1 / 47

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.

stuart
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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>.

More Related