Development of Light-Activated LXR Agonists.

Activation of the oxysterol-sensing transcription factor liver X receptor (LXR) has been studied as a therapeutic strategy in metabolic diseases and cancer but is compromised by the side effects of LXR agonists. Local LXR activation in cancer treatment may offer an opportunity to overcome this issue suggesting potential uses of photopharmacology. We report the computer-aided development of photoswitchable LXR agonists based on the T0901317 scaffold, which is a known LXR agonist. Azologization and structure-guided structure-activity relationship evaluation enabled the design of an LXR agonist, which activated LXR with low micromolar potency in its light-induced (Z)-state and was inactive as (E)-isomer. This tool sensitized human lung cancer cells to chemotherapeutic treatment in a light-dependent manner supporting potential of locally activated LXR agonists as adjuvant cancer treatment.

Concise Synthesis of Glycerophospholipids.

Glycerophospholipids are major components of cellular membranes and provide important signaling molecules. Besides shaping membrane properties, some bind to specific receptors to activate biological pathways. Untangling the roles of individual glycerophospholipids requires clearly defined molecular species, a challenge that can be best addressed through chemical synthesis. However, glycerophospholipid syntheses are often lengthy due to the contrasting polarities found within these lipids. We now report a general strategy to quickly access glycerophospholipids via opening of a phosphate triester epoxide with carboxylic acids catalyzed by Jacobsen's Co(salen) complex. We show that this method can be applied to a variety of commercially available fatty acids, photoswitchable fatty acids, and other carboxylic acids to provide the corresponding glycerophosphate derivatives.

Photopharmacological control of cell signaling with photoswitchable lipids.

Many aspects of cell signaling are controlled by lipids. Several signaling lipids have been functionalized with an azobenzene photoswitch to control underlying signaling dynamics with light. Herein, we provide an overview of signaling photolipids developed to date focusing on their biological applications. These include immunomodulation, kinase translocation, apoptosis, ion channel activation, G-protein coupled receptor activation, and neurogenesis.

Spatial Anion Control on Palladium for Mild C-H Arylation of Arenes.

C-H arylation of arenes without the use of directing groups is a challenge, even for simple molecules, such as benzene. We describe spatial anion control as a concept for the design of catalytic sites for C-H bond activation, thereby enabling nondirected C-H arylation of arenes at ambient temperature. The mild conditions enable late-stage structural diversification of biologically relevant small molecules, and site-selectivity complementary to that obtained with other methods of arene functionalization can be achieved. These results reveal the potential of spatial anion control in transition-metal catalysis for the functionalization of C-H bonds under mild conditions.

A ß-diketiminate manganese catalyst for alkene hydrosilylation: substrate scope, silicone preparation, and mechanistic insight.

The dimeric ß-diketiminate manganese hydride compound, [(2,6-iPr2PhBDI)Mn(µ-H)]2, was prepared by treating [(2,6-iPr2PhBDI)Mn(µ-Cl)]2 with NaEt3BH. This compound was characterized by single crystal X-ray diffraction and found to feature high-spin Mn centres that exhibit strong magnetic coupling by EPR spectroscopy. Once characterized, [(2,6-iPr2PhBDI)Mn(µ-H)]2 was found to mediate the hydrosilylation of a broad scope of alkenes at elevated temperature. Aliphatic alkenes were found to undergo anti-Markovnikov hydrosilylation, while the hydrosilylation of styrenes using [(2,6-iPr2PhBDI)Mn(µ-H)]2 afforded Markovnikov's product. Importantly, this catalyst has also been employed for the cross-linking of industrially-relevant silicones derived from vinyl-terminated poly(dimethylsiloxane) and 1,2,4-trivinylcyclohexane with catalyst loadings as low as 0.05 mol%. To gain a mechanistic understanding of [(2,6-iPr2PhBDI)Mn(µ-H)]2-catalyzed olefin hydrosilylation, 4-tert-butylstyrene was added to [(2,6-iPr2PhBDI)Mn(µ-H)]2 and conversion to the monomeric Mn alkyl complex, (2,6-iPr2PhBDI)Mn(CH(CH3)(4- t BuPh)), was observed. Isolation of this secondary alkyl intermediate confirms that olefin insertion into the Mn-H bond dictates the observed regioselectivities. The importance of our mechanistic findings as they relate to recent advances in Mn hydrosilylation catalysis is described herein.

Isolation of Mn(I) Compounds Featuring a Reduced Bis(imino)pyridine Chelate and Their Relevance to Electrocatalytic Hydrogen Production.

