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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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slide1
The Mannich Reaction:

New Light On An Old Story

Literature meeting

Julie Côté

November 27, 2007

the mannich reaction
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.

dr ulrich franz carl mannich
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.

limitation of the mannich reaction
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.

presentation
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

aldimine in direct asymmetric mannich reaction unmodified ketones
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.

aldimine in direct asymmetric mannich reaction unmodified aldehyde
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.

aldimine in direct asymmetric mannich reaction ionic liquids
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.

aldimine in direct asymmetric mannich reaction protecting group
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.

aldimine in direct asymmetric mannich reaction anti selective
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.

aldimine in direct asymmetric mannich reaction anti selective1
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.

aldimine in direct asymmetric mannich reaction anti selective2
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.

aldimine in direct asymmetric mannich reaction anti selective3
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.

aldimine in direct asymmetric mannich reaction anti selective4
Aldimine in Direct AsymmetricMannichReaction :Anti-Selective

Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.

1 3 dicarbonyls and acyl aldimines with cinchona alkaloids catalyst
1,3-Dicarbonyls and AcylAldimineswithCinchonaAlkaloidsCatalyst

Brandon, M. Lou, S.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257.

malonates and acyl aldimines with bifunctional cinchona alkaloids catalyst
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.

asymmetric mannich reaction adducts with quaternary carbon centers
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.

asymmetric mannich reaction adducts with quaternary carbon centers1
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.

asymmetric mannich reaction adducts with quaternary carbon centers2
AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters

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

asymmetric nitro mannich reaction
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.

asymmetric nitro mannich reaction1
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.

asymmetric nitro mannich reaction2
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.

three component mannich reaction
Three-Component Mannich Reaction

List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.

three component mannich reaction1
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.

mechanism of the proline catalized mannich reaction
Mechanism of the Proline catalizedMannichReaction

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

mechanism of the proline catalized mannich reaction1
Mechanism of the Proline catalizedMannichReaction

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

three component mannich reaction optimization
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.

three component mannich reaction optimization1
Three-Component Mannich Reaction Optimization

Reducing the time of reaction

Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888-2891.

access to chiral 1 2 and 1 4 diamines
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.

green three component mannich reaction
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.

synthesis of interesting 1 3 diaryl 5 spirohexahydropyrimidines
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.

mechanism
Mechanism

Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.

application in synthesis
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.

bifunctional bronsted acid activation of the mannich reaction
Bifunctional Bronsted Acid Activation of the MannichReaction

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

bifunctional bronsted acid activation of the mannich reaction1
Bifunctional Bronsted Acid Activation of the MannichReaction

Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523.

bifunctional bronsted acid activation of the mannich reaction2
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.

bifunctional bronsted acid activation of the mannich reaction3
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.

vinylogous mannich reaction
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.

vinylogous mannich reaction1
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.

vinylogous mannich reaction2
VinylogousMannichReaction

Lactam

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

vinylogous mannich reaction3
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.

vinylogous mannich reaction4
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.

vinylogous mannich reaction5
VinylogousMannichReaction

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

vinylogous mannich reaction application in synthesis
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.

summary
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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