La lecture en ligne est gratuite
Le téléchargement nécessite un accès à la bibliothèque YouScribe
Tout savoir sur nos offres
Télécharger Lire

Ring opening of epoxides by chelated amino acid ester enolates [Elektronische Ressource] / vorgelegt von Ameer Fawad Zahoor

De
154 pages
Ajouté le : 01 janvier 2010
Lecture(s) : 25
Signaler un abus
















































Ring Opening Of Epoxides By Chelated Amino Acid
Ester Enolates


Dissertation
zur Erlangung des Grades
des Doktors der Naturwissenschaften
der Naturwissenschaftlich-Technischen Fakultät III
Chemie, Pharmazie, Bio- und Werkstoffwissenschaften
der Universität des Saarlandes



vorgelegt von
Ameer Fawad Zahoor

Saarbrücken
2010 Die vorliegende Arbeit wurde von April 2007 bis Juni 2010 unter Anleitung von Herrn Prof.
Dr. U. Kazmaier an der Naturwissenschaftlich-Technischen Fakultät III der Universität des
Saarlandes angefertigt.
























Tag des Kolloquiums: 14-01-2011
Dekan: Prof. Stefan Diebels
Berichterstatter: Prof. Dr. Uli Kazmaier
Prof. Dr. Dr. h. c. Theophil Eicher
Akad. Mitarbeiter: Dr. Angelika Ullrich
































My Grandfather (Late) and my pare nts!






Acknowledgement

In the name of Allah, the most Beneficent, the Mmerocsitful, the most Gracious. I would
have been nothing without His grace. My faith remnsa incomplete without the respect for
Holy Prophet Muhammad (PBUH), the great Messenger, Who conveyed the message of
Truth and showed us the right way to live.
These are moments of great pleasure and satisfacnt ifor me while I am finishing my Ph.D
thesis…………….a dream soon coming true. When I look back o n my academic journey, time
seizes and mind wanders through various corridors fo memories of life reminding me of the
best days of my life spent with my class felrlioewnsd,s afnd my family. Starting from Prep.
class to the highest level of education was a jloounrgn ey and at each step I was fortunate to
have nice, sincere people who made this journeyi era asnd easier as the time went on. In
my success, many people around me have a great ro wleho I would like to thank.
I would like to take this opportunity to thank umpye rvsisor Prof. Dr. Uli kazmaier for
taking me as a PhD student. I feel very lucky tov eh aworked under his guidance. He was
always there to guide and encourage me whenever Ia hd difficulties in my research work. He
gave me the freedom to use my ideas during my work .As a student I learnt a lot from him
and he is a true role model as a research supervri. s o
I am thankful to my group fellows who were reaololpye rcative during my stay. Special
thanks to Gawas, Angelika, Ulrike and Ramendra fsopre nding their time to correct my thesis
and for their selfless help during my research w. oIr khad a nice company with Alexander,
Frauke, Jens, Saskia and Nivedita, and I enjoyleod ta w hile working with them. Other group
members were also helpful whenever required forc wh hIi thank Christina, Daniel, Jan, Steffi,
Katharina, Sarah, Lisa W., Bukovec, Judith, Dom, iLniisca K., and Anton.
I acknowledge Mr. Rudi for carrying out HRMS and Miss Röser for doing elemental
analyses for me.
I share my golden memories with my ‘Oldy Goldy’ efnrdis Sheikh Khalid, Sajjad Ahmed,
Arslan Ali, Ali Irfan and Rafiq for providing rmale smupoport in difficult times. We enjoyed
wonderful times together. I would like to thankm t hfeor being my great friends.
I owe Bushra a lot who stood by me through thick da tnhin, gave me sincere advices and
prayed for my welfare. I would like to say her ksth ans a feeling of gratitude though
‘Thanks’ is such a small for her sincerity ande rpsr afyor me. I wish her all the best in her life.
My stay in Saarbrücken became more memorable as nIj oeyed the company of Abbas
bhai, Habib, Hameed, Javaid, Raja Hamza, Waqar b, hAami ir, Imran, Safdar bhai, Zeeshan,
Manish, Talha, Arif, Iftikhar, Touseef, Hussa ilni.v eWde like a family and spent a wonderful
time in Germany.
I am grateful to Higher Education Commission Paakni satnd DAAD (Germany) for giving
me a PhD scholarship.


