Improved Methodology for the Preparation of Chiral Amines

170 Pages·2009·0.9 MB·English

Improved Methodology for the Preparation of
Chiral Amines
(Important Chiral Building Blocks in Pharmaceutical
Drugs and Natural Products Synthesis)

Mohamed Mahmoud El-Shazly
A thesis submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
in
Organic Synthetic Chemistry

Approved Thesis Committee
Prof. Dr. Thomas Nugent
Professor of Organic Chemistry
Jacobs University Bremen
Prof. Dr. Nikolai Kuhnert
Professor of Organic Chemistry
Jacobs University Bremen
Dr. Pralhad Ganeshpure
Indian Petrochemicals Corporation Limited,
India
Date of Defense: August 03, 2009

School of Engineering and Science, Jacobs University, Bremen, Germany.
Declaration

I herewith declare that this thesis is my own work and that I have used
only the sources listed. No part of this thesis has been accepted or is
currently being submitted for the conferral of any degree at this
university or elsewhere.

Mohamed El-Shazly Bremen
This dissertation is dedicated to all those people
who have always given me the love, trust, and support
to come to this stage of my life

-To My Family-
Abstract

The importance of α-chiral amines as building blocks in pharmaceutical drugs, natural
products, fine chemicals and agrochemicals have encouraged scientists to develop different
methodologies for their preparation. Their main goal was to develop a step wise efficient and
low waste production methodology which utilizes inexpensive starting material for the
synthesis of α-chiral amines in high yields and enantioselectivity. Different methodologies
have been developed aiming to meet these criteria. These strategies are discussed and their
importance and limitations are critically analyzed.

Reductive amination is a powerful methodology for the synthesis of chiral amines in high
yields and enantioselectivity. It is a two step strategy beginning from the prochiral carbonyl
compound to the primary chiral amine. The historical development and the latest milestones
in this field are discussed in chapter three. Different drugs and natural products which are
prepared utilizing reductive amination as a key step in their synthesis are summarized in
chapter four.

Reductive amination utilizing chiral auxiliary/Lewis acid/ heterogeneous catalyst/ molecular
hydrogen has been investigated in our group over the last five years. This combination
allowed the preparation of alkyl-alkyl’ α-chiral amines in mediocre to good yields and
enantioselectivities. This group of amines is known historically to be difficult synthetic task.
We developed a new asymmetric reductive amination procedure using Yb(OAc) (50-110
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mol %) that allows increased diastereoselectivity (6-15% units) for alkyl-alkyl’ α-chiral
amines that previously only provided mediocre to good diastereoselectivity. Different Lewis
acids were tested under different reaction conditions of temperature, pressure and solvents
and the results of these experiments are discussed in chapter five.

1d O Yb(OAc)3,MeOH-THF (S,S)-2d HN Ph Pd-C (S)-3d NH2
+
H2N Ph Raney-Ni,H2(120psi) H2(60psi)
(S)-α-MBA 86%de 85%ee
The use of catalytic Lewis acids in reductive amination has never been reported in literatures.
We demonstrated the beneficial use of 10-15 mol % of Yb(OAc) orCe(OAc) or Y(OAc) in
3 3 3
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suppressing alcohol formation and promoting reductive amination in good yield but without
enhanced stereoselectivity. Despite the fact that the use of Brønsted acids in reductive
amination is well established no literature reports are available. We have performed and
extensive study on the use of commercially available Brønsted and mineral acids in reductive
amination. The scope of the reaction and the substrate categories are summarized in chapter
six.

A mechanism for the reaction has been proposed and the basic mechanistic experiments have
been performed. An in situ cis- to trans-ketimine isomerization mechanism, promoted by
Yb(OAc) , has been proposed to account for the observed increase in diastereoselectivity.
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The experiments and the proposed mechanism are summarized in chapter seven

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Acknowledgement

All the work reported in this thesis have been carried out at the Department of Chemistry,
School of Engineering and Science, Jacobs University, Bremen, Germany since joining here
on August 2006 till August 2009. I would like to thank Jacobs University for the financial
support and all the laboratory facilities during my stay here. In this regard I would like to
thank Prof. Dr. h. c. Bernhard Kramer for approving my PhD scholarship.

