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Metallocene based peptidomimetics and chiral catalysts

Maricic, Suzana LU (2002)
Abstract
Several optically active organometallic Phe-AAn-Phe peptidomimetics and macrocyclic Phe-(Phe)n peptides have been synthesized by either intra- or intermolecular peptide bond formation of the corresponding bis(amino acid) derivatives. The key bis(amino acid) derivatives were available from an improved multi-step synthetic route, utilising Horner-Wadswort-Emmons olefination of organometallic aldehydes with phosphonylglycine reagents, enantioselective hydrogenation of didehydro amino acids and classical solution and/or solid phase peptide synthesis methodology.



The stereochemically well characterised Phe-AAn-Phe peptidomimetics were incorporated in small neurotransmitter peptides, substance P and Leu(5)-enkephalin, with the... (More)
Several optically active organometallic Phe-AAn-Phe peptidomimetics and macrocyclic Phe-(Phe)n peptides have been synthesized by either intra- or intermolecular peptide bond formation of the corresponding bis(amino acid) derivatives. The key bis(amino acid) derivatives were available from an improved multi-step synthetic route, utilising Horner-Wadswort-Emmons olefination of organometallic aldehydes with phosphonylglycine reagents, enantioselective hydrogenation of didehydro amino acids and classical solution and/or solid phase peptide synthesis methodology.



The stereochemically well characterised Phe-AAn-Phe peptidomimetics were incorporated in small neurotransmitter peptides, substance P and Leu(5)-enkephalin, with the goal to test whether the effect of the incorporation mimic the bioactive conformations. Conformational analysis of the peptide analogues was undertaken with computational energy minimisation, CD and various NMR-experiments. It revealed that the modification of substance P and Leu(5)-enkephalin induced random coil and b-turn like conformations, respectively. NMR titration and UV-Vis spectroscopic studies of ferrocene or ruthenocene based derivatives of phenylalanine, indicated that in contrast to ruthenocenylamino acids the ferrocenylamino acids were easily air oxidised in aqueous solution at pH?{5-7}.



A series of chiral ferrocene based mono- and bis(amino alcohol) derivatives were also synthesized from the mono- and bis(amino acids), respectively. These were further evaluated as catalysts in asymmetric addition of diethylzinc to benzaldehyde. The results revealed that indeed all ferrocene based amino alcohol derivatives worked as catalysts and that the catalytic effect was not positively influenced by the introduction of one extra amino alcohol arm. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Ett antal optiskt aktiva metalloorganiska Phe-AAn-Phe subenheter har syntetiserats via intramolekulär cyklisering av motsvarande bis(aminosyra)derivat. Bis(aminosyra)derivaten var i sin tur erhållna från en förbättrad multistegssyntes, vars nyckelsteg är Horner-Wadswort-Emmons olefinering av metalloorganiska aldehyder med fosfonylglycin-reagens, enantioselektiv hydrogenering av didehydroaminosyror och klassisk lösnings- och/eller fastfas peptid syntetisk metodologi.



De stereokemiskt välkarakteriserade Phe-AAn-Phe subenheterna inkorporerades i neurotransmittorer substans P och Leu(5)-enkefalin med målet att härma de bioaktiva konformationerna som hittas hos de naturligt... (More)
Popular Abstract in Swedish

Ett antal optiskt aktiva metalloorganiska Phe-AAn-Phe subenheter har syntetiserats via intramolekulär cyklisering av motsvarande bis(aminosyra)derivat. Bis(aminosyra)derivaten var i sin tur erhållna från en förbättrad multistegssyntes, vars nyckelsteg är Horner-Wadswort-Emmons olefinering av metalloorganiska aldehyder med fosfonylglycin-reagens, enantioselektiv hydrogenering av didehydroaminosyror och klassisk lösnings- och/eller fastfas peptid syntetisk metodologi.



De stereokemiskt välkarakteriserade Phe-AAn-Phe subenheterna inkorporerades i neurotransmittorer substans P och Leu(5)-enkefalin med målet att härma de bioaktiva konformationerna som hittas hos de naturligt förekommande peptiderna vid inbindning på respektive receptor. Konformationsanalys av de erhållna analogerna utfördes med molekylmodellering, CD- och olika typer av NMR-experiment. Resultaten tydde på att de modifierade derivaten av substans P och Leu(5)-enkefalin betedde sig som oorganiserad kedja respektive beta-böj konformation. NMR titreringar och UV-Vis spektoskopiska studier av ickenaturliga aminosyror som var antingen ferrocen- eller ruthenocenbaserade derivat av fenylalanin, avslöjade att ferrocenylaminosyror tillskillnad från ruthenocenylaminosyraderivat var lättoxiderbara i svagt sur vattenlösning (pH?{5-7}) och i närvaro av luft.



