by Foad Tehrani Najafian

423 Pages·2016·19.3 MB·English

From Cucurbiturils to Amino Acids: Taking Advantage of Mild
Catalysis for Reaction Rate Acceleration and Pharmaceutical Drug
Syntheses
by
Foad Tehrani Najafian
A thesis submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy in Chemistry

Approved Dissertation Committee
Prof. Dr. Thomas Nugent (supervisor)
Professor of Organic Chemistry, Jacobs University Bremen
Prof. Dr. Werner Nau
Professor of Chemistry, Jacobs University Bremen
Prof. Dr. Stephen Connon
Professor of Organic Chemistry, Trinity College Dublin

Date of Defense: April 20, 2016
Declaration of Authorship

I, Foad Tehrani Najafian, hereby declare that the thesis I am submitting is entirely my own
original work unless where clearly indicated otherwise. I have used only the sources, the data
and the support that I have clearly mentioned. This PhD thesis has not been submitted for
conferral of degree elsewhere.
I confirm that no rights of third parties will be infringed by the publication of this thesis.

Bremen, March 27, 2016

Signature

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ACKNOWLEDGMENTS

First of all, sincere thanks to my supervisor Prof. Thomas Nugent for his guidance and expert
advices during my Ph.D. research. Working with Nugent was highly inspiring even during the
frustrating periods when a project was giving me a hard time, talking to him was always
encouraging. I would like to especially indicate that his support was beyond academicals
guidance to every aspect of life.
I also would like to thank my thesis committee members, Prof. Dr. Werner Nau, for his advice
and support during my Ph.D. research, his support has led the achievement of this Ph.D. thesis. I
also thank Prof. Dr. Stephen Connon, Trinity College Dublin for his kind acceptance of being my
external committee member.
I wish to acknowledge the support of DFG (Deutsche Forschungsgemeinschaft) and Jacobs
University Bremen for the full scholarship and funding of the research.
A special thanks to my fiancé, Dr. Hande Karaköse for her support during my Ph.D. I would also
like to thank my colleagues Andrei Dragan,Hussein Ali El Damrany Hussein, Ishtiaq Hussain,
Khaleel Assaf, for their assistance during the experimental work of the study. My gratitude
extend to my friends Diana Sirbu, Obaida Kasas, Georgi Dragolov Khodr Saifan, Aous Shahen.
Finally, my warmest thanks belong to my parents Asia and Abd El Nabi and my brothers Farouk
and Meshaal, for their confidence in me and for being always supportive and interested in my
work.

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Abbreviations
Ar Aryl
bs Broad singlet (1HNMR)
Bn Benzyl group
Boc tertiary-butyl carbamates
conv Conversion
CD Circular dichrosim
CDCl Deuterated chloroform
3
d Doublet (1HNMR)
DNBSA 2,4-Dinitrobenzene sulfonic acid
dd Doublet of doublet (1HNMR)
dq Doublet of quartet (1H NMR)
DCM Dichloromethane
de Diastereomeric excess
dr Diastereomeric ratio
DMF N,N-Dimethylfomamide
DMSO Dimethylsulfoxide
δ Chemical shift (1HNMR)
ee Enantiomeric excess
equiv Equivalent
ESI Electrospray ionization (Mass spectroscopy)
Et Ethyl
EtOH Ethanol
EtOAc Ethylacetate
GC Gas chromatography
h Hours
HPLC High performance liquid chromatography
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HRMS High resolution mass spectrometry
Hz Hertz
IR Infrared spectroscopy
J Coupling constant (1HNMR)
m Multiplate (1HNMR)
M Molar
Me Methyl
min Minutes
MS Mass spectroscopy
MW Molecular weight
m/z Mass/charge
m Meta
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
q Quartet (1HNMR)
R Alkyl group
Ref Reference
rt Room Temperature
s Singlet (1HNMR)
t Triplet (1HNMR)
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tBu Tertiary butyl
tert Tertiary
temp Temperature
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
TMS Trimethylsilane
CB Cucurbituril
CPD Cyclopentadiene
MCPD methylcyclopentadiene
DCPD Dicyclopentadiene
DMDCPD Dimethyldicyclopentadiene
MDCPD Methyldicyclopentadiene

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Abstract

Catalysis is a central theme of many current endeavors within synthetic organic chemistry.
Within this thesis I describe how catalysis implementation has allowed three distinct
contributions to the areas of reaction rate acceleration, site-selectivity, and more step-efficient
synthesis of pharmaceutical drugs.
Site-selectivity is an emerging field within organic chemistry in which two or more of the same
functional groups are differentiated on the same molecule. The tactic of site-selectivity holds the
potential to free the synthetic chemist from protection/deprotection protocols during a natural
product or drug synthesis for improved yield and step-efficiency. In particular, aldol site-
selectivity for 4-substituted diketones with high chemo-, regio-, diastereo- and enantioselectivity
has been shown. The aldol products there from have been converted to lactones (three
stereogenic centers) and 1,3-diols (four stereogenic centers), and one lactone was successfully
used to achieve the first enantioselective synthesis of an Alzheimer drug precursor in the highest
overall yield to date.
Developing mild Michael reaction conditions that can tolerate the presence of acid spectator
functionality is an active theme within our research. In this regard, I was able to contribute by
applying earlier findings to guide a proof of concept initial catalyst optimization of the critical
Michael step that has allowed me to achieve the shortest, and the first enantioselective synthesis
of Pristiq ((-)-O-desvenlafaxine), a top selling antidepressant drug.
Finally, cucurbituril (CB7) was used to catalyze Diels-Alder reaction of cyclopentadiene
dimerization. I proved that using CB7 as a catalyst can accelerate the dimerization reaction up to
150 thousand fold in compare to the neat reaction. Cucurbituril ability in selectively catalyzing
the dimerization of methylcyclopentadiene and co-dimerization of cyclopentadiene with
methylcyclopentadiene was also noted.

