University of Groningen Conformational study of cinchona and ephedra alkaloids Dijkstra, Gerard PDF
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University of Groningen Conformational study of cinchona and ephedra alkaloids Dijkstra, Gerard Durk Henk IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1991 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Dijkstra, G. D. H. (1991). Conformational study of cinchona and ephedra alkaloids. [Thesis fully internal (DIV), University of Groningen]. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 17-03-2023 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-
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