1. Acknowledgements: I would like to thank Martin and the Wills group for their support and encouragement during this project. I would also like to thank my industrial supervisors Gary Woodwood and Gordon Docherty and the EPSRC and Rhodia for financial support. Introduction: Amines have been used in catalysts since 1902, when pyridine was used by Dobner in a modification of the Knoevenagel Condensation. 1 The first use of a chiral amine in catalysis was the use of proline in the Haios- Parrish-Eder-Sauer-Wiechert reaction in the 1970s. 2 Since then proline and it’s derivatives have been used as organocatalysts in a number of reactions, including conjugate additions to nitrostyrenes, 3 Diels-Alder reactions 4 and aldol reactions. 5 These reactions can be performed with good activity and selectivity with moderate catalyst loadings. DPEN is often used as a chiral ligand in metal centred catalysts, most famously in the system reported by Noyori. 6 Derivatives of DPEN are used in the Wills group to form tethered catalysts for asymmetric reductions of ketones and imines where it acts to both impart chirality to the catalyst and act as a hydrogen source in the reduction step. 7 Recently, DPEN derivatives have been investigated for use as organocatalysts. One of the more successful results has been for the Michael addition of ketones to nitrostyrenes. 8,9 Asymmetric catalysis using DPEN and proline derivatives Charles V. Manville a, Martin Wills a, Gordon Docherty, b Ranbir Padda b and Gary Woodwood b. a: Department of Chemistry, University of Warwick, Coventry, CV4 7AL b: Rhodia Consumer Specialities Ltd, PO Box 80, Trinity Street, Warley, Oldbury, B69 4LN References: 1O. Doebner. Berichte der deutschen chemischen Gesellschaft, 1902, 35, 1136-1147 2Z. G. Hajos, D. R. Parrish. J. Org. Chem. 1974, 39, 1615-1621; U. Eder, G. Sauer and R. Wiechert, Angew. Chem. Int. Ed. 1971, 10, 496-497. 3B. List, P. Pojarliev and H. J. Martin. Org. Lett. 2001, 3, 2423; J.M. Betancort, K. Sakthivel, R. Thayumanavan, C.F. Barbas III. Tetrahedron Lett. 2001,42, 4441 4H. Sundén, R. Rios, Y. Xu, L. Eriksson and A. Córdova. Adv. Synth. Catal. 2007, 349, 2549-2555 5Q. Gu, X-F. Wang, L. Wang, X-Y. Wu and Q-L. Zhou. Tetrahedron Asymmetry, 2006, 17, 1537-1540 6H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, F. Katayama, A.F. England, T. Ikariya and R. Noyori. Angew. Chem. Int. Ed. 1998, 37, 1703-1707 7For recent work see: J.E.D. Martins, G.J. Clarkson and M. Wills, Org Lett, 2009, 11, 847-850; J.E.D. Martins, D.J. Morris and M. Wills, Tetrahedron Lett. 2009, 50, 688-692 8S. B. Tsogeova and S. Wei, Chem. Commun. 2006, 1451-53 9D. J. Morris, A. S. Partridge, C. V. Manville, D.T. Racys, G. Woodward, G. Docherty and M. Wills, Tetrahedron Lett. 2010, 51, 209-212 10For recent work see: Z. Zhou, L. Wu, Catalysis Communications, 2008, 9, 2539-2542; J. Mao and J. Guo, Chirality, 2010, 22, 173-181 Azo Coupling It has been shown that derivatives of DPEN and proline, containing a diphenyl phophinamide group, can catalyse the addition of acetone to nitrostyrenes, but is unsuccessful when using other aldehydes. 9 It was attempted to improve the scope of the catalyst by coupling the PODPEN to proline. These catalysts proved to be unreactive in the Michael addition, but were able to catalyst the coupling of DEAD to aldehydes. Derivatives using TsDPEN were also made and tested New catalyst synthesised by coupling proline and a DPEN derivative. R = Ph 2 P(O), Ts. 148 hr0% 2No Reaction 348 hre.e. = 85% (R) 44 hre.e. = 52% (R) 324 hre.e. = 81% (R) 46 hre.e. = 74% (R) 31 hre.e. = 93% (R) 445 mine.e. = 87% (R) a: N-Boc-(S)-proline, ethyl chloroformate, Et 3 N, THF. b: 20%Me 2 S-DCM, triisopropylsilane, TFA, 0 °C. c: Formic acid, 0 °C LigandR1R1 R2R2 Conv. (%) a e.e. (%) a Conf. b 3PhMe10090R 4PhMe10083R 