We report the preparation and electronic structure determination of chelate-reduced Mn(I) compounds that are relevant to electrocatalytic proton reduction mediated by [(Ph2PPrPDI)Mn(CO)][Br]. Reducing [(Ph2PPrPDI)Mn(CO)][Br] with excess Na-Hg afforded a neutral paramagnetic complex, (Ph2PPrPDI)Mn(CO). This compound was found to feature a low spin Mn(I) center and a PDI radical anion as determined by magnetic susceptibility measurement (1.97 µB), EPR spectroscopy ( S = 1/2), and density functional theory calculations. When [(Ph2PPrPDI)Mn(CO)][Br] was reduced with K-Hg, Mn(I) complexes with highly activated CO ligands were obtained. Recrystallization of the reduced product from diethyl ether solution allowed for the isolation of dimeric [(κ4-Ph2PPrPDI)Mn(µ-η1,η1,η2-CO)K(Et2O)]2 (νCO = 1710 cm-1, 1656 cm-1), while methyl tert-butyl ether treatment afforded dimeric [(κ4-Ph2PPrPDI)Mn(µ-η1,η1-CO)K(MTBE)2]2 (νCO = 1695 cm-1, MTBE = methyl tert-butyl ether). Addition of 18-crown-6 to these products, or conducting the K-Hg reduction of [(Ph2PPrPDI)Mn(CO)][Br] in the presence of 18-crown-6, allowed for the isolation of a monomeric example, (κ4-Ph2PPrPDI)Mn(µ-η1,η2-CO)K(18-crown-6) (νCO = 1697 cm-1). All three complexes were found to be diamagnetic and were characterized thoroughly by multinuclear 1D and 2D NMR spectroscopy and single crystal X-ray diffraction. Detailed analysis of the metrical parameters and spectroscopic properties suggest that all three compounds possess a Mn(I) center that is supported by a PDI dianion. Importantly, (κ4-Ph2PPrPDI)Mn(µ-η1,η2-CO)K(18-crown-6) was found to react instantaneously with either HBF4·OEt2 or HOTf to evolve H2 and generate the corresponding Mn(I) complex, [(Ph2PPrPDI)Mn(CO)][BF4] or [(Ph2PPrPDI)Mn(CO)][OTf], respectively. These products are spectroscopically and electrochemically similar to previously reported [(Ph2PPrPDI)Mn(CO)][Br]. It is believed that the mechanism of [(Ph2PPrPDI)Mn(CO)][Br]-mediated proton reduction involves intermediates that are related to the compounds described herein and that their ambient temperature isolation is aided by the redox active nature of Ph2PPrPDI.

Mechanistic Investigation of Bis(imino)pyridine Manganese Catalyzed Carbonyl and Carboxylate Hydrosilylation.

We recently reported a bis(imino)pyridine (or pyridine diimine, PDI) manganese precatalyst, (Ph2PPrPDI)Mn (1), that is active for the hydrosilylation of ketones and dihydrosilylation of esters. In this contribution, we reveal an expanded scope for 1-mediated hydrosilylation and propose two different mechanisms through which catalysis is achieved. Aldehyde hydrosilylation turnover frequencies (TOFs) of up to 4900 min-1 have been realized, the highest reported for first row metal-catalyzed carbonyl hydrosilylation. Additionally, 1 has been shown to mediate formate dihydrosilylation with leading TOFs of up to 330 min-1. Under stoichiometric and catalytic conditions, addition of PhSiH3 to (Ph2PPrPDI)Mn was found to result in partial conversion to a new diamagnetic hydride compound. Independent preparation of (Ph2PPrPDI)MnH (2) was achieved upon adding NaEt3BH to (Ph2PPrPDI)MnCl2 and single-crystal X-ray diffraction analysis revealed this complex to possess a capped trigonal bipyramidal solid-state geometry. When 2,2,2-trifluoroacetophenone was added to 1, radical transfer yielded (Ph2PPrPDI·)Mn(OC·(Ph)(CF3)) (3), which undergoes intermolecular C-C bond formation to produce the respective Mn(II) dimer, [(µ-O,Npy-4-OC(CF3)(Ph)-4-H-Ph2PPrPDI)Mn]2 (4). Upon finding 3 to be inefficient and 4 to be inactive, kinetic trials were conducted to elucidate the mechanisms of 1- and 2-mediated hydrosilylation. Varying the concentration of 1, substrate, and PhSiH3 revealed a first order dependence on each reagent. Furthermore, a kinetic isotope effect (KIE) of 2.2 ± 0.1 was observed for 1-catalyzed hydrosilylation of diisopropyl ketone, while a KIE of 4.2 ± 0.6 was determined using 2, suggesting 1 and 2 operate through different mechanisms. Although kinetic trials reveal 1 to be the more active precatalyst for carbonyl hydrosilylation, a concurrent 2-mediated pathway is more efficient for carboxylate hydrosilylation. Considering these observations, 1-catalyzed hydrosilylation is believed to proceed through a modified Ojima mechanism, while 2-mediated hydrosilylation occurs via insertion.

A Pentacoordinate Mn(II) Precatalyst That Exhibits Notable Aldehyde and Ketone Hydrosilylation Turnover Frequencies.

