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Rohrbacher F.,Laboratorium For Organische Chemie | Deniau G.,Polyphor Ltd. | Luther A.,Polyphor Ltd. | Bode J.W.,Laboratorium For Organische Chemie | Bode J.W.,Nagoya University
Chemical Science | Year: 2015

The α-ketoacid-hydroxylamine (KAHA) ligation with 5-oxaproline enables the direct cyclization of peptides upon cleavage from a solid support, without coupling reagents, protecting groups, or purification of the linear precursors. This Fmoc SPPS-based method was applied to the synthesis of a library of 24 homoserine-containing cyclic peptides and was compared side-by-side with the synthesis of the same products using a standard method for cyclizing side-chain protected substrates. A detailed mechanistic study including 2H and 18O labeling experiments and the characterization of reaction intermediates by NMR and mass spectrometry is reported. This journal is © The Royal Society of Chemistry.

Abdel-Rahman M.A.,ETH Zurich | Schweizer B.W.,Laboratorium For Organische Chemie | Oleg L.,ETH Zurich | Zhang A.,ETH Zurich | Schluter A.D.,ETH Zurich
Macromolecular Chemistry and Physics | Year: 2010

The synthesis of high-molar-mass first- and second-generation, aromatic sulfonamide-based dendronized polymers PG1(CH3) and PG1(NO 2) aswell as PG2(CH3) and PG2(NO2) has been achieved. For PG3(CH3) at least oligomeric material could be obtained. The polymers exhibit glass transition temperatures in the range of 135-162 8C and are valuablecomponents for a presently ongoing in depth analysis of the persistence length of dendronized polymers by SANS. The corresponding monomers MG2(CH3) and MG2(NO2) were crystallized and their structures in the crystal determined by XRD. These single crystals are the first ever obtained of dendritic macromonomers. The polymerizable units were found not to be in a proper spatial relation to allow for a solid-state polymerization. ©; 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PubMed | Laboratorium For Organische Chemie and ETH Zurich
Type: | Journal: ChemMedChem | Year: 2017

In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives three compounds exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in delta-position of a N-butyl group as a common structural feature. An adjacent fluorine substituent in gamma-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituents in delta-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit leading to a spiro-pyrrolidinium salt. The chemical lability of delta-monofluorinated or gamma,delta-difluorinated N-butyl piperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to molecular design of partially fluorinated alkylamines.

Yoshinari T.,Laboratorium For Organische Chemie | Gessier F.,Laboratorium For Organische Chemie | Noti C.,Laboratorium For Organische Chemie | Beck A.K.,Laboratorium For Organische Chemie | Seebach D.,Laboratorium For Organische Chemie
Helvetica Chimica Acta | Year: 2011

The preparation of (2S,3S)- and (2R,3S)-2-fluoro and of (3S)-2,2-difluoro-3-amino carboxylic acid derivatives, 1-3, from alanine, valine, leucine, threonine, and β 3h-alanine (Schemes 1 and 2, Table) is described. The stereochemical course of (diethylamino)sulfur trifluoride (DAST) reactions with N,N-dibenzyl-2-amino-3-hydroxy and 3-amino-2-hydroxy carboxylic acid esters is discussed (Fig. 1). The fluoro-β-amino acid residues have been incorporated into pyrimidinones (11-13; Fig. 2) and into cyclic β-tri- and β-tetrapeptides 17-19 and 21-23 (Scheme 3) with rigid skeletons, so that reliable structural data (bond lengths, bond angles, and Karplus parameters) can be obtained. β-Hexapeptides Boc[(2S)-β 3hXaa(αF)] 6OBn and Boc[β 3hXaa(α,αF 2)] 6-OBn, 24-26, with the side chains of Ala, Val, and Leu, have been synthesized (Scheme 4), and their CD spectra (Fig. 3) are discussed. Most compounds and many intermediates are fully characterized by IR- and 1H-, 13C- and 19F-NMR spectroscopy, by MS spectrometry, and by elemental analyses, [α] D and melting-point values. Copyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich, Switzerland.

Kastl R.,Laboratorium For Organische Chemie | Arakawa Y.,Laboratorium For Organische Chemie | Duschmale J.,Laboratorium For Organische Chemie | Wiesner M.,Laboratorium For Organische Chemie | Wennemers H.,Laboratorium For Organische Chemie
Chimia | Year: 2013

Conjugate addition reactions of aldehydes to nitroolefins provide synthetically useful γ-nitroaldehydes. Here we summarize our research on peptide-catalyzed conjugate addition reactions of aldehydes to differently substituted nitroolefins. We show that peptides of the general type Pro-Pro-Xaa (Xaa = acidic amino acid) are not only highly active, robust and stereoselective catalysts but have also remarkable chemoselectivities. © Schweizerische Chemische Gesellschaft.

