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Dieter Seebach - One of the best experts on this subject based on the ideXlab platform.
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Preparation of the β3‐Homoselenocysteine Derivatives Fmoc‐β3hSec(PMB)‐OH and Boc‐β3hSec(PMB)‐OH for Solution and Solid‐Phase‐Peptide Synthesis and Selenoligation
Helvetica Chimica Acta, 2007Co-Authors: Oliver Flögel, Giulio Casi, Donald Hilvert, Dieter SeebachAbstract:The title compounds, 4 and 7, have been prepared from the corresponding α-amino acid derivative selenocystine (1) by the following sequence of steps: cleavage of the SeSe bond with NaBH4, p-methoxybenzyl (PMB) protection of the SeH group, Fmoc or Boc protection at the N-atom and Arndt–Eistert Homologation (Schemes 1 and 2). A β3-heptapeptide 8 with an N-terminal β3-hSec(PMB) residue was synthesized on Rink amide AM resin and deprotected (‘in air’) to give the corresponding diselenide 9, which, in turn, was coupled with a β3-tetrapeptide thiol ester 10 by a seleno-ligation. The product β3-undecapeptide was identified as its diselenide and its mixed selenosulfide with thiophenol (Scheme 3). The differences between α- and β-Sec derivatives are discussed.
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Design, synthesis and structural investigations of a β-peptide forming a 314-helix stabilized by electrostatic interactions
Chemistry (Weinheim an der Bergstrasse Germany), 2004Co-Authors: Magnus Rueping, Yogesh R. Mahajan, Bernhard Jaun, Dieter SeebachAbstract:Two different strategies have been employed for the synthesis of Fmoc-protected beta(3)-homoarginine; the Arndt-Eistert Homologation of alpha-arginine and the guanidinylation of beta(3)-homoornithine. Solid-phase beta-peptide synthesis was used for the preparation of beta-heptapeptide 1, which was designed to form a helix stabilized by electrostatic interactions through positively (beta(3)hArg) and negatively charged (beta(3)hGlu) amino acid residues. CD measurements and corresponding NMR investigations in MeOH and aqueous solutions do indeed show that the beta-peptidic 3(14)-helix can be stabilized by salt-bridge formation.
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Synthesis and biological evaluation of a cyclo-β-tetrapeptide as a somatostatin analogue
Angewandte Chemie, 1999Co-Authors: Karl Gademann, Martin Ernst, Daniel Hoyer, Dieter SeebachAbstract:Cyclo-beta-tetrapeptide I, a beta-peptidic analog of octreotide, was prepd. from beta-amino acid building blocks synthesized by Arndt-Eistert Homologation of appropriately protected alpha-amino acids. The affinity of I for five different human somatostatin receptors was measured using radioligand-binding assays. I had affinity, although the concns. were in the micromolar and not in the nanomolar range as for somatostatin and octreotide. The authors have demonstrated that a small beta-peptide (consisting of only four beta-amino acids) can mimic a natural peptide hormone and display biol. activity and micromolar affinity for human receptors. Thus, beta-peptides can, in principle, be considered as peptidomimetics.
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Linear and cyclic β3-oligopeptides with functionalised side-chains (-CH2OBn, -CO2Bn, -CH2CH2CO2Bn) derived from serine and from aspartic and glutamic acid
Journal of the Chemical Society Perkin Transactions 1, 1998Co-Authors: Jennifer L. Matthews, Karl Gademann, Bernhard Jaun, Dieter SeebachAbstract:The natural β-amino acid derivative Boc-Asp(β-OH)-OBn, as well as Boc-β-HGlu(OBn)-OH and Boc-β-HSer(OBn)-OH (prepared from appropriately protected glutamic acid and serine, respectively, by Arndt–Eistert Homologation), were employed as building blocks for the synthesis of linear (11–20) and cyclic (21–23) β-oligopeptides consisting of two to six β-amino acids [using trichloroethyl (TCE) ester groups for C-terminal protection and pentafluorophenyl-ester activation for macrocyclisation]. While the linear derivatives are soluble enough for reactions and structural investigations in solution, the cyclo-β-tri- and -hexapeptides are not (according to FT-IR measurements they form networks of hydrogen bonds, perhaps consisting of so-called nanotubes). The CD spectra of the Boc–OTCE-protected (19) and of the unprotected (20) β-hexapeptides [β-Asp(OBn)-β-HGlu(OBn)-β-HSer(OBn)]2 differ drastically, and only the unprotected form shows the familiar pattern of a negative Cotton effect between 210 and 220 nm (indicative of a 314 helix). An NMR analysis in methanol of the β-hexapeptide 20 with free termini reveals the presence of a single, central, left-handed helix turn (14-membered hydrogen-bonded ring). The results are discussed and compared with those obtained previously for analogous β-peptides carrying non-functionalised side chains.
