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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. - PowerPoint PPT Presentation
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MULTICOMPONENT REACTIONS
PRESENTED BY – AKUL MEHTA
VIRGINIA COMMONWEALTH UNIVERSITYSCHOOL OF PHARMACYDEPARTMENT OF MEDICINAL CHEMISTRY
FOR MORE PRESENTATIONS VISIT www.pharmaxchange.info
WHY LOOK AT MULTICOMPONENT REACTIONS (MCRs)?
2
MULTI-COMPONENTREACTIONS
MCRs
NaturalProducts
Drug discovery
Scaffold Generation
HO
NH
OH
O
O
HO OH
Cl3C N
O
CCl3
NHO
N
S
N
N
MeO
NH2
MeO
MeO
OMe
NCl
HN N
O NH
O
N
N
O
NH
O
O
N
O
HN
O
N
O
HN NH
O
Picture from: http://img.dailymail.co.uk/i/pix/2007/08_02/mosquito_468x343.jpghttp://www.abcam.com/ps/datasheet/images/18251-final.jpgPicture from: http://mikroby.blox.pl/resource/actinomycetes.jpg, http://www.starfish.ch/Fotos/sponge-Schwamm/Dysidea-sp-1.jpg
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OUTLINE
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
3
FOR MORE PRESENTATIONS VISIT 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. 4
Ideal Reaction
Simple
100% Yield
Ready available starting
materialsEnviron-ment
Friendly
Resource Effective
One Pot
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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
21
Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.5
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H
O
HCN
NH3
NH2
CN
H+
Strecker Synthesis
6
AN EXAMPLE OF A SIMPLE MULTICOMPONENT REACTION
H
NH
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Multistep Reactions Divergent Reactions
One step after another
Low Efficiency Low Diversity per
Step7
MULTICOMPONENT V/S MULTISTEP REACTIONS
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
DE
FGHI
P Q
R
P-Q-R
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1838- Laurent and Gerhardt – serendipitous MCR
Reference: Domling, A. et al. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 8
HISTORY OF MULTICOMPONENT REACTIONS
H
O+ NH3
+HCN
NH2
CN
aminobenzyl cyanide
1850- Strecker synthesis of α-amino acids
R
H
O+ NH3
+HCNR NH2
COOH
α-amino acidsα-cyano amines
R NH2
CN
H+ / H2O
1917- Robinson synthesized alkaloid tropinone
NMe
COOMe
COOMe
O
Tropinone
succinicdialdehyde
methylamine dimethyl acetonedicarboxylate
+CH3
NH2+ MeOOC COOMe
OCHO
CHO
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9
HISTORY OF MULTICOMPONENT REACTIONS ISOCYANIDE BASED MCRS 1921- Mario Passerini developed the first
MCR involving isocyanides.
R1
O
OH
+R2
O
H
+ R3NC
isocyanide
R1
O
O
R2
O
HN
R3
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10
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)
R1 H
O
+
R2
O
OH
+ R3NC +NH2
R4
R2
O
N
R1
O
HN
R3
R4
α-aminoacyl amides
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TYPE OF REACTION
GENERAL REACTION SCHEME
TYPE Ie.g. Certain types of Strecker
ReactionTYPE IIe.g. Passerini Reaction and Ugi
ReactionsTYPE IIIe.g. Generally seen in biological
systemsReference: Ugi, I. et al. Molecules 2003, 8, 53-66.11
TYPES OF MULTICOMPONENT REACTIONS
A + B C ..... O P
A + B C ..... O P
A + B C ..... O P
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Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs
Passerini Reaction Ugi Reaction
12
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
•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
13
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
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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
Reference: Tojino, M. et al. Free-radical-mediated Multicomponent Coupling Reactions. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 169-198. 14
FREE RADICAL MEDIATED MULTICOMPONENT REACTIONS
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Reference: Tsuchii, K. et al. Angew. Chem. Int. Ed. 2003, 42, 3490-3493. 15
AN EXAMPLE OF A FREE RADICAL MEDIATED MCR
EtOOC +OMe
+CN
+ (PhSe)2
ethylpropiolate 2-methoxypropene
acrylonitrile diphenyldiselenide
hv >300nm30°C, 2hours
CN SePh
SePh
COOEt
OMe
61%
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CN
COOEtOMe
SePhNC
16
MECHANISM OF THE REACTION
(PhSe)2h
PhSe
5-exo
MeO
SePh
CN
COOEt
PhSe
MeO
SePh
CN
COOEt
SePh
COOEt +MeO
COOEtOMe
SePh
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
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; 169-198. picture from- http://www.gosmiley.com/living/smiley_punk.gif 17
WHY FREE RADICAL MEDIATED MCRs ARE NOT THAT COMMON?
