Synthesis, characterization and application of α/β-oligopeptides [alpha-beta-oligopeptides] as bifunctional organocatalysts for the aldol reaction [Elektronische Ressource] / vorgelegt von Valerio D'Elia

Valerio

Informations

• Publié par: universitat_regensburg
• Publié le: 01 janvier 2009
• Nombre de lectures: 20
• Langue: Deutsch
• Poids de l'ouvrage: 16 Mo

Extrait

Synthesis, characterization and application ofα /β-oligopeptides
as bifunctional organocatalysts for the aldol reaciton

Dissertation

zur Erlangung des Doktorgrades der Naturwissenschtaefn (Dr. rer. nat.)
Naturwissenschaftliche Fakultät IV – Chemie und Pharmazie –
der Universität Regensburg









vorgelegt von
Valerio D´Elia
aus
Avezzano (Italia)
2009

Die vorliegende Arbeit wurde in der Zeit von März 2005 bis Dezember 2008 am Institut für
Organische Chemie der Universität Regensburg unter der Leitung von Prof. Dr. O. Reiser
angefertigt.













Promotionsgesuch eingereicht im Januar 2009

Mündliche Prüfung: 04. Februar 2009


Prüfungsausschuss: Prof. Dr. S. Elz (Vorsitzend)e r
Prof. Dr. O. Reiser (Erstgutachter)
Prof. Dr. R. M. Gschwind (Zweitgutachter)
Prof. Dr. J. Heilmann (Drittpruefer)




Mein besonderer Dank gilt Herrn Prof. Dr. O. Reiser für die Überlassung des interessanten
Themas, die Möglichkeit zur Durchführung dieser Arb eit, seine wissenschaftlichen Anregungen
und seine stetige Unterstützung.


Weiterhin bedanke ich mich sehr herzlich bei:

Allen Mitarbeitern der analytischen Abteilungen der Fakultät für die Aufnahme de NMR- und
Massenspektren.

Meinen Laborkollegen für das angenehme Arbeitsklima und die gute Zusammenarbeit































Alla mia grande….
...e alla mia piccola
famiglia.








Index
Page
List of abbreviations
Introduction 1


CHAPTER 1: β -ACC as a useful building block for the synthesoisf
bifunctional organocatalysts 1 5

1.1 β-ACCs- based peptides and foldamers 15
1.1.1 β-ACCs and β-turns 17
1.2 Synthesis of the cis-β-aminocyclopropanecarbloicx yacids
(β-ACCs) 18
1.3 Synthesis of dipeptides and diastereomer sepatiroan 2 1
1.4 Synthesis of di- and tripeptides as organocaytsatsl 2 3
1.5 Tripeptides not containing the β-ACC units. 2 5
1.6 Synthesis of tetra- and pentapeptides 26


CHAPTER 2: Organocatalysis 28

2.1 Screening of the catalysts in the test aldoal crteion 2 8
2.1.1 Optimization of the reaction conditions 32
2.1.2 Scope of the catalysts 35
2.2 Organocatalyzed aldol reaction between cyclice ktones and
Aldehydes 3 9
2.2.1 β-ACC containing tripeptides as catalysts f otrhe aldol reaction
of cyclic ketones 41
2.3 Intramolecular aldol reactions 45
2.3.1 “Enolendo” intramolecular aldol reaction 49
2.4 Other Reactions 5 0
2.4.1 Mannich Reaction 51
2.4.2 Michael addition 52


CHAPTER 3: Development and applications of new claytsats 55

3.1 Development of new catalysts 55
3.2 Catalysis 60
3.2.1 Intramolecular aldol reaction 66
3.2.2 Catalyst Recovery 67
3.3.3 NaCl as a useful additive for the aldoilo nre a ct 68


CHAPTER 4: Structural analysis 71

4.1 NMR Studies 71
4.1.1 Cis/trans isomerism 73
4.1.2 Residual dipolar coupling 77
4.2 IR studies 80
4.3 Models for the transition state 81
4.4 Conclusion 83

References 85

Experimental 93

E.1 General Information 93
E.2 General procedure for catalytic asymmetric aldl oreaction 94
E.2.1 Intermolecular aldol reactions of acetone 94
E.2.2 Intermolecular aldol reactions of cyclohexannoe 95
E.2.3 Intramolecular aldol reaction 96
E.3 Synthesis of peptides 97
E.4 Catalysis products 1 1 4
E.5 Copies of NMR spectra 123

List of Abbreviations

p-TsOH p-toluenesulfonic acid
DMF dimethylformamide
DMAP 4-dimethylaminopyridine
TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl

DMSO dimethylsulfoxide
TEA triethylamine
DCM dichlormethane
p-TSA p-toluenesulfonic acid
Boc- tert-butoxycarbonyl-
TBDMS- tert-butyldimethylsilyl-
TBS- tert-butylsilyl-
TMS- trimethylsilyl-
THF tetrahydrofurane
Cbz- carbobenzyloxy-
DABCO 1,4-diazabicyclo[2.2.2.]octane
TBDPS tert-butyldiphenylsilyl
β-ACC β-aminocyclopropanecarboxylic acid
trans-ACHC trans-aminocyclohexanecarboxylic acid
trans-ACPC t r a n s-aminocyclopentanecarboxylic acid
Ph- phenyl-
EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodidime i
hydrochloride
Bn- benzyl-
r. t. room temperature
cat catalyst
Ac- acetyl-
NOE nuclear overhauser effect
RDC residual dipolar coupling
PDMS polydimethylsiloxane
DNA deoxyribonucleic acid
MD molecular dynamics
Et- ethyl-
Me- methyl-
d doublet
m multiplet
q quartet
s singlet
brs broad singlet
dd doublet of doublets


INTRODUCTION 1

INTRODUCTION

1During the current decade organocatalysis has met an unprecedented interest. Although
the idea of using substoichiometric amounts of orgnaic molecules to promote chemical
transformations may look obvious and reminiscent o fthe natural activity of many
2enzymes, only few, scattered reports appeared in tihs field before that List and Barbas
showed proline´s ability to catalyze the asymmetri cintermolecular aldol reaction. While
up to that date the attention had been largely resreved to metal containing catalysts, it is
clear that the use of organocatalysts presents som einteresting advantages; as they are
more robust and inexpensive than most metal-ligandc omplexes and they allow us to
bypass the toxicity issues that limit the use of mteal containing catalysts, for instance, in
the pharmaceutical industry.

Organocatalysis, development and classification

3In 1960P, racejus was the first to report the use of an enantioseleticve organocatalyst,
showing that 1% of quinidine was able to promote teh transformation of ketenes in
optically active (ee: 60%α)- phenyl-propionic acid esters (scheme 1); in thev esneties, the
remarkable properties of proline as organocatalystw here explored for the first time in
4 5the intramolecular aldol reaction by Eder, Sauer, Weichert and Hajos, Parrish (scheme
2).


Scheme 1.T he asymmetric, organocatalytic, synthesis ofα -phenyl propionic acid esters proposed by Pracejuisn 1960