Heating (THF)2MnCl2 in the presence of the pyridine-substituted bis(imino)pyridine ligand, (PyEt)PDI, allowed preparation of the respective dihalide complex, ((PyEt)PDI)MnCl2. Reduction of this precursor using excess Na/Hg resulted in deprotonation of the chelate methyl groups to yield the bis(enamide)tris(pyridine)-supported product, (κ(5)-N,N,N,N,N-(PyEt)PDEA)Mn. This complex was characterized by single-crystal X-ray diffraction and found to possess an intermediate-spin (S = (3)/2) Mn(II) center by the Evans method and electron paramagnetic resonance spectroscopy. Furthermore, (κ(5)-N,N,N,N,N-(PyEt)PDEA)Mn was determined to be an effective precatalyst for the hydrosilylation of aldehydes and ketones, exhibiting turnover frequencies of up to 2475 min(-1) when employed under solvent-free conditions. This optimization allowed for isolation of the respective alcohols and, in two cases, the partially reacted silyl ethers, PhSiH(OR)2 [R = Cy and CH(Me)((n)Bu)]. The aldehyde hydrosilylation activity observed for (κ(5)-N,N,N,N,N-(PyEt)PDEA)Mn renders it one of the most efficient first-row transition metal catalysts for this transformation reported to date.

Carbon Dioxide Promoted H(+) Reduction Using a Bis(imino)pyridine Manganese Electrocatalyst.

Heating a 1:1 mixture of (CO)5MnBr and the phosphine-substituted pyridine diimine ligand, (Ph2PPr)PDI, in THF at 65 °C for 24 h afforded the diamagnetic complex [((Ph2PPr)PDI)Mn(CO)][Br] (1). Higher temperatures and longer reaction times resulted in bromide displacement of the remaining carbonyl ligand and the formation of paramagnetic ((Ph2PPr)PDI)MnBr (2). The molecular structure of 1 was determined by single crystal X-ray diffraction, and density functional theory (DFT) calculations indicate that this complex is best described as low-spin Mn(I) bound to a neutral (Ph2PPr)PDI chelating ligand. The redox properties of 1 and 2 were investigated by cyclic voltammetry (CV), and each complex was tested for electrocatalytic activity in the presence of both CO2 and Brønsted acids. Although electrocatalytic response was not observed when CO2, H2O, or MeOH was added to 1 individually, the addition of H2O or MeOH to CO2-saturated acetonitrile solutions of 1 afforded voltammetric responses featuring increased current density as a function of proton source concentration (icat/ip up to 2.4 for H2O or 4.2 for MeOH at scan rates of 0.1 V/s). Bulk electrolysis using 5 mM 1 and 1.05 M MeOH in acetonitrile at -2.2 V vs Fc(+/0) over the course of 47 min gave H2 as the only detectable product with a Faradaic efficiency of 96.7%. Electrochemical experiments indicate that CO2 promotes 1-mediated H2 production by lowering apparent pH. While evaluating 2 for electrocatalytic activity, this complex was found to decompose rapidly in the presence of acid. Although modest H(+) reduction activity was realized, the experiments described herein indicate that care must be taken when evaluating Mn complexes for electrocatalytic CO2 reduction.

A highly active manganese precatalyst for the hydrosilylation of ketones and esters.

The reduction of ((Ph2PPr)PDI)MnCl2 allowed the preparation of the formally zerovalent complex, ((Ph2PPr)PDI)Mn, which features a pentadentate bis(imino)pyridine chelate. This complex is a highly active precatalyst for the hydrosilylation of ketones, exhibiting TOFs of up to 76,800 h(-1) in the absence of solvent. Loadings as low as 0.01 mol % were employed, and ((Ph2PPr)PDI)Mn was found to mediate the atom-efficient utilization of Si-H bonds to form quaternary silane products. ((Ph2PPr)PDI)Mn was also shown to catalyze the dihydrosilylation of esters following cleavage of the substrate acyl C-O bond. Electronic structure investigation of ((Ph2PPr)PDI)Mn revealed that this complex possesses an unpaired electron on the metal center, rendering it likely that catalysis takes place following electron transfer to the incoming carbonyl substituent.

Investigation of formally zerovalent Triphos iron complexes.

The reduction of Triphos [PhP(CH(2)CH(2)PPh(2))(2)] iron halide complexes has been explored, yielding formally zerovalent (κ(3)-Triphos)Fe(κ(2)-Triphos) and (κ(3)-Triphos)Fe(κ(2)-Bpy). Electrochemical analysis, coupled with the metrical parameters of (κ(3)-Triphos)Fe(κ(2)-Bpy), reveal an electronic structure consistent with a π-radical monoanion bipyridine chelate that is antiferromagnetically coupled to a low spin, Fe(I) metal center.