3 C HexMe250- 4 C HexMe400- 34-MeO phenylMe7686R 44-MeO phenylMe9257R 32-MeO phenylMe5474R 42-MeO phenylMe9565R 34-Cl phenylMe9088R 44-Cl phenylMe10071R 32-Cl phenylMe10085R 42-Cl phenylMe10064R 3PhEt6684R 4PhEt8478R 3Ph C Hex632R 4Ph C Hex657R LigandConv. (%) a e.e. (%) a Conf. b 3877R 44578R LigandR1R1 R2R2 Conv. (%) a e.e. (%) a Conf. b 5PhMe9986R 6PhMe10083R 5c5c PhMe1112R 6c6c PhMe1324R 5 C HexMe5468R 6 C HexMe2266R 54-MeO phenylMe6383R 64-MeO phenylMe9077R 52-MeO phenylMe6665R 62-MeO phenylMe9853R 54-Cl phenylMe10087R 64-Cl phenylMe9879R 52-Cl phenylMe9980R 62-Cl phenylMe9966R 5PhEt8286R 6PhEt9080R 5Ph C Hex8286R 6Ph C Hex9080R 6PhCH 2 C l 10081R LigandXRnConv. (%) a e.e. (%) b Conf. c 5CH21475R 6CH24898R 6d6d CH2 96R 5CH19971R 6CH110091R 6CH36189R 6C7-Me14389R 6C6-OMe21385R 6CFuran285 e R 6OH296 e R 6O6-Cl21186R 6SH210092R Asymmetric Transfer Hydrogenation Derivatives of both DPEN 6,7 and proline 10 have been used as ligands for the asymmetric transfer hydrogenation of ketones using metal centres. The Ts-DPEN derivatives were tested as ligands, and were found to be successful when used with a ruthenium p-cymene metal centre in water, using sodium formate as the hydrogen donor, at a catalyst loading of 1 mol%. These results show that for a ruthenium centre the selectivity of the catalysts is mainly determined by the proline portion of the ligand, with the most selective catalyst being the one using (S)-proline coupled to (R,R)-TsDPEN as the ligand (3). The (S)- proline / (S,S)-TsDPEN ligand (4) forms a faster catalyst in most cases Further ligands were synthesised by coupling two Boc-(S)-prolines to a central DPEN unit, using the same conditions as for the coupling of Boc-(S)-proline to TsDPEN. a: N-Boc-(S)-proline, ethyl chloroformate, Et 3 N, THF. b: 20%Me 2 S-DCM, triisopropylsilane, TFA, 0 °C. 1 2 3 4 5 6 Catalyst loading; 1 mol%. a. Determined by G.C. b. Determined by comparison of G.C. and optical rotation with literature data. Catalyst loading; 1 mol%. a. Determined by G.C. b. Determined by comparison of G.C. and optical rotation with literature data. c. [RhCl 2 (Cp*)] 2 used instead of [RuCl 2 (p-cymene)] 2 Catalyst loading; 1 mol%. a. Determined by G.C. b. Determined by G.C. unless shown. c. Determined by comparison of G.C. and optical rotation with literature data. d. 2 mol% catalyst used. e. Determined by HPLC LigandR1R1 R2R2 Conv. (%) a e.e. (%) a Conf. b 3PhMe947R 4PhMe0-- 34-MeO phenylMe538R 34-Cl phenylMe3329R 44-Cl phenylMe3314R LigandR1R1 R2R2 Conv. (%) a e.e. (%) a Conf. b 3PhMe1384R 4PhMe2167S 3 C HexMe220- 4 C HexMe280- 34-MeO phenylMe363R 44-MeO phenylMe752S 34-Cl phenylMe2183R 44-Cl phenylMe6885S 32-Cl phenylMe4159R 42-Cl phenylMe3750S 3PhEt1028R 4PhEt722S a. Determined by G.C. b. Determined by comparison of G.C. and optical rotation with literature data. (R,R) (S,S) (R,R) (S,S) Reactions were also run using Rh(Cp*) and Ir(Cp*) as the metal centres. These catalysts gave much lower conversions and e.e.s for all of the tested ketones, than the corresponding Ru(p-cymene) catalyst. The use of an iridium metal centre changes the major determination of product chirality from the proline part of the ligand to the DPEN part of the ligand When these new ligands were tested, using the same conditions used for ligands 3 and 4, in the transfer hydrogenation of ketones, they proved to be faster than the TsDPEN ligands, but had a lower selectivity for linear ketones. However, the hydrogenation of cyclic indanone and tetralone like ketones gave good to high e.e.s in all of the tested ketones when using ligand 6. For the cyclic ketones the ligand formed from the coupling of two (S)-prolines to (S,S)-DPEN (6) proves to form a faster and more selective catalyst for all of the tested substrates than the (S)-proline / (R,R)-DPEN ligand (5).