Remko J. Detz

Enantioselective Copper‐Catalysed Propargylic Substitution: Synthetic Scope Study and Application in Formal Total Syntheses of (+)‐Anisomycin and (−)‐Cytoxazone

A copper catalyst with a chiral pyridine-2,6-bisoxazoline (pybox) ligand was used to convert a variety of propargylic esters with different side chains (R=Ar, Bn, alkyl) into their amine counterparts in very high yields and with good enantioselectivities (up to 90% enantiomeric excess (ee)). Different amine nucleophiles were applied in the reactions and the highest enantioselectivities were obtained for aniline and its analogues. Interestingly, some carbon nucleophiles could also be used and with indoles excellent ee values were obtained (up to 98% ee). The versatility of the propargylic amines obtained was demonstrated by their further elaboration to formal total syntheses of the antibiotic (+)-anisomycin and the cytokine modulator (-)-cytoxazone.

Precise supramolecular control of selectivity in the Rh-catalyzed hydroformylation of terminal and internal alkenes.

In this study, we report a series of DIMPhos ligands L1-L3, bidentate phosphorus ligands equipped with an integral anion binding site (the DIM pocket). Coordination studies show that these ligands bind to a rhodium center in a bidentate fashion. Experiments under hydroformylation conditions confirm the formation of the mononuclear hydridobiscarbonyl rhodium complexes that are generally assumed to be active in hydroformylation. The metal complexes formed still strongly bind the anionic species in the binding site of the ligand, without affecting the metal coordination sphere. These bifunctional properties of DIMPhos are further demonstrated by the crystal structure of the rhodium complex with acetate anion bound in the binding site of the ligand. The catalytic studies demonstrate that substrate preorganization by binding in the DIM pocket of the ligand results in unprecedented selectivities in hydroformylation of terminal and internal alkenes functionalized with an anionic group. Remarkably, the selectivity controlling anionic group can be even 10 bonds away from the reactive double bond, demonstrating the potential of this supramolecular approach. Control experiments confirm the crucial role of the anion binding for the selectivity. DFT studies on the decisive intermediates reveal that the anion binding in the DIM pocket restricts the rotational freedom of the reactive double bound. As a consequence, the pathway to the undesired product is strongly hindered, whereas that for the desired product is lowered in energy. Detailed kinetic studies, together with the in situ spectroscopic measurements and isotope-labeling studies, support this mode of operation and reveal that these supramolecular systems follow enzymatic-type Michaelis-Menten kinetics, with competitive product inhibition.

Beyond Classical Reactivity Patterns: Hydroformylation of Vinyl and Allyl Arenes to Valuable β- and γ-Aldehyde Intermediates Using Supramolecular Catalysis

In this study, we report on properties of a series of rhodium complexes of bisphosphine and bisphosphite L1-L7 ligands, which are equipped with an integral anion binding site (the DIM pocket), and their application in the regioselective hydroformylation of vinyl and allyl arenes bearing an anionic group. In principle, the binding site of the ligand is used to preorganize a substrate molecule through noncovalent interactions with its anionic group to promote otherwise unfavorable reaction pathways. We demonstrate that this strategy allows for unprecedented reversal of selectivity to form otherwise disfavored β-aldehyde products in the hydroformylation of vinyl 2- and 3-carboxyarenes, with chemo- and regioselectivity up to 100%. The catalyst has a wide substrate scope, including the most challenging substrates with internal double bonds. Coordination studies of the catalysts under catalytically relevant conditions reveal the formation of the hydridobiscarbonyl rhodium complexes [Rh(Ln)(CO)2H]. The titration studies confirm that the rhodium complexes can bind anionic species in the DIM binding site of the ligand. Furthermore, kinetic studies and in situ spectroscopic investigations for the most active catalyst give insight into the operational mode of the system, and reveal that the catalytically active species are involved in complex equilibria with unusual dormant (reversibly inactivated) species. In principle, this involves the competitive inhibition of the recognition center by product binding, as well as the inhibition of the metal center via reversible coordination of either a substrate or a product molecule. Despite the inhibition effects, the substrate preorganization gives rise to very high activities and efficiencies (TON > 18,000 and TOF > 6000 mol mol(-1) h(-1)), which are adequate for commercial applications.

Rhodium-P,O-bidentate coordinated ureaphosphine ligands for asymmetric hydrogenation reactions

We present new ureaphosphine ligands that coordinate in a P,O-bidentate fashion to rhodium(i). The ureaphosphine-Rh(i)-complexes were effectively used in the asymmetric hydrogenation of cyclic enamides giving high conversions and enantioselectivity.