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Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs
Passerini Reaction Ugi Reaction
18
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
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Broad range of reactivity
This led to the development of MCRs involving organoboronic acid derivatives
19
MULTICOMPONENT REACTIONS WITH ORGANOBORON COMPOUNDS
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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; 199-223. 20
AN EXAMPLE OF A MCR INVOLVING ORGANOBORON COMPOUNDS
R2N
R1
H R3
O
R4 R5B
OR
OR
+ +
amine carbonyl boronate
R2N
R1
R3 R4
R5
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R2N
R1
OH
R3 R4
aminol
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
R2N
R1
H R3
O
R4
amine carbonyl
+ N
R1
H
amine
R2
R2N
R1
R3 R4
N
R1
R2
R5B
OR
OR
/
R5B
OR
OR
N
R1
R2
R2N
R1
R3 R4
R5 -B(OR)2OH
NR1R2
R4R3
imine
R5B
OR
OR
boronate
+
R5B
OR
OR
OH
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Reference: Petasis, N. A. et al. J. Am. Chem. Soc. 1997, 119, 445-446. 22
APPLICATION OF THE REACTION- AMINOACID SYNTHESIS
R2N
R1
H R3
O
R4 R5B
OR
OR
+ +
amine carbonyl boronate
-COOH
i.e R2N
R1
H R3
O
R5B
OR
OR
+ +
amine boronateO
OH
alpha-ketoacid
R2N
R1
R3
R5
OH
O
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Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs
Passerini Reaction Ugi Reaction
23
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
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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
Reference: Balme, G. et al. Metal-catalyzed Multicomponent Reactions. In Multicomponent Reactions; Zhu, J., Bienayme, H., Wiley-VCH: Weinheim, 2005; 224-276. 24
METAL CATALYZED MCR
Pd46
Ni28
Ru44
Co27
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Uses Cobalt transition metal Yields cyclopentenone derivatives
Reference: Hanson, B. E. Comments on Inorganic Chemistry, 2002, 23, 289-318. 25
EXAMPLE OF METAL CATALYSED MCR- PAUSON KHAND REACTION
+ CO +
Co2(CO)8
O
ATMOSPHEREOFCO
Co27
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Reference: Magnus, P. et. al.; Tetrahedron Lett.1985, 26, 4851-4854.26
PAUSON KHAND METAL CATALYZED MCR- PROPOSED MECHANISM
Co Co
OC
OC
COOC
CO COOC CO
R1R2 +Co Co
C C
COOC
CO COOC CO
R2 R1
2 -CO
Co Co
C C
COOC
COOC CO
R2 R1
-CO+
Co Co
C C
COOC
COOC CO
R2 R1
+ CO
Co Co
C C
COOC
COOC CO
R2 R1
CO
Co Co
C C
COOC
COOC CO
R2 R1
O CO
O
R2 R1(OC)3Co
Co(CO)3
+2CO
O
R2 R1
TOP VIEW
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Reference: Gibson S. E.; et al. Journal of Organometallic Chemistry, 2004, 689, 3873-3890. 27
USES OF THE PAUSON KHAND REACTION
O
C5H11
(CH2)3COOH
O
O
C5H11
(CH2)5COOR
OH
(CH2)5COOCH3
C7H15
O
O
O
OHOH
TEI - 9826
methylenomycin
pentenomycin
15-deoxy-PG-J2
PG-A1
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Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs
Passerini Reaction Ugi Reaction
28
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
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CII Carbon resonates with the CIV form Reaction of both
nucleophiles and electrophiles at the carbon atom
α-acidity- like carbonyl
Reference: Ugi, I. et al. Chem. Int. Ed. 1965, 4, 474-484. 29
WHAT MAKES ISOCYANIDES SO SPECIAL??
N C N C
CIV CII
NC
HH
H+
NC
H
-
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Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs
Passerini Reaction Ugi Reaction
30
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
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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. 31
PASSERINI REACTION
R1
O
OH
+R2
O
H
+ R3NC
isocyanide
1881-1962
α-acyloxycarboxamides
R1
O
O
R2
O
HN
R3
Mario Passeriniwww.pharmaxchange.info
R1 O
O
R2
OH
H
R3NC
+
Reference: Banfi, L. et. al. Organic Reactions; Charette A. B. ed. Wiley, New York, 2005, vol. 65, p 1. 32
SUGGESTED MECHANISM FOR THE PASSERINI REACTION
R1 OH
O
R1 O
O
R2
OH
H
R2CHO+ +
-
R3
N O
H
OO
H R2
R1
R3
N O
H
OO
H R2
R1
R1 O
O R2
O
HN
R3
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MeOO
O
N
O
H
NH
O
ON
HO
O
AcO
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. 33
APPLICATIONS OF THE PASSERINI REACTION
Acid component
Aldehyde component
Isocyanide component
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The reaction
34
APPLICATIONS OF THE PASSERINI REACTION
Reference: Armstrong, R. W. et al. Tetrahedron Lett. 1991, 32, 3807-3810.
