1 Chiral Phosphoric Acids-Catalyzed Multi-Component Reactions for Synthesis of Structurally Diverse Nitrogenous Compounds Feng Shi Dec. 18th, 2010

2 Multi-component Reactions (MCR) The reaction between three or more reagents in a single vessel which have been added together (or nearly) to form a new compound that contains significant portions of all the components. The definition of MCR: The advantages of MCR: superior atom economy, atom utilization and selectivity lower level of by-products simpler procedures and equipment lower costs, time, and energy more environmentally friendly Introduction:

3 Amino-acid derivatives Brønsted acids Lewis bases Nucleophilic Carbenes Chiral Organocatalyzed Multi-component Reactions Chiral Organocatalysts: Combined catalysis of organo and metal catalysts

4 Chiral Brønsted Acids For review, see: T. Akiyama*, Chem. Rev. 2007, 107, 5744.

5 Other newly developed Brønsted Acids:

6 The first examples of Phosphoric Acids-catalyzed Reactions T. Akiyama*, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int. Ed. 2004, 43, D. Uraguchi, M. Terada*, J. Am. Chem. Soc. 2004, 126, 5356.

7 For related reviews, see: (a) M. Terada*, Synthesis, 2010, 1929; (b) A. Zamfir, S. Schenker, M. Freund, S. B. Tsogoeva*, Org. Biomol. Chem., 2010, 8, 5262; (c) S. J. Connon*, Angew. Chem. Int. Ed. 2006, 45, The Structural Features of Chiral Phosphoric Acids:

8 Chiral Phosphoric Acids-Catalyzed Multi-Component Reactions Biginelli Reaction Cyclization Reactions 1,3-Dipolar Cycloaddition Kabachnik–Fields Reaction Friedel-Crafts AminoalkylationHantzsch Reaction Povarov Reaction Direct Mannich Reaction Aza-D-A Reaction Ugi-type reaction

9 Q.-X. Guo, H. Liu, C. Guo, S.-W. Luo, Y. Gu, L.-Z. Gong*, J. Am. Chem. Soc. 2007, 129, Direct Mannich Reaction: Transition state

10 G. Dagousset, F. Drouet, G. Masson, J. Zhu*, Org. Lett., 2009, 11, Using Enecarbamates as Nucleophiles

11 M. Sickert, F. Abels, M. Lang, J. Sieler, C. Birkemeyer, C. Schneider*, Chem. Eur. J. 2010, 16, Vinylogous Mannich Reaction

12 Biginelli Reaction: P. G. Biginelli*, Chim. Ital. 1893, 23, 360. General mechanism:

13 X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun, L.-Z. Gong*, J. Am. Chem. Soc. 2006, 128, The first organocatalytic highly enantioselective Biginelli reaction

14 N. Li, X.-H. Chen, J. Song, S.-W. Luo*, W. Fan, L.-Z. Gong*, J. Am. Chem. Soc. 2009, 131, Biginelli and Biginelli-Like Condensations Reversal of the stereochemistry by tuning the 3,3’- disubstituents of phosphoric acids

15 Reaction Mechanism

16 Synthetic applications:

17 Asymmetric Amplification in Phosphoric Acid- Catalyzed Biginelli Reaction: N. Li, X.-H. Chen, S.-M. Zhou, S.-W. Luo, J. Song, L. Ren, L.-Z. Gong*, Angew. Chem. Int. Ed. 2010, 49, Positive nonlinear effect

18 J. Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao, L.-Z. Gong*, Angew. Chem. Int. Ed. 2008, 47, Cyclization Reactions Leading to Dihydropyridine Derivatives: Synthetic applications:

19 Reaction Mechanism:

20 J. Jiang, J. Qing, L.-Z. Gong*, Chem. Eur. J. 2009, 15, Cyclization leading to dihydropyridinone derivatives:

21 Reaction Mechanism: formal [4+2] cycloaddition

22 Hantzsch reaction: C. G. Evans, J. E. Gestwicki*, Org. Lett. 2009, 11, 2957.

23 Aza-Diels-Alder Reaction : H. Liu, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong*, Org. Lett. 2006, 8, 6023.

