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MULTICOMPONENT REACTIONS

FOR MORE PRESENTATIONS VISIT www.pharmaxchange.info. MULTICOMPONENT REACTIONS. PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY. www.pharmaxchange.info. WHY LOOK AT MULTICOMPONENT REACTIONS (MCRs)?. MULTI- COMPONENT REACTIONS.

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MULTICOMPONENT REACTIONS

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  1. FOR MORE PRESENTATIONS VISIT www.pharmaxchange.info MULTICOMPONENT REACTIONS PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITYSCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY

  2. www.pharmaxchange.info WHY LOOK AT MULTICOMPONENT REACTIONS (MCRs)? 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 Picture from: http://mikroby.blox.pl/resource/actinomycetes.jpg, http://www.starfish.ch/Fotos/sponge-Schwamm/Dysidea-sp-1.jpg

  3. What is an ideal reaction? Definition of Multicomponent Reactions (MCRs) Comparison of MCRs with Multistep Reactions History of MCRs Types of Multicomponent Reactions A closer look at some MCRs Solid Phase MCRs Use of MCRs in Drug Discovery Use of MCRs to Create Scaffolds Union Concept of MCRs Conclusion FOR MORE PRESENTATIONS VISIT www.pharmaxchange.info OUTLINE

  4. www.pharmaxchange.info WHAT IS AN IDEAL REACTION? Reference: Wender, P. A.; Handy, S; Wright, D. L; Towards the ideal synthesis. Chem. Ind. 1997, 765.

  5. 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. www.pharmaxchange.info DEFINITION OF MULTICOMPONENT REACTIONS (MCRs) Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.

  6. Strecker Synthesis www.pharmaxchange.info AN EXAMPLE OF A SIMPLE MULTICOMPONENT REACTION

  7. Multistep Reactions • Divergent Reactions • One step after another • Low Efficiency • Low Diversity per Step www.pharmaxchange.info MULTICOMPONENT V/S MULTISTEP REACTIONS • Multicomponent Reactions • Convergent Reactions • Reaction in one pot • Higher Efficiency • High Diversity per Step P Q C F G H I P-Q-R A + B E D R + C A + B A-B A-B-C P +Q+R P-Q-R

  8. 1838- Laurent and Gerhardt – serendipitous MCR www.pharmaxchange.info HISTORY OF MULTICOMPONENT REACTIONS • 1850- Strecker synthesis of α-amino acids • 1917- Robinson synthesized alkaloid tropinone aminobenzyl cyanide Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. α-cyano amines α-amino acids methylamine dimethyl acetonedicarboxylate succinicdialdehyde Tropinone

  9. www.pharmaxchange.info HISTORY OF MULTICOMPONENT REACTIONS • ISOCYANIDE BASED MCRS • 1921- Mario Passerini developed the first MCR involving isocyanides.

  10. www.pharmaxchange.info HISTORY OF MULTICOMPONENT REACTIONS • 1959-Ivar Ugi developed one of the most important and most studied MCRs involving isocyanides and having 4 components now popularly known as the Ugi Reaction (U-4CR) α-aminoacyl amides

  11. www.pharmaxchange.info TYPES OF MULTICOMPONENT REACTIONS Reference: Ugi, I. et al. Molecules2003, 8, 53-66.

  12. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS • Variations of Ugi Reaction • Stereocontrol

  13. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS

  14. Free radicals take part in polymerization In essence this can be a multicomponent reaction if steps occur in a controlled manner This has led to some free radical mediated multicomponent reactions www.pharmaxchange.info FREE RADICAL MEDIATED MULTICOMPONENT REACTIONS Reference: Tojino, M. et al. Free-radical-mediated Multicomponent Coupling Reactions. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 169-198.

  15. www.pharmaxchange.info AN EXAMPLE OF A FREE RADICAL MEDIATED MCR hv>300nm 30°C, 2hours 61% Reference: Tsuchii, K. et al. Angew. Chem. Int. Ed. 2003, 42, 3490-3493.

