Chiral Phosphoric Acids-Catalyzed Multi-Component Reactions for Synthesis of Structurally Diverse Nitrogenous Compounds

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Chiral Phosphoric Acids-Catalyzed Multi-Component
Reactions for Synthesis of Structurally Diverse
Nitrogenous Compounds
Feng Shi
Dec. 18th, 2010
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Introduction
Multi-component Reactions (MCR)
The definition of 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 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

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Chiral Organocatalyzed Multi-component Reactions
Chiral Organocatalysts

• Amino-acid derivatives
• Brønsted acids
• Lewis bases
• Nucleophilic Carbenes

Combined catalysis of organo and metal catalysts
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Chiral Brønsted Acids
For review, see T. Akiyama, Chem. Rev. 2007,
107, 5744.
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Other newly developed Brønsted Acids
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The first examples of Phosphoric Acids-catalyzed
Reactions
T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe,
Angew. Chem. Int. Ed. 2004, 43, 1566.
D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004,
126, 5356.
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The Structural Features of Chiral Phosphoric
Acids
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, 3909.
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Chiral Phosphoric Acids-Catalyzed Multi-Component
Reactions
Cyclization Reactions
Aza-D-A Reaction
Direct Mannich Reaction
Biginelli Reaction
1,3-Dipolar Cycloaddition
Ugi-type reaction
KabachnikFields Reaction
Povarov Reaction
Friedel-Crafts Aminoalkylation
Hantzsch Reaction
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Direct Mannich Reaction
Transition state
Q.-X. Guo, H. Liu, C. Guo, S.-W. Luo, Y. Gu,
L.-Z. Gong, J. Am. Chem. Soc. 2007, 129, 3790.
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Using Enecarbamates as Nucleophiles
G. Dagousset, F. Drouet, G. Masson, J. Zhu,
Org. Lett., 2009, 11, 5546.
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Vinylogous Mannich Reaction
M. Sickert, F. Abels, M. Lang, J. Sieler, C.
Birkemeyer, C. Schneider, Chem. Eur. J. 2010,
16, 2806.
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Biginelli Reaction
P. G. Biginelli, Chim. Ital. 1893, 23, 360.
General mechanism
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The first organocatalytic highly
enantioselective Biginelli reaction
X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun, L.-Z.
Gong, J. Am. Chem. Soc. 2006, 128, 14802.
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Biginelli and Biginelli-Like Condensations

• Reversal of the stereochemistry by tuning the
  3,3-disubstituents of phosphoric acids

N. Li, X.-H. Chen, J. Song, S.-W. Luo, W. Fan,
L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 15301.
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• Reaction Mechanism

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Synthetic applications
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Asymmetric Amplification in Phosphoric
Acid-Catalyzed Biginelli Reaction

• Positive nonlinear effect

N. Li, X.-H. Chen, S.-M. Zhou, S.-W. Luo, J.
Song, L. Ren, L.-Z. Gong, Angew. Chem. Int. Ed.
2010, 49, 6378.
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Cyclization Reactions Leading to Dihydropyridine
Derivatives
Synthetic applications
J. Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao, L.-Z.
Gong, Angew. Chem. Int. Ed. 2008, 47, 2458.
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Reaction Mechanism
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Cyclization leading to dihydropyridinone
derivatives
J. Jiang, J. Qing, L.-Z. Gong, Chem. Eur. J.
2009, 15, 7031.
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Reaction Mechanism
formal 42 cycloaddition
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Hantzsch reaction
C. G. Evans, J. E. Gestwicki, Org. Lett. 2009,
11, 2957.
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Aza-Diels-Alder Reaction
H. Liu, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang, L.-Z.
Gong, Org. Lett. 2006, 8, 6023.
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Povarov reaction
An inverse electron-demand aza-Diels-Alder
reaction between 2-azadienes and electron-rich
olefins.
H. Liu, G. Dagousset, G. Masson, P. Retailleau,
J. Zhu, J. Am. Chem. Soc. 2009, 131, 4598.
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Ugi-type reaction
T. Yue, M.-X. Wang, D.-X. Wang, G. Masson, J.
Zhu, Angew. Chem. Int. Ed. 2009, 48, 6717.
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1,3-Dipolar cycloaddition
X.-H. Chen, W.-Q. Zhang, L.-Z. Gong, J. Am.
Chem. Soc. 2008, 130, 5652.
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Methyleneindolinones as dipolarophiles to
synthesize Spiropyrrolidin-3,3-oxindoles
with unusual regiochemistry
X.-H. Chen, Q. Wei, H. Xiao, S.-W. Luo, L.-Z.
Gong, J. Am. Chem. Soc. 2009, 131, 13819.
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Reaction mechanism
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Imine as dipolarophile to synthesize
imidazolidines
W.-J. Liu, X.-H. Chen, L.-Z. Gong, Org. Lett.
2008, 10, 5357.
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2,3-Allenoate as dipolarophiles to create
pyrrolidines along with CC double bond


J. Yu, L. He, X.-H. Chen, J. Song, W.-J. Chen,
L.-Z. Gong, Org. Lett. 2009, 11, 4946.
Kinetic Resolution of Racemic 2,3-Allenoates
J. Yu, W.-J. Chen, L.-Z. Gong, Org. Lett. 2010,
12, 4050.
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1,4-Naphthoquinone as dipolarophile to synthesize
isoindolines
C. Wang, X.-H. Chen, S.-M. Zhou, L.-Z. Gong,
Chem. Commun. 2010, 1275.
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KabachnikFields 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, 5079.
L. Wang, S.-M. Cui, W. Meng, G.-W. Zhang, J. Nie,
J.-A. Ma, Chin. Sci. Bull. 2010, 55, 1729.
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Friedel-Crafts aminoalkylation
G.-W. Zhang, L. Wang, J. Nie, J.-A. Ma, Adv.
Synth. Catal. 2008, 350, 1457.
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Combined catalysis of phosphoric acid and metal
catalysts
Cooperative Catalysis
Relay Catalysis
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Cooperative Catalysis
Mannich-type multi-component reaction
W. Hu, X. Xu, J. Zhou, W.-J. Liu, H. Huang, J.
Hu, L. Yang, L.-Z. Gong, J. Am. Chem. Soc. 2008,
130, 7782.
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Reaction mechanism
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X. Xu, J. Zhou, L. Yang, W. Hu, Chem. Commun.
2008, 48, 6564.
X. Xu, Yu Qian, L. Yang, W. Hu, Chem. Commun.
ASAP, DOI 10.1039/c0cc03024d
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Relay Catalysis
Consecutive Intramolecular Hydroamination/
Asymmetric Transfer Hydrogenation
Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J.
Am. Chem. Soc. 2009, 131, 9182.
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Intermolecular Hydroamination and Transfer
Hydrogenation Reactions
X.-Y. Liu, C.-M. Che, Org. Lett., 2009, 11,
4204.
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Povarov reaction and subsequent intramolecular
hydroamination
C. Wang, Z.-Y. Han, H.-W. Luo, L.-Z. Gong, Org.
Lett., 2010, 12, 2266.
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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.
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Sincere thanks for your attention and kind help!