DOCSLIB.ORG

Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols Byron Peters ©Byron Kennedy Peters, Stockholm University 2015 ISBN 978-91-76492-79-6 Printed in Sweden by Holmbergs, Malmö 2015 Distributor: Department of Organic Chemistry, Stockholm University ii Abstract The work described in this thesis is focused on exploring the efficacy of asymmetric iridium catalysis in the hydrogenation of challenging substrates, including precursors to chiral sulfones and chiral cyclohexanes. Further- more, iridium catalysis was used to isomerise allylic alcohols to aldehydes, and in a formal total synthesis of Aliskiren (a renin inhibitor). A large varie- ty of unsaturated sulfones (cyclic, acyclic, vinylic, allylic and homoallylic) were prepared and screened in the iridium catalysed hydrogenation reaction using a series of previously developed N,P-ligated Ir-catalysts. The outcome was a highly enantioselective (>90% ee) protocol to prepare sulfones bearing chiral carbon scaffolds, sometimes having purely aliphatic substituents at the stereogenic centre. Furthermore, performing the Ramberg-Bäcklund reaction on the chiral products, under optimised conditions, produced cyclic and acy- clic unsaturated derivatives without erosion of enantiomeric excess. This hydrogenation protocol was also successful in the hydrogenation of a num- ber of cyclohexene-containing compounds. Minimally functionalised, func- tionalised and heterocycle-containing cyclohexenes were hydrogenated in up to 99% ee. Hitherto, both chiral sulfones and chiral cyclohexanes have been challenging targets for most catalytic asymmetric methodologies. Although the preparation of aldehydes and ketones by isomerisation of the correspond- ing allylic alcohol is well established, there has been limited success in the development of good enantioselective protocols. For the isomerisation of a number -allylic alcohols to the corresponding chiral aldehydes, high enan- tioselectivities (up to >99% ee) and modest yields were achieved using an N,P-iridium catalyst. Noteworthy is the high selectivity obtained for isomeri- sation of Z and dialkyl -allylic alcohols, which prior to this study had been difficult to isomerise in high enantioselectivity. Preparation of a key inter- mediate used in the synthesis of Aliskiren, a renin inhibitor drug was also accomplished. Using a convergent synthesis strategy, two allylic alcohol fragments were hydrogenated with high enantiomeric excess (>92% ee). These fragments were then joined using a Julia-Kocienski reaction, provid- ing >95% E geometry around the C=C bond, which was crucial for the sub- sequent steps in the synthesis. iii Contents 1) Introduction ......................................................................................................... 1 a) Chirality and Asymmetric Synthesis[1] ....................................................... 1 b) Catalytic Asymmetric Hydrogenation ........................................................ 4 c) Aims of this Thesis ........................................................................................ 8 2) Asymmetric Hydrogenation of Sulfones ......................................................... 9 a) Sulfones ........................................................................................................... 9 i) Organocatalytic Methods .................................................................... 9 ii) Transition Metal Catalysed Methods .............................................. 10 b) Synthesis ....................................................................................................... 11 c) Evaluation of Unsaturated Sulfones in the Asymmetric Hydrogenation Reaction ......................................................................................................... 13 d) Conclusion ..................................................................................................... 20 3) Asymmetric Isomerisation of Allylic Alcohols .............................................. 21 a) Isomerisation of Allylic Alcohols ............................................................... 21 b) Evaluation of Iridium Catalysts in the Isomerisation ............................ 24 c) Conclusion ..................................................................................................... 28 4) Formal Total Synthesis of Aliskiren ............................................................... 29 a) Introduction .................................................................................................. 29 b) Synthesis of Key Intermediate in the Preparation of Aliskiren ........... 30 c) Asymmetric Hydrogenation of the Allylic Alcohol Fragments.............. 32 d) Connecting the Pieces ................................................................................. 35 e) Conclusions ................................................................................................... 37 5) Enantio- and Regioselective Hydrogenation of Minimally and Densely Decorated Unsaturated Carbocycles ............................................................. 38 a) Introduction .................................................................................................. 38 b) Discussion ..................................................................................................... 39 c) Conclusion ..................................................................................................... 42 6) Concluding Remarks and Outlook ................................................................. 44 7) Summary in Swedish ....................................................................................... 