  16. www.pharmaxchange.info MECHANISM OF THE REACTION Reference: Tsuchii, K. et al. Angew. Chem. Int. Ed. 2003, 42, 3490-3493.

  17. Free radicals are notorious • Highly reactive • Give many side reactions In General - Very difficult to control hence low applicability www.pharmaxchange.info WHY FREE RADICAL MEDIATED MCRs ARE NOT THAT COMMON? Reference: Tojino, M. et al. Free-radical-mediated Multicomponent Coupling Reactions. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 169-198. picture from- http://www.gosmiley.com/living/smiley_punk.gif

  18. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS

  19. Broad range of reactivity This led to the development of MCRs involving organoboronic acid derivatives www.pharmaxchange.info MULTICOMPONENT REACTIONS WITH ORGANOBORON COMPOUNDS

  20. Reaction with amines, carbonyls and boronic acids or boronates to yield derivatives www.pharmaxchange.info AN EXAMPLE OF A MCR INVOLVING ORGANOBORON COMPOUNDS Reference: Petasis, N. A.; Multicomponent Reactions with Organoboron Compounds. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 199-223.

  21. MECHANISM OF THE REACTION www.pharmaxchange.info Reference: Petasis, N. A.; Multicomponent Reactions with Organoboron Compounds. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 199-223.

  22. www.pharmaxchange.info APPLICATION OF THE REACTION- AMINOACID SYNTHESIS -COOH i.e Reference: Petasis, N. A. et al. J. Am. Chem. Soc. 1997, 119, 445-446.

  23. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS

  24. Transition Metals They have multi bond forming capabilities Milder Reaction conditions Chemo and regio selectivity Hence they can be used in MCRs www.pharmaxchange.info METAL CATALYZED MCR Co27 Ni28 Ru44 Pd46 Reference: Balme, G. et al. Metal-catalyzed Multicomponent Reactions. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 224-276.

  25. Uses Cobalt transition metal Yields cyclopentenone derivatives www.pharmaxchange.info EXAMPLE OF METAL CATALYSED MCR- PAUSON KHAND REACTION Co27 • Reference: Hanson, B. E. Comments on Inorganic Chemistry, 2002, 23, 289-318.

  26. www.pharmaxchange.info PAUSON KHAND METAL CATALYZED MCR- PROPOSED MECHANISM TOP VIEW • Reference: Magnus, P. et. al.; Tetrahedron Lett.1985, 26, 4851-4854.

  27. www.pharmaxchange.info USES OF THE PAUSON KHAND REACTION Reference: Gibson S. E.; et al. Journal of Organometallic Chemistry, 2004, 689, 3873-3890.

  28. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS

  29. CII Carbon resonates with the CIV form • Reaction of both nucleophiles and electrophiles at the carbon atom α-acidity- like carbonyl www.pharmaxchange.info WHAT MAKES ISOCYANIDES SO SPECIAL?? Reference: Ugi, I. et al. Chem. Int. Ed. 1965, 4, 474-484.

  30. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS

  31. First isocyanide based MCR Developed in 1921 by Mario Passerini Simple 3 component reaction www.pharmaxchange.info PASSERINI REACTION Mario Passerini 1881-1962 α-acyloxycarboxamides • References: 1. Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. • 2. Domling, A. Chem. Rev. 2006, 106, 17-89.

  32. www.pharmaxchange.info SUGGESTED MECHANISM FOR THE PASSERINI REACTION Reference: Banfi, L. et. al. Organic Reactions; Charette A. B. ed. Wiley, New York, 2005, vol. 65, p 1.

  33. Synthesis of analogs of Azinomycin – a DNA binding and alkylating antibiotic by Armstrong et al. www.pharmaxchange.info APPLICATIONS OF THE PASSERINI REACTION Aldehyde component Isocyanide component Acid component Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.

  34. The reaction www.pharmaxchange.info APPLICATIONS OF THE PASSERINI REACTION Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.

