Lanthanide Replacement in Organic Synthesis: Calcium-mediated Luche-type Reduction of α,β-functionalised Ketones A thesis submitted by Nina Viktoria Forkel In partial fulfilment of the requirement for a degree of Doctor of Philosophy Imperial College London Department of Chemistry South Kensington Campus SW7 2AZ London United Kingdom September 2013 Lanthanide Replacement in Organic Synthesis: Calcium-mediated Luche-type Reduction of α,β-functionalised Ketones “Man kann sich die Weite und Möglichkeiten des Lebens gar nicht unerschöpflich genug denken.” (Rainer Maria Rilke) This thesis is dedicated to all my loved ones. Declaration of originality and statement of copyright Declaration of originality I, Nina V. Forkel, certify that the research described within this thesis was carried out in the Department of Chemistry at Imperial College London between October 2009 and September 2012. It was accomplished under the primary supervision of Dr Matthew J. Fuchter, Imperial College London, along with supervision from Dr David A. Henderson, Pfizer Ltd. The entire body of work is that of the author, unless otherwise stated to the contrary, and has not been submitted previously for a degree at this or any other university. Statement of copyright The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes, and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. …………………………… Nina V. Forkel London, 28th September 2013 iv Acknowledgements Acknowledgements Firstly, I would like to thank my supervisor Dr Matthew Fuchter for the great opportunity to work in his research group and for his guidance, support, and enthusiasm throughout this project, but also for the freedom he has given me in pursuit of my research. I must also acknowledge Dr David Henderson from Pfizer for his CASE supervision and interest, especially during my three month placement. I would like to thank the EPSRC and Pfizer for funding this project as well as Imperial College London and the ACS, RSC, GDCh and Imperial College Trust for financial support which aided my attendance at several conferences. Furthermore, I would like to thank Peter Haycock and Dick Sheppard for all their help with NMR spectroscopy, John Barton and Lisa Haigh for mass spectroscopy services, and Stephen Boyer for microanalysis. Many thanks to the administrative staff for their help: Katie, Graeme and especially Rachael. I have to acknowledge my team of proof-readers for their time and advice: Dr Frauke Thrun, Dr Marko Weimar, Dr Gudrun Schindler, Nadine Kandziora, Fu-Howe Lee, Adelle Vandersteen, Kathrin Forkel, and Stephanie Reid. I am very grateful for all their efforts in helping to perfect my thesis. I would like to thank the past and present members of the Fuchter and Barrett groups for a wonderful time during my PhD, especially Christine and Stephanie, my fume hood neighbours and also calcium specialists, who were fun to work and chat with, and not only about calcium chemistry. Finally, huge thanks go to all my family for their confidence, support, and motivation in all situations throughout my PhD, particularly in the last months of writing up my thesis. Thank you so much! v Abbreviations Abbreviations Å Ångstrom (10-10 metres) Ac acetyl alk alkyl anal. analysis Ar aryl ar aromatic Bn benzyl bp boiling point Boc tert-butyloxycarbonyl Box bisoxazoline br broad Bu butyl Bz benzoyl C carbon °C degree Celsius c concentration ca. circa calc. calculated cat. catalytic Cat. catalyst Cbz carboxybenzyl CI chemical ionisation cm centimetre CN coordination number conc. concentrated conv. conversion Cy cyclohexyl cyc cyclic d doublet dd doublet of doublets dq doublet of quartets δ chemical shift DCE 1,2-dichloroethane DEAD diethyl azodicarboxylate vi Abbreviations dr diastereomeric ratio DIBAL-H di-iso-butylaluminium hydride DIPEA di-iso-propylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DppONH2 ortho-diphenylphosphinyl hydroxylamine E° reduction potential ee enantiomeric excess EI electron ionisation Eq. equation equiv. equivalent(s) ES electrospray Et ethyl et al. et alii Et3N triethylamine Et2O diethylether EtOAc ethylacetate EtOH ethanol EWG electronwithdrawing group f f-orbital(s) Fmoc fluorenyloxycarbonyl GC/MS gas chromatography/mass spectroscopy GP general procedure h hour(s) het heteroaromatic HFIP hexafluoro-iso-propoxide HMDS hexamethyldisilizane HMPA hexamethylphosphoramide HPLC high-performance liquid chromatography HRMS high resolution mass spectroscopy HSAB hard and soft acids and bases (M)Hz (mega)Hertz i iso IR infrared spectroscopy vii Abbreviations International Union of Pure and