Catalyst Stabilities, Low-Abundance Conformers, Intermediates And R

210 Pages·2016·11.74 MB·English

NMR Spectroscopic
Investigations On Small Organic
Molecules: Catalyst Stabilities,
Low-Abundance Conformers,
Intermediates And Reaction
Mechanisms

Dissertation
Zur Erlangung des Doktorgrades
der Naturwissenschaften (Dr. rer. nat.)
der Fakultät für Chemie und Pharmazie
der Universität Regensburg
vorgelegt von
Michael Haindl
aus Mühldorf am Inn
Februar 2016

Die vorliegende Dissertation beruht auf Arbeiten, die zwischen Oktober 2011 und
Februar 2016 im Arbeitskreis von Frau Professor Dr. Ruth M. Gschwind am Institut
für organische Chemie der Universität Regensburg durchgeführt wurden.

Promotionsgesuch eingereicht am: 18. Februar 2016
Die Arbeit wurde angeleitet von: Prof. Dr. Ruth M. Gschwind
Prüfungsausschuss:
Vorsitzender: Prof. Dr. Olga Garcia Mancheño
1. Gutachter: Prof. Dr. Ruth M. Gschwind
2. Gutachter: Prof. Dr. Werner Kremer
3. Prüfer: PD Dr. Sabine Amslinger

Danksagung
Zuerst gebührt mein Dank all denjenigen, die zum Erfolg dieser Dissertation bei-
getragen haben. Meiner Doktormutter Prof. Dr. Ruth M. Gschwind möchte ich für die
Überlassung des spannenden Themas und die hohe mir übertragene Eigenverant-
wortung danken, die mich stets motiviert hat. Allen beteiligten Kollegen und Koope-
rationspartnern danke ich für die vielen fruchtbaren Anregungen und Diskussions-
runden. Bei meinem Vorgänger Dr. Markus Schmid bedanke ich mich für die ausge-
zeichneten Vorarbeiten und „Steilvorlagen“, die ihren Teil zum Gelingen dieser Ar-
beit beigetragen haben.
Meinen lieben Kollegen und Freunden an der Universität Regensburg danke ich für
die lockere und angenehme Arbeitsatmosphäre, die Kochabende (meistens Diens-
tags), die tiefgreifenden Gespräche und die vielen lustigen Momente und Geschichten,
die das gemeinsame Leben an der Universität Regensburg geschrieben hat. Sie wer-
den mir immer in Erinnerung bleiben.
Bei meinen Eltern Inge und Holger Haindl möchte ich mich besonders bedanken. Ihr
habt mir das Leben geschenkt und seid seitdem immer da, wenn ich euch brauche.
Danke!
Auch meinen Schwiegereltern Eva und Martin Wengbauer gebührt großer Dank. Eure
offene und herzliche Art hat mir immer imponiert.
Der größte Dank aber gilt meiner lieben Ehefrau Judith Haindl und meinem einjähri-
gen Sohn Simon Haindl. Durch eure Zuneigung, euer Lachen, euer Weinen, euer Ver-
ständnis, eure offenen Ohren und eure ständige, nicht nachlassende Unterstützung
habt ihr mir gezeigt, was das Wichtigste ist im Leben – die eigene Familie.

