-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
1/15
Hugo Kubinyi, www.kubinyi.de
CombinatorialChemistry
Technology
Hugo Kubinyi
Germany
E-Mail [email protected] www.kubinyi.de
Hugo Kubinyi, www.kubinyi.de
Combinatorial Diversity in Nature
20 natural amino acids yield
400 dipeptides
8,000 tripeptides ...
64,000,000 hexapeptides and, in principle,
10400 proteins with MW 30 kD
100 chemically modified amino acids yield
e.g. 1,000,000,000,000 hexapeptides,
and ... 4 nucleic bases encode all organisms !
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
2/15
Hugo Kubinyi, www.kubinyi.de
Number of organic molecules with MW < 500(C, H, O, N, P, S,
F, Cl, Br, I)
1 000 000 000 000 000 000 000 000 000 000000 000 000 000 000 000
000 000 000 000000 000 000 000 000 000 000 000 000 000000 000 000
000 000 000 000 000 000 000
or more or less ....
Hugo Kubinyi, www.kubinyi.de
Principles of Combinatorial Chemistry
Combinatorial Chemistry generates a multitude of
chemically related (congeneric) compounds,
so-called combinatorial libraries"
In the last years, combinatorial chemistry in drug
research changed more and more to automated
parallel synthesis and parallel purification.
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
3/15
Hugo Kubinyi, www.kubinyi.de
CH3
NH
O
OMe
CH3
NH2
+
Cl
O
OMe=
Classical organicsynthesis:
1 educt x 1 educt = 1 product
Combinatorial synthesis:R1 NH
2+
Cl R2
O= N
O
R2R1
e.g. 50 educts x 20 educts =1,000 products
Multicomponent reaction (e.g. Ugi reaction):
R4
O
N
R1
R2
O
N R3
H
H
e.g. 50 x 20 x 5 x 200 educts = 1 million products
R1-NH2 + R2-CHO + R3-NC + R4-COOH =
Multistep combinatorialsynthesis:
e.g. 50 x 20 x 20 educts =20,000 products
Hugo Kubinyi, www.kubinyi.de
Combinatorial Library
N
R5R
6
R7R
8
R4
N
R10
R9
R3R
1 R2
O
*
*
Building blocks with 68 different residues in 10positions (R1 -
R10 are 5, 10, 10, 4, 2, 5, 5, 2, 5, and 20residues) generate a
library of 20 million differentcompounds. Consideration of both
steric centers (*)increases this number by a factor of four, i.e.
to80 million different compounds.
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
4/15
Hugo Kubinyi, www.kubinyi.de
Solid Phase Synthesis: Beads
Cross-linked polystyrene
(1.0-1.5% divinylbenzene)
Ph
Ph
Ph
Ph Ph Ph
PhPh
Ph
Ph
Ph
Ph
Ph
PhPh
Ph
Cl
Cl
Cl
Cl
Functionalizationof the beads by
chloromethylationand further chemicalreactions
Hugo Kubinyi, www.kubinyi.de
Tentagel Beads (Polystyrene, Grafted with Polyoxy-ethylene),
Rapp Polymers, Tbingen, Germany
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
5/15
Hugo Kubinyi, www.kubinyi.de
The Principle of Solid Phase Synthesis
bead(40-80 m)and linker
scaffold withfunctional groups
product
immobilization
three-step
synthesis
cleavage
immobilized product
Hugo Kubinyi, www.kubinyi.de
The Combination of Scaffolds and Building Blocks
3 building blocks A1-A3and3 building blocks B1-B3
yield 9 productsA1B1 A3B3 .
In the same manner,10 x 10 x 10 buildingblocks yield
1,000products A1B1C1 A10B10C10 .
