Alexander M. Kluwer

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.

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.

A Fluorescence-Based Screening Protocol for the Identification of Water Oxidation Catalysts

Efficient catalysts are crucial for the sustainable generation of fuel by splitting water. A versatile screening protocol would simplify the identification of novel and better catalysts by using high throughput experimentation. Herein, such a screening approach for the identification of molecular catalysts for chemical oxidation of water is reported, which is based on oxygen-sensitive fluorescence quenching using an OxoDish. More than 200 reactions were performed revealing several catalysts, for example, a dinuclear Fe complex that produced oxygen under the used reaction conditions. Clark electrode measurements confirmed a similar rate in oxygen evolution, making the developed parallel screening approach a robust and versatile tool to screen for molecular water oxidation catalysts using chemical oxidants under acidic and neutral conditions.

Selective C-H Bond Activation with Na2PtCl4 in inverted micelles.

The selective C−H activation of n-heptane and methylcyclohexane with Na2PtCl4 under mild conditions in water in inverted micelles is described.