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γ‐Peptides Forming More Stable Secondary Structures than α‐Peptides: Synthesis and helical NMR‐solution structure of the γ‐hexapeptide analog of H‐(Val‐Ala‐Leu)2‐OH
Helvetica Chimica Acta, 1998Co-Authors: Tobias Hintermann, Karl Gademann, Bernhard Jaun, Dieter SeebachAbstract:For a comparison with the corresponding alpha- and beta-hexapeptides H-(Val-Ala-Leu)2-OH (A) and H-(beta-HVal-beta-HAla-beta-HLeu)2-OH (B), the corresponding gamma-hexapeptide (I), built from the homochirally similar (S)-4-aminobutanoate, (R)-4-amino-5-methylhexanoate, and (R)-4-amino-6-methylheptanoate, was prepd. The precursors were obtained either by double Arndt-Eistert Homologation of protected Boc-Val-OH, Boc-Ala-OH, and Boc-Leu-OH, or by the superior route involving olefination/hydrogenation of the corresponding aldehydes, Boc-valinal, Boc-alaninal, and Boc-leucinal. Conventional peptide coupling (EDC/HOBt) furnished I through the intermediate gamma-di- and gamma-tripeptide. NMR measurements in (D5)pyridine and CD3OH soln. (COSY, TOCSY, HSQC, HMBC, ROESY) reveal that I adopts a right-handed helical structure [(P)-2.61 helix of .apprx.5-.ANG. pitch, contg. 14-membered H-bonded rings] which is to be compared with the left-handed helix of beta-peptide B [(M)-31 helix of 5-.ANG. pitch, 14-membered H-bonded rings] and with the familiar right-handed, so-called alpha-helix of alpha-peptides [(P)-3.61 helix of 5.4-.ANG. pitch, 13-membered rings]. Like the helix sense, the helix dipole reverses when going from alpha-(N->C) to beta-(C->N) to gamma-peptides (N->C). The surprising difference between the natural alpha-, and the analogous beta- and gamma-peptides is that the helix stability increases upon Homologation of the residues.
Jeffrey W. Bode - One of the best experts on this subject based on the ideXlab platform.
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Enantioselective, Chromatography-Free Synthesis of β3-Amino Acids with Natural and Unnatural Side Chains
Organic Process Research & Development, 2012Co-Authors: Thibaud Gerfaud, Ying-ling Chiang, Imants Kreituss, Justin A. Russak, Jeffrey W. BodeAbstract:β3-Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β3-amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt–Eistert Homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β3-amino acids possessing unnatural side chains.
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Enantioselective, Chromatography-Free Synthesis of β3-Amino Acids with Natural and Unnatural Side Chains
2012Co-Authors: Thibaud Gerfaud, Ying-ling Chiang, Imants Kreituss, Justin A. Russak, Jeffrey W. BodeAbstract:β3-Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β3-amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt–Eistert Homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β3-amino acids possessing unnatural side chains
Vass Elemér - One of the best experts on this subject based on the ideXlab platform.
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Turn szerkezeti elemeket tartalmazó modell vegyületek szintézise és spektroszkópiai jellemzése (cirkuláris dikroizmus - CD, vibrációs spektroszkópia - FTIR, mágneses rezonancia - NMR) = Synthesis and spectroscopic studies on turn structured models
OTKA, 2007Co-Authors: Deckerné Dr. Majer Zsuzsanna, Norbert Sewald, Radics Gábor, Samu János, Vass ElemérAbstract:A kanyarszerkezetek spektroszkópiai vizsgálatára választott ciklopeptid modellekben egy α-aminosavat kicseréltünk a megfelelő β-aminosavra és az így bekövetkezett konformációváltozást mértük. N-védett α-aminosavból Arndt-Eistert lánchosszabbítással enantiomer-tisztán előállítható a N-védett β3-aminosav (β-homo-aminosav). β-homo-aminosav tartalmú ciklotetra-, ciklopenta- és ciklohexapeptidek sorozatát állítottuk elő szilárd fázisú szintézissel, a ciklizációt oldatfázisban végezve. A vegyületeket HPLC-vel tisztítottuk és FAB-, illetve ESI-MS mérések alapján azonosítottuk.A modelleket és ezek kation-kötő képességét különböző oldószerekben vizsgáltuk CD- és FTIR-spektroszkópiával; néhány vegyületet NMR-spektroszkópiai adatokkal is jellemeztünk. A CD/FTIR spektroszkópiai analízis eredményei a következők: - a kis gyűrűméretű, erősen feszült ciklotetrapeptideknél a β-aminosavegységek jelenléte a szomszédos α-aminosavegységek körül γ-kanyart (C7) indukált - a ciklopentapeptidekél a β-homo-aminosavegység hajlékonyabb peptidgerincet biztosít és pszeudo-β-, vagy pszeudo-γ-kanyarok jönnek létre a β-aminosavegység körül. - CD/FTIR adataink segítségével a γ- és pszeudo-γ-kanyarszerkezet különböző oldószerekben jól jellemezhető. Több oligopeptid térszerkezetvizsgálatánál használtuk eredményesen a CD/FTIR komplex spektroszkópiai módszert.