! " # !"! ! # $%& $! "" %%! ' ( ) * ))(() $$&+& 8!" %( DT7I r rprr GvthqPyrsv Bear in mind that the wonderful things you learn in your schools are the work of many generations. All this is put in your hands as your inheritance in order that you may receive it, honor it, add to it, and, one day, faithfully hand it on to your children. Albert Einstein Till Petra och Zion Scientific advisor Prof. Pher G. Andersson Department of Biochemistry and Organic Chemistry Uppsala University Faculty opponent Prof. Lise-Lotte Gundersen Department of Chemistry University of Oslo Examination committee Dr. Sverker Hansson AstraZeneca AB Södertälje Prof. Mats Larhed Department of Medicinal Chemistry Organic Pharmaceutical Chemistry Uppsala University Prof. David Tanner Department of Chemistry Organic Chemistry Technical University of Denmark Dr. Jan Vågberg iNovacia AB Stockholm Prof. Björn Åkermark Department of Organic Chemistry Stockholm University List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Mattias Engman; Jarle Diesen; Alexander Paptchikhine; Pher G. Andersson. Iridium-Catalyzed Asymmetric Hydrogenation of Fluori- nated Olefins Using N,P-Ligands: A Struggle with Hydrogenolysis and Selectivity. Journal of the American Chemical Society, 2007, 129, 4536–4537. II Päivi Kaukoranta; Mattias Engman; Christian Hedberg; Jonas Ber- gquist; Pher G. Andersson. Iridium Catalysts with Chiral Imidazole- Phosphine Ligands for Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins. Advanced Synthesis & Catalysis, 2008, 350, 1168–1176. III Mattias Engman; Pradeep Cheruku; Päivi Tolstoy; Jonas Bergquist; Sebastian F. Völker; Pher G. Andersson. Highly Selective Iridium- Catalyzed Asymmetric Hydrogenation of Trifluoromethyl Olefins: A New Route to Trifluoromethyl-Bearing Stereocenters. Advanced Synthesis & Catalysis, 2009, 351, 375–378. IV Päivi Tolstoy; Mattias Engman; Alexander Paptchikhine; Jonas Ber- gquist; Tamara L. Church; Abby W.-M. Leung; Pher G. Andersson. Irid- ium-Catalyzed Asymmetric Hydrogenation yielding Chiral Diarylmethi- nes with either Coordinating or Non-Coordinating Substituents (Manuscript) Reprints were made with permission from the publishers. Contribution Report The author wishes to clarify his contribution to the papers I–IV in the thesis I Performed a significant part of the experimental work and the develop- ment of new methods for chiral separation of the products; contributed significantly to interpreting the results and writing the paper. II Contributed significantly to the experimental work, development of separation methods and interpretation of the results mainly concerning fluorine substrates; contributed in the preparation of the manuscript. III Performed a significant part of the experimental work; developed a ma- jority of the methods needed for separation of products; contributed sig- nificantly to the interpretation of the results and partly to the writing of the paper. IV Performed a significant part of the experimental work; contributed sig- nificantly to separating the products, interpreting the results and prepar- ing the manuscript. Contents 1 Introduction ................................................................................................ 11 1.1 Chirality.............................................................................................. 11 1.2 Asymmetric hydrogenation ............................................................... 13 2 Asymmetric Hydrogenation using Iridium Complexes — Focus on Fluorine-Containing Substrates (Paper I and II)............................................. 15 2.1 Introduction ........................................................................................ 15 2.2 Catalysts.............................................................................................. 18 2.3 Olefin synthesis.................................................................................. 19 2.4 Hydrogenations .................................................................................. 22 2.4.1 Hydrogenolysis: Defluorination............................................... 22 2.4.2 Hydrogenation of other substrates ............................................ 25 2.4.3 Evaluation of catalysts with imidazole-based ligands for the hydrogenation of fluoroolefins............................................................... 29 2.5 Hydrogenation of <-chlorocinnamic ester and the corresponding alcohol .......................................................................................................... 