45 8) Acknowledgements ........................................................................................... 46 9) References ......................................................................................................... 48 iv v List of Publications This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I. Enantioselective Synthesis of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to the Preparation of Chiral Allylic and Homoallylic Compounds., T. Zhou, B. K. Pe- ters, M. F. Maldonado, T. Govender, and P. G. Andersson, Journal of the American Chemical Society, 2012, 134, 13592-13595. II. Highly Enantioselective Asymmetric Isomerization of Primary Al- lylic Alcohols with an Iridium–N,P Complex. J. Li, B. K. Peters, and P. G. Andersson. Chemistry – A European Journal 2011, 17, 11143- 11145. III. An Enantioselective Approach to the Preparation of Chiral Sul- fones by Ir-Catalyzed Asymmetric Hydrogenation. B. K. Peters, T. Zhou, J. Rujirawanich, A. Cadu, T. Singh, W. Rabten, S. Kerdphon, and P G. Andersson. Journal of the American Chemical Society, 2014, 136, 16557–16562. IV. Formal Total Synthesis of Aliskiren. B. K. Peters, J. Liu, C. Margari- ta and P. G. Andersson. Chemistry – A European Journal, 2015, 21, 7292-7296. V. Enantio- and Regioselective Hydrogenation of Minimally and Densely Decorated Unsaturated Carbocycles. B. K. Peters, J. Liu, C. Margarita, W. Rabten, S. Kerdphon, A. Paptchikhine, and P. G. An- dersson. Manuscript in preparation (supplementary information availa- ble). Reprints were made with permission from the respective publishers. vi Contribution Report I. Contribution: Synthesized six of the substrates and performed 20 % of their evaluation in the hydrogenation. Prepared one of the catalysts re- ported in the paper. Contributed to the discussion of the selectivity model. Carried out the Ramberg-Bäcklund reaction on three of the compounds reported in the paper. Carried out characterization of a por- tion of the synthesis of novel compounds. II. Contribution: Prepared two substrates. Synthesized the most selective and active catalyst. Carried out 20 % of the testing and optimization of the reaction conditions. Participated only in a small part of the writing of the paper. III. Contribution: Carried out preparation of a major portion of the starting materials (65 %, 20 substrates). Conducted all testing of substrates I prepared as well as characterisation of most of my substrates. Wrote the introduction, the origins of selectivity and 50 % of the discussion. IV. Contribution: Had a major contribution to the synthesis. Prepared one of the two fragments, performed the coupling of the fragments, also completed the synthesis all the way to the key intermediate (our target). Synthesised the representative substrate that was used as a mimic to op- timise the Julia-Kocienski conditions. Also performed all of the optimi- sations for the Julia-Kocienski reaction. Took part in some of the char- acterisation of novel compounds. Co-wrote the paper with my supervi- sor. V. Contribution: Had a major contribution to the synthesis. Prepared all compounds presented in the chapter. Carried out 25 % of the character- isation of the novel compounds. vii Papers not Included in this Thesis I. The cyclobuta[b]quinoline alkaloid cyclomegistine from Teclea gerrardii I.Verd. (Toddalioideae: Rutaceae). P. H. Coombes, E. M. Mwangi, B. K. Peters, N. R. Crouch, D. A. Mulholland. Biochemical Systematics and Ecology 2009, 37, 494-496. II. Synthesis of (S)-3-aminoethyl-1,2,3,4-tetrahydroisoquinoline (TIQ- diamine) via the Mitsunobu protocol. R. B. Kawthekar, B. K. Peters, T. Govender, H. G. Kruger, G. E .M. Maguire. South African Journal of Chemistry 2009, 63, 195-198. III. Synthesis of tetrahydroisoquinoline-diamine ligands and their
Load more

Recommended publications
  • Modern-Reduction-Methods.Pdf
    Modern Reduction Methods Edited by Pher G. Andersson and Ian J. Munslow Related Titles Yamamoto, H., Ishihara, K. (eds.) Torii, S. Acid Catalysis in Modern Electroorganic Reduction Organic Synthesis Synthesis 2008 2006 ISBN: 978-3-527-31724-0 ISBN: 978-3-527-31539-0 Roberts, S. M. de Meijere, A., Diederich, F. (eds.) Catalysts for Fine Chemical Metal-Catalyzed Cross- Synthesis V 5 – Regio and Coupling Reactions Stereo-Controlled Oxidations 2004 and Reductions ISBN: 978-3-527-30518-6 2007 Online Book Wiley Interscience Bäckvall, J.-E. (ed.) ISBN: 978-0-470-09024-4 Modern Oxidation Methods 2004 de Vries, J. G., Elsevier, C. J. (eds.) ISBN: 978-3-527-30642-8 The Handbook of Homogeneous Hydrogenation 2007 ISBN: 978-3-527-31161-3 Modern Reduction Methods Edited by Pher G. Andersson and Ian J. Munslow The Editors All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and Prof. Dr. Pher G. Andersson publisher do not warrant the information Uppsala University contained in these books, including this book, to Department of Organic Chemistry be free of errors. Readers are advised to keep in Husargatan 3 mind that statements, data, illustrations, 751 23 Uppsala procedural details or other items may Sweden inadvertently be inaccurate. Dr. Ian J. Munslow Library of Congress Card No.: Uppsala University applied for Department of Biochemistry and Organic Chemistry Husargatan 3 British Library Cataloguing-in-Publication Data 751 23 Uppsala A catalogue record for this book is available from Sweden the British Library. Bibliographic information published by the Deutsche Nationalbibliothek Die Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografi e; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.
