THESISONNATURALANDEXACTSCIENCESB97 Asymmetric Organocatalytic Michael and Aldol Reactions Mediated by Cyclic Amines MARJU LAARS PRESS TALLINNUNIVERSITYOFTECHNOLOGY FacultyofScience DepartmentofChemistry DissertationwasacceptedforthedefenceofthedegreeofDoctorofPhilosophyin NaturalandExactSciencesonOctober6th,2010 Supervisor: ProfessorTõnisKanger,DepartmentofChemistry, TallinnUniversityofTechnology,Estonia Opponents: ProfessorAndreiMalkov,DepartmentofChemistry, LoughboroughUniversity,UK Dr.AskoUri,InstituteofChemistry,UniversityofTartu,Estonia Defenceofthethesis:November25,2010 Declaration: HerebyIdeclarethatthisdoctoralthesis,myoriginalinvestigationandachievement, submittedforthedoctoraldegreeatTallinnUniversityofTechnologyhasnotbeen submittedforanyacademicdegree. MarjuLaars Copyright:MarjuLaars,2010 ISSN1406-4723 ISBN978-9949-23-038-9 LOODUS-JATÄPPISTEADUSED B97 Asümmeetriline organokatalüütiline Michaeli ja aldoolreaktsioon tsükliliste amiinide toimel MARJU LAARS Contents List of publications ................................................................................................. 6 Author’s contribution ............................................................................................ 6 Abbreviations .......................................................................................................... 7 Introduction ............................................................................................................ 8 1. Literature overview ....................................................................................... 9 1.1. Introduction and background ........................................................................ 9 1.1.1. Mechanistic insights into aminocatalysis ................................................... 9 1.2. Organocatalytic Michael reaction ............................................................... 10 1.2.1. Stereodifferentiation in Michael reactions ........................................... 11 1.2.2. Examples of organocatalytic Michael addition.................................... 12 1.3. Organocatalytic aldol reaction .................................................................... 17 1.3.1. Stereoselectivity in the aldol reaction .................................................. 18 1.3.2. Proline-catalysed aldol reaction ........................................................... 19 1.3.3. Other organocatalysts in aldol reaction ............................................... 20 1.4. Summary of asymmetric Michael and aldol reactions ................................ 23 1.5. Aims of the present work ............................................................................ 24 2. Synthesis of BM derivatives, BP derivatives and morpholine-3-carboxylic acid salts ................................................................................................................ 25 2.1. Synthesis of BM and BP derivatives (Articles II, IV and V) ...................... 26 2.2. Synthesis of (S)-morpholine-3-carboxylic acid and its salts (Article VIII) ...................................................................................................... 28 3. Asymmetric organocatalytic Michael reaction .............................................. 30 3.1. Michael reaction catalysed by iPrBM and iPrBP derivatives (Articles II and VI) ............................................................................................. 30 3.2. (S)-morpholine-3-carboxylic acid salts catalysed Michael reaction (Article VIII) ...................................................................................................... 34 4. BM and BP derivatives catalysed asymmetric organocatalytic aldol reaction .................................................................................................................. 38 4.1. Intramolecular aldol reaction (Articles I, II, III, IV, V and VII) ................. 38 4.2. Intermolecular aldol reaction (Articles II, III, IV, V and VII) .................... 41 Conclusions ........................................................................................................... 44 5. Experimental ..................................................................................................... 45 Acknowledgements ............................................................................................... 52 Abstract ................................................................................................................. 53 Kokkuvõte ............................................................................................................. 54 References ............................................................................................................. 55 Curriculum Vitae .................................................................................................. 58 Elulookirjeldus ..................................................................................................... 60 5 List of publications This thesis is based on the following publications, referred to in the text by the Roman numerals I-VIII. I Kriis, K.; Kanger, T.; Laars, M.; Kailas, T.; Müürisepp, A.-M.; Pehk, T.; Lopp, M. Enantioselective synthesis of Wieland-Miescher ketone trough bimorpholine-catalyzed organocatalytic aldol condensation. Synlett 2006, 1699-1702. II Sulzer-Mossé, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Synthesis and use of 3,3′-bimorpholine derivatives in asymmetric Michael addition and intramolecular aldol reaction. Synthesis 2007, 1729-1732. III Kriis, K.; Laars, M.; Lippur, K.; Kanger, T. Bimorpholines as alternative organocatalysts in asymmetric aldol reactions. Chimia 2007, 61, 232-235. IV Kanger, T.; Kriis, K.; Laars, M.; Kailas, T.; Müürisepp, A.-M.; Pehk, T.; Lopp, M. Bimorpholine-mediated enantioselective intramolecular and intermolecular aldol condensation. J. Org. Chem. 2007, 72, 5168-5173. V Laars, M.; Kriis, K.; Kailas, T.; Müürisepp, A.-M.; Pehk, T.; Kanger, T.; Lopp, M. Structural constraints for C -symmetric heterocyclic organo- 2 catalysts in asymmetric aldol reactions. Tetrahedron: Asymmetry 2008, 19, 641-645. VI Laars, M.; Ausmees, K.; Uudsemaa, M.; Tamm, T.; Kanger, T.; Lopp, M. Enantioselective organocatalytic Michael addition of aldehydes to β-nitrostyrenes. J. Org. Chem. 2009, 74, 3772-3775. VII Uudsemaa, M.; Laars, M.; Kriis, K.; Tamm, T.; Lopp, M.; Kanger, T. Influence of protonation upon the conformations of bipiperidine, bimorpholine, and their derivatives. Chem. Phys. Lett. 2009, 417, 92-96. VIII Laars, M.; Raska, H.; Lopp, M.; Kanger, T. Cyclic amino acid salts as catalysts for the asymmetric Michael reaction. Tetrahedron: Asymmetry 2010, 21, 562-565. Author’s contribution Articles I-IV: performed a large part of the experiments; played a minor part in writing the manuscript. Article VII: synthesis of investigated compounds. Articles V, VI and VIII: extensive contribution to the experiments; main person responsible for planning and writing the manuscript. 