| Cyclic peptides in which one α-amino acid is replaced by its β-amino acid analogy are also suitable for the conformational investigation of turn structures induced by β-amino acids in cyclic peptides. Enantiomerically pure β3-amino acids (β-homo-amino acids) were prepared from N-protected α-amino acids by Arndt-Eistert Homologation reaction. A series of cyclic tetra-, penta- and hexapeptides containing β3-amino acid residue was synthesized on solid phase, cyclized in solution phase, purified by HPLC and characterised with FAB- and ESI-MS. The models and their cation-binding ability were investigated systematically by FTIR and CD spectroscopy in different solvents; some of them were studied by NMR spectroscopy, too. The combined CD/FTIR studies clearly show the followings: - the cyclic tetrapeptides are small and rather rigid molecules where the β-homo-amino acid residue induces a γ-turn (C7) which is centered on the neighbouring α-amino acid(s). - cyclic pentapeptides with β-homo-amino acid give rise to a more flexible peptide backbone and measured pseudo-β-turn or pseudo-γ-turns, which centered on the β-homo-amino acid.- the γ- and pseudo-γ-turn are well characterized in different solvents using CD- and FTIR spectroscopy. We investigated also the secondary structure of biologically active oligopeptides by combined CD/FTIR method
Jean-paul Mazaleyrat - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of terminally protected (S)-β3-H-DOPA by Arndt–Eistert Homologation: an approach to crowned β-peptides
Tetrahedron: Asymmetry, 2005Co-Authors: Anne Gaucher, Laurence Dutot, Olivier Barbeau, Wahib Hamchaoui, Michel Wakselman, Jean-paul MazaleyratAbstract:Abstract Terminally protected Boc-(S)-β3-H-DOPA-OMe has been synthesized from l -DOPA by the Arndt–Eistert Homologation procedure. During the synthesis, the side-chain catechol group was temporarily protected by benzylation. The absence of racemization was demonstrated by 19F NMR analysis of the (+)-(R)- and (−)-(S)-α-methoxy-α-trifluoromethyl-α-phenyl-acetamide derivatives. The catechol function of Boc-(S)-β3-H-DOPA-OMe may be used for crown-ether formation, a step towards the construction of crowned β-peptides.
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Synthesis of [18-C-6]-β3-(L)-DOPA, first β-amino acid with a crown-ether receptor side-chain
Tetrahedron Letters, 2002Co-Authors: Anne Gaucher, Olivier Barbeau, Wahib Hamchaoui, Michel Wakselman, Lucie Vandromme, Karen Wright, Jean-paul MazaleyratAbstract:Abstract Terminally protected Boc-β3-(L)-DOPA-OMe has been synthesized from (L)-DOPA by the Arndt–Eistert Homologation procedure. Then, a first crown-ether derivative, Boc-[18-C-6]-β3-(L)-DOPA-OMe, has been obtained by bis-O-alkylation of the catechol function with cyclization, using Cs2CO3 as base and pentaethyleneglycol ditosylate as alkylating agent, in DMF at 60°C.
Thibaud Gerfaud - One of the best experts on this subject based on the ideXlab platform.
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Enantioselective, Chromatography-Free Synthesis of β3-Amino Acids with Natural and Unnatural Side Chains
Organic Process Research & Development, 2012Co-Authors: Thibaud Gerfaud, Ying-ling Chiang, Imants Kreituss, Justin A. Russak, Jeffrey W. BodeAbstract:β3-Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β3-amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt–Eistert Homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β3-amino acids possessing unnatural side chains.
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Enantioselective, Chromatography-Free Synthesis of β3-Amino Acids with Natural and Unnatural Side Chains
2012Co-Authors: Thibaud Gerfaud, Ying-ling Chiang, Imants Kreituss, Justin A. Russak, Jeffrey W. BodeAbstract:β3-Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β3-amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt–Eistert Homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β3-amino acids possessing unnatural side chains
