zn has been synthesized and fully characterized. It has been further associated with a neocarzinostatin variant, NCS-3.24, to generate a new artificial metalloenzyme following the so-called ‘Trojan horse’ strategy. This new 1-Zn-NCS-3.24 biocatalyst showed an interesting catalytic activity as it was found able to catalyze the hydrolysis of the RNA model HPNP with a good catalytic efficiency (kcat/KM = 13.6 M−1 s−1 at pH 7) that places it among the best artificial catalysts for this reaction. Molecular modeling studies showed that a synergy between the binding of the steroid moiety and that of the BisPyPol into the protein binding site can explain the experimental results, indicating a better affinity of 1-Zn for the NCS-3.24 variant than testosterone and testosterone-hemisuccinate themselves. They also show that the artificial cofactor entirely fills the cavity, the testosterone part of 1-Zn being bound to one the two subdomains of the protein providing with good complementarities whereas its metal ion remains widely exposed to the solvent which made it a valuable tool for the catalysis of hydrolysis reactions, such as that of HPNP. Some possible improvements in the ‘Trojan horse’ strategy for obtaining better catalysts of selective reactions will be further studied.
Metal: ZnLigand type: Poly-pyridineHost protein: Neocarzinostatin (variant 3.24)Anchoring strategy: SupramolecularOptimization: ---Reaction: Hydrolytic cleavageMax TON: ---ee: ---PDB: ---Notes: kcat/KM = 13.6 M-1 * s-1