University of Groningen Conformational study of cinchona and ephedra alkaloids Dijkstra, Gerard

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University of Groningen

Conformational study of cinchona and ephedra alkaloids
Dijkstra, Gerard Durk Henk
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Dijkstra, G. D. H. (1991). Conformational study of cinchona and ephedra alkaloids. [Thesis fully internal
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CONFORMATIONAL STUDY OF CINCHONA
AND EPHEDRA ALKALOIDS
CONFORMATIONAL STUDY OF CINCHONA
AND EPHEDRA ALKALOIDS
Ter vedrrijging van het doaoraat in de
Wiskunde en Natuurw-
aan de Rijksunivrsiteit Gmningen
op gezag van de
Rector Ma@hs Dr. L. J. Engels
inhetopenboarteverddgenap
vrijdq 5 april1991
des nemiddags te 4.00 uur
door
Gerard Durk Henk Dijkstra
geboren op 21 fcbnuui 1958
teGNmingen
EERSTE PROMOTOR: PROF. DR. R. M. KELUXiG
TWEDE PROMOTOR: PROF. DR. H. WUNBERG
The computer md molecular modelling facilities used for this work were provided by Royd
Dutch Shell
Aan allen die hebben bijgedragen aan het tot stand komen van dit proef-
schrift betuig ik mijn hartelijke dank
voor mijn oudcrs
voor emmy en wouter
CONTENTS
...............................................
CHAPTBR 2 MOLECULAR EWCHANICS CALCULATIONS 27
......................................................................................................................
2.1 Inmtion 27
......................................................................................
2.2 Uoleculu rncch8nicd cllcullionr 29
.........................................................
2.3 Moleculum cchrnicr uulpir an dacbwr abloida 32
..............................................................................................................
2.3.1 32
.....................
2.32 Rdtr,o f molecular ma:lmia calc&km an chhnar lkrloida 35
..............................
2.4 Mdcculu mecbimiu aualyai~on ephedr8 alkaloids
........................................................
2.5 Rigid fitting betwan epbedn md chchau dkdoidr 57
..............................................................................................................................
2.6 RCfmea~ed 59
CHAPTER 3 CONFORMATIONAL ANALYSIS OF CINCHONA
................................................................................
ALKALOIDS IN SOLUTION 63
..........................................................................................................................
3.1 lnmbctiM . 64
..................................................................................
3. 2 NMRmaly~i~oncincbolrrakal~ 65
.........................................
3.2.1 hipmead IHN MR rpscm of ciocha~oa kaloids 67
.................................................
32.2 Confdoaula saignumt of chbma& doids 78
................................. ....,...... .......................
3.2.3 Confomatioo of the quiuuclidine ring 89
................................................................................................................
3.3 B e a p t . 92
..............................................................................................................................
3.4 Refaemced 92
CHAPTER 4 CONFORMATIONAL EFFmxs OF CINCHONA
......................................................
ALKALOIDSUBSTRATE INTERACIIONS 95
...........................................................................................................................
4.1 Introduction %
.................................................................................
4.2 Complexation with osmium tetraoxide %
........................................
4.3 Effect of protonation on the confonuation of cincha lkaloids 105
............................................................................... ..............
4.4 Asymmetric Michael addition " 108
.............................................................................................................
4.4.1 InOoductio n. 108
............................................................................
4.42 MoI~dynnmicscalcuWom 1 1
.............................................
4.4.3 Mokculudocking8tudyofa~dcompba 119
................................................................
4.4.4 NMR sady of alkaloid-thiol iukmdom 121
.......................................................................................................... ....
4.43 Discumi on. 123
.................................................................................................. .............
4.5 Fkp&~~~~uoLl " 127
..................................................................... ......................................................
4.6 Rcf~u~:es , 128
...................
CHAPTER 5 MO ANALYSIS ON CINCHONA AND BPHEDRA ALKALOIDS 131
..........................................................................................................................
5.1 Introduction 131
................................................
5.2 MO dyaia an ciachona alk8Ioidr aad model c o m ~ 133
.......................................................................................................
5.2.1 MO cakulai- 133
...................................................................
5.22 M0calculrtiomoncinclunu.Ihbidr 134
...................................................................
5.2.3 MO calculatiom on model compaunds 136
....................................... ..............................................
5.2.4 AbUl-8dutc ~IWXW~~OIU 149
.................................................................. ...........................................
5.2.5 Diacusriaa , 151
....................................................................................................
5.3 MO d p ba n epbedrina 155
............................................. ..................................................................
