MULTICOMPONENT REACTIONS

MULTICOMPONENT REACTIONS

PRESENTED BY – AKUL MEHTA

VIRGINIA COMMONWEALTH UNIVERSITYSCHOOL OF PHARMACYDEPARTMENT OF MEDICINAL CHEMISTRY

FOR MORE PRESENTATIONS VISIT www.pharmaxchange.info

http://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




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




H

O

HCN

NH3

NH2

CN

H+

Strecker Synthesis

6

AN EXAMPLE OF A SIMPLE MULTICOMPONENT REACTION

H

NH


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


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


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


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


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


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




13



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


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%


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.


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?




18



Broad range of reactivity

This led to the development of MCRs involving organoboronic acid derivatives

19

MULTICOMPONENT REACTIONS WITH ORGANOBORON COMPOUNDS


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


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


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




23



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


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


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


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




28



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

-




30



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


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


The reaction

34


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


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


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




36



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.


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


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


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


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.


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%


(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


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%


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


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


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


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'


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


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


Synthesis of the tubulin inhibitor:

Reference: Van Leusen, A. M. et al. J. Org. Chem., 1977, 42, 1153-1159.51


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


Synthesis of the tubulin inhibitor:

52


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.


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%


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


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


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"


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


Reference: Domling, A.; Ugi, I; Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168-3210. 58

UNION OF MULTICOMPONENT REACTIONS

MCR1

MCR3MCR2


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%


60

CONCLUSION

PAST PRESENT FUTURE

Over 150 Years of development

MCRs

NaturalProducts

Drug discovery

Scaffold Generation

MCR1

MCR3

MCR2




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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MULTICOMPONENT REACTIONS