O
O
N
O
H
OEt
OO
CNOEt
O
+OH
OO
O
+
73%
Azinomycin and its derivatives
EtOAc25C24hrs1-naphthoic acid
ethyl isocyanoacetate2-methylglycidal
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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. 35
APPLICATIONS OF THE PASSERINI REACTION
MeOOC NC
+OHC NHZ
+ PhCOOHCH2Cl2
room temperature48hrs
MeOOCHN
O
O
NHZ
Ph
O
85%
MeOOCHN
O
O
NHZ
Ph
O
85%
HN
O
NH
O O
NH
O
HN
O
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Free Radical Mediated MCRs MCRs with Organoboron Compounds Metal Catalyzed MCRs Isocyanide Based MCRs
Passerini Reaction Ugi Reaction
36
TAKING A CLOSER LOOK AT SOME MULTICOMPONENT REACTIONS
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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
37
UGI REACTION
R1 H
O
+
R2
O
OH
+ R3NC +NH2
R4
R2
O
N
R1
O
HN
R3
R4
α-acylamino carboxamides
1930 - 2005
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. 38
MECHANISM OF THE UGI REACTION
R1
O
H
NH2
R2R1
N
H
R2
+
R1
N
H
R2
R3
O
OH R1
N
H
R2H
R3
O
O+
+
R1
N
H
R2HC
N
R4
R3
O
O+ +
N R2H
R1
H
N
O
O
R3
R4
N R2H
R1
H
N
O
O
R3
R4
R3
O
N
R1
R2 O
HN
R4
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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. 39
APPLICATIONS OF THE UGI REACTION
AcOOAc
COOH
Et O
O
CHO
NC
NH2
+
+
+
MeOH 50°C
AcOOAc
O
NNH
O
O
OEt
75%
AcOOAc
O
NNH
O
O
OEt
75%
HO
NH
OH
O
O
HO OH
HO
NH
OH
O
O
HO OH
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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. 40
APPLICATIONS OF THE UGI REACTION
N
S
NC
+
+
+
MeNH2
Cl3CCOOH Cl3C
CHO
methanol
room temp65hrs
31%
Cl3C N
O
CCl3
NHO
N
S
Cl3C N
O
CCl3
NHO
N
S
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Reference: Domling, A. et al, Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 41
VARIATIONS OF THE FUNCTIONAL GROUPS OF UGI REACTION
R1 H
O
+
R2
O
OH
+ R3NC +NH2
R4
Majority of the variations can be
madeat 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 orhydroxylamines can be used.
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Reference: Basso, A. et. al; Tetrahedron lett. 2004, 45, 6109-6111. 42
EXAMPLE OF A VARIATION USING HYDROXYLAMINE
O
NH2
+
O
+ +OH
O
NC
O-Benzyl hydroxylamine
H
THF
48hoursroom temperature
N
OO N
H
O
H2,Pd/BaSO4
MeOHN
OO N
H
OH
N
OO N
H
O
45% 75%
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(CH2)n(CH2)n
(CH2)n
N
O
HN
O
43
CYCLIC VARIATIONS OF UGI REACTION
R1 H
O
+
R2
O
OH
+ R3NC +NH2
R4R2
O
N
R1
O
HN
R3
R4
(CH2)n
(CH2)n
(CH2)n
(CH2)n
HN
O
N
O
(CH2)n
(CH2)n
HN N
O
O
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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. 44
EXAMPLE OF A CYCLIC VARIATION OF A UGI REACTION
HOOC
OH
NH2+
+
O
H
NC
N
O
HO
ONH
MeOH
0°C48hrs
58%
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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
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. 45
STEREOCONTROL IN UGI REACTIONS
NH2
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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. 46
LIMITATION OF UGI AND PASSERINI REACTIONS
R1 H
O
+
R2
O
OH
+ R3NC +NH2
R4
Ugi ReactionPasserini Reaction
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Solid Phase MCRs are More efficient Allow easy separation
Isocyanide component is generally incorporated into the solid phase resin
47
SOLID PHASE MULTICOMPONENT REACTIONS
R1 H
O
+
R2
O
OH
+ R3NC +NH2
R4
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Reference: Chen, J. J. et al.; Tetrahedron Lett. 2002, 43, 4083-4085. 48
