Recent Advances in Late-Stage Construction of Stapled Peptides via C−H Activation

Stapled peptides have been widely applied in many fields, including pharmaceutical chemistry, diagnostic reagents, and materials science. However, most traditional stapled peptide preparation methods rely on prefunctionalizations, which limit the diversity of stapled peptides. Recently, the emergence of late-stage transition metal-catalyzed C−H activation in amino acids and peptides has attracted wide interest due to its robustness and applicability for peptide stapling. In this review, we summarize the methods for late-stage construction of stapled peptides via transition metal-catalyzed C−H activation.     

Photochemical C−H Activation: An Early Story

An early investigation in the author‘s laboratory into photochemical C−H bond activation and functionalization is recounted. Specifically, d⁸ Ir(I) and Rh(I) carbonyl phosphine complexes were found to promote benzene C−H bond activtion and functionalization to give benzaldehyde upon near-UV irradiation. The carbonylation of benzene is thermodynamically unfavorable resulting in only low yields of benzaldehyde. The photochemical process was suggested as ligand dissociation to yield a 14 e⁻ Ir(I) or Rh(I) intermediate capable of benzene C−H oxidative additions. The research set the stage for subsequent photochemical C−H activation and functionalization studies by others in the late 1980’s.     

Effects of Cα -Oxidation in the Fungal Metabolism of Lignin

C_α-Oxidation (benzyl alcohol oxidation) is a prominent reaction in the degradation of lignin by white-rot fungi. This study showed that such oxidation markedly retards metabolism of a nonphenolic β-O-4 model compound, 1-(3-methoxy-4-ethoxyphenyl)-2-(o-methoxyphenoxy)propane-1,3-diol, by cultures of Phanerochaete chrysosporium Burds. Surprisingly, however, selective chemical C_α -oxidation of spruce lignins enhanced their depolymerization by the cultures. Thus the decrease in intrinsic degradability of substructures is more than compensated by another effect of C_α-oxidation in lignin. One possibility is that the oxidation increases the accessibility of the lignin to enzymes by decreasing its steric complexity. This study also revealed that the β-O-4 model, like lignin in wood, is degraded in part via C_α-oxidation by P. chrysosporium. Reduction of the α-carbonyl groups thus formed does not occur. Addition of L-glutamate to ligninolytic cultures completely suppresses their competence to degrade the model compound, as it does their ability to oxidize lignin to CO₂. This result strengthens past evidence indicating that substructure models are metabolized by the same enzyme system as lignin.     

Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

A successful design of peptidomimetics must come to terms with χ-space control. The incorporation of χ-space constrained amino acids into bioactive peptides renders the χ(1) and χ(2) torsional angles of pharmacophore amino acids critical for activity and selectivity as with other relevant structural features of the template. This review describes histidine analogues characterized by replacement of native α and/or β-hydrogen atoms with alkyl substituents as well as analogues with α, β-didehydro unsaturation or C(α)-C(β) cyclopropane insertion (ACC derivatives). Attention is also dedicated to the relevant field of β-aminoacid chemistry by describing the synthesis of β(2)- and β(3)-models (β-hHis). Structural modifications leading to cyclic imino derivatives such as spinacine, aza-histidine and analogues with shortening or elongation of the native side chain (nor-histidine and homo-histidine, respectively) are also described. Examples of the use of the described analogues to replace native histidine in bioactive peptides are also given.     

New Trends and Future Opportunities in the Enzymatic Formation of C−C,C−N,and C−O bonds

Organic chemistry provides society with fundamental products we use daily. Concerns about the impact that the chemical industry has over the environment is propelling major changes in the way we manufacture chemicals. Biocatalysis offers an alternative to other synthetic approaches as it employs enzymes, Nature's catalysts, to carry out chemical transformations. Enzymes are biodegradable, come from renewable sources, operate under mild reaction conditions, and display high selectivities in the processes they catalyse. As a highly multidisciplinary field, biocatalysis benefits from advances in different areas, and developments in the fields of molecular biology, bioinformatics, and chemical engineering have accelerated the extension of the range of available transformations (E. L. Bell et al., Nat. Rev. Meth. Prim. 2021 , 1, 1–21). Recently, we surveyed advances in the expansion of the scope of biocatalysis via enzyme discovery and protein engineering (J. R. Marshall et al., Tetrahedron 2021 , 82, 131926). Herein, we focus on novel enzymes currently available to the broad synthetic community for the construction of new C−C, C−N and C−O bonds, with the purpose of providing the non-specialist with new and alternative tools for chiral and sustainable chemical synthesis.     

