Selective oxidation of aliphatic C-H bonds stands as an unsolved problem in organic synthesis, with the potential to offer novel paths for preparing molecules of biological interest. The quest for ...reagents that can perform this class of reactions finds oxygenases and their mechanisms of action as inspiration motifs. Among the numerous families of synthetic catalysts that have been explored, complexes with linear tetraazadentate ligands combining two aliphatic amines and two aromatic amine heterocycles display a structural versatility proven instrumental in the design of C-H oxidation reactions showing site and enantioselectivities, not accessible by conventional oxidants. This manuscript makes a review of recent advances in the field.
α‐Amino acids represent a valuable class of natural products employed as building blocks in biological and chemical synthesis. Because of the limited number of natural amino acids available, and of ...their widespread application in proteomics, diagnosis, drug delivery and catalysis, there is an increasing demand for the development of procedures for the preparation of modified analogues. Herein, we show that the use of bioinspired manganese catalysts and H2O2 under mild conditions, provides access to modified α‐amino acids via γ‐C−H bond lactonization. The system can efficiently target 1°, 2° and 3° γ‐C−H bonds of α‐substituted and achiral α,α‐disubstituted α‐amino acids with outstanding site‐selectivity, good to excellent diastereoselectivity and (where applicable) enantioselectivity. This methodology may be considered alternative to well‐established organometallic procedures.
Bioinspired stereoselective γ‐aliphatic C−H bond lactonization of α‐amino acids using a manganese catalyst and H2O2 is reported. This method allows the oxidation of 1°, 2° and 3° C−H bonds and the enantioselective preparation of chiral α,α‐disubstituted‐α‐amino acid derivatives.
Aliphatic C–H bond functionalization is at the frontline of research because it can provide straightforward access to simplified and cost-effective synthetic procedures. A number of these ...methodologies are based on hydrogen atom transfer (HAT), which, as a consequence of the inert character of C–H bonds, often represents the most challenging step of the overall process. Because the majority of organic molecules contain multiple nonequivalent C–H bonds that display similar chemical properties, differentiating between these bonds with high levels of selectivity represents one of the most challenging issues. Clarification of the factors that govern the relative reactivity of C–H bonds toward HAT reagents is thus of primary importance in order to develop selective functionalization procedures. In this Account we describe, through the combination of kinetic studies employing a genuine HAT reagent such as the cumyloxyl radical, along with oxidations performed with H2O2 and iron or manganese catalysts, our contribution toward the development of selective C–H functionalization methodologies. Despite the different nature of these reagents, an oxygen-centered radical and a metal–oxo species, congruent reactivity and selectivity patterns have emerged, providing strong evidence that both reactions proceed via HAT. Consequently, selectivity in this class of metal catalyzed C–H oxidations can be reasonably predicted and synthetically exploited. Amides have been identified as preferential functional groups for governing selectivity on the basis of electronic, steric, and stereoelectronic effects. Torsional effects have proven moreover to be particularly important C–H directing factors in the oxidation of cyclohexane scaffolds where a delicate balance of these effects, in synergistic combination with catalyst design, enables highly chemoselective and enantioselective oxidations. Medium effects have been also shown to govern the relative HAT reactivity of C–H bonds in proximity to polar, hydrogen bond acceptor (HBA) functional groups. By engaging in hydrogen bonding with these groups, fluorinated alcohols strongly deactivate proximal C–H bonds toward HAT-based oxidation. As a result, alcohols, ethers, amines, and amides, which are electron rich and effective proximal C–H activating groups toward HAT reagents in conventional solvents, become oxidatively robust deactivating functionalities that direct C–H oxidation toward remote positions. These deactivating effects enable moreover the accomplishment of product chemoselective methylenic hydroxylations. Overall, clarification of the factors that govern HAT-based reactions has served to provide unique examples of catalytic methodologies for chemoselective and enantioselective oxidation of nonactivated aliphatic C–H bonds of potential utility in organic synthesis.
Replacement of C−H by C−F bonds provides lipophilicity and chemical stability to organic molecules. These properties make organofluorides interesting compounds in agrochemistry, medicinal chemistry ...and also in materials. However, the same properties hamper their chemical degradation, resulting in an increasingly concerning environmental persistence, which is fueling the quest for biological and chemical reagents that could cleave the C−F bonds. The first part of this review makes an overview of oxidative enzymes known to defluorinate organic molecules. The second part reviews coordination complexes, originally designed as functional models of oxidative enzymes, that can also engage in related defluorination reactions. The manuscript is hoped to provide ideas for the development of novel catalytic methodologies.
Due to their environmental persistence, decomposition of fluorinated compounds is a highly desired process. The present review summarizes those systems with oxidative C−F bond defluorination activity. Heme and nonheme oxygenases as well as model complexes based on copper, iron, and manganese are competent to perform this chemistry and they are all reviewed.