En serie av kirala ferrocenbaserade mono- och bis(aminoalkohol)derivat var också syntetiserade från mono- respektive bis(aminosyror). Dessa var vidare testade som kirala ligander i en asymmetrisk additions av dietylzink till benzaldehyd. Resultaten avslöjade att den katalytiska effekten ej påverkades positivt med införande av en extra aminoalkohol arm. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Lector Skrydstrup, Troels, University of Aarhus, Department of Chemistry, DK-8000 Aarhus
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Organic chemistry, Organisk kemi, asymmetric catalysis., metallocene based amino alcohols, one-pot macrocyclisation, cyclic peptides, Organometallic substance P and Leu(5)-enkephalin, conformational analysis
pages
64 pages
publisher
Organic Chemistry, Lund University
defense location
Lecture hall F at Chemical Center
defense date
2002-11-15 10:15:00
ISBN
91-7422-011-X
language
English
LU publication?
yes
additional info
Article: This thesis is based on the following papers, referred to in the text by the Roman numerals indicated below. Article: I Maricic, S.; Ritzén, A.; Berg, U.; Frejd, T. Article: Synthesis and conformational studies of a 1,1´-ferrocenophane lactam mimetic of Substance PTetrahedron 2001, 57, 6523?6529. Article: II Maricic, S.; Berg, U.; Frejd, T. Article: Synthesis and conformational studies of a Leu-enkephalin amide analogue containing a ferrocene substructureTetrahedron 2002, 58, 3085?3093. Article: III Maricic, S.; Frejd, T. Article: Synthesis and conformational analysis of optically active ferrocene containing macrocyclic peptidesJ. Org. Chem. 2002, in press. Article: IV Maricic, S.; Frejd, T.Synthesis and spectroscopic studies of ferrocene and ruthenocene based non-natural amino acids in moderately protic mediaIn manuscript. Article: V Maricic, S.; Frejd, T. Article: Mono- and 1,1´-disubstituted ferrocenyl amino alcohols as chiral catalysts in asymmetric diehtylzinc addition to benzaldehydeIn manuscript. Article: Paper I and II are reproduced by permission of Elsevier Science. Paper III are reproduced by permission of The American Chemical Society. The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
id
3a797983-8aa6-496f-94ec-8f6a6208b28a (old id 465110)
date added to LUP
2016-04-04 10:14:54
date last changed
2018-11-21 20:57:40
@phdthesis{3a797983-8aa6-496f-94ec-8f6a6208b28a,
  abstract     = {Several optically active organometallic Phe-AAn-Phe peptidomimetics and macrocyclic Phe-(Phe)n peptides have been synthesized by either intra- or intermolecular peptide bond formation of the corresponding bis(amino acid) derivatives. The key bis(amino acid) derivatives were available from an improved multi-step synthetic route, utilising Horner-Wadswort-Emmons olefination of organometallic aldehydes with phosphonylglycine reagents, enantioselective hydrogenation of didehydro amino acids and classical solution and/or solid phase peptide synthesis methodology.<br/><br>
<br/><br>
The stereochemically well characterised Phe-AAn-Phe peptidomimetics were incorporated in small neurotransmitter peptides, substance P and Leu(5)-enkephalin, with the goal to test whether the effect of the incorporation mimic the bioactive conformations. Conformational analysis of the peptide analogues was undertaken with computational energy minimisation, CD and various NMR-experiments. It revealed that the modification of substance P and Leu(5)-enkephalin induced random coil and b-turn like conformations, respectively. NMR titration and UV-Vis spectroscopic studies of ferrocene or ruthenocene based derivatives of phenylalanine, indicated that in contrast to ruthenocenylamino acids the ferrocenylamino acids were easily air oxidised in aqueous solution at pH?{5-7}.<br/><br>
<br/><br>
A series of chiral ferrocene based mono- and bis(amino alcohol) derivatives were also synthesized from the mono- and bis(amino acids), respectively. These were further evaluated as catalysts in asymmetric addition of diethylzinc to benzaldehyde. The results revealed that indeed all ferrocene based amino alcohol derivatives worked as catalysts and that the catalytic effect was not positively influenced by the introduction of one extra amino alcohol arm.},
  author       = {Maricic, Suzana},
  isbn         = {91-7422-011-X},
  language     = {eng},
  publisher    = {Organic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Metallocene based peptidomimetics and chiral catalysts},
  year         = {2002},
}