  35. Synthesis of the natural prolylendopeptidase inhibitor Eurystatin A by Schmidt et al. www.pharmaxchange.info APPLICATIONS OF THE PASSERINI REACTION Reference: Schmidt, U. et al. J. Chem. Soc., Chem. Commun. 1994, 1003.

  36. Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs • Passerini Reaction • Ugi Reaction www.pharmaxchange.info TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS

  37. 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 www.pharmaxchange.info UGI REACTION 1930 - 2005 α-acylamino carboxamides • References: Domling, A. Chem. Rev. 2006, 106, 17-89.

  38. www.pharmaxchange.info MECHANISM OF THE UGI REACTION • Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.

  39. Synthesis of antibiotic bicyclomycin which is isolated from Streptomycessapporonensisby Fukujama et al. www.pharmaxchange.info APPLICATIONS OF THE UGI REACTION Reference: Fukujama, T. et al. Tetrahedron Lett. 1981, 27, 4155-4158.

  40. Synthesis of toxin Dysidenin from the sponge Dysideaherbacea www.pharmaxchange.info APPLICATIONS OF THE UGI REACTION • Reference: De Laszlo, S. E. et al. J. Am. Chem. Soc.1985, 107, 199-203.

  41. www.pharmaxchange.info VARIATIONS OF THE FUNCTIONAL GROUPS OF UGI REACTION Few changes can be made to the amine. Derivatives of ammonia such as hydrazine, hydrazides or hydroxylamines can be used. Majority of the variations can be made at the carboxylic acids. For eg. Use of cyanic acids, hydrogen thiocyanate, hydrazoic acid Reference: Domling, A. et al, Angew. Chem. Int. Ed. 2000, 39, 3168-3210.

  42. www.pharmaxchange.info EXAMPLE OF A VARIATION USING HYDROXYLAMINE 45% 75% Reference: Basso, A. et. al; Tetrahedron lett. 2004, 45, 6109-6111.

  43. www.pharmaxchange.info CYCLIC VARIATIONS OF UGI REACTION

  44. One step formation of β-Lactam ring as seen in nocardicin-A derivatives. www.pharmaxchange.info EXAMPLE OF A CYCLIC VARIATION OF A UGI REACTION Reference: Kehagia, K. et al.; Tetrahedron, 1995, 51, 9523-9530.

  45. As such poor stereocontrol. Stereocontrol can be induced using chiral starting materials. Most effective is to use a chiral amine component. E.g. 1-phenylethylamines - >90%de Other components not as effective for stereocontrol www.pharmaxchange.info STEREOCONTROL IN UGI REACTIONS Reference: Banfi, L.; Asymmetric Isocyanide-based MCRs. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 1-32.

  46. Overlap between Ugi reaction and Passerini reaction • Side products of each other • Limited use of amines in Passerini Reaction • Lower yields www.pharmaxchange.info LIMITATION OF UGI AND PASSERINI REACTIONS Ugi Reaction Passerini Reaction Reference: Banfi, L. et. al. Organic Reactions; Charette A. B. ed. Wiley, New York, 2005, vol. 65, p 1.

  47. Solid Phase MCRs are • More efficient • Allow easy separation Isocyanide component is generally incorporated into the solid phase resin www.pharmaxchange.info SOLID PHASE MULTICOMPONENT REACTIONS

  48. www.pharmaxchange.info EXAMPLE OF A SOLID PHASE UGI MCR RINK TYPE RESIN • Reference: Chen, J. J. et al.; Tetrahedron Lett. 2002, 43, 4083-4085.

  49. www.pharmaxchange.info USE OF MCRS IN DRUG DISCOVERY • Reference: Domling, A.; Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem. Rev. 2006, 106, 17-89.

  50. Abbott scientists developed potent Tubulin inhibitors using van Leussen 3 component reaction which could be used for cancer therapeutics. www.pharmaxchange.info • USE OF MCRS IN DRUG DISCOVERY- TUBULIN INHIBITORS • Reference: Wang, L. et al.; J. Med. Chem.2002, 45, 1697-1711.

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