EXAMPLE OF A SOLID PHASE UGI MCR
RINK TYPE RESIN
NC + + +R H
O
R'
NH2
HN
HOOC
FMOC
NH
O
R
N
O
HNFMOC
R'
MeOH/THF,16hrs
NH
N
O
O
R
R'
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Reference: Domling, A.; Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem. Rev. 2006, 106, 17-89. 49
USE OF MCRS IN DRUG DISCOVERY
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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, 1697-1711.50
USE OF MCRS IN DRUG DISCOVERY- TUBULIN INHIBITORS
N
N
MeO
NH2
MeO
MeO
OMe
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Synthesis of the tubulin inhibitor:
Reference: Van Leusen, A. M. et al. J. Org. Chem., 1977, 42, 1153-1159.51
USE OF MCRS IN DRUG DISCOVERY- TUBULIN INHIBITORS
OMe
OMeMeO
NCS
O O
+MeNH2
+OMe
NH2
O
H
ToluenesulfonylmethylisocyanideTOSMIC N
N
MeO
NH2
MeO
MeO
OMe
K2CO3
EtOH
Base (K2CO3)
OMe
OMeMeO
NCS
O O
OMe
NH2
NMe
H
N
N
MeO
NH2
MeO
MeO
OMe
S O
O
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Synthesis of the tubulin inhibitor:
52
USE OF MCRS IN DRUG DISCOVERY- TUBULIN INHIBITORS
N
N
MeO
NH2
MeO
MeO
OMe
S O
O
N
N
MeO
NH2
MeO
MeO
OMe
S
O OH
+
Reference: Van Leusen, A. M. et al. J. Org. Chem., 1977, 42, 1153-1159.
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Reference: Musonda, C. C. et al. Bioorg. Med. Chem. Lett. 2004, 14, 3901-3905. 53
USE OF MCRS IN DRUG DISCOVERY- ANTIMALARIAL DRUGS
chloroquine
On thebasis of which
NCl
HNN
NCl
HN N
O NH
O
NNCl
HN N
O NH
O
NNCl
HN N
O NH
O
N
NCl
HN N
O NH
O
N
48hrs60%
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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. 54
USE OF MCRS IN DRUG DISCOVERY- SERINE PROTEASE INHIBITORS
NH
H2NNH
O
HN
N
O
N
OMe
O O
HO
OH
OH
OH
NH
H2NNH2
O O
HO
OH
OH
OHCHO
N
O
N
OMeCN
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55
USE OF MCRS TO CREATE SCAFFOLDS
N
O
HN
O
HN
O
N
O
HN N
O
O
MORE RECENTLY
N
O
2-oxazolines
NH
O
O
benzoxazinones
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56
USE OF MCRS TO CREATE SCAFFOLDS-2-OXAZOLINES N
O
2-oxazolines
Reference: Fan, L. et al. Org. Lett. 2007, 9, 2015-2017.
R
O
OMs
+ + +
-Ketone-Mesylate
NH3
NC
R"R'
O
OH
HNR'
OR
OMs
O
NH
R"
O
NR'
R
O
NH
R"
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57
USE OF MCRS TO CREATE SCAFFOLDS-BENZOXAZINONES NH
O
O
benzoxazinones
Reference: Banfi, L. et al. Mol. Divers. 2008, 12, 187-190.
R
OH
O
OH+
+
+
OH
H
O
R2 NH2 R3 NC
MeOH
roomtemp.
R
OH
O
N O
HN R3
OH
R2
diethylazodicarboxylate(DEAD)PPh3
MitsunobuReactionConditions
OH
O
N O
HN R3
R2
K2CO3
O
O
N O
HN R3
R2
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Reference: Domling, A.; Ugi, I; Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 58
UNION OF MULTICOMPONENT REACTIONS
MCR1
MCR3MCR2
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Br CHO
+ NaSH
+ NH3
+
CHO
+ MeOH
+ CO2
+
NC
N
S
N
S
OO
HN
O
59
EXAMPLE OF A UNION MULTICOMPONENT REACTION7 COMPONENT REACTION
Reference: Domling, A.; Ugi, I.; The Seven-Component Reaction. Angew. Chem. Int. Ed. Engl. 1993, 32, 563-564.
43%
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60
CONCLUSION
PAST PRESENT FUTURE
Over 150 Years of development
MCRs
NaturalProducts
Drug discovery
Scaffold Generation
MCR1
MCR3
MCR2
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Dr. Umesh Desai
Dr. Qibing Zhou (Department of Chemistry, VCU)
The Desai Group
Department of Medicinal Chemistry at VCU
61
ACKNOWLEDGEMENTS
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