    [Show full text]
  • Design and Synthesis of Chiral Ligands and Their Applications in Transition
    The Pennsylvania State University The Graduate School Department of Chemistry DESIGN AND SYNTHESIS OF CHIRAL LIGANDS AND THEIR APPLICATIONS IN TRANSITION METAL-CATALYZED ASYMMETRIC REACTIONS A Dissertation in Chemistry by Wei Li 2012 Wei Li Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2012 The dissertation of Wei Li was reviewed and approved* by the following: Gong Chen Assistant Professor of Chemistry Dissertation Advisor Chair of Committee Tom Mallouk Evan Pugh Professor of Material Chemistry and Physics Alex Radosevich Assistant Professor of Chemistry Qing Wang Associate Professor of Material Science and Engineering Xumu Zhang Professor of Chemistry Special Member Barbara J. Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry *Signatures are on file in the Graduate School iii ABSTRACT Transition metal catalyzed reactions are among the most powerful and direct approaches for the synthesis of organic molecules. During the past several decades, phosphorous-containing ligands have been extensively studied in transition metal - catalyzed transformations particularly asymmetric hydrogenations. Development of new chiral ligands and efficient catalyst systems for various prochiral unsaturated substrates in asymmetric hydrogenations are the focus of this dissertation. An important family of atropisomeric biaryl bisphosphine ligands, C3*-TunePhos and related bisaminophosphines have been designed and synthesized. The Ru catalysts of the highly modular C3*-TunePhos have been proved to be highly efficient (up to 99.8% ee, up to 1,000,000 TON) for practical asymmetric hydrogenations of a wide range of unfunctionalized ketones as well as α-, β- keto esters and N-2-substituted allylphthalimides. The synthetic utility of bisaminophosphine ligands was studied for rhodium-catalyzed asymmetric hydrogenations of α-dehydroamino acid esters, affording up to 98% ee’s.
    [Show full text]
  • MICROREVIEW Substrate Activation in the Catalytic Asymmetric
    MICROREVIEW B. Balakrishna, J. L. Núñez-Rico, A. Vidal-Ferran This is the peer reviewed version of the following article: Eur. J. Org. Chem. 2015, 5293–5303, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201500588/pdf. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." Substrate Activation in the Catalytic Asymmetric Hydrogenation of N-Heteroarenes Bugga Balakrishna,[a] José Luis Núñez-Rico[a] and Anton Vidal-Ferran*[a],[b] Keywords: Asymmetric catalysis / Enantioselectivity / Iridium / Palladium / Nitrogen heterocycles / Hydrogenation. Different methods for transforming N-heteroarenes into more reactive derivatives for catalytic asymmetric hydrogenation are highlighted. The first strategy consists of facilitating hydrogenation by the formation of positively charged derivatives of the heteroarene. Catalyst deactivation processes arising upon binding of the substrate to the metal center can thus be prevented and, additionally, hydrogenation of positively charged heteroarenes may also be more favored than that of their neutral analogues. The second strategy is based on introducing a ligating group onto the substrate to assist its coordination to the metal center and facilitate hydrogenation by chelation assistance. The last strategy involves breaking the aromaticity of the heteroarene by inducing a doublebond migration process. This microreview summarizes advances made in the above strategies, which have allowed the development of highly enantioselective catalytic hydrogenation of N-heteroarenes for the production of fully or partially saturated chiral heterocycles. Introduction synthesizing fully or partly reduced heteroaromatic derivatives in Enantiopure organic compounds are important constituents of enantiomerically pure form (Scheme 1).[8] This synthetic strategy commercially produced chemicals including plastics, active also benefits from a great diversity of starting materials.
