Transcript MULTICOMPONENT REACTIONS

FOR MORE PRESENTATIONS VISIT www.pharmaxchange.info
PRESENTED BY – AKUL MEHTA
VIRGINIA COMMONWEALTH UNIVERSITY
SCHOOL OF PHARMACY
DEPARTMENT OF MEDICINAL CHEMISTRY
www.pharmaxchange.info
Natural
Products
MULTICOMPONENT
REACTIONS
Scaffold
Generation
MCRs
Drug
discovery
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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
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Simple
One Pot
100% Yield
Ideal
Reaction
Resource
Effective
Environment
Friendly
Ready
available
starting
materials
Reference: Wender, P. A.; Handy, S; Wright, D. L; Towards the ideal synthesis. Chem.
Ind. 1997, 765.
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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.
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PRODUCT
Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
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Strecker Synthesis
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Multistep Reactions
 Divergent Reactions
C
A+B
D
E
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Multicomponent Reactions
 Convergent Reactions
P
F
G
H
I
Q
P-Q-R
 One step after another
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R
Reaction in one pot
+C
A+B
A-B
P+Q+R
A-B-C
 Low Efficiency
 Low Diversity per Step
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P-Q-R
Higher Efficiency
High Diversity per Step
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1838- Robinson
18501917Strecker
Laurent and
synthesis
synthesized
Gerhardt
of α-amino
alkaloid
– serendipitous
acids
tropinone
MCR
methylamine
succinic
dialdehyde
dimethyl
acetonedicarboxylate
α-cyano amines
α-amino acids
aminobenzyl cyanide
Tropinone
Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
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ISOCYANIDE BASED MCRS
1921- Mario Passerini developed the first MCR
involving isocyanides.
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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
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TYPE OF
REACTION
TYPE I
e.g.
TYPE II
e.g.
TYPE III
e.g.
GENERAL REACTION SCHEME
Certain types of Strecker Reaction
Passerini Reaction and Ugi Reactions
Generally seen in biological systems
Reference: Ugi, I. et al. Molecules 2003, 8, 53-66.
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
•Variations of Ugi Reaction
•Stereocontrol
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
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Free radicals take part in polymerization
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In essence this can be a multicomponent
reaction if steps occur in a controlled manner
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This has led to some 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; 169198.
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hv >300nm
30°C, 2hours
61%
Reference: Tsuchii, K. et al. Angew. Chem. Int. Ed. 2003, 42, 3490-3493.
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Reference: Tsuchii, K. et al. Angew. Chem. Int. Ed. 2003, 42, 3490-3493.
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Free radicals are notorious
 Highly reactive
 Give many side reactions
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In General - Very difficult to control hence low
applicability
Reference: Tojino, M. et al. Free-radical-mediated Multicomponent Coupling Reactions.
In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 169198.
picture from- http://www.gosmiley.com/living/smiley_punk.gif
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
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Broad range of reactivity
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This led to the development of MCRs
involving organoboronic acid derivatives
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Reaction with amines, carbonyls and boronic
acids or boronates to yield derivatives
Reference: Petasis, N. A.; Multicomponent Reactions with Organoboron Compounds. In
Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 199223.
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Reference: Petasis, N. A.; Multicomponent Reactions with Organoboron Compounds. In
Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 199223.
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-COOH
i.e
Reference: Petasis, N. A. et al. J. Am. Chem. Soc. 1997, 119, 445-446.
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
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Transition Metals
They have multi bond forming capabilities
Milder Reaction conditions
Chemo and regio selectivity
Hence they can be used in MCRs
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.
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Co27
Uses Cobalt transition metal
Yields cyclopentenone derivatives
Reference: Hanson, B. E. Comments on Inorganic Chemistry, 2002, 23, 289-318.
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TOP VIEW
Reference: Magnus, P. et. al.; Tetrahedron Lett.1985, 26, 4851-4854.
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Reference: Gibson S. E.; et al. Journal of Organometallic Chemistry, 2004, 689, 38733890.
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
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CII Carbon resonates
with the CIV form
 Reaction of both
nucleophiles and
electrophiles at the
carbon atom
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α-acidity- like carbonyl
Reference: Ugi, I. et al. Chem. Int. Ed. 1965, 4, 474-484.
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
