Brian V. Popp

Structure-selective modification of aromatic side chains with dirhodium metallopeptide catalysts.

The combination of peptide molecular recognition and residue-selective dirhodium catalysis allows modification of aromatic side chains that is selective for coil structures. A rate enhancement of >10(3) relative to nonselective dirhodium modification was observed. The increased reactivity of this approach creates the first selective chemical modification of the phenylalanine residue.

Mechanism of Pd(OAc)2/Pyridine Catalyst Reoxidation by O2: Influence of Labile Monodentate Ligands and Identification of a Biomimetic Mechanism for O2 Activation

The mechanism of catalyst oxidation by O(2) in Pd-catalyzed aerobic oxidation reactions has been the subject of considerable debate, particularly with respect to the reactivity of Pd(II)-hydride species. Here, we describe the use of unrestricted DFT computational methods to investigate the mechanism of catalyst reoxidation with the Pd(OAc)(2)/pyridine catalyst system, one of the most widely used catalysts. These studies probe four different pathways for the formation of a Pd(II)-hydroperoxide species from the reaction of O(2) from the corresponding Pd(II)-hydride [(py)(n)Pd(II)(H)OAc]: 1) a homolytic pathway involving hydrogen-atom abstraction by O(2); 2) AcOH reductive elimination to yield a Pd(0) species that subsequently reacts with O(2); 3) migratory insertion of O(2) into a Pd-H bond; and 4) oxidative addition of O(2) to Pd(II) to yield a Pd(IV)(eta(2)-peroxo) species. In contrast to previous studies of reactions between O(2) and Pd-hydride species, the reductive-elimination pathway (mechanism 2) is significantly more favorable than any of the other pathways. This outcome is traced to the presence of labile ligands (pyridine) that can readily dissociate from Pd to enable the hydride and acetate ligands to occupy cis-coordination sites. These results strongly support the involvement of Pd(0) as an intermediate in the catalytic cycle. Investigations of the mechanism of the reaction of O(2) with the Pd(0) intermediate revealed a novel, previously unrecognized mechanism that yields a Pd-OOH product without proceeding through the intermediacy of a Pd(II)(eta(2)-peroxo) species. This mechanism resembles pathways commonly observed in biological O(2) activation and suggests that noble-metal and biological oxidation mechanisms may be more similar than previously appreciated.

Site-specific protein modification with a dirhodium metallopeptide catalyst.

A new method for chemical protein modification is presented utilizing a dirhodium metallopeptide catalyst. The combination of peptide-based molecular recognition and a dirhodium catalyst with broad side-chain scope enables site-specific protein functionalization. The scope and utility of dirhodium-catalyzed biomolecule modification is expanded to allow reaction at physiological pH and in biologically relevant buffer solutions. Specific protein modification is possible directly in E. coli lysate, demonstrating the remarkable activity and specificity of the designed metallopeptide catalyst. Furthermore, a new biotin-diazo conjugate 1b is presented that allows affinity tagging of target proteins.

Mechanistic Studies of Wacker-Type Intramolecular Aerobic Oxidative Amination of Alkenes Catalyzed by Pd(OAc)2/Pyridine

Wacker-type oxidative cyclization reactions have been the subject of extensive research for several decades, but few systematic mechanistic studies of these reactions have been reported. The present study features experimental and DFT computational studies of Pd(OAc)(2)/pyridine-catalyzed intramolecular aerobic oxidative amination of alkenes. The data support a stepwise catalytic mechanism that consists of (1) steady-state formation of a Pd(II)-amidate-alkene chelate with release of 1 equiv of pyridine and AcOH from the catalyst center, (2) alkene insertion into a Pd-N bond, (3) reversible β-hydride elimination, (4) irreversible reductive elimination of AcOH, and (5) aerobic oxidation of palladium(0) to regenerate the active trans-Pd(OAc)(2)(py)(2) catalyst. Evidence is obtained for two energetically viable pathways for the key C-N bond-forming step, featuring a pyridine-ligated and a pyridine-dissociated Pd(II) species. Analysis of natural charges and bond lengths of the alkene-insertion transition state suggest that this reaction is best described as an intramolecular nucleophilic attack of the amidate ligand on the coordinated alkene.