NMR Spectroscopic
Investigations On Small Organic
Molecules: Catalyst Stabilities,
Low-Abundance Conformers,
Intermediates And Reaction
Mechanisms
Table of Contents
1 Introduction and Outline .................................................................................... 3
2 The Proline Enamine Formation Pathway Revisited in Dimethyl Sulfoxide: Rate
Constants Determined via NMR ................................................................................ 7
2.1 Abstract ....................................................................................................... 8
2.2 Manuscript ................................................................................................... 9
2.3 Additions .................................................................................................... 24
2.4 Supporting Information .............................................................................. 25
2.5 References ................................................................................................. 63
3 What Is Your Actual Catalyst? TMS Cleavage Rates of Diarylprolinol Silyl Ethers
Studied by in situ NMR ............................................................................................ 67
3.1 Abstract ..................................................................................................... 68
3.2 Manuscript ................................................................................................. 69
3.3 Supporting Information .............................................................................. 75
3.4 References ................................................................................................. 79
4 Conformational Preferences in Small Peptide Models – The Relevance of
Cis/Trans Conformations ......................................................................................... 81
4.1 Abstract ..................................................................................................... 82
4.2 Manuscript ................................................................................................. 83
4.3 Supporting Information ............................................................................. 96
4.4 References ................................................................................................ 141
5 Organocatalytic One-Pot Nitroalkene Dimerization-Rearrangement to Enynes
and Cyclic Nitronates: a NMR Study ...................................................................... 145
5.1 Abstract .................................................................................................... 146
5.2 Manuscript ................................................................................................ 147
5.3 Supporting Information ............................................................................ 157
5.4 Additional Findings ................................................................................... 183
5.5 References ................................................................................................ 199
6 Summary and Outlook .................................................................................... 202
1 Introduction and Outline
1 Introduction and Outline
For decades, the field of NMR spectroscopy is divided into two parts, i.e. the investi-
gation of large molecules, mostly biological macromolecules like proteins or nucleic
acids and the investigation of small molecules, which includes all compounds below
a molecular weight of about 1500 Da. In the year 1999 the “large molecules” field
was so dominant, that the “small molecules” scientific NMR community, together
with sponsors of the industry, decided to name their, until today, largest US/Europe-
an conference on that topic SMASH (“Small Molecules Are Still Hot”). About at the
same time the “gold rush” (Angew. Chem. Int. Ed. 2008, 47, 6138.; Chem. Soc. Rev.
2009, 38, 2178.) in organocatalysis had its starting point and until today, this re-
search field was so successful, that it even developed to an independent area in a-
symmetric catalysis. While, from day one, synthetic explorations pushed organoca-
talysis forward, investigations on the underlying reaction mechanisms were rare at
the beginning. It was small molecules NMR which enabled the in situ detection and
characterization of the elusive proline, prolinol and prolinol ether enamines, central
intermediate species in organocatalysis and showed the power and elegance of that
methodology in organic chemistry (Schmid M. B, Ph.D. Thesis, University of Regens-
burg, 2011).
Based on that pioneering work, this thesis uses the generated momentum of NMR in
organocatalysis and more general in the field of small molecules in order to shed
more light into reaction mechanisms and involved intermediates in proline catalysis
and a new type of nitro chemistry, to identify reaction conditions that ensure catalyst
stabilities and to detect and characterize low abundant dipeptide conformers.
In chapter 2 the reaction mechanism of the enamine formation pathway in the
proline catalyzed self-aldolization/self-condensation reaction of aldehydes is revis-
ited. It was unclear, whether the enamine is formed from the iminium ion or from
the oxazolidinone species. The methodic innovation in this work is the combination
of 1D selective EXSY spectroscopy together with the initial rate approximation (IRA)
approach. It enables, for the first time, the determination of rate constants in be-
tween interconnected intermediate species during the ongoing reaction (in situ). To-
gether with top-notch theoretical calculations, including one of the most accurate
solvent models available today (DCOSMO-RS), the results of this study show that the
active reaction mechanism can strongly depend on the applied reaction conditions.
While the direct precursor in this reaction and under these conditions was identified
to be the iminium ion and not the oxazolidinone as earlier studies suggested, the
exact pathway is variable. Depending on the catalyst amount, water concentration
3
1 Introduction and Outline
and additive addition three different pathways can be active including e.g. internal
or external deprotonation steps or the assistance of water in the mechanism.
In chapter 3 the reaction conditions for the cleavage of the TMS protecting group
from the very popular organocatalyst diphenylprolinol trimethylsilyl ether (Jørgen-
sen-Hayashi catalyst) is investigated. In this study a very systematic approach is a-
dopted. The influence on the TMS cleavage rates is determined of eight solvents with
different combinations of dielectric constants (ε ) and hydrogen bond acceptor pro-
r
perties (β) as well as seven acidic and basic additives. It can be shown that unless in
DMSO and DMF, very polar (high ε values) and at the same time strong hydrogen
r
bond accepting (high β values) solvents, the catalyst is very robust. However, a com-
bination of those solvents with weak acids like benzoic acid dramatically accelerates
the TMS cleavage and the catalyst completely degrades within only a few hours.
The relevance of cis-conformers of a pseudo-dipeptide (double-protected glycin) is
eludicated in chapter 4. In computational publications it was often decided to ignore
the possible existence of cis-conformers in short peptides and proteins that are not
stemming from proline amino acids. The herein presented evidence for the popula-
tion of low-abundant cis-conformers in a pseudo-dipeptide makes this decision very
questionable. In combination with detailed theoretical calculations, a full character-
ization by NMR in terms of thermodynamic and kinetic constants shows that this
cis-peptides are in deed very low abundant but in the samt time are formed with high
rates. Peptide bond isomerization rate constants are again determined by the com-
bination of 1D selective EXSY spectra with the IRA approach. The deduced rates show
that a number of molecules exceeding the whole population of the main trans-con-
former in one minute reaction time isomerizes once to those cis-isomers which
makes them very relevant in terms of their kinetic accessibility.
Finally, in chapter 5, a refinement is presented of a preliminary study on a new se-
condary amine catalyzed nitroalkene dimerization reaction followed by a fragmen-
tation towards conjugated enynes. A two-pathway crossroad reactivity is discovered
enabling, not only the generation of conjugated enynes but also that of 5-membered
cyclic nitronates at the same time. Both, enynes and cyclic nitronates, are very valu-
able structural motifs which can be found in a variety of commercial drugs and drug
candidates. The reaction is splitted into two parts by identification of conditions that
allow for the isolation of the organocatalytic nitroalkene dimerization product. The
underlying reaction mechanisms are investigated in detail by in situ NMR. 1H reac-
tion monitoring together with 13C15N-coupling constant analysis and standard 2D
NMR experiments lead to the detection and identification of a completely new biciclic
intermediate species which sits at the crossroad for the two discovered reactions.
4