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Table of Contents
Chapter.1 ...................................................................................................................................................... 1
1.1 Introduction to the World of Organocatalysis .................................................................................... 2
1.2 Enantioselective Enamine Organocatalysis ........................................................................................ 3
1.2.1 The Enamine Mechanism of a Primary and Secondary Amine Based Catalyst ............................ 5
1.2.2 Characterization of Enamine Organocatalysts ............................................................................. 7
1.2.3 4-Substitutued Cyclohexanone Desymmetrization ................................................................... 25
1.3 Introduction to Site Selectivity .......................................................................................................... 36
1.4 Supramolecular Catalysis .................................................................................................................. 41
Chapter 2. .................................................................................................................................................... 48
2.1. Picolylamine a New Catalyst Framework ......................................................................................... 49
2.1.1 Modified Synthesis of Picolylamine (PicAm) Catalyst ................................................................ 49
2.1.2 PicAm as a Site-selective Aldol Catalyst of 4-Substituted Diketone .......................................... 50
2.1.3 Aldol Reaction of Cyclic versus Acyclic Ketones Catalyzed by PicAm ........................................ 51
2.1.4 Aldol Products of 4-Substituted Diketones ................................................................................ 55
2.1.5 The Crude Aldol Products of Diketone 50 with Different Aldehydes ........................................ 70
2.1.6 The Effect of the Counter Ion on the Catalyst Selectivity .......................................................... 75
2.2 Proline Based Catalysts for the 4-Substituted Diketone Aldol Reaction .......................................... 81
2.2.1 trans-4-(tert-Butyldiphenylsilyloxy)-L-proline (13) and L-Proline (1) as a Site-selective Aldol
Catalysts .............................................................................................................................................. 81
2.2.2 Baeyer Villiger Products of the Site-selectively Formed Aldol Products (Catalyst 13) .............. 84
2.3 The Synthesis of the Alzheimer Drug Precursor ............................................................................... 88
2.4 The Full Synthesis of Enantiopure Pristiq.......................................................................................... 93
2.4.1 Pristiq, Between Racemic and Enantiopure Drug. ..................................................................... 93
2.5 Cucurbituril as a Diels Alder Reaction Catalyst ................................................................................. 98
2.5.1. The Cyclopentadiene Self-dimerization by Cucurbituril ........................................................... 98
2.5.2 Following the dimerization of CPD by 1H-NMR .......................................................................... 99
2.5.3 Discerning Host from Non-Host Effects ................................................................................... 101
2.5.4 Kinetics Study of the CPD Dimerization Catalyzed by CB7 ....................................................... 103
2.5.5 Catalytic efficiency of Cucurbituril ........................................................................................... 104
2.5.6 Inhibition of CB7 during the Dimerization Reaction ................................................................ 105
2.5.7 Reactivation of CB7 .................................................................................................................. 105
2.5.8 Reducing the Concentration of CB7 to Overcome the Inhibition Problem. ............................ 107
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2.5.9 Current Mechanistic Understanding ........................................................................................ 108
2.6 Future Plan ...................................................................................................................................... 109
2.6.1 DMDCPD and Co-dimer ............................................................................................................ 109
2.6.2 Self Dimerization of MCPD inside CB7 ..................................................................................... 110
2.6.3 Codimerization of CPD and MCPD ........................................................................................... 112
Chapter 3. .................................................................................................................................................. 121
3.1 Picolylamine a New Catalyst Framework ........................................................................................ 123
3.1.1 Procedure for the Synthesis of the Diamine Catalyst (PicAm) (10) ......................................... 123
3.1.2 General Procedure for the Aldol Reaction: .............................................................................. 129
3.1.3 General Procedure for the Diol Reaction ................................................................................. 130
3.1.4 General Procedure for The Baeyer Villiger Reaction ............................................................... 131
3.1.5 Aldol reaction of PicAm with cyclic and acyclic ketones .......................................................... 131
3.1.6 The purification of 4-Substituted Diketone Aldol Products 62A and 62B ............................... 134
3.1.7 The tested aldehydes for the diketone 50 Aldol Reaction catalyzed by (R)-PicAm (10) ......... 153
3.1.8 The Reduction of Aldol Products to Diol .................................................................................. 175
3.1.9 Baeyer Villiger Reaction Products of Aldol products ............................................................... 206
3.1.10 The Effect of the Counter ions on PicAm 10 Selectivity ......................................................... 234
3.2 The Experimental Related to Proline Based Catalysts .................................................................... 257
3.2.1 General Procedure and Characterization of Keto-Lactones .................................................... 257
3.3 Alzheimer drug Precursor Synthesis and Compound Characterization .......................................... 328
3.4 The Enantiopure Synthesis of Pristiq and Compound Characterization ......................................... 381
3.5 Cucurbituril as Diels-Alder Reaction Catalyst .................................................................................. 407
3.5.1 General procedure for the self Diels Alder reaction of cyclopentadiene and the Diels-Alder
reaction of cyclopentadiene with methylcyclopentadiene .............................................................. 408
3.5.2 Inhibition of CB7 by amantadine ............................................................................................. 409
3.5.3 Initial Rate of the CPD Dimerization ........................................................................................ 409

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Introduction

Chapter.1

Introduction

1