Last but not the least, I thank my family for rstuinppg othroughout my life. Without their
love and support, I would not have been able to tgoe tthe place where I stand today.

Ameer Fawad Zahoor











































Abstract
Epoxides are very versatile building blocks in niocrg asynthesis. High ring strain in
epoxides (greater than 20 kcal/mol) ensures theyinr thsetic utility for nucleophilic ring
opening reactions. Until now different methodolso ghiaeve been developed for the ring
opening of epoxides but use of chelated amino aecsitde r and dipeptide enolates has not
been reported so far for such reactions.
This thesis deals with the ring opening of epox iwdeisth chelated amino acid ester
enolates. Different epoxides (aryl and alkyl stubtesdt)i were used for regioselective ring
opening reactions. Depending on the substitution tptearn, the reaction proceeds either in a
S 1-type (aryl epoxides) or a 2S-type (alkyl epoxides) fashion, giving rise tyodr oγx-yh α-N N
amino acids. The products of ring opening reacti ow nesre successfully subjected to further
synthetic applications. Ring opening products oyfl aerpoxides were used in synthesis of a
wide range of modified β-substituted phenylalandienrei vatives. On the other hand, ring
opening products of alkyl epoxides were oxidized d anthe ketones obtained were
successfully subjected to various carbonyl addsi tieo.ng., Passerini and Reformatsky
reactions as well as to allylations and methysl. aMtoiroenover, the methodology was also
successfully applied to peptide modifications.

Kurzfassung

Epoxide sind sehr vielseitige Synthesebausteined eirn organischen Chemie. Die große
Ringspannung der Epoxide (>20 kcal/mol) ist veranotrwtlich für ihre gute Reaktivität
gegenüber Nukleophilen (Ringöffnung). Zwar wurden ibs heute zahlreiche Methoden
entwickelt, um Epoxide zu öffnen, aber die Verwnegn vdoun chelatisierten Aminosäureester-
und Dipeptidenolaten ist bis dato nicht beschrie.b en
Diese Arbeit befasst sich mit der regioselektivein göRffnung unterschiedlich
substituierter Epoxide durch chelatisierte Aminroeseäsuterenolate. Abhängig vom
Substitutionsmuster kann die Ringöffnung sowohl hn aceinem S1-Mechanismus N
(Arylepoxide) als auch nach einem 2-SMechanismus (Alkylepoxide) ablaufen. Die so N
erhaltenen γ-Hydroxy- α-aminosäuren wurden in zaehilcrhen synthetischen Anwendungen
eingesetzt. So konnten die bei der Verwendung vonA rylepoxiden erhaltenen Produkte zu
β-modifizierten Phenylalaninderivaten umgesetzt dwene.r Die Produkte der Alkylepoxide
wiederum wurden oxidiert und die erhaltene ketone naschließend erfolgreich in
verschiedenen Carbonylreaktionen (z.B.: PasserinRie,f ormatsky) eingesetzt. Außerdem
wurde diese Methode erfolgreich bei Peptidmodifizriueng verwendet.