A DFT Survey of the Effects of d-Electron Count and Metal Identity on the Activation and Functionalization of C−H Bonds for Mid to Late Transition Metals

The contribution of metal identity to the activation and functionalization of methane by a series of three-coordinate imide complexes is evaluated in silico for a 3-by-3 block of metals from Fe to Pt. Three mechanisms were studied: oxidative addition (OA) to the metal; hydrogen atom abstraction (HAA) by the imide nitrogen; and, [2+2] addition across the metal-imide bond. In no studied case, was a [2+2] mechanism preferred, perhaps suggesting this mechanism is largely (entirely?) the domain of d⁰ imides. There is a diagonal relationship within the nonet of metals studied in that OA is preferred for earlier, heavier (5d) members of the series, transitioning to an HAA mechanism for later, lighter (3d) imides. DFT indicates that important parameters in partitioning between HAA and OA mechanisms include the strength of the metal-imide π-bond, the ability of larger metals to accommodate increases in formal oxidation state and coordination number, and the soft acid/base compatibility of larger transition metals with soft hydride and methyl ligands     

Nickel-Catalyzed Benzylation of C−H Bonds in Aromatic Amides with Benzyltrimethylammonium Halides

Nickel-catalyzed benzylation reactions of C−H bonds in aromatic amides with benzyltrimethylammonium halides are developed by using a 5-chloro-8-aminoquinoline derivative as a bidentate directing group. Benzylation occurs selectively at the ortho-C−H bonds in aromatic amides, and no methylation was detected. The presence of a 5-chloro-8-aminoquinoline moiety is essential for the success of this reaction, in which a variety of functional groups can be tolerated.     

Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?

The adipocyte-derived ‘satiety promoting’ hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an ‘adipostat’, whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its ‘anti-obesity’ effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin’s metabolic effects while retaining leptin’s permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.     

The effect of Cl− on the kinetics of the anodic dissolution of Pd in H2SO4 solutions

The electrodissolution kinetics of palladium have been studied in deoxygenated

solutions at 25°C. The chloride concentration was varied between 0.01 and 0.5 M and the ionic strength was maintained at 1 M. For all the chloride concentrations an anodic Tafel slope of approximately 58 mV decade⁻¹ and an electrochemical anodic reaction order of 1.1 were obtained. The kinetic equation consistent with the experimental results is

which is consistent with the theoretical equation derived from the proposed mechanism, with the assumption that the adsorbed intermediate, (PdCl⁻₂)_ad follows Temkin adsorption behavior.     

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics,Kinase Pathways,and Cell Metabolism in Cancer Therapeutics

Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.     

Retention of Vitamin C in Drying Processes of Fruits and Vegetables—A Review

This article presents a review of drying processes of fruits and vegetables in which vitamin C degradation was considered. Vitamin C is an important and essential nutrient for humans and it can be taken as an index of nutrient quality of processes. Many researchers have reported the effect of different drying methods and the influence of drying conditions on the vitamin C content. In addition, the effect of other parameters related to the sample structure or to pretreatments on the final quality of the dried product is discussed. Vitamin C degradation mechanisms proposed in the literature, models applied to describe its kinetics, and recent advances in drying processes aiming high retention of this nutrient are also provided.     