6 Abbreviations: BP (2R, 2’R)-bipiperidine BM (3S, 3’S)-bimorpholine Bn benzyl 13C carbon (NMR) cat catalyst d day(s) DCM dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide d.r. diastereomeric ratio DSS 4,4-dimethyl-4-silapentane-1-sulfonic acid ee enantiomeric excess GC gas chromatography h hour(s) 1H proton (NMR) HOMO highest occupied molecular orbital HPLC high performance liquid chromatography IR infrared LUMO lowest unoccupied molecular orbital M unspecified metal MCA (S)-morpholine-3-carboxylic acid MS mass spectrometry PE petroleum ether R unspecified substituent r.r. regioisomeric ratio rt room temperature SOMO singly occupied molecular orbital TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl TS transition state Tf trifluoromethanesulfonic TfOH trifluoromethanesulfonic acid UV ultraviolet 7 Introduction In synthetic organic chemistry today, the discovery of new methods, new reagents and new catalysts has become increasingly focused on achieving high levels of regioselectivity, chemoselectivity, and possibly most importantly, stereoselectivity. In modern times, the foundations of stereoselectivity lie in asymmetric synthesis. The activity of a biologically significant molecule is commonly linked to only one of the possible stereoisomers present and the development of new highly selective strategies to access enatiomerically enriched, or pure, compounds is at the forefront of synthetic organic chemistry. Organocatalysis1,2,3,4,5,6,7,8,9,10, the use of small organic molecules to catalyse organic transformations, is a popular field within the domain of chiral molecule (or enantioselective) synthesis. The term ‘organocatalysis’ describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound.11 Organocatalysis has become the third main branch in catalytic asymmetric synthesis along with enzymatic and organometallic catalysis. Although organocatalysis has been known about for several decades12,13, the approach under that name has mostly taken place within the last decade, fuelling the development of a number of outstanding catalysts and applications. Generic modes of activation commonly used in organocatalysis are enamine and iminium, hydrogen-bonding, SOMO and counterion catalysis. 8 1. Literature overview 1.1. Introduction and background Organocatalysis is not a new methodology although it has grown explosively only in the last decade: some examples can be found in the literature since the beginning of the last century or even earlier (for example the Knoevenagel reaction14). During the 1970s, the proline-catalysed intramolecular aldol process was reported simultaneously by Hajos, Parrish, Wiechert, Eder and Sauer15,16, but the studies on the use of small organic molecules as catalysts for asymmetric reactions were viewed more as unique chemical reactions than as integral parts of a larger, interconnected field. In the late 1990s, however, things began to change when Shi17, Denmark18 and Yang19 demonstrated that enantiomerically pure ketones could be used to catalyse the enantioselective epoxidation of simple alkenes. The field of organocatalysis was effectively launched in 2000 by two publications by Barbas III20 (on enamine catalysis) and MacMillan21 (on iminium catalysis) that appeared almost simultaneously, early reports were mainly from those two research groups. Organocatalysis has emerged during the last decade as a concept with a significant number of synthetic applications and it has become the third main branch of catalytic asymmetric synthesis, along with enzymatic and organometallic catalysis. Organocatalytic reactions catalysed by amines, especially secondary amines, are widespread, as secondary amines are capable of both enamine and iminium catalysis. 1.1.1. Mechanistic insights into aminocatalysis The efficiency and the scope of organocatalysis and, particularly, aminocatalysis22 have been broadly established. Covalently bonded aminocatalysts operate through two mechanisms, by converting carbonyl substrates either into activated nucleophiles (enamine intermediates) or electrophiles (iminium intermediates) (Scheme 1). In iminium catalysis23,24, the addition of the amine catalyst to the carbonyl substrate generates an iminium ion as the active species, with lowered LUMO energy, which can react with a nucleophile, whereas in enamine catalysis25,26,27, the deprotonation of the iminium ion provides the nucleophilic enamine intermediate, with increased HOMO energy, which can attack the electrophile. 9 iminiumcatalysis: O N R R' N R H HX R' Nu- enaminecatalysis: O N N -H+ N H E+ R' R R R R' R' iminium enamine Scheme 1. Iminium and enamine catalysis. This thesis describes the investigation of organocatalytic Michael and aldol reactions, and therefore this chapter gives an overview of Michael28 and aldol29,30,31,32 reactions catalysed by an enamine pathway. 1.2. Organocatalytic Michael reaction The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound or to a double bond connected with a strongly electron-withdrawing substituent (e. g. nitroolefins).33 The organocatalytic Michael addition to an α,β-unsaturated carbonyl compound follows an iminium pathway, whereas, in addition to nitroalkenes, a nucleophile is derived from the carbonyl compound via an enamine pathway. The general mechanistic features of the reaction via the enamine pathway are outlined in Scheme 2. In the first step, an iminium ion A is generated by the reversible reaction between a chiral amine catalyst and a carbonyl compound and can be easily deprotonated to form the enamine nucleophilic intermediate B, due to the increase of C-H acidity. This enolate equivalent can react with an electron- deficient olefin in order to create a new C-C bond. Subsequent hydrolysis of the α- modified iminium ion C affords the Michael adduct and restores the aminocatalyst, which is ready to participate in a new catalytic cycle. The Michael reaction of nitroolefins represents a convenient access to branched nitroalkanes, which are versatile intermediates in organic synthesis. 10