    [Show full text]
  • The Noyori Asymmetric Hydrogenation Reaction Chem 115
    Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115 Reviews: Mechanism: 1/n {[(R)-BINAP]RuCl2}n Noyori, R. Angew. Chem. Int. Ed. 2013, 52, 79–92. • Catalytic cycle: 2 CH3OH Kitamura, M.; Nakatsuka, H. Chem. Commun. 2011, 47, 842–846. Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069. Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40–73. [(R)-BINAP]RuCl2(CH3OH)2 H2 OCH3 Original Report by the Noyori Group: O HCl CH3OH O [(R)-BINAP]RuHCl(CH3OH)2 CH3 H2 2 CH OH H2 (100 atm) 3 O O OH O RuCl2[(R)-BINAP] (0.05 mol %) OCH3 CH3 OCH3 CH3 OCH3 CH3OH, 36 h, 100 °C O [(R)-BINAP]RuCl(CH3O)(CH3OH)2 [(R)-BINAP]HClRu 96%, >99% ee O OCH 3 CH3 O OCH3 HO O Noyori, R., Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akuragawa, S. CH OH CH3 3 J. Am. Chem. Soc. 1987, 109, 5856–5858. [(R)-BINAP](CH3OH)ClRu 2 CH3OH O CH3 • Both enantiomers of BINAP are commercially available. Alternatively, both enantiomers can be Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993, prepared from the relatively inexpensive (±)-1,1'-bi-2-naphthol. pp. 56–82. • The reduction of methyl 2,2-dimethyl-3-oxobutanoate proceeds in high yield and with high enantioselectivity, providing evidence that the reduction proceeds through the keto form of the !-keto ester. However, pathways that involve hydrogenation of the enol form of other !-keto esters cannot be OH PPh2 PPh2 ruled out. + OH PPh2 PPh2 H2 (100 atm) O O OH O RuCl2[(R)-BINAP]–Ru (±)-1,1'-Bi-2-naphthol (R)-(+)-BINAP (S)-(–)-BINAP CH3 OCH3 CH OH, 23 °C CH3 OCH3 20% 20% 3 CH3 CH3 CH3 CH3 99%, 96% ee Takaya, H.; Akutagawa, S.; Noyori, R.
    [Show full text]
  • Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of Δ‐Lactams
    Angewandte Communications Chemie How to cite: Asymmetric Catalysis Hot Paper International Edition: doi.org/10.1002/anie.202016771 German Edition: doi.org/10.1002/ange.202016771 Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of d-Lactams Tobias Wagener+, Lukas Lckemeier+, Constantin G. Daniliuc, and Frank Glorius* Dedicated to Professor David A. Evans on the occasion of his 80th birthday Abstract: Metal-catalyzed hydrogenation is an effective method to transform readily available arenes into saturated motifs, however, current hydrogenation strategies are limited to the formation of CÀH and NÀH bonds. The stepwise addition of hydrogen yields reactive unsaturated intermediates that are rapidly reduced. In contrast, the interruption of complete hydrogenation by further functionalization of unsaturated intermediates offers great potential for increasing chemical complexity in a single reaction step. Overcoming the tenet of full reduction in arene hydrogenation has been seldom demonstrated. In this work we report the synthesis of sought- after, enantioenriched d-lactams from oxazolidinone-substi- tuted pyridines and water by an interrupted hydrogenation mechanism. Metal-catalyzed hydrogenation is known to be a simple and powerful method to increase molecular complexity.[1] In particular, the hydrogenation of easily accessible N-hetero- arenes such as pyridines offers access to important saturated azacycles.[2] This established reaction is limited solely to the formation of new CÀH and NÀH bonds; additional synthetic Figure 1. Mechanistic pathways of unsaturated intermediates in arene manipulations are required to introduce further chemical hydrogenation and this work. Aux =chiral auxiliary. functionality.[3] The stepwise transfer of molecular hydrogen in arene hydrogenation yields intermediates with double synthesized using iridium-catalyzed hydride transfer followed bonds remaining, which in principle offer the possibility of by hydroxymethylation.
