1. The Mannich Reaction: New Light On An Old Story Literature meeting Julie Côté November 27, 2007

2. The Mannich Reaction Applications: Polymer chemistry (hardeners, cross-linkers and reaction accelerators) Plant protections Pharmaceutical area Cribrochalina Potent cytotoxic agent Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S.J. J. Am. Chem. Soc. 2005, 127,4596-4598.

3. Dr. Ulrich Franz Carl Mannich Mechanism was discover in 1912 Organic chemists in this area argue that this reaction has become the most important C-C bond-forming reaction! Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

4. Limitation of the Mannich Reaction This type was first used in early 20th century but neaded drastic reaction and long reaction time The first methods developed were non-catalytic and employed preformed enolates and enamine with chiral auxiliary control Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070. Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 981.

5. Presentation Organocatalytic Mannich reaction Proline catalyst Cinchona alkaloids catalyst Thiourea catalyst Bronsted acid catalyst Avancement in direct asymmetric mannich reaction Aldimine MR Anti-selective MR Quaternary carbon center MR Nitro MR One pot three component MR Indirect MR with Bronsted acid catalyst Vinylogous MR

6. Aldimine in Direct Asymmetric Mannich Reaction : Unmodified Ketones Very low yields and ee’s High amount of catalyst long reaction time Notz, W. Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, III, C.F. Tetrahedron Lett. 2001, 42, 199-201.

7. Aldimine in direct asymmetric Mannich Reaction : Unmodified Aldehyde Proceed smoothly with excellent enantioselectivity Higher diastereoselectivities were achived with increased bulkiness of the substituents on the aldehyde Cordova, A.; Watanabe. S. I.; Tanaka, F.; Notz, W.; Barbas, III, C. F.. J. Am. Chem. Soc. 2002, 124, 1866-1867.

8. Aldimine in Direct Asymmetric Mannich Reaction : Ionic Liquids - non volatile - Tunable polarity - High thermal stability - Great abily to dissolve catalyst - « Green » solvent Faster reaction in ionic liquids: result from ionic based activation of the imine electrophile. Solvent and catalyst are readily recycled Can be performed on a multi-gram scale Chowdari, N.S.; Ramachary, D.B.; Barbas, III, C. F. Synlett, 2003, 12, 1906-1909.

9. Aldimine in Direct Asymmetric Mannich Reaction : Protecting Group A Drastic oxidative condition Harmful reagents: (NH 4 )Ce(NO 3 ) 6, (CAN) B Easy clivage of Boc Provides stable crystalline compounds without purification Initially homogenous reaction mixture After consumption of the starting material : precipitation Yang, J. W.; Stadler, M. List, B. Angew. Chem. Int. Ed. 2007, 46, 609-611.

10. Aldimine in Direct Asymmetric Mannich Reaction :Anti-Selective Moderate yields and ee Cordova, A.; Barbas, III, C.F. Tetrahedron Lett. 2002, 43, 7749-7752. (E)-Enamine predominate Si-face of imine is attacked by enamine si- face Facial selection is controlled by proton transfer Lacking the stereodirecting carboxylate of proline, the topicity is altered Si-face of imine is now attacked by re-face of the enamine

11. Aldimine in Direct Asymmetric Mannich Reaction :Anti-Selective Structural features at the 5-position were installed to fix the enamine conformation Acid position to affect control of enamine and imine facial selection To avoid steric interaction between the substituents at the 5 the imine, substituents 3- and 5- are in trans - configuration EntryR1R1 R2R2 Time (h) Yield ( %) dr anti :syn ee (%) 1 i-Pr Et 3 8598 :2 99 2 n-Bu Et 1 7197 :3 99 3 n-Pent Et 3 8097 :3 >99 4 i-Pr 1 9297 :3 98 5 n-Pent i-Pr 1 8596 :4 >99 Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.

12. Aldimine in direct asymmetric Mannich Reaction :Anti-Selective Ineffective in MR with ketones. Hypothesis: origined from the relatively slow formation of the enamine intermediates due to steric interaction with Me group of the catalyst Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.

13. Aldimine in Direct Asymmetric Mannich Reaction :Anti-Selective Furnish three contiguous stereocenters in one step in good % The asymmetric reductive MTR proceed via a catalytic asymmetric domino reaction and furnish amino acid Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.

14. Aldimine in Direct Asymmetric Mannich Reaction :Anti-Selective Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.

15. Aldimine in Direct Asymmetric Mannich Reaction :Anti-Selective

16. 1,3-Dicarbonyls and Acyl Aldimines with Cinchona Alkaloids Catalyst Brandon, M. Lou, S.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257.

17. Malonates and Acyl Aldimines with Bifunctional Cinchona Alkaloids Catalyst Cinchona alkaloid derivatives bearing a thiourea functionnality might act as efficient bifunctional catalysts for malonates with simple imines Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048-6049.

18. Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centers Chowdari, N. S.; Suri, J. F.; Barbas, III, C. F. Org. Lett. 2004, 6, 2507-2510. R 1 and R 2 need to be very diffirent to access good syn/anti ratio

19. Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centers (DHQD)2PYR Interesting solvent effect was demonstrated which gave drastic changes in stereoselectivity CH 2 Cl 2 Toluene Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M. Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 2896-2899.

20. Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centers Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003-2006.