O2insertion into a palladium(II)-hydride bond: Observation of mechanistic crossover between HX-reductive-elimination and hydrogen-atom-abstraction pathways

The reaction of molecular oxygen with palladium(II)–hydrides is a key step in Pd-catalyzed aerobic oxidation reactions, and the mechanism of such reactions has been the focus of considerable investigation and debate. Here we describe the reaction of O2 with a series of electronically varied PdII–H complexes of the type trans-(IMes)2Pd(H)(O2CAr), with different para-substituted benzoates as the ArCO2− ligand. Analysis of the oxygenation rates of these complexes revealed a non-linear Hammett plot, and further kinetic studies demonstrated that reaction of O2 with the most electron-rich para-methoxybenzoate derivative proceeds via two parallel mechanisms, one initiated by rate-limiting reductive elimination of the carboxylic acid (HXRE) and the other involving hydrogen-atom abstraction by O2 (HAA). DFT computational studies support these conclusions and reveal that the preferred mechanism for the O2insertion reaction changes from HAA to HXRE as the para substituent on the benzoate ligand shifts from electron-donating to electron-withdrawing.

Palladium-Catalyzed Oxidation Reactions: Comparison of Benzoquinone and Molecular Oxygen as Stoichiometric Oxidants

Palladium-catalyzed oxidation reactions are among the most diverse methods available for the selective oxidation of organic molecules, and benzoquinone is one of the most widely used terminal oxidants for these reactions. Over the past decade, however, numerous reactions have been reported that utilize molecular oxygen as the sole oxidant. This chapter outlines the fundamental reactivity of benzoquinone and molecular oxygen with palladium(0) and their catalyst reoxidation mechanisms. The chemical similarities between benzoquinone and dioxygen are reinforced by catalytic reactions that undergo successful catalytic turnover with either or both of these oxidants. The results highlight substantial opportunities for the development of new aerobic oxidation reactions.

Functionalized Carbon Nanohoops: Synthesis and Structure of a [9]Cycloparaphenylene Bearing Three 5,8-Dimethoxynaphth-1,4-diyl Units

A functionalized [9]cycloparaphenylene ([9]CPP) bearing three evenly spaced 5,8-dimethoxynaphth-1,4-diyl units and two macrocyclic [6]CPP precursors have been synthesized. The Diels-Alder reaction between (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene and 1,4-benzoquinone followed by methylation produces cis-5,8-bis(4-bromophenyl)-5,8-dihydro-1,4-dimethoxynaphthalene as the key intermediate for the construction of the hooplike structures. The nickel-mediated homocoupling reactions followed by aromatization led to the functionalized [9]CPP.

Proximity-driven metallopeptide catalysis: Remarkable side-chain scope enables modification of the Fos bZip domain

Coiled-coil assembly of substrate peptides with dirhodium metallopeptide catalysts enables side-chain modification on the basis of molecular shape. A wide range of amino acids are effectively modified, including the first examples of carboxamide (glutamine and asparagine) modification. The method is used to achieve covalent modification of the c-Fos bZip domain at different residues, depending on the metallopeptide structure. By combining promiscuous catalytic reactivity with specific molecular recognition, this work establishes a general strategy for protein modification on the basis of molecular shape. A broad range of peptide–protein interactions are potentially amenable to this approach.

Helix induction by dirhodium: access to biocompatible metallopeptides with defined secondary structure.

The use of carboxylate side chains to induce peptide helicity upon binding to dirhodium centers is examined through experimental and computational approaches. Dirhodium binding efficiently stabilizes alpha helicity or induces alpha helicity in otherwise unstructured peptides for peptides that contain carboxylate side chains with i, i+4 spacing. Helix induction is furthermore possible for sequences with i, i+3 carboxylate spacing, though in this case the length of the side chains is crucial: ligating to longer glutamate side chains is strongly helix inducing, whereas ligating the shorter aspartate side chains destabilizes the helical structure. Further studies demonstrate that a dirhodium metallopeptide complex persists for hours in cellular media and exhibits low toxicity toward mammalian cells, enabling exploitation of these metallopeptides for biological applications.

Hybrid organic-inorganic inhibitors of a PDZ interaction that regulates the endocytic fate of CFTR.

Together strong: Cooperative binding of organic (see picture, red) and inorganic fragments provides a strategy for the potent inhibition of protein-protein interactions. By targeting specific Lewis basic side chains in peripheral regions of the binding site for coordination to a rhodium(II) center, the affinity of otherwise weak ligands is improved.