34 2.6 Further studies on the new catalyst (R)-II........................................ 35 3 Hydrogenation of trifluoromethyl-substituted olefins (Paper III) .......... 37 3.1 Introduction ........................................................................................ 37 3.2 Hydrogenation.................................................................................... 38 4 Formation of 1,1-diarylmethine stereocenters (Paper IV)....................... 45 4.1 Introduction ........................................................................................ 45 4.2 Hydrogenation.................................................................................... 46 4.2.1 Unfunctionalized olefins............................................................ 48 4.2.2 Esters, alcohols and acetates ..................................................... 50 5 Enantiodiscrimination................................................................................ 52 5.1 Introduction ........................................................................................ 52 5.2 Fluorine- and trifluoromethyl-substituted olefins............................ 54 5.3 1,1-Diaryl olefins ............................................................................... 57 6 Conclusions and Outlook .......................................................................... 59 Acknowledgements .......................................................................................... 61 Summary in Swedish........................................................................................ 63 References......................................................................................................... 65 Abbreviations * Chiral center Abs. Conf. Absolute configuration Ac Acetyl Ar Aryl - BArF Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate B3LYP Becke’s 3 parameter hybrid functional using the Lee- Yang-Parr correlation functional B-DM Astec CHIRALDEX -cyclodextrin (dimethyl) column Caro’s acid Peroxysulfuric acid, H2SO5 Cat. Catalyst COD Cyclooctadiene Conv. Conversion Cy Cyclohexyl c-EWG Conjugated electron-withdrawing group de Diastereomeric excess DCM Dichloromethane DFT Density functional theory DIBAL Diisobutylaluminium hydride DNA Deoxyribonucleic acid ee Enantiomeric excess Et Ethyl EWG Electron-withdrawing group GC Gas chromatography h Hour(s) HPLC High performance liquid chromatography HWE Horner-Wadsworth-Emmons (reaction) i-Pr Isopropyl LACVP Los Alamos effective core valence potential LCD Liquid crystal display mCPBA meta-Chloroperoxybenzoic acid Me Methyl MS Mass spectrometer n-BuLi n-Butyllithium NCS N-Chlorosuccinimide NMR Nuclear magnetic resonance NOE Nuclear overhauser effect (N,P)* Chiral N,P ligand o.n. Overnight Pd/C Palladium on carbon Ph Phenyl rac Racemic r.t. Room temperature RNA Ribonucleic acid THF Tetrahydrofuran Å Ångström Catalyst numbering: Ph Ph Ph Ph Ph BArF Ph BAr BArF P F R P Ir P N Ir O Ir N N N Ph Ph Ph Ph S S O II III I a: R = Me b: R = Bn Ar Ar Ar Ar BArF Ar Ar BArF BArF P P P Ir Ir Ir N N N N R R Ph N O R' S VI IV V a: Ar = o-tol, R = i-Pr, R' = H a: Ar = Ph, R = H a: Ar = Ph b: Ar = Ph, R = Ph, R' = Ph b: Ar = 3,5-dimethylphenyl b: Ar = Ph, R = Ph c: Ar = Ph, R = i-Pr, R' = H c: Ar = o-tol c: Ar = o-tol, R = 3,5-dimethylphenyl d: Ar = Cy, R = Ph, R' = Ph 1 Introduction 1.1 Chirality A molecule containing a carbon with four different substituents can occur in two forms that are mirror images of each other. These will have the same physical properties, such as boiling point, molecular weight, hardness, color etc. However, since the beginning of the 19th century scientists have ob- served that these so-called enantiomers also have different properties. For example, Louis Pasteur separated the enantiomers of sodium ammonium tartrate manually by a pair of tweezers and studied how they rotated plane- polarized light in different directions.1 In the 1960s, we learned more about how two enantiomers interact differently with our world, when the effects of thalidomide (named Neurosedyn on the Swedish market) were revealed.2,3 Children whose mothers had been taking thalidomide to alleviate morning sickness and to help them sleep during pregnancy were born with malformed extremities. Investigations revealed that one of the two mirror forms had the wanted therapeutic effect, and the other one caused the toxic effects (Figure 1) In the same way, the two forms of limonene taste and smell different. (R)- Limonene smells like orange and (S)-limonene like lemon.