Contents
1 Preface .................................................................. 1
2 Introduction ............................................................. 4
2.1 Synthesis of epoxides ........................................................ 4
2.1.1 Darzens glycidic ester condensation ......................................... 4
2.1.2 Corey-Chaykovsky epoxidation........................................... 6
2.2 Ring opening of epoxides by nucleophiles.. . ........................ 9
2.2.1 Carbon nucleophiles ........................................................ 9
2.2.2 Nitrogen nucleophiles ...................................................... 19
3 Results and Discussion ...................................................... 24
3.1 Aim of thesis .................................................................. 24
3.2 First attempt for ring opening ........................................... 25
3.3 Optimization of reaction parameters ............................... 26
3.3.1 Screening of electrophile equivalen..t.s. .............................. 26
3.3.2 Screening of metal salts ............................................................. 28
3.3.3 Effect of protecting groups ................................................ 29
3.3.4 Effect of temperature ....................................................... 30
3.4 Synthesis of substrates ..................................................... 31
3.4.1 Synthesis of aromatic epoxides ......................................... 31
3.4.2 Synthesis of aryl glycidyl ethers ......................................... 33
3.5 Ring opening reactions of epoxides ..................................... 34
3.5.1 Ring opening of aromatic epoxides ..................................... 34
3.5.2 Ring opening of aliphatic epoxides .................................... 35
3.5.3 Ring opening of aryl glycidyl ethers ........................................... 36
3.5.4 Intramolecular ring opening of epoxide..s. ............................... 37
3.5.5 Ring opening ofg em-dichloro styrene oxide ................... . ...... 39
3.6 Synthetic applications ...................................................... 39
3.6.1 Synthesis of γ-keto amino acid est1e1rs . ................................. 40
3.6.2 Allylation of γ-keto amino acid e1s1te r.s. ............................... 42
3.6.3 Methylation of γ-keto amino acid est1e1rs . ............................ 42
3.6.4 Passerini & Ugi reactions of γ-keto aminiod eascters 11 ......... 43
3.6.5 Reformatsky reaction of γ-keto amino acited ress 11............... 45
3.6.6 Grignard reaction of γ-keto amino acid estse 1r1 ..................... 46
3.6.7 Synthesis of heterocyclic based on aminod aecstiers ............. 47
3.6.8 Synthesis of constrained peptides ....................................... 48

3.6.9 Synthesis of β-substituted phenylalan i..n..e.s........................... 49
3.6.10 Application to peptide modification.s. ...................................... 52
4 Experimental ........................................................... 56
4.1 General information ......................................................... 56
4.2 General experimental procedures ....................................... 58
4.3 Synthesis of compounds ..................................................... 62
5 Summary ........................................................................... 135
6 References ................................................................ 138



Abbreviations

abs. absolute
Ac Acetyl, [C–HCO] 3
AIBN Azo-bis-(isobutyronitril), [NC)–(C–HN=N–C(CH ) –CN] 3 2 3 2
Ar Aromatic
Bn Benzyl, [HC –CH ] 6 5 2
Boc tert-Butyloxycarbonyl, [(C)HC–O–CO] 3 3
Bu n-Butyl, [CH–(CH ) –CH ] 3 2 2 2
tBu tert-Butyl, [(CH) C] 3 3
+ –nBuLi n-Butyllithium, C[H Li] 9 4
CI Chemical Ionization
Cy Cyclohexyl, [HC ] 6 11
dba Dibenzylidenacetone, [(CH –CH=CH) CO] 5 6 2
t t td bpe 1,2-Bis-(dtie-rt-butylphosphino)-ethan,B u[ P–CH –CH –P Bu ] 2 2 2 2
DBPO Dibenzoylperoxid, [(CH –COO) ] 6 5 2
DIAD Diisopropylazodicarboxylate, [)(CH–O–CO) N ] 3 2 2 2
DMSO Dimthylsulfoxide
dr Diastereomeric ratio
ds Diastereoselectivity
EA Ethyl acetate, [C–HCOO–CH –CH ] 3 2 3
Et Ethyl, [HC ] 2 5
fac facial Configuration
g Gram
GC Gaschromatography
h hour
Hex Hexyl, [CH ] 6 13
HPLC High Performance Liquid Chromatography
HRMS High Resolution Mass Spectrometry
HSQC Heteronuclear Single Quantum Coherence
J Coupling constant
+ –LHMDS Lithiumhexamethylsisilazane, ([(CLHi ) Si)N ] 3 3 2
mCPBA meta-Chloroperbenzoic acidm, -[Cl–CH –CO–OOH] 6 4
M.Pt. Melting point
Me Methyl, [CH ] 3
MHz Megahertz
min Minute
mg Milligram
mmol Millimole

Un pour Un
Permettre à tous d'accéder à la lecture
Pour chaque accès à la bibliothèque, YouScribe donne un accès à une personne dans le besoin