Organic-inorganic hybrid solution-processed H2-evolving photocathodes

Here we report for the first time an H2-evolving photocathode fabricated by a solution-processed organic-inorganic hybrid composed of CdSe and P3HT. The CdSe:P3HT (10:1 (w/w)) hybrid bulk heterojunction treated with 1,2-ethanedithiol (EDT) showed efficient water reduction and hydrogen generation. A photocurrent of -1.24 mA/cm(2) at 0 V versus reversible hydrogen electrode (V(RHE)), EQE of 15%, and an unprecedented Voc of 0.85 V(RHE) under illumination of AM1.5G (100 mW/cm(2)) in mild electrolyte were observed. Time-resolved photoluminescence (TRPL), internal quantum efficiency (IQE), and transient photocurrent measurements were carried out to clarify the carrier dynamics of the hybrids. The exciton lifetime of CdSe was reduced by one order of magnitude in the hybrid blend, which is a sign of the fast charge separation upon illumination. By comparing the current magnitude of the solid-state devices and water-splitting devices made with identical active layers, we found that the interfaces of the water-splitting devices limit the device performance. The electron/hole transport properties investigated by comparing IQE spectra upon front- and back-side illumination evidenced balanced electron/hole transport. The Faradaic efficiency is 80-100% for the hybrid photocathodes with Pt catalysts and ∼70% for the one without Pt catalysts.

Nickel-based dye-sensitized photocathode towards proton reduction using a molecular nickel catalyst and an organic dye.

To construct an efficient dye‐sensitized photo‐electrochemical tandem cell for hydrogen production, it is crucial to understand the working principles of both the photoanode and the photocathode. Herein, the anchoring of a proton‐reduction catalyst and an organic dye molecule on metal oxides is studied for the preparation of a photocathode. On TiO2, the Ni catalyst behaves as a good electrocatalyst (−250 μA cm−2) in acidic water (pH 2). The Ni catalyst and the organic dye were co‐immobilized on NiO to form a solely Ni‐based photocathode. The electron‐transfer steps were investigated by using various techniques (IR, UV/Vis, and fluorescence spectroscopy, and (photo)electrochemistry). Despite the observed successful single‐electron‐transfer steps between all of the components, photocatalysis did not yield any hydrogen gas. Possible bottlenecks that prevent photocatalytic proton reduction are poor electron transfer because of aggregation, charge recombination from the catalyst to the NiO, or instability of the catalyst after the first reduction.

Epimerization-Free C-Terminal Peptide Activation

Peptides constitute a very important compound class in drug research. Thus, racemization-free peptide synthesis is of key importance to acquire the required peptide chains in diastereomerically pure form. In general, the way to synthesize peptides with full stereointegrity is by elongation at the N terminus. On the other hand, methods that allow epACHTUNGTRENNUNGiACHTUNGTRENNUNGmer ACHTUNGTRENNUNGization-free C-terminal peptide activation would greatly enhance the available routes and would be a highly valuable synthetic tool for obtaining the desired peptides. Especially for the convergent solution-phase synthesis of peptides by segment coupling a reliable and epimerization-free C-terminal activation methodology is required. Recently, Danishefsky showed the utility of peptide 4-nitrophenyl esters in peptide segment couplings. These esters were prepared by EDCl/HOBt-mediated coupling of the amino acid 4-nitrophenylesters to the C terminus of peptides. Due to otherwise inevitable epimerization this methodology is restricted by the requirement of a glycine residue at the C-terminal penultimate position. Herein, we disclose our initial results on the development of a racemization-free C-terminal peptide activation through the copper(II)-mediated Chan–Lamtype coupling between peptides and arylboroxines and subsequent amine-coupling reactions (Scheme 1). Recently, the group of Cheng reported the CuACHTUNGTRENNUNG(OTf)2mediated reaction of benzoic acids with arylboronic acids to provide facile access to arylesters. The single example of an aliphatic acid, that is, phenylacetic acid, that reacted efficiently with phenylboronic acid to give the ester in near quantitative yield prompted us to expand this chemistry towards the peptide series. The suggested mechanistic course of this reaction and the mild conditions make epimerization very unlikely. Therefore, the Chan–Lam approach may be a suitable method for activation of peptides bearing a chiral C-terminal amino acid. To evaluate and optimize the Chan–Lam-type esterification of peptides, Boc-Trp-Phe-OH was selected as the substrate. The first coupling attempt was performed using the conditions reported by Cheng and co-workers, that is, stirring of the carboxylic acid, phenylboronic acid (3 equiv), CuACHTUNGTRENNUNG(OTf)2 (0.4 equiv), and urea (1 equiv) at elevated temperature (60 8C) under air using EtOAc as the solvent. Gratifyingly, after running the reaction for 12 h, Boc-Trp-Phe-OPh could be isolated in a yield of 40 %. The reaction proceeded in a rather clean fashion, and besides the recovered peptide phenol and diphenyl ether were isolated as the main side products. It should also be noted that all three nitrogen atoms bearing acidic protons, that is, the indole-NH, amideNH and Boc-NH, showed no reactivity under these mild conditions. After screening several other bidentate N-centered ligands, ureas stood out as the ligand class of choice. Replacing urea with 1,3-diethylurea gave a homogeneous reaction mixture and the yield further improved to 50 %. The formation of phenol could be suppressed by starting from phenylboroxine, further enhancing the yield to 69 %. By decreasing the concentration of the carboxylic acid to 0.05 m, slightly increasing the temperature to 65 8C, and adding Et3N as the base (1 equiv), yields of up to 82 % were obtained, albeit now requiring 1 equiv of CuACHTUNGTRENNUNG(OTf)2 (Scheme 2). To check the stereointegrity of the copper(II)catalyzed peptide esterification, Boc-Trp-d-Phe-OPh was prepared in 70 % isolated yield, and after comparison of the H NMR spectra and chiral HPLC traces with Boc-Trp-Phe[a] S. Popovic, H. Bier ugel, J. A. A. Koole, D. E. Streefkerk, Prof. Dr. H. Hiemstra, Dr. J. H. van Maarseveen Van t Hoff Institute for Molecular Sciences University of Amsterdam, Science Park 904 1098XH Amsterdam (The Netherlands) E-mail : j.h.vanmaarseveen@uva.nl Homepage: http://hims.uva.nl/soc [b] Dr. R. J. Detz, Dr. A. M. Kluwer InCatT, Science Park 904, 1098XH Amsterdam (The Netherlands) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303347. Scheme 1. Copper(II)-mediated and classical peptide arylester synthesis and subsequent elongation.