5.4 Eapuhnfrl p81L , 162
............................................................................................................................
5.5 Refamces 162
...................................................................
CHAPTER 6 AND DISCUSSION 165
-.
.........................................................................................................................
6.1 Intfoductio n. 165
..........................................
6.2 Bphedn daivrtivw M chinl camly8111i n heM ichwl diitioa 166
.............................................................................................................................
6.3 Diacunaiaa 174
.................................................................................................................
6.4 Eapuhnpl put 180
..............................................................................................................................
6.5 Rcfwencw 181
..................................................................................................................................
SUMMARY 183
...............................................................................................................................
SAMBNVAlTlNG 187
INTRODUCTION
1.1 SCOPE OF THIS THESIS
Chirality and Natun an closely associated. Living organisms use chiral catalysts
(enzymes) to synthesize many of their chemical constituents. Over millions of
years the complex compositions of enzymes have developed into efficient and
specific catalysts for the synthesis (and breakdown) of chiral organic compounds.
Because of the complexity of mynatic reactha, it is difficult to study the details
of their reaction mechanisms directly from experiments. Recently several
breakthroughs in the design and the synthesis of organic catalysts have taken
place. With these catalysts it is possible to control the stereoselectivity of some
reactions with efficiencies rivalling those of enzymes. In many casts th-e chiral
organic catalysts am, like cnzymea, natclral products or their derivatives. However,
such catalysts are much smaller than enzymes and are thus better suited to
.
mechanistic studies. A recent example is given by lnouel With the dipeptide
cyclo-phcnyldaninc-histidinea s chiral caEatyst in a reaction between beaualdehyde
and hydrogen cyanide he obtained R-mandelonitrile (enantiomeric excess 97%) in
almost quantitative yield (Figure 1.1).
P i 1.1 Reaction between benzaldehyde and hydrogen cyanide, proposed model for
het ransition state.
For at least two reasons such studha are in-. Firqtly, detailed howledge of
the mechanism of catalytic 8ter~oselectives yntheses is fundamental to under-
stangling the essentials of recognition processes at a molecular level and the
mqhauistic rules which govern these. Secondly, this mechanistic knowledge is
essential for optimizing existing asymmetric routes or designing new ones. In
particular, this area of endeavor has wide-ranging practical applications for the
chemical, agmchemical, and phamaceutical industries.
Both in our labomto$ and elsewhere3 many successful applications have been
made of cinchona and ephedra alkaloids as chiral organic catalysts in stereo-
selective syntheses. In contrast to the large amount of experimental data, much less
&known about the mechanism of action of these alkaloids and their derivatives.
Therefore, we have canicd out a detailed conformational study on cinchona and
ephcdra alkaloids.
In chapter one we will briefly introduce the cinchona and ephedra alkaloids, and
we will establish some notions regarding stereoselective synthesis. In chapter two
the results will be given of a conformational analysis using molecular mechanics
calculations on cinchona and ephedra alkaloids. lhis knowledge of the preferred
conformations of cinchona alkaloids in the gas phase has been used to study their
conformational behavior in solution. These mults are obtained with a NMR study,
and are presented in chapter three. In chapter four a study of conformational
changes caused by cinchona alkaloid-substrate interactions is described. The
results arc used to discuss some mechanistic aspects of the asymmetric Michael
addition between aromatic thiols and a,()-unsaturated ketones. A quantum
mechanical analysis on the confonnational behavior of cinchona and ephedra
alkaloids is presented in chapter 5. An attempt is made to rationalize in detail the
experimentally obtained conformational data Finally, m chapter 6 we will give the
preliminary results of improved catalyst design. Comparison of results obtained
with cinchona and ephedra alkaloids as chiral catalysts in a Michael addition
between aromatic thiols and conjugated ketones will be used as basis for dis-
cussion and outlook.
1.2 CINCHONA AND EPHEDRA ALKALOIDS
1.2.1 The Alkaloids
.
The alkaloids ate a large class of naturally occurring amines4 ~ertundiso lated
the first alkaloid, morphine, in pure form (1805). He described morphine as basic,
salt-forming and ammonia-like, and used the tenn 'organic alkali'. The term
alkaloid, or 'alkali-like', was fvst proposed by ~ e i s s(d181 9). Basic organic
nitrogen compounds of (chiefly) plant origin are in general classified as alkaloids.
Many alkaloids are marked by a noticeable biological activity in humans. Already
long before the isolation of the first pure compound they were used as medicines
and poisons. The alkaloids have provided our society with some potent phanna-