    [Show full text]
  • Application of Hydrogen Bonding in Asymmetric
    APPLICATION OF HYDROGEN BONDING IN ASYMMETRIC HYDROGENATION By JIALIN WEN A dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Chemistry and Chemical Biology Written under the direction of Professor Xumu Zhang And approved by _____________________________________ _____________________________________ _____________________________________ _____________________________________ New Brunswick, New Jersey October, 2016 ABSTRACT OF THE DISSERTATION Application of Hydrogen Bonding in Asymmetric Hydrogenation By JIALIN WEN Dissertation Director: Xumu Zhang Hydrogen bonding has been widely observed in biosynthesis and enzyme catalysis. It plays an important role in such fields as molecular recognition, supramolecular chemistry and small molecule catalysis. A new concept of organocatalysis emerged in recent two decades. Hydrogen bonding is the keystone for thiourea catalysis or phosphoric acid catalysis. With high turnover numbers and excellent enantioselectivity, transition metal catalysis not only is the arts in academia, but also find its merit in industrial application. Homogeneous hydrogenation, among many successful transition metal catalyzed reactions, has been serving the synthetic communities for many years, both in academia or in industry. The success of secondary interaction and hydrogen bonding offer us an alternative: the combination of hydrogen bonding and steric hindrance help to create a chiral environment in which substrates could be reduced efficiently. ii Guided by this rationale, a ferrocene-based bisphosphine/thiourea ligand, ZhaoPhos was synthesized in our group. It was applied in the asymmetric hydrogenation of nitroolefins with hydrogen bonding between the ligand and substrates. Thiourea- carbonyl hydrogen bonding is another model of non-covalent interaction.
    [Show full text]
  • Asymmetric Hydrogenation As Ideal Green Chemistry
    AsymmetrProc Indianic Natn Hydrog Sci Acadenation 72 asNo.4 Ideal pp. 267-273Green Chemistry (2006) 267 Review Article Asymmetric Hydrogenation as Ideal Green Chemistry RYOJI NOYORI RIKEN, Wako, Saitama 351-0198, Japan, and Department of Chemistry and Research Center of Materials Science, Nagoya University, Chikusa, Nagoya 464-8062, Japan (Received 4 November 2006; Accepted 16 December 2006) We should be proud of being chemists. Chemistry is more important compounds in a cost-effective, energy-saving, than a science of observing and understanding Nature. and environmentally benign manner. The world maket It is characterized by the capability of generating high of catalysts is ca. 12B USD, and the chemical production values from almost nothing. Therefore, synthesis is not through catalysis is estimated to be 1.2-6.0T USD. merely an intellectual challenge but also a practical Therefore, chemists must develop practical catalytic technology for the survival of our species. Man-made processes using heterogeneous, homogeneous, and substances and materials determine the quality of life. biological catalysts. In fact, throughout the history of humankind, chemistry Since long before the significance of Green has been essential to the prosperity of society [1]. Its Chemistry became apparent, I have pursued significance is ever increasing. hydrogenation, the ultimate Green Technology. In 2003, the National Academy of Engineering in Hydrogen is a clean and abundant resource and has the US characterized the 20th century as “A Century of unlimited applicability to basic and applied science, Innovation” and selected 20 greatest technologies that technology, and industry at large. In particular, decisively changed our lives during that period [2].