24 Povarov reaction: H. Liu, G. Dagousset, G. Masson,* P. Retailleau, J. Zhu*, J. Am. Chem. Soc. 2009, 131, An inverse electron-demand aza-Diels-Alder reaction between 2-azadienes and electron-rich olefins.

25 Ugi-type reaction: T. Yue, M.-X. Wang,* D.-X. Wang, G. Masson, J. Zhu*, Angew. Chem. Int. Ed. 2009, 48, 6717.

26 1,3-Dipolar cycloaddition: X.-H. Chen, W.-Q. Zhang, L.-Z. Gong*, J. Am. Chem. Soc. 2008, 130, 5652.

27 X.-H. Chen, Q. Wei, H. Xiao, S.-W. Luo, L.-Z. Gong*, J. Am. Chem. Soc. 2009, 131, Methyleneindolinones as dipolarophiles to synthesize Spiro[pyrrolidin-3,3’-oxindoles] with unusual regiochemistry

28 Reaction mechanism:

29 W.-J. Liu, X.-H. Chen, L.-Z. Gong*, Org. Lett. 2008, 10, Imine as dipolarophile to synthesize imidazolidines

30 J. Yu, L. He, X.-H. Chen, J. Song, W.-J. Chen, L.-Z. Gong*, Org. Lett. 2009, 11, ,3-Allenoate as dipolarophiles to create pyrrolidines along with C=C double bond Kinetic Resolution of Racemic 2,3-Allenoates J. Yu, W.-J. Chen, L.-Z. Gong*, Org. Lett. 2010, 12, ‘ ‘

31 1,4-Naphthoquinone as dipolarophile to synthesize isoindolines C. Wang, X.-H. Chen, S.-M. Zhou, L.-Z. Gong*, Chem. Commun. 2010, 1275.

32 Kabachnik–Fields reaction: The reaction of a carbonyl compound, an amine, and a phosphite by in situ imine hydrophosphonylation. X. Cheng, R. Goddard, G. Buth, B. List*, Angew. Chem. Int. Ed. 2008, 47, L. Wang, S.-M. Cui, W. Meng, G.-W. Zhang, J. Nie, J.-A. Ma*, Chin. Sci. Bull. 2010, 55, 1729.

33 Friedel-Crafts aminoalkylation: G.-W. Zhang, L. Wang, J. Nie, J.-A. Ma*, Adv. Synth. Catal. 2008, 350, 1457.

34 Combined catalysis of phosphoric acid and metal catalysts: Relay Catalysis Cooperative Catalysis

35 W. Hu*, X. Xu, J. Zhou, W.-J. Liu, H. Huang, J. Hu, L. Yang, L.-Z. Gong*, J. Am. Chem. Soc. 2008, 130, Mannich-type multi-component reaction: Cooperative Catalysis:

36 Reaction mechanism:

37 X. Xu, J. Zhou, L. Yang, W. Hu*, Chem. Commun. 2008, 48, X. Xu, Yu Qian, L. Yang, W. Hu*, Chem. Commun. ASAP, DOI: /c0cc03024d

38 Consecutive Intramolecular Hydroamination/ Asymmetric Transfer Hydrogenation Relay Catalysis : Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong*, J. Am. Chem. Soc. 2009, 131, 9182.

39 Intermolecular Hydroamination and Transfer Hydrogenation Reactions X.-Y. Liu, C.-M. Che*, Org. Lett., 2009, 11, 4204.

40 C. Wang, Z.-Y. Han, H.-W. Luo, L.-Z. Gong*, Org. Lett., 2010, 12, Povarov reaction and subsequent intramolecular hydroamination

41 Conclusions 1. Many asymmetric multi-component reactions have been successfully established by chiral PA. 2. Tremendous progress has been made in the development of chiral PA catalysts. 3. Combined catalysis of PA and metal catalysts is a new orientation. Outlook 1. There are still numerous multi-component reactions to be transformed into their asymmetric versions. 2. Further elaboration of novel PA derived from other types of chiral backbones is needed. 3. A more detailed mechanistic understanding of PA catalysis is needed. 4. It is full of challenge and opportunity to develop combined catalysis of PA and metal catalysts.

42 Sincere thanks for your attention and kind help!