Chemical Replacement of Noggin with Dorsomorphin Homolog 1 for Cost-Effective Direct Neuronal Conversion.

The direct conversion of adult human skin fibroblasts (FBs) into induced neurons (iNs) represents a useful technology to generate donor-specific adult-like human neurons. Disease modeling studies rely on the consistently efficient conversion of relatively large cohorts of FBs. Despite the identification of several small molecular enhancers, high-yield protocols still demand addition of recombinant Noggin. To identify a replacement to circumvent the technical and economic challenges associated with Noggin, we assessed dynamic gene expression trajectories of transforming growth factor-ß signaling during FB-to-iN conversion. We identified ALK2 (ACVR1) of the bone morphogenic protein branch to possess the highest initial transcript abundance in FBs and the steepest decline during successful neuronal conversion. We thus assessed the efficacy of dorsomorphin homolog 1 (DMH1), a highly selective ALK2-inhibitor, for its potential to replace Noggin. Conversion media containing DMH1 (+DMH1) indeed enhanced conversion efficiencies over basic SMAD inhibition (tSMADi), yielding similar ßIII-tubulin (TUBB3) purities as conversion media containing Noggin (+Noggin). Furthermore, +DMH1 induced high yields of iNs with clear neuronal morphologies that are positive for the mature neuronal marker NeuN. Validation of +DMH1 for iN conversion of FBs from 15 adult human donors further demonstrates that Noggin-free conversion consistently yields iN cultures that display high ßIII-tubulin numbers with synaptic structures and basic spontaneous neuronal activity at a third of the cost.

Calix[4]pyrrolato Aluminate Catalyzes the Dehydrocoupling of Phenylphosphine Borane to High Molar Weight Polymers.

High molar weight polyphosphinoboranes represent materials with auspicious properties, but their preparation requires transition metal-based catalysts. Here, calix[4]pyrrolato aluminate is shown to induce the dehydropolymerization of phosphine boranes to high molar mass polyphosphinoboranes (up to Mn =43 000 Da). Combined GPC and 31 P DOSY NMR spectroscopic analyses, quantum chemical computations, and stoichiometric reactions disclose a P-H bond activation by the cooperative action of the square-planar aluminate and the electron-rich ligand framework. This first transition metal-free catalyst for P-B dehydrocoupling overcomes the problem of residual d-block metal impurities in the resulting polymers that might interfere with the reproducibility of the properties for this emerging class of inorganic materials.

A new generation of terminal copper nitrenes and their application in aromatic C-H amination reactions.

Copper nitrene complexes are highly reactive species and are known as intermediates in the copper catalyzed C-H amination. In this study, three novel copper tosyl nitrene complexes were synthesized at low temperatures, stabilized with heteroscorpionate ligands of the bis(pyrazolyl)methane family. The copper nitrenes were obtained by the reaction of a copper(i) acetonitrile complex with SPhINTs in dichloromethane. We show that the ligand design has a major influence on the catalytic activity and the thermal stability of the copper nitrene complex. Not only the choice of the third N donor, but also the substituent in the 5-position of the pyrazolyl moiety, have an impact on the stability. Furthermore, the novel copper nitrene complexes were used for catalytic aziridination of styrenes and C-H amination reactions of aromatic and aliphatic substrates under mild reaction conditions. Even challenging substrates like benzene and cyclohexane were aminated with good yields. The copper nitrene complexes were characterized using UV/Vis spectroscopy, low temperature Evans NMR spectroscopy, density functional theory, domain-based local pair natural orbital coupled cluster calculations (DLPNO-CCSD(T)) and cryo-UHR mass spectrometry.

Stimulation of Redox-Induced Electron Transfer by Interligand Hydrogen Bonding in a Cobalt Complex with Redox-Active Guanidine Ligand.