Precise delivery of a proton plays a key role in O2 activation at iron oxygenases, enabling the crucial O−O cleavage step that generates the oxidizing high‐valent metal–oxo species. Such a proton is ...delivered by acidic residues that may either directly bind the iron center or lie in its second coordination sphere. Herein, a supramolecular strategy for enzyme‐like H2O2 activation at a biologically inspired manganese catalyst, with a nearly stoichiometric amount (1–1.5 equiv) of a carboxylic acid is disclosed. Key for this strategy is the incorporation of an α,ω‐amino acid in the second coordination sphere of a chiral catalyst via remote ammonium‐crown ether recognition. The properly positioned carboxylic acid function enables effective activation of hydrogen peroxide, leading to catalytic asymmetric epoxidation. Modulation of both amino acid and catalyst structure can tune the efficiency and the enantioselectivity of the reaction, and a study on the oxidative degradation pathway of the system is presented.
Amino acid supramolecular recognition in the 2nd coordination sphere of a bioinspired manganese catalyst allows efficient enzyme‐like activation of H2O2 by locating the carboxylic acid moiety in proper position to access the 1st coordination sphere of the metal.
The selective oxidation of hydrocarbons is a challenging reaction for synthetic chemists, but common in nature. Iron oxygenases activate the O–O bond of dioxygen to perform oxidation of alkane and ...alkenes moieties with outstanding levels of regio-, chemo- and stereoselectivity. Along a bioinspired approach, iron coordination complexes which mimic structural and reactivity aspects of the active sites of nonheme iron oxygenases have been explored as oxidation catalysts. This review describes the evolution of this research field, from the early attempts to reproduce the basic reactivity of nonheme iron oxygenases to the development of effective iron oxidation catalysts. The work covers exclusively nonheme iron complexes which rely on H
2
O
2
or O
2
as terminal oxidants. First, it delineates the key steps and the essential catalyst design principles required to activate the peroxide bond at nonheme iron centers without (or at least minimizing) the release of free-diffusing radicals. It follows with a critical description of the mechanistic pathways which govern the reaction between iron complexes and H
2
O
2
to generate the oxidizing species. Eventually, the work presents a state-of-the-art report on the use of these catalysts in aliphatic C–H oxidation, olefin epoxidation and alkene
syn
-dihydroxylation, under substrate-limiting conditions. A special focus is given on the main strategies elaborated to tune catalyst activity and selectivity by modification of its structure. The work is concluded by a concise discussion on the essential progresses of these oxidation catalysts together with the challenges that remain still to be tackled.
Graphical Abstract
Fullerene extracts are easily available from fullerene soot, but finding an efficient strategy to obtain them in pure form remains elusive, especially for higher fullerenes (Cx, x > 70). The ...properties of the latter remain unclear and their potential application to multiple research fields has not been developed mainly due to their purification difficulties. In this Tutorial Review we cover the use of molecular receptors for the separation of fullerenes by means of host-guest interactions. This strategy allows gaining selectivity, no specialized equipment is required and, ideally, recyclable systems can be designed. We focus on the metallosupramolecular receptors using the metal-ligand coordination approach, which offers a controlled and versatile strategy to design fullerene hosts, and the latest strategies to release the fullerene guest will be described. The field is probably in its beginnings but it is rapidly evolving and we are confident that this tutorial review will help researchers to rapidly gain a general overview of the main works and concepts that are leading this promising strategy and that may lead towards a useful methodology to purify fullerenes.
Aliphatic C−H oxidation is the most straightforward approach to functionalize hydrocarbon skeletons. The main challenge of this reaction is the control of site selectivity, given the multiple C−H ...bonds present in any organic molecule. Natural enzymes elegantly solve this problem through the interplay of different interactions that geometrically orient the substrate to expose a single C−H bond to the active unit, thus overriding intrinsic reactivity patterns. A combination of molecular catalysts and supramolecular receptors can be a promising way to replicate such control. This strategy indeed unlocks hydroxylation of C−H bonds that are not accessible with conventional methodologies, in which the selectivity is dictated by the geometry of the substrate–receptor adduct. Herein, we review the reports of recognition‐driven C−H oxidation reactions and highlight the key design principles that inspired these works.
The use of supramolecular interactions to bind and orient the substrate can unlock novel selectivities in C−H oxidation. In this Minireview different, bioinspired strategies towards this goal are discussed.
Predictability is a key requirement to encompass late‐stage C−H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for ...complex substrate structures and elusive transformations such as remote C(sp3)−H oxidation, as it requires distinguishing a specific C−H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C−H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host‐guest adduct by NMR analysis. These analyses indicate which remote C−H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late‐stage C(sp3)−H oxidation of amino‐steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.
Analysis of the substrate binding mode of amino‐steroids to a supramolecular catalyst enables rational prediction of site selectivity in C(sp3)−H oxidation of amino‐steroids. This strategy was applied to late‐stage C(sp3)−H oxidation of amino‐steroids at C15 (or C16), with a selectivity tunable by modification of the catalyst chirality and metal.
PDF