Insights into Activation of Cobalt Pre-Catalysts for C(sp2)−H Functionalization

The activation of readily prepared, air-stable cobalt(II) bis(carboxylate) pre-catalysts for the functionalization of C(sp²)−H bonds has been systematically studied. With the pyridine bis(phosphine) chelate, ^iPrPNP, treatment of 1 - (O₂C^tBu)₂ with either B₂Pin₂ or HBPin generated cobalt boryl products. With the former, reduction to (^iPrPNP)Co^IBPin was observed while with the latter, oxidation to the cobalt(III) dihydride boryl, trans-(^iPrPNP)Co(H)₂BPin occurred. The catalytically inactive cobalt complex, Co[PinB(O₂C^tBu)₂]₂, accompanied formation of the cobalt-boryl products in both cases. These results demonstrate that the pre-catalyst activation from cobalt(II) bis(carboxylates), although effective and utilizes an air-stable precursor, is less efficient than activation of cobalt(I) alkyl or cobalt(III) dihydride boryl complexes, which are quantitatively converted to the catalytically relevant cobalt(I) boryl. Related cobalt(III) dihydride silyl and cobalt(I) silyl complexes were also synthesized from treatment of trans-(^iPrPNP)Co(H)₂BPin and (^iPrPNP)CoPh with HSi(OEt)₃, respectively. No catalytic silylation of arenes was observed with either complex likely due to the kinetic preference for reversible C−H reductive elimination rather than product- forming C−Si bond formation from cobalt(III). Syntheses of the cobalt(II) bis(carboxylate) and cobalt(I) alkyl of ^iPrPONOP, a pincer where the methylene spacers have been replaced by oxygen atoms, were unsuccessful due to deleterious P−O bond cleavage of the pincer. Despite their structural similarity, the rich catalytic chemistry of ^iPrPNP was not translated to ^iPrPONOP due to the inability to access stable cobalt precursors as a result of ligand decomposition via P−O bond cleavage.     

Control of oxygen deficiency in Ca1−x La x MnO3−δ and its cathodic properties in alkaline solution

Ceramic samples of composition Ca_0.9La_0.1MnO_3– having various oxygen contents were prepared by a quenching method under nitrogen atmosphere. As the 3 – value decreased from 2.97 to 2.79, the sample conductivity decreased from 10² to 10^–1 S cm^–1. The porous ceramic samples showed good properties as cathode materials in alkaline solution without using conductive material such as graphite, but the discharge capacity decreased with decreasing sample conductivity. The discharge termination is explained by a simple model considering dissipation of the conductive path (high conductivity core) present in the porous sintered ceramic.     

Research of the Activity of Catalysts on the Base of H3PW12O40 in Partial Oxidative Conversion of C3–C4 alkanes

Catalysts from heteropoly acid H₃PW₁₂O₄₀ and its Cs, Na, Ba, Pb, Ca, Cd, Cr, Mn, V, La salts supported on clinoptilolite, alumosilicate are highly active in oxidative conversion of propane–butane (OCPB) mixture and formation of C₂–C₄ olefins, oxygen-containing compounds at temperatures T = 100–800 °C. Optimum yields of ethylene and propylene are achieved on heteropoly acid its Cs and Cr salts. The processes of oxidative dehydrogenation (ODPB) and cracking are concurrent in formation of olefins. High activity is caused by dispersity of supported catalysts (XRD, IRS) both formation of crystal hydrates and an amorphous phase of heteropoly acid in a condition of interaction with the carrier.     

Site-Selective Pyridination of Benzylic and Allylic C−H bonds via Radical-Radical Cross-Coupling

Herein, we report a modular photocatalytic platform for the site-selective pyridination of saturated hydrocarbon compounds employing organic photoredox catalysis to forge new carbon-carbon bonds. The site-selective C−H pyridination could couple benzylic/allylic C−H bonds with pyridylphosphonium salts, which installed directly and regioselectively from C−H heteroarenes through a radical-radical cross coupling mechanism. This synthetic methodology could tolerate a variety of functional groups, complex heteroarenes, even late-stage functionalization of pharmaceuticals selectively.     

Diversification of NH-Aryl Sulfoximines through Iridium-Catalyzed ortho- and meta-Selective C−H Borylation

Herein, the selective ortho- and meta-C−H bond borylation of NH-aryl sulfoximines is reported. Regioselectivity is achieved by the choice of commercially available ligands giving fast excess to valuable borylated aryl sulfoximine building blogs. The utility of the borylated products is demonstrated for the formation of C−O, C−C, C−N, C−D, and C−I bonds.     

Selective C−H Bond Functionalization of Unprotected Indoles by Donor-Acceptor Carbene Insertion

Copper catalysts containing alkoxydiaminophosphine (ADAP) ligand catalyze the selective C3−H functionalization of unprotected indoles upon carbene transfer from donor-acceptor diazo compounds, the N−H bond remaining unaltered during the transformation. Mechanistic studies, including DFT calculations, allows proposing the existence of two competitive pathways, none of them occurring through the formation of cyclopropane intermediates, at variance with previously reported systems.