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

The Mannich Reaction: New Light On An Old Story Literature meeting Julie Côté November 27, 2007. The Mannich Reaction. Applications: Polymer chemistry ( hardeners , cross- linkers and reaction accelerators ) Plant protections Pharmaceutical area. Cribrochalina.

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

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

  2. The MannichReaction • Applications: • Polymerchemistry(hardeners, cross-linkers and reactionaccelerators) • 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 MannichReaction 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 AsymmetricMannichReaction : UnmodifiedKetones • 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 asymmetricMannichReaction : UnmodifiedAldehyde • 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 AsymmetricMannichReaction : IonicLiquids • Solvent and catalyst are readily recycled • Faster reaction in ionic liquids: result from ionic based activation of the imine electrophile. • Can be performed on a multi-gram scale • - non volatile • Tunable polarity • High thermal stability • Great abily to dissolve catalyst • « Green » solvent Chowdari, N.S.; Ramachary, D.B.; Barbas, III, C. F. Synlett, 2003, 12, 1906-1909.

  9. Aldimine in Direct AsymmetricMannichReaction : Protecting Group Initially homogenous reaction mixture After consumption of the starting material : precipitation B A • Easy clivage of Boc • Provides stable crystalline • compounds without purification • Drastic oxidative condition • Harmful reagents: (NH4)Ce(NO3)6, • (CAN) Yang, J. W.; Stadler, M. List, B. Angew. Chem. Int. Ed. 2007, 46, 609-611.

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

  11. Aldimine in Direct AsymmetricMannichReaction :Anti-Selective Structural features at the 5-position were installed to fix the enamine conformation To avoid steric interaction between the substituents at the 5 the imine, substituents 3- and 5- are in trans -configuration Acid position to affect control of enamine and imine facial selection Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.

  12. Aldimine in direct asymmetricMannichReaction :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 AsymmetricMannichReaction :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 AsymmetricMannichReaction :Anti-Selective Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.

  15. Aldimine in Direct AsymmetricMannichReaction :Anti-Selective

  16. 1,3-Dicarbonyls and AcylAldimineswithCinchonaAlkaloidsCatalyst Brandon, M. Lou, S.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257.

  17. Malonates and AcylAldimineswithBifunctionalCinchonaAlkaloidsCatalyst • 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. AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters R1 and R2 need to be very diffirent to access good syn/anti ratio Chowdari, N. S.; Suri, J. F.; Barbas, III, C. F. Org. Lett. 2004, 6, 2507-2510.

  19. AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters (DHQD)2PYR Interesting solvent effect was demonstrated which gave drastic changes in stereoselectivity Toluene CH2Cl2 Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M. Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 2896-2899.

  20. AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003-2006.

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

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

  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 catalizedMannichReaction List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.

  27. Mechanism of the Proline catalizedMannichReaction 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 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 The reaction might take place at the interface of organic materiels with water in heterogeneous system. • Low loading of catalyst • Good yields • Clean reaction • Need vigourous stirring • Environmentally benign 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 Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.

  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 MannichReaction Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 21, 6756-6761.

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

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

  39. Bifunctional Bronsted Acid Activation of the MannichReaction The addition of a stoichiometric achiral proton source isrequired to accomplish a catalytic cycle of chiral bronstedacidcatalyts Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.

  40. VinylogousMannichReaction • 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. VinylogousMannichReaction Access to lactam • Addition to the si-face of the imine Battistini, L.; Rassu, G.; Pinna, L.; Zanardi, F.; Casiraghi, G. Tetrahedron Asymmetry, 1999, 10, 765-773.

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

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

  44. VinylogousMannichReaction • 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. VinylogousMannichReaction Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.

  46. VinylogousMannichReaction: Application in Synthesis • The indole alkaloids of Ergot family have attracted the attention of synthetic chemists for decades • The mostwell-knownrepresentative of this class islysergicacid and rugulovasines A and B representnovel types withinthisfamily 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 <PMP-free protocols>.

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