Chiral Pyridyl Phosphinite Catalysts and the Development of Structure Selectivity Relationships in the Asymmetric Hydrogenation of Trisubstituted Alkenes Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von David Harrison Woodmansee aus San Diego, USA Basel 2010 Original document stored on the publication server of the University of Basel edoc.unibas.ch This work is licenced under the agreement „Attribution Non-Commercial No Derivatives – 2.5 Switzerland“. The complete text may be viewed here: creativecommons.org/licenses/by-nc-nd/2.5/ch/deed.en Attribution-Noncommercial-No Derivative Works 2.5 Switzerland You are free: to Share — to copy, distribute and transmit the work Under the following conditions: Attribution. You must attribute the work in the manner specified by the author or licensor (but not in any way that suggests that they endorse you or your use of the work). Noncommercial. You may not use this work for commercial purposes. No Derivative Works. You may not alter, transform, or build upon this work. • For any reuse or distribution, you must make clear to others the license terms of this work. The best way to do this is with a link to this web page. • Any of the above conditions can be waived if you get permission from the copyright holder. • Nothing in this license impairs or restricts the author's moral rights. Your fair dealing and other rights are in no way affected by the above. This is a human-readable summary of the Legal Code (the full license) available in German: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/legalcode.de Disclaimer: The Commons Deed is not a license. It is simply a handy reference for understanding the Legal Code (the full license) — it is a human-readable expression of some of its key terms. Think of it as the user-friendly interface to the Legal Code beneath. This Deed itself has no legal value, and its contents do not appear in the actual license. Creative Commons is not a law firm and does not provide legal services. Distributing of, displaying of, or linking to this Commons Deed does not create an attorney-client relationship. Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/deed.en Datum: 3.4.2009 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Andreas Pfaltz Prof. Dr. Thomas Ward Basel, den 25.5.2010 Prof. Dr. Eberhard Parlow Dekan This thesis was supervised by Prof. Dr. Andreas Pfaltz from February 2006 to May 2010 at the University of Basel, Department of Chemistry. Acknowledgements I would like to thank my supervisor Professor Dr. Andreas Pfaltz for the opportunity to work in his research group, for his support and the freedom in developing my project. I would like to thank Professor Dr. Thomas R. Ward for co-examination of this thesis and Prof. Dr. Helma Wennemers for chairing the defense. I am very grateful to Marc-André Müller, Denise Rageot, and Felix Voss for their hard work in their masters’ research and the continuous support for my own endeavors. I thank Dr. Axel Franzke, Dr. Stephen Kaiser, and Dr. Rui Fraga for the many insightful and stimulating discussions. I am grateful to Markus Neuburger for collecting X-ray data and his hard work in solving problematic structures. I thank Dr. Daniel Häussinger for supporting my own NMR-measurments. I thank Jaroslav Padevet for solving numerous computer and NMR problems. I am grateful to Lars Tröndlin and Dominik Frank for their help with instruments and chemicals. I thank Marina Mambelli-Johnson for her constant support and her willingness to go beyond what was required. I thank Dr. Heinz Nadig measured the EI and FAB mass spectra and Werner Kirsch determined all elemental analyses. I thank the members of the workshop for technical support, especially Mr. Koller for his support with the glove box. I thank all the past and present members of the Pfaltz group who made my time in Basel enjoyable. The colleagues in lab 208 are especially acknowledged for the good working atmosphere. I am grateful to Dr. Hong Liu and Dr. Yu Ge, my industrial mentors for their support and sound advice, without which I would not have pursued a Ph.D. in a foreign country. I am very grateful to my parents for their support throughout my education. I am very grateful to meinen Schwiegereltern Barbara und Hendrik, for their support and occasional medical attention. I am deeply grateful and indebted to my wife Constanze Treugut for her advice, support and sacrifice. Summary The current trend in developing asymmetric catalysts is towards creating specialized molecules with tailored functions for increased selectivity in classes of substrates rather than general catalysts capable of broad application. In addition, the capacity to generate groups of catalysts with incremental changes to overall structure allows for a more detailed analysis of contributions to the structure selectivity relationships for a variety of substrates. This information can then be used to identify ideal catalysts or improve selectivity and activity of for a particular system. Asymmetric hydrogenation of substituted alkenes with chiral iridium N,P complexes that were developed from the achiral Crabtree Complex have proven to be extraordinary selective and active catalysts. Screening a series of trisubstituted alkenes on 1st and 2nd generation catalysts indicated a strong enantioselectivity dependence on the phosphorus and pyridine substituents. In particular, the substituents in the ortho position of the pyridine ring were found to have significant control over the catalyst. The synthesis of the 3rd generation of chiral pyridyl phosphinite catalysts takes advantage of a flexible late phase incorporation of the functional groups which govern the selectivity of the asymmetric hydrogenation to span a range of steric and electronic properties. The screening of these catalysts in the asymmetric hydrogenation of several classes of trisubstituted alkenes provided clear insight to the factors controlling enantioselectivity which were proven to vary greatly with the nature of the substrate and catalyst. Several catalysts with exceptional selectivity were identified for multiple examples of trisubstituted alkenes which had proven difficult with previous system. CHAPTER 1 .......................................................................................................................................................... 1 IRIDIUM CATALYZED ASYMMETRIC HYDROGENATION OF ALKENES WITH CHIRAL N,P AND C,N LIGANDS ...................................................................................................................................................... 1 1.1 INTRODUCTION ..................................................................................................................................................... 2 1.2 MECHANISTIC STUDIES ........................................................................................................................................ 3 1.2.1 Initial Studies: An Unexpected Anion Effect ................................................................................................ 3 1.2.2 NMR Investigations of Iridium PHOX Hydride Complexes ......................................................................... 5 1.2.3 Computational Studies and Additional Experiments.................................................................................... 7 1.3 ASYMMETRIC HYDROGENATION OF TRISUBSTITUTED ALKENES ........................................................................ 10 1.3.1 Asymmetric Hydrogenation of Standard Test Substrates ........................................................................... 10 1.3.2 Asymmetric Hydrogenation of Purely Alkyl Substituted Alkenes ............................................................... 18 1.3.3 Asymmetric Hydrogenation of Fluorinated Alkenes .................................................................................. 21 1.3.4 Asymmetric Reduction of Vinylboronates .................................................................................................. 22 1.3.5 Diastereoselective Reduction of Alkenes.................................................................................................... 23 1.3.6 Redox Rearrangement of Allylic Alcohols to Chiral Aldehydes ................................................................. 25 1.3.7 Conjugate Reduction .................................................................................................................................. 25 1.4 ASYMMETRIC HYDROGENATION OF 1,1’-DISUBSTITUTED ALKENES .................................................................. 33 1.5 ASYMMETRIC HYDROGENATION OF TETRASUBSTITUTED ALKENE .................................................................... 35 1.6 ASYMMETRIC HYDROGENATION OF TRISUBSTITUTED ALKENES WITH HETEROATOMS...................................... 38 1.6.1 Enol Esters and Ethers ............................................................................................................................... 38 1.6.2 Asymmetric Hydrogenation of Furans and Chromenes ............................................................................. 42 1.6.3 ASYMMETRIC HYDROGENATION OF ENAMINES AND INDOLES ....................................................................... 44 1.6.4 Asymmetric Hydrogenation of Quinolines and Pyridines .........................................................................