Multi Component Reactions
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The document discusses multicomponent reactions (MCRs), highlighting their advantages in natural products drug discovery and scaffold generation. It outlines the definition, types, and historical development of MCRs, particularly focusing on key reactions such as the Passerini and Ugi reactions. The significance of MCRs in synthesizing biologically active compounds and their potential applications is emphasized.
Multi Component Reactions
- 2. 2 WHY LOOK AT MULTICOMPONENT REACTIONS (MCRs)? MCRs Natural Products Drug Discovery Scaffold Generation MULTI- COMPONENT REACTIONS Picture from: http://img.dailymail.co.uk/i/pix/2007/08_02/mosquito_468x343.jpg http://www.abcam.com/ps/datasheet/images/18251-final.jpg
- 3. 3 OUTLINE • What is an ideal reaction? • Definition of Multicomponent Reactions (MCRs) • Comparison of MCRs with Multistep Reactions • History of MCRs • Types of Multicomponent Reactions • Passerini Reacton • Ugi Reaction • Biginelli Reaction • Conclusion
- 4. 4 WHAT IS AN IDEAL REACTION? Ideal Reaction Simple 100% Yield Ready available starting materials Eco-Friendly Resource Effective One Pot Reference: Wender, P. A.; Handy, S; Wright, D. L; Towards the ideal synthesis. Chem. Ind. 1997, 765.
- 5. 5 DEFINITION OF MULTICOMPONENT REACTIONS (MCRs) • Reactions in which more than two starting compounds react to form a product in such a way that the majority of the atoms of the starting material can be found in the product are called multicomponent reactions. PRODUCT 3 2 1 Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
- 6. 6 • Multistep Reactions – Divergent Reactions – One step after another – Low Efficiency – Low Diversity per Step Multicomponent Reactions Convergent Reactions Reaction in one pot Higher Efficiency High Diversity per Step A + B A-B + C A-B-C P + Q + R P-Q-R A + B C D E F G H I P Q R P-Q-R
- 7. 7 TYPE OF REACTION GENERAL REACTION SCHEME TYPE I e.g. Certain types of Strecker Reaction TYPE II e.g. Passerini Reaction and Ugi Reactions TYPE III e.g. Generally seen in biological systems Reference: Ugi, I. et al. Molecules 2003, 8, 53-66.
- 8. 8 • Isocyanide Based MCRs – Passerini Reaction – Ugi Reaction
- 9. 9 • First isocyanide based MCR • Developed in 1921 by Mario Passerini • Simple 3 component reaction References: 1. Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 2. Domling, A. Chem. Rev. 2006, 106, 17-89. 1881-1962 α-acyloxycarboxamides Mario Passerini
- 10. Reference: Banfi, L. et. al. Organic Reactions; Charette A. B. ed. Wiley, New York, 2005, vol. 65, p 1. 10
- 11. 11 • Synthesis of analogs of Azinomycin – a DNA binding and alkylating antibiotic by Armstrong et al. Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810. Acid component Aldehyde component Isocyanide component
- 12. 12 The reaction Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.
- 13. 13 • Isocyanide Based MCRs – Passerini Reaction – Ugi Reaction
- 14. 14 • Developed in 1959 by Ivar Ugi • The most studied and used MCR • Involves an isocyanide, a carboxylic acid, an amine and a carbonyl compound to yield α-aminoacyl amides α-acylamino carboxamides 1930 - 2005 References: Domling, A. Chem. Rev. 2006, 106, 17-89. Ivar Ugi
- 15. Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 15
- 16. 16 • Synthesis of toxin Dysidenin from the sponge Dysidea herbacea Reference: De Laszlo, S. E. et al. J. Am. Chem. Soc. 1985, 107, 199-203.
- 17. 17 Fukuyama et al. have reported the synthesis of a marine tunicate, Ecteinascidin 743, which has extremely potent antitumor acitivity, using the Ugi reaction as a key step.
- 18. Reference: Domling, A. et al, Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 18 Majority of the variations can be made at the carboxylic acids. For eg. Use of cyanic acids, hydrogen thiocyanate, hydrazoic acid Few changes can be made to the amine. Derivatives of ammonia such as hydrazine, hydrazides or hydroxylamines can be used.
- 19. 19 • Overlap between Ugi reaction and Passerini reaction – Side products of each other – Limited use of amines in Passerini Reaction – Lower yields Reference: Banfi, L. et. al. Organic Reactions; Charette A. B. ed. Wiley, New York, 2005, vol. 65, p 1. Ugi Reaction Passerini Reaction
- 20. • Developed in 1893 by Italian Chemist, Pietro Biginelli. • A classical non-isocyanide-based multicomponent process. • Involves an acid catalysed condensation of β-keto esters, aldehyde and urea (or thiourea) in alcohol gives Dihydropyrimidinones. 20
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- 22. 22 • They have been found to exhibit a wide spectrum of biological effects including antiviral, antitumor, antibacterial and anti-inflammatory activities. • A batzelladine alkaloids A and B which are efficient HIV gp-120-CD4 inhibitors
- 23. 23 PAST PRESENT FUTURE Over 150 Years of development
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