Applied IUPAC Chemistry J coupling constant k rate constant K Kelvin L ligand L litre lit. literature LG leaving group Ln lanthanide(s) m mass µ micro (10-6) m multiplet M metal(s) M molar Ms methanesulfonyl MSH ortho-mesitylenesulfonyl hydroxylamine m/z mass-to-charge ratio max maximal m-CPBA meta-chloroperbenzoic acid Me methyl min minute(s) MeOH methanol mL millilitre(s) mmol millimole(s) mol mole(s) mp melting point MS mass spectroscopy MVK methyl vinyl ketone MW molecular weight n normal N normal concentration ND not determined NCS N-chlorosuccinimide NMM N-methylmorpholine NMR nuclear magnetic resonance viii Abbreviations o ortho OMs mesylate OTf triflate p para PET petroleum ether Ph phenyl PhMe toluene ppm part(s) per million Pr propyl q quartet quint quintet r ionic radius or radii R general substituent rac racemic Rf retention factor RSM recovered starting material rt room temperature rxn reaction(s) sat. saturated SMP sample t or tert tertiary t triplet t time T temperature TMS trimethylsilyl TES triethylsilyl Tf triflouromethane sulfonyl (triflic) THF tetrahydrofurane TIPS tri-iso-propylsilyl TLC thin layer chromatography TOF MS time-of-flight mass spectroscopy Tol tolyl Tr triphenylmethyl (tritiyl) TptBu hydrotris(3-tert-butylpyrazolyl)borate Ts para-toluenesulfonyl (tosyl) UV ultra violet ix Abbreviations ν wave length V Volt VAPOL 2,2’-diphenyl-3,3’-biphenanthryl-4,4’diyl Z charge x Abstract Abstract Complexes of alkaline earth metals (Ca, Sr, and Ba) exhibit lanthanide-like reactivity and coordination behaviour, thus it is not surprising that such alkaline earth metals are also often compared to early f-block lanthanides. Attention has been focused on calcium-catalysed reactions as calcium, the fifth most abundant element in the Earth’s crust, is not only a cheaper alternative to lanthanide salts but is also less toxic, due to its high biocompatibility. As a result, the use of calcium complexes to catalyse a broad range of reactions in organic synthesis has increased tremendously over the past two decades. One such reaction where catalyst modification is suitable is the Luche reduction. The Luche reduction is one of the standard protocols for the selective reduction of α,β-unsaturated ketones to form allylic alcohols; however, the use of cerium chloride as a stoichiometric additive is not desirable for industrial-scale reactions (Scheme A1). O OH OH Ca(OTf)2, NaBH4 1 1 1 R R THF/MeOH, rt R R R R R, R1 = (cyclo)alkyl, (hetero)aromatic selectivities up to 100:0 Scheme A1. Calcium-mediated 1,2-reduction of α,β-unsaturated ketones Successful reaction conditions for the calcium-mediated selective 1,2-reduction of challenging enones have been developed. Even the challenging substrate 2-cyclopentenone was reduced to its corresponding allylic alcohol in high 92:8 selectivity (allylic alc.:sat. alc.). The developed conditions were employed to a large variety of enone substrates. Our chemistry showed high selectivity, in some cases the selectivity was even better than the selectivity obtained under classic Luche conditions. Preliminary studies have also shown that the stereoselective reduction of α,β-epoxy and α,β-aziridinyl ketones to the corresponding alcohols in the presence of calcium triflate resulted in excellent diastereoselectivity (Scheme A2). O OH OH X Ca(OTf)2, NaBH4 X X 1 R R1 MeOH/THF, rt R R R R1 X = O, NR2 X = O up to 100:0 dr 2 R, R1 = alkyl, (hetero)aromatic X = NR up to 95:5 dr 2 R = Bn, allyl, Ts, Cbz Scheme A2. Calcium-mediated diastereoselective reduction of α,β-functionalised ketones xi Table of contents Table of Contents Declaration of originality .......................................................................................................... iv Acknowledgements ...................................................................................................................... v Abbreviations ............................................................................................................................ vi Abstract ..................................................................................................................................... xi I Introduction ................................................................................. 1 1 The importance of sustainable and green processes in organic synthesis ................................................................................................ 1 2 Characteristics of alkaline earth metals ............................................ 3 3 Comparison of alkaline earth metals to lanthanides .......................