    [Show full text]
  • Asymmetric Hydrogenation of Heteroaromatic Compounds
    Acc. Chem. Res. 2007, 40, 1357–1366 Scheme 1. Pioneering Works on Asymmetric Hydrogenation of Asymmetric Hydrogenation of Heteroaromatic Compounds Heteroaromatic Compounds YONG-GUI ZHOU* Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China Received April 17, 2007 ABSTRACT Asymmetric hydrogenation of heteroaromatic compounds has emerged as a promising new route to saturated or partially saturated chiral heterocyclic compounds. In this Account, we outline recent advances in asymmetric hydrogenation of het- eroaromatic compounds, including indole, quinoline, isoquinoline, furan, and pyridine derivatives, using chiral organometallic catalysts and organocatalysts. Introduction Catalytic asymmetric hydrogenations of prochiral unsat- urated compounds, such as olefins, ketones, and imines, have been intensively studied and are considered a versatile method for access to chiral compounds.1 On the other hand, asymmetric hydrogenation of aromatic/ heteroaromatic compounds is much less explored, pre- Cl(R-BINAP)(µ-Cl )][NH Et ]. The patent literature con- sumably because of the following reasons: (1) The high 3 2 2 tains the filing6 by Lonza AG in 1996 on asymmetric stability of aromatic compounds usually requires elevated hydrogenation of pyrazinecarboxylic acid derivatives, with temperatures and pressures and thereby adversely affect- ing the enantioselective reduction.2 (2) Deactivation and/ an ee up to 78% using homogeneous [Rh(COD)Cl]2/ or poisoning of catalysts by heteroaromatic compounds diphosphine/MeOH at 50 atm. In 1998, Bianchini devel- containing nitrogen and sulfur atoms may occur. (3) The oped an orthometalated dihydride iridium complex for lack of a secondary coordinating group in simple aromatic hydrogenation of 2-methylquinoxaline to 1,2,3,4-tetrahy- 7 compounds, as contrast to functionalized alkenes and dro-2-methylquinoxaline with up to 90% ee (Scheme 1), ketones, to interact with the central metal atom, must although conversion is not satisfactory.
    [Show full text]
  • Asymmetric Synthesis of C2-Symmetric Bimorpholines and Their Application As Chiral Ligands in the Transfer Hydrogenation of Aromatic Ketones
    Asymmetric Synthesis of C2-Symmetric Bimorpholines and Their Application as Chiral Ligands in the Transfer Hydrogenation of Aromatic Ketones KADRI KRIIS TALLINN UNIVERSITY OF TECHNOLOGY Department of Chemistry Chair of Organic Chemistry Dissertation in Organic Chemistry to be publicly examined at Tallinn University of Technology, on January 20, 2004 for the Degree of Doctor of Philosophy Supervisors: Professor Margus Lopp, Ph. D. Associate Professor Tõnis Kanger, Ph. D. Opponents: Professor Asko Uri, Ph. D., Institute of Organic and Bioorganic Chemistry, University of Tartu, Estonia Senior Research Scientist Lauri Vares, Ph. D., AstraZeneca AB, Sweden Copyright Kadri Kriis 2003 ISSN 1406-4723 ISBN 9985-59-412-6 Abstract The chiral heteroatom-containing compounds are valuable synthons in the asymmetric synthesis. The combination of C2-symmetry and the rigidity of the heterocycles can be a determining factor for effectiveness in the asymmetric reactions. The chiral ligands in the conformationally restricted chelation with metal can increase the stereodifferentiation for various metal mediated reactions. They can cause an efficient chirality transfer from the heterocycle to the newly formed bonds, thereby generating new stereogenic centers with high asymmetric induction. Based on these positive properties, in the first part of this thesis the synthesis of two new chiral N,O-containing bicycles - 2S,2´S- and 3S,3´S-bimorpholine has been studied. (R,R)-tartaric acid ester, as a very convenient precursor, was chosen for the synthesis of both target compounds. The general scheme for the synthesis of these C2-symmetric bimorpholines consists of three major steps: introduction of the nitrogen-containing functionality into the tartaric acid derivative, O-alkylation of hydroxyl groups with a functionalised C2 unit, and subsequent intramolecular cyclisation.
    [Show full text]
  • New Directions for Bis-Adamantane Chemistry and Reactivity
    New Directions for Bis-Adamantane Chemistry and Reactivity by Yumeela Ganga-Sah B. Sc. (Hons.), University of Mauritius, 2011 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Department of Chemistry Faculty of Science Yumeela Ganga-Sah 2017 SIMON FRASER UNIVERSITY Spring 2017 Approval Name: Yumeela Ganga-Sah Degree: Master of Science (Chemistry) Title: New Directions for Bis-Adamantane Chemistry and Reactivity Examining Committee: Chair: Dr. Charles J. Walsby Associate Professor Dr. Daniel B. Leznoff Senior Supervisor Professor Dr. Andrew J. Bennet Co-Supervisor Professor Dr. Robert N. Young Supervisor Professor Dr. Jeffrey J. Warren Supervisor Assistant Professor Dr. Peter D. Wilson Internal Examiner Associate Professor Date Defended/Approved: January 27, 2017 ii Abstract Bulky chiral ligands have gained tremendous attention in metal coordination chemistry as they influence greatly coordination geometry and reactivity and are critical features of asymmetric catalysts. In this thesis, the design and synthesis of sterically congested chiral alcohol and amine ligands based on a bis-adamantane framework, are explored. Optimization of the ligand synthesis and purification were conducted on the racemic ketone, while the chiral synthetic pathway utilized an enzymatic hydrolysis as the key step. In another aspect of bis-adamantane chemistry, the bromonium ion of adamantylideneadamantane (Ad=Ad) has provided valuable mechanistic information about electrophilic addition of bromine and undergoes a fast “Br+” transfer process to alkenes. However, the Ad=Ad isomer SesquiAdAd only reacts with [AdAdBr+] and not with Br2. This thesis also investigated the rearrangement of SesquiAdAd to Ad=Ad catalyzed by [AdAdBr+] via the formation of the potentially high energy intermediate SesquiAdAdBr+, probed by 1H NMR spectroscopy and kinetics.