Rational Design Rules for Molecular Water Oxidation Catalysts based on Scaling Relationships

Lowering the overpotential required for water oxidation is of paramount importance for the efficient production of carbon-neutral fuels. This article highlights the intrinsic influence of the water oxidation mechanism used by molecular catalysts on the theoretically achievable minimal overpotential, based on scaling relationships typically used for heterogeneous catalysts. Due to such scaling relationships, catalysts that operate through the water nucleophilic attack mechanism have a fundamental minimal overpotential of about 0.3 V, whereas those that follow the dinuclear radical oxo coupling mechanism should in principle be able to operate with a lower overpotential. Therefore, it is recommended to design catalysts operating through the latter mechanism to achieve very efficient water oxidation systems.

Rational Optimization of Supramolecular Catalysts for the Rhodium-Catalyzed Asymmetric Hydrogenation Reaction

Abstract Rational design of catalysts for asymmetric transformations is a longstanding challenge in the field of catalysis. In the current contribution we report a catalyst in which a hydrogen bond between the substrate and the catalyst plays a crucial role in determining the selectivity and the rate of the catalytic hydrogenation reaction, as is evident from a combination of experiments and DFT calculations. Detailed insight allowed in silico mutation of the catalyst such that only this hydrogen bond interaction is stronger, predicting that the new catalyst is faster. Indeed, we experimentally confirmed that optimization of the catalyst can be realized by increasing the hydrogen bond strength of this interaction by going from a urea to phosphine oxide H‐bond acceptor on the ligand.

Combinatorial Strategies to find New Catalysts for Asymmetric Hydrogenation Based on the Versatile Coordination Chemistry of METAMORPhos Ligands

To extend the toolbox and find improved catalysts, anionic METAMORPhos ligands and neutral amino‐acid‐based ligands were used separately and in mixtures to form Rh complexes used in the asymmetric hydrogenation of eight industrially relevant substrates. Spectroscopic studies showed that under the catalytic conditions, the mononuclear complex with two different ligands (the heterocombination) is the main complex in solution if both the anionic and neutral ligands have the same chirality. If the neutral ligand and the anionic ligand have the opposite chirality at the P atom, monometallic and bimetallic heterocomplexes were detected by NMR spectroscopy and MS. For the majority of substrates evaluated in this study, higher enantioselectivities were obtained if the complexes used were based on the heterocombination of an anionic and a neutral ligand compared to respective homocombinations. After we found the initial leads, higher turnover numbers and enantioselectivities could be obtained easily by further exploring focused ligand libraries. The superior activity of the complexes based on the different ligands is highlighted by their robustness: significant divergence from a 1:1 ratio between the ligands does not lower the selectivity of the catalyst, although more of the competing homocomplexes are formed under these conditions.