Octahedrally coordinated cobalt(II) complexes with a redox-active bisguanidine ligand and acac co-ligands were synthesized and their redox chemistry analysed in detail. The N-H functions in a bisguanidine ligand with partially alkylated guanidino groups form N-H⋅⋅⋅O hydrogen bonds with the acac co-ligands, thereby massively influencing the redox chemistry. For all complexes, the first one-electron oxidation is metal-centred, leading to CoIII complexes with neutral bisguanidine ligand units. Further one-electron oxidation is ligand-centred in the case of Co-bisguanidine complexes with fully alkylated guanidino groups, giving CoIII complexes with radical monocationic bisguanidine ligands. On the other hand, the hydrogen-bond strengthening upon oxidation of the Co-bisguanidine complex with partially alkylated guanidino groups initiates metal reduction (CoIII →CoII ) and two-electron oxidation of the guanidine ligand, providing the first example for the stimulation of redox-induced electron transfer by interligand hydrogen bonding.

Desymmetrization of Dicationic Diboranes by Isomerization Catalyzed by a Nucleophile.

Cationic monoboranes exhibit a rich chemistry. By constrast, only a few cationic diboranes are known, that all are symmetrically substituted. In this work, the first unsymmetrically substituted dicationic diboranes, featuring sp2 -sp2 -hybridized boron atoms, are reported. The compounds are formed by intramolecular rearrangement from preceding isomeric symmetrically substituted dicationic diboranes, a process that is catalyzed by nucleophiles. From the temperature-dependence of the isomerization rate, activation parameters for this unprecedented rearrangement are derived. The difference in fluoride ion affinity between the two boron atoms and the bonding situation in these unique unsymmetrical dicationic diboranes are evaluated.

On the Metal Cooperativity in a Dinuclear Copper-Guanidine Complex for Aliphatic C-H Bond Cleavage by Dioxygen.

Selective oxidation reactions of organic compounds with dioxygen using molecular copper complexes are of relevance to synthetic chemistry as well as enzymatic reactivity. In the enzyme peptidylglycine α-hydroxylating monooxygenase (PHM), the hydroxylating activity towards aliphatic substrates arises from the cooperative effect between two copper atoms, but the detailed mechanism has yet to be fully clarified. Herein, we report on a model complex showing hydroxylation of an aliphatic ligand initiated by dioxygen. According to DFT calculations, the proton-coupled electron-transfer (PCET) process leading to ligand hydroxylation in this complex benefits from cooperative effects between the two copper atoms. While one copper atom is responsible for dioxygen binding and activation, the other stabilizes the product of intramolecular PCET by copper-ligand charge transfer. The results of this work might pave the way for the directed utilization of cooperative effects in oxidation reactions.

Catalytic Aerobic Phenol Homo- and Cross-Coupling Reactions with Copper Complexes Bearing Redox-Active Guanidine Ligands.

Due to their large importance in synthetic chemistry, catalytic C-C coupling reactions of phenols are currently intensively studied. Herein, new copper catalysts for the C-C coupling reaction of phenols using dioxygen as a green oxidizing reagent are reported. By using redox-active guanidine ligands, the activity as well as chemoselectivity in the cross-coupling reaction of non-complementary phenols (between an electron-rich phenol and a less nucleophilic second phenol) is significantly improved. Based on the collected data for several test reactions, a reaction mechanism is proposed.

Oxidation of Organic Molecules with a Redox-Active Guanidine Catalyst.

Herein, we report the first examples of the use of redox-active guanidines as catalysts in the green oxidation of organic molecules with dioxygen. In one half-reaction, the oxidized form of the redox-active guanidine is converted into the reduced, protonated state, thereby enabling dehydrogenative oxidation of the substrate (3,5-di-tert-butylcatechol→ortho-benzoquinone, benzoin→benzil, and 2,4-di-tert-butylphenol→biphenol). In the other half-reaction, efficient re-oxidation of the guanidine to the oxidized state is achieved with dioxygen in the presence of a copper catalyst. These results pave the way for the broader use of redox-active guanidines as oxidation catalysts.