21. Asymmetric Nitro-Mannich Reaction Metal-free of the nitro-Mannich reaction have recently evolved Limitations: proceeded smoothly with imine which contains an electron- withdrawing substituent and need prolonged reaction time with electron- donating group. Aza-Henry Reaction Yamada, K. I.; Harwood, S. J.; Gröger, H.; Shibasaki, M. Angew. Chem. Int. Ed. 1999, 38, 3504-3506.

22. Asymmetric Nitro-Mannich Reaction Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org Lett. 2004, 6, 625-627. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.

23. Asymmetric Nitro-Mannich Reaction Future work includes the expansion of the methodology to different substrates and investigation of the synthetic utility of the addition products. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476. The Thiourea moiety play a role in activation of N-Boc imine in the nucleophilic addition step and in nitroalkane deprotonation

24. Three-Component Mannich Reaction List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.

25. Three-Component Mannich Reaction JACS, 2002, 124 827 List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.

26. Mechanism of the Proline catalized Mannich Reaction List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.

27. Mechanism of the Proline catalized Mannich Reaction List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.

28. Three-Component Mannich Reaction Optimization Accelerates the reaction but also suppresses side reactions Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208-11209.

29. Three-Component Mannich Reaction Optimization Entry R mol % of catalyst Power (W) Temp (°C) Time (h) Yield ( %) ee (%) 1 H 20 154728097 2 H 10 15462,59698 3 H 5 15452,59398 4 H 1 154848997 5 H 0,5 154638398 6 OMe 10 15472,57195 7 OMe 10 452,58195 8 Ome 1 104738494 9 i-Pr 10 4537197 10 i-Pr 5 15513,58897 11 i-Pr 0,5 154948697 Reducing the time of reaction Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888-2891.

30. Access to Chiral 1,2- and 1,4 Diamines Protecting group dependent regioselectivity Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, III, C. F. Org Lett. 2006, 8, 2839-2842.

31. Green Three-Component Mannich Reaction Low loading of catalyst Good yields Clean reaction Need vigourous stirring Environmentally benign The reaction might take place at the interface of organic materiels with water in heterogeneous system. Azizi, N.; Torkiyan, L.; Saidi, M.R. Org. Lett. 2006, 8, 2079-2082.

32. Synthesis of interesting 1,3-Diaryl-5- spirohexahydropyrimidines Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.

33. Mechanism

34. Mechanism

35. Application in Synthesis Antibiotic that inhibits the biosynthesis of chitin in cell wall by competitively inhibiting chitin synthase Hayashi, Y.; Urushima, T.; Shin, M.; Shoji, M. Tetrahedron 2005, 61, 11393-11404.

36. Bifunctional Bronsted Acid Activation of the Mannich Reaction EntryXTime (h)Yields (%)ee (%) 1 2-OH 13 9889 2 4-OH 33 2820 3 2-OMe 46 563 4H437635 Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 21, 6756-6761.

37. Bifunctional Bronsted Acid Activation of the Mannich Reaction Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523.

38. Bifunctional Bronsted Acid Activation of the Mannich Reaction Possible intramolecular hydrogen bonding Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.

39. Bifunctional Bronsted Acid Activation of the Mannich Reaction The addition of a stoichiometric achiral proton source is required to accomplish a catalytic cycle of chiral bronsted acid catalyts Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.

40. Vinylogous Mannich Reaction The VMR is rapidly emerging as an important process for the construction of derivatives of –aminocarbonyl compounds Because the iminium and dienol components employed in this addition may be either acyclic or cyclic, a wide variety of adducts may be converted into a broad array of alkaloids and nitrogen heterocyclicles. Martin, S. F. Acc. Chem. Res. 2002, 35, 895-904.

41. Vinylogous Mannich Reaction Addition to the si-face of the imine Access to lactam Battistini, L.; Rassu, G.; Pinna, L.; Zanardi, F.; Casiraghi, G. Tetrahedron Asymmetry, 1999, 10, 765-773.

42. Vinylogous Mannich Reaction Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233. Lactam

43. Vinylogous Mannich Reaction Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233. 1-Bidentate chelation with aldimine 2-The catalyst-bond imine may react with the siloxyfuran by an endo type addition 3- Intramolecular desilylation by the lewis basic amide 4-Product release is facilited by iPrOH

44. Vinylogous Mannich Reaction Vinyloxirane is a valuable and highly reactive species Ring-opening and/or rearrangement processes are promoted by Lewis acids or transition-metal catalysts. Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.

45. Vinylogous Mannich Reaction EntrySolventTime (h)ABC 1 MeOH 4 8400 2 Benzene 24 trace775 3Benzene10trace53 Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.

46. Vinylogous Mannich Reaction: Application in Synthesis The indole alkaloids of Ergot family have attracted the attention of synthetic chemists for decades The most well-known representative of this class is lysergic acid and rugulovasines A and B represent novel types within this family Liu, T. Y.; Cui, H. L.; Long, J.; Li, B. J.; Wu, Y.; Ding, L. S. Chen, Y. C. J. Am. Chem. Soc. 2007, 129, 1878-1879.

47. Summary Significant advancements have been reported in the direct asymmetric MR. High yields, dr and ee are possible using organocatalysis with relatively mild reaction conditions. Highly functionallized products are possible (ie. Nitro-Mannichs, quaternary carbon centers, 3 contiguous chiral centers). Usage in total synthesis still relatively rare. The use of the PMP protecting group remains widespread, although some work has been done to develop relatively.