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Mario Passerini
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First isocyanide
based MCR
Developed in
1921 by Mario
Passerini
Simple 3
component
reaction
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.
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Reference: Banfi, L. et. al. Organic Reactions; Charette A. B. ed. Wiley, New York, 2005,
vol. 65, p 1.
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Synthesis of analogs of Azinomycin – a DNA binding
and alkylating antibiotic by Armstrong et al.
Aldehyde component
Acid component
Isocyanide component
Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.
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The reaction
Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.
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Synthesis of the natural prolyl endopeptidase
inhibitor Eurystatin A by Schmidt et al.
Reference: Schmidt, U. et al. J. Chem. Soc., Chem. Commun. 1994, 1003.
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Free Radical Mediated MCRs
MCRs with Organoboron Compounds
Metal Catalyzed MCRs
Isocyanide Based MCRs
 Passerini Reaction
 Ugi Reaction
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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
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1930 - 2005
α-acylamino
carboxamides
References: Domling, A. Chem. Rev. 2006, 106, 17-89.
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Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
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Synthesis of antibiotic bicyclomycin which is
isolated from Streptomyces sapporonensis by
Fukujama et al.
Reference: Fukujama, T. et al. Tetrahedron Lett. 1981, 27, 4155-4158.
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Synthesis of toxin Dysidenin from the sponge
Dysidea herbacea
Reference: De Laszlo, S. E. et al. J. Am. Chem. Soc. 1985, 107, 199-203.
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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.
Reference: Domling, A. et al, Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
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45%
Reference: Basso, A. et. al; Tetrahedron lett. 2004, 45, 6109-6111.
75%
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One step formation of β-Lactam ring as seen
in nocardicin-A derivatives.
Reference: Kehagia, K. et al.; Tetrahedron, 1995, 51, 9523-9530.
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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
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Other components not as effective for
stereocontrol
Reference: Banfi, L.; Asymmetric Isocyanide-based MCRs. In Multicomponent
Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 1-32.
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Passerini Reaction
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Ugi Reaction
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.
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Solid Phase MCRs are
 More efficient
 Allow easy separation
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Isocyanide component is generally
incorporated into the solid phase resin
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RINK TYPE RESIN
Reference: Chen, J. J. et al.; Tetrahedron Lett. 2002, 43, 4083-4085.
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Reference: Domling, A.; Recent Developments in Isocyanide Based Multicomponent
Reactions in Applied Chemistry. Chem. Rev. 2006, 106, 17-89.
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Abbott scientists developed potent Tubulin inhibitors
using van Leussen 3 component reaction which
could be used for cancer therapeutics.
Reference: Wang, L. et al.; J. Med. Chem. 2002, 45, 1697-1711.
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Synthesis of the tubulin inhibitor:
Reference: Van Leusen, A. M. et al. J. Org. Chem., 1977, 42, 1153-1159.
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Synthesis of the tubulin inhibitor:
Reference: Van Leusen, A. M. et al. J. Org. Chem., 1977, 42, 1153-1159.
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On the
basis of
which
chloroquine
48hrs
60%
Reference: Musonda, C. C. et al. Bioorg. Med. Chem. Lett. 2004, 14, 3901-3905.
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Morphochem discovered highly selective and
orally bioavailable factor Xa inhibitors.
Reference: Nerdinger, S.; Fuchs, T.; Illgen, K.; Eckl, R.; Aryl amides that inhibit factor Xa
activity. WO 2002068390, September 6, 2002.
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MORE RECENTLY
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Reference: Fan, L. et al. Org. Lett. 2007, 9, 2015-2017.
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Reference: Banfi, L. et al. Mol. Divers. 2008, 12, 187-190.
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MCR1
MCR2
MCR3
Reference: Domling, A.; Ugi, I; Multicomponent Reactions with Isocyanides. Angew.
Chem. Int. Ed. 2000, 39, 3168-3210.
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43%
Reference: Domling, A.; Ugi, I.; The Seven-Component Reaction. Angew. Chem. Int. Ed.
Engl. 1993, 32, 563-564.
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PAST
PRESENT
FUTURE
Natural
Over 150Years of development
Products
MCR1
MCRs
MCR2
Scaffold
Generation
MCR3
Drug
discovery
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
Dr. Umesh Desai

Dr. Qibing Zhou
(Department of Chemistry, VCU)

The Desai Group

Department of Medicinal Chemistry at VCU
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