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- 1. Introduction
- 2. Our proposal
- 3. Results
- 4. Conclusions
Contents
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Pyrrolidinodiones in Enol-Ugi, Enol-Passerini and anomalous - - PowerPoint PPT Presentation
Pyrrolidinodiones in Enol-Ugi, Enol-Passerini and anomalous - - PowerPoint PPT Presentation
Pyrrolidinodiones in Enol-Ugi, Enol-Passerini and anomalous enol-Passerini condensations Ana G. Neo,* Carlos F. Marcos* Laboratory of Bioorganic Chemistry & Membrane Biophysics, School of Veterinary Sciences, University of Extremadura,
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3
Introduction
- Isocyanides
- Multicomponent reactions of isocyanides
- Diversity of MCRI
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Introduction
Isocyanides
Reactions of isocyanides:
- Cycloadditions
- Insertions
- Multicomponent reactions (MCRIs)
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Introduction
Classic MCRIs
Passerini three-component condensation Ugi four-component condensation
Passerini, M. Gazz. Chim. Ital 1921, 51, 126. Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
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Introduction
- Atom economy
- Efficient
- Sustainable
- Structural diversity
- Post-condensation transformations
- Single replacement reactions (SRR)
Dömling, A. Chem. Rev. 2006, 106, 17-89; Ganem, B. Acc Chem Res 2009, 42, 463. Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235.
Advantages of MCRIs
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Introduction
Single replacement reactions (SRR)
Acid Amine
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Our proporsal
O R2 R1 R3 NH2 + N R2 R1 R3 H R4 CN N R2 R1 N R4 H R3 OH R6 R5 EWG O R6 R5 EWG N R2 R1 N R4 R3 O R6 R5 EWG H N R2 R1 N R4 H R3 O EWG R5 Primary adduct N R2 R1 N R4 R3 O EWG R5 H Peptidomimetic enamines R6 R6
Enols act as the acid component in the Ugi reaction
Single replacement reactions (SRR)
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Pyrrolidinodiones in MCRIs
Vaughan, W. R.; Covey, I. S. J. Am. Chem. Soc. 1958, 80, 2197.
Our proporsal
1. Predominant enolic form 2. pKa < 5 3. Michael acceptor
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Our proporsal
Peifer, C et al. J. Med. Chem. 2008, 51, 3814; Lampe, J. W et al. J. Med. Chem. 1993, 36, 1041; Rose,
- R. et al. Angew. Chem. Int. Ed. 2010, 49, 4129; Jourdan, F. et al. ChemInform 2006, 37.
Biologically relevant pyrrolidinones
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Results
Enol-Ugi condensation of pyrrolidinodiones
39 examples Yields up to 95%
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Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org. Lett. 2012, 14, 6218.
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Results
N Ph Ph N Ph O O N Ph Ph NC NC O N Ph NC S O O N O O NC Ph NC CN CN O O N O OH EtO2C Ph N Ph O OH EtO2C Ph N Ph O OH EtO2C O O N Ph O OH EtO2C F N Ph O OH EtO2C Cl N Ph O OH EtO2C H3CO
Scope
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Enol-Ugi condensation of pyrrolidinodiones
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Results
Enol-Passerini condensation
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14 examples Yields up to 92%
Neo, A. G.; Marcos, C. F. Org. Lett. 2018, 20, 3875.
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Results
Enol-Passerini condensation
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Scope
Ph O O NC NC NC CN CN O O N O OH EtO2C N Ph O OH EtO2C Ph N Ph O OH EtO2C O O O O O Br O NO2 N Ph O OH EtO2C Cl N Ph O OH EtO2C H3CO
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Results
Enol-Passerini condensation
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Mechanism
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Results
Anomalous enol-Passerini condensations
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17 examples Yields up to 67%
Neo, A. G.; Marcos, C. F. Org. Lett. 2018, 20, 3875.
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Results
Anomalous enol-Passerini condensation
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Scope
Ph O O NC NC CN CN O O N O OH EtO2C N Ph O OH EtO2C Ph R N Ph O OH EtO2C O O R= H, F, Cl, OMe O O O Br O R R= CH3, NO2 MeO Ph NC
Bulky isocyanides do not react
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Results
Anomalous enol-Passerini condensations
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Mechanism
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Conclusions
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We have used enols for the first time as the acid component in Ugi and Passerini-type reactions. Careful control of the reaction conditions allows us to obtain Ugi, Passerini or pseudo-enol-Ugi products selectively. The use of enols as acidic partners in MCRI is an excellent strategy for the preparation of new pyrrolidinones having peptidic or pseudo-peptidic groups on carbon 3.
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Acknowledgements
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