Seebach D.,Laboratorium For Organische Chemie | Sun X.,Laboratorium For Organische Chemie | Sparr C.,Laboratorium For Organische Chemie | Ebert M.-O.,Laboratorium For Organische Chemie | And 2 more authors.
Helvetica Chimica Acta | Year: 2012

By combining enamines, derived from aldehydes and diphenylprolinol trimethylsilyl ether (the Hayashi catalyst), with nitroethenes ((D 6)benzene, 4-Å molecular sieves, room temperature) intermediates of the corresponding catalytic Michael-addition cycles were formed and characterized (IR, NMR, X-ray analysis; Schemes 3-6 and Fig. 1-3). Besides cyclobutanes 2, 1,2-oxazine N-oxide derivatives 3-6 and 8 have been identified for the first time, some of which are very stable compounds. It may not be a lack of reactivity (between the intermediate enamines and nitro olefins) that leads to failure of the catalytic reactions (Schemes 3-5) but the high stability of catalyst resting states. The central role zwitterions play in these processes is discussed (Schemes 1 and 2). Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich, Switzerland.

Patora-Komisarska K.,Tokyo University of Science | Patora-Komisarska K.,Laboratorium For Organische Chemie | Benohoud M.,Tokyo University of Science | Ishikawa H.,Tokyo University of Science | And 2 more authors.
Helvetica Chimica Acta | Year: 2011

The amine-catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid-catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4-NO2-C6H 4OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol-% (Tables 2-5). Fast formation of an amino-nitro-cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all-trans-isomers of cyclobutanes (Fig. 3) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid-catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino-nitro-cyclobutanes with H2O led to mixtures of 4-nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6-9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C-bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6, which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13. While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Table 1-5). Various acid-catalyzed steps have been identified. The cyclobutanes 12 may be considered an off-cycle 'reservoir' of catalyst, and the zwitterions 5 the 'key players' of the process (bottom part of Scheme 2 and Scheme 3). Copyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich, Switzerland.

Seebach D.,Laboratorium For Organische Chemie | Sun X.,Laboratorium For Organische Chemie | Ebert M.-O.,Laboratorium For Organische Chemie | Schweizer W.B.,Laboratorium For Organische Chemie | And 8 more authors.
Helvetica Chimica Acta | Year: 2013

The stoichiometric reactions of enamines prepared from aldehydes and diphenyl-prolinol silyl ethers (intermediates of numerous organocatalytic processes) with nitro olefins have been investigated. As reported in the last century for simple achiral and chiral enamines, the products are cyclobutanes (4 with monosubstituted nitro-ethenes), dihydro-oxazine N-oxide derivatives (5 with disubstituted nitro-ethenes), and nitro enamines derived from γ-nitro aldehydes (6, often formed after longer reaction times). The same types of products were shown to be formed, when the reactions were carried out with peptides H-Pro-Pro-Xaa-OMe that lack an acidic H-atom. Functionalized components such as alkoxy enamines, nitro-acrylates, acetamido-nitro-ethylene, or hydroxylated nitro olefins also form products carrying the diphenyl-prolinol silyl ether as a substituent. All of these products must be considered intermediates in the corresponding catalytic reactions; the investigation of their chemical properties provided useful hints about the rates, the conditions, the catalyst resting states or irreversible traps, and/or the limitations of the corresponding organocatalytic processes. High-level DFT and MP2 computations of the structures of alkoxy enamines and thermodynamic data of a cyclobutane dissociation are also described. Some results obtained with the stoichiometrically prepared intermediates are not compatible with previous mechanistic proposals and assumptions. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

Seebach D.,Laboratorium For Organische Chemie | Yoshinari T.,Laboratorium For Organische Chemie | Beck A.K.,Laboratorium For Organische Chemie | Ebert M.-O.,Laboratorium For Organische Chemie | And 3 more authors.
Helvetica Chimica Acta | Year: 2014

Under the 'best anhydrous' conditions, we were able to achieve, the bicyclic oxazolidinones derived from proline and pivalaldehyde (or cyclohexanone) equilibrate with added carbonyl compounds in (D6)DMSO and in (D6)benzene. With (18O)cyclohexanone, no incorporation of the label into the 1,3-oxazolidinone ring was observed (in-situ NMR investigations; Figs. 1, 3, and 4). Since an iminium-carboxylate zwitterion might be involved in this process, we also studied the reaction of N-isopropylidene-pyrrolidinium perchlorate with cyclohexanone in anhydrous CDCl3 (Fig. 5). We speculated that an interconversion between iminium and carbonyl species might occur in the absence of H2O or other impurities, i.e., formally a metathesis through 1,3-oxazetidinium ions (Schemes 2 and 3). A theoretical investigation with various DFT methods, ranging all the way to CCSD(T)/aug-cc-pVTZ//MP2/def2-QZVPP, shows (Figs. 8-11) that oxazetidinium ions are stable species (more or less equi-energetic with the reactants iminium ion+carbonyl system), but that the transition states leading to these cations are too high in energy for a reaction taking place in the gas phase at room temperature. Further investigations are proposed to study the iminium-carbonyl interconversion mechanism. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

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