I would like to convey my kind regards to my supervisor Prof. Thomas C. Nugent and thank
him for all his kind suggestions and deeply appreciate his skillful guidance throughout my
research. It was due to his relentless efforts that I could master the various techniques and
learn to solve the different scientific challenges that came by my way. Lastly, I would also
acknowledge his patience and kind understanding.

I would thank Prof. Nikolai Kuhnert for his kind consent to become the internal examiner of
this thesis.

I would also thank Dr. Pralhad Ganeshpure, Research Centre, Indian Petrochemicals
Corporation Limited, 391 346 Vadodara, India (B-21, Kinnari Duplex Ellora Park, Vadodara,
Gujarat 390023, India) for his kind consent to become the external examiner of this thesis.

My sincere appreciation goes to all my lab mates, Dr. Rashmi R. Mohanty, Dr. Vijay N.
Wakchaure, Dr. Abhijit Ghosh, Ahson J. Shaikh, Mohammad Naveed Umar, Mohammad
Shoaib, A. Alvaradomendez, Abdul Sadiq, Dan Hu, Ahtaram Bibi, Satish Wakchaure, Andrei
Dragan, Andrei Iosub and Daniela Negru for their constant help and encouragement in all
respect. I would also thank Mrs. Müller for her continuous help.

All my deepest veneration goes to my parents for everything that they have given to me. I
would convey my regards to my sister and all my uncles and aunts for their constant support.
I would also thank all professors and colleagues in Egypt. Especially I would like to thank
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Prof. Mohamed El-Azizi, Prof. Abdel-Nasser Singab and Prof. Nahla Ayoub for their support
and help over the past years.

I would like to thank all friends at Jacobs University, Iyad Tumar, Khaled Hassan, Dr. Raed
Mesleh, Mohamed Noor, Hamdy El-Sheshtawy, Salahaldin Juba, Ahmed Moussa, Ahmed El-
Moasry, Hany Elgala and all other friends in Germany and Egypt for their continuous support

,

,

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Abbreviations

Ac Acetyl
AcOH Acetic acid
aq. Aqueous
Ar Aryl
bs Broad singlet (1H-NMR)
BINOL 1,1'-Bi-2-naphthol
BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl.
BOC tert-Butyl carbamates
iBu iso-Butyl
nBu n-Butyl
conv. Conversion
cat. Catalyst
CDCl Deuterated chloroform
3
COD Cycloctadiene
d Doublet (1H-NMR)
dd Doublet of doublet (1H-NMR)
DCM Dichloromethane
de Diastereomeric excess
DIBAL-H Diisobutyl aluminium hydride
DME 1,2-Dimethoxyethane
DMF N,N’-Dimethylfomamide
DMSO Dimethylsulfoxide
δ Chemical shift (1H-NMR)
ee Enantiomeric excess
equiv. Equivalent
ESI Electron spray ionization (Mass
spectroscopy)
v
Et Ethyl
EtOH Ethanol
EtOAc Ethylacetate
GC Gas chromatography
h Hours
HPLC High performance liquid chromatography
HRMS High resolution mass spectrometry
Hz Hertz
J Coupling constant (1H-NMR)
KHMDS Potassium hexamethyldisilazide
LDA Lithium diisopropylamide
m Multiplate (1H-NMR)
M Molar
MBA Methyl Benzyl Amine
Me Methyl
min. Minutes
MS Molecular sieves
MS Mass spectroscopy
MTBE Methyl-tert-butyl ether
MW Molecular weight
m/z Mass/charge
m Meta
NaOtBu Sodium tert-butoxide
NBD N-Bornadiene
NMR Nuclear Magentic Resonance
o Ortho
p Para
Pd-C Palladium on carbon
Ph Phenyl
iPr iso-Propyl
nPr n-Propyl
Pt-C Platinum on carbon
pyr Pyridine
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q Quartet (1H-NMR)
Raney-Ni Raney-Nickel
Ref. Reference
Rh-C Rhodium on carbon
s Singlet (1H-NMR)
t Triplet (1H-NMR)
t-Bu tert-Butyl
tert Tertiary
temp Temperature
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
TMS Trimethylsilane
Ts Tosyl
TsOH p-Toluenesulfonic acid
tBuLi tert-Butyllithium
Ti(OiPr) Titanium(IV) isopropoxide
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