    [Show full text]
  • Ryoji Noyori
    ASY M METRIC CATALYSIS: SCIE NCE A N D OPP ORT U NITIES Nobel Lecture, Dece mber 8, 2001 by R Y OJI N OY O RI Depart ment of Che mistry, Graduate School of Science, and Research Center of Materials Scie nce, Nagoya U niversity, C hikusa, Nagoya 464-8602, Japa n. PR OL OGUE C hirality ( ha n de d ness; left or rig ht) is a n i ntri nsic u niversal feat ure of vari o us levels of matter[1]. Molec ular c hirality plays a key role i n scie nce a n d tec h- n ol o gy. I n p arti c ul ar, lif e d e p e n ds o n m ol e c ul ar c hir ality, i n t h at m a ny bi ol o- gical functions are inherently dissy m metric. Most physiological pheno mena arise fro m highly precise molecular interactions in which chiral host mo- lecules recog nize t wo e na ntio meric guest molecules i n differe nt ways. T here are nu merous exa mples of e na ntio mer effects w hic h are freque ntly dra matic. Enantio mers often s mell and taste differently. The structural difference bet wee n e na natio mers ca n be serio us wit h res pect to t he actio ns of sy nt hetic drugs. C hiral receptor sites i n t he hu ma n body i nteract o nly wit h drug mo- lecules havi ng t he proper absolute co n figuratio n, resulti ng i n marked diffe- rences in the phar macological activities of enantio mers.
    [Show full text]
  • Co-Crystallization Induced Spontaneous Deracemization
    I UNIVERSITÉ CATHOLIQUE DE LOUVAIN INSTITUTE OF CONDENSED MATTER AND NANOSCIENCES (IMCN) Laboratory of Crystal Engineering Prof. Tom Leyssens Laboratory of Organic Chemistry Prof. Olivier Riant Development and Optimization of a new general thermodynamic deracemization method: Co-crystallization Induced Spontaneous Deracemization Thèse présentée en vue de l'obtention du grade de docteur en Sciences par Michael Guillot Louvain-la-Neuve Septembre 2020 II Jury Members Prof. Y. Cartigny Université de Rouen Normandie Prof. S. Kuhn Katholieke Universiteit Leuven Prof. M. Singleton Université catholique de Louvain Dr. K. Robeyns Université catholique de Louvain Prof. Y. Garcia (President) Université catholique de Louvain Prof. T. Leyssens (Promotor) Université catholique de Louvain Prof. O. Riant (Co-promotor) Université catholique de Louvain III Acknowledgements Je tiens tout d’abord à remercier mon promoteur, le professeur Tom Leyssens de m’avoir offert la chance de faire partie de son laboratoire pendant ces 4 années qui furent épanouissantes sur tous les plans. Je le remercie pour son encadrement tout au long de ma thèse, pour son soutien tant scientifique que personnel (surtout pendant « the dark year » où plus rien ne semblait marcher, je pense que tu vois de quel moment je parle Tom ;)) et pour la proximité qu’il sait créer au sein de son équipe. Je le remercie pour les congrès et séjours scientifiques que j’ai pu réaliser grâce à lui et qui ont tant participé à mon apprentissage autant scientifique que personnel. Je tiens tout aussi à remercier mon co-promoteur, le professeur Olivier Riant, pour ses conseils et corrections tout au long de ces quatres années de thèse.
    [Show full text]