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
6/15
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
7/15
Hugo Kubinyi, www.kubinyi.de
Linkers: Merrifield and Wang linkers
Cl
OOH
OO
O
R (several steps)
RCOOH
(product)50% TFA
Merrifield resin
Wang resin("Wang linker")
Hugo Kubinyi, www.kubinyi.de
Linkers: a) Merrifield Peptide Synthesis
Boc-NHCHR1COO-Cl
OO
HR1
NHBoc
OO
HR1
N
H
O
R2
NHBoc
H
1) HCl / CH3COOH
2) Boc-NHCHR2COO- / DCCI
50% TFA
SN2
OHO
HR1
NH
O
R2
NH2
H Dipeptide
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
8/15
Hugo Kubinyi, www.kubinyi.de
Other linkers
OOH
OMe
OMe
Rink acidlinker
O
NHFmoc
OMe
OMe
protectedRink amidelinker
O
NHFmoc
OprotectedSieberlinker
Cl
Trityllinker
Hugo Kubinyi, www.kubinyi.de
Safety catch linkers
S O R
stable
S O R
OO
labilebase
S
OO
+ R-OH
NH
O
SN
O O
R
O
Product
R = H: stable
OH-
product-COOH
HNR1R2
product-CONR1R2
+ CH2N2 R = CH3: labile
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
9/15
Hugo Kubinyi, www.kubinyi.de
Traceless (safety catch) linker
NH
NHO R
stable
Cu(OAc)2
NH2
R
N
H
O+ N2 +
Polymer-supported solution phase syntheses
Polymeric reagents
A + BC
A-B
reagent
Hugo Kubinyi, www.kubinyi.de
Solid Phase-Supported Synthesis of ()-Epibatidine
9.
NCl
OH
NO2
N
NH
H
85%endo
()
()
basicepimerization
8. NMe3BH4
Cl
7. Mesyl-Cl
N NN
ClNH
H
()-Epibatidine
(exo:endo = 3:1)
4.
5.
6. NMe3BH4
NMe2
OTBS
NCl
Cl
O
NCl
OH
NO2
2.
1. NMe3BH4
NMe3RuO4
3. NMe3OH
+ MeNO2
N NP
Et2N N-tBu
R. J. Booth and J. C. Hodges, J. Am. Chem. Soc. 119, 4882-4886
(1997)
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
10/15
Hugo Kubinyi, www.kubinyi.de
Solid Phase-Supported Synthesis of ()-Oxomaritidineand
()-Epimaritidine
NMe3+ BH4
-
()-Oxomaritidine
NMe3+ RuO4
-OH
OMe
OMeCH2Cl2100 % OMe
OMe
CHOOH
NH2
MeOH90 %
1.
2.
HMeO
N
OH
MeO
MeO
N
OH
O CF3
MeO
N N
(F3CCO)2O
99 %
I(OCOCX3)2
X = H or F
MeO N
O
O
CF3
MeO
NEt3+ HCO3
-
N
O
MeO
MeOMeOH100 %
H2 / Pd / C
MeOH
95 %
CuSO4 or NiCl2MeOH
90 %
()-Epimaritidine
N
OH
MeO
MeO N
O
MeO
MeO
F3CCH2OH
70 %
NMe3+ BH4
-
S. V. Ley et al.,J. Chem. Soc.Perkin Trans. 1,1251-1252
(1999)
Hugo Kubinyi, www.kubinyi.de
Polymeric scavengers for building blocks, sideproducts and
reagents
A + excess BX
X-BA-B +A-B + B
A + BX
X-DA-B +A-B + sideproduct D
A + BX
X-CA-B +
reagentC
A-B + C
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
11/15
Hugo Kubinyi, www.kubinyi.de
Scavenger Reagents: Ion Exchange Resins,Polymeric Acids and
Bases, Isocyanates, etc.
O
Me
O
+
NHNH2
COOH
1 equivalent 1.2 equivalentsNCO
N
O
NN
COOH
Me
Cl O
O
1.
2. R-NH2N
N
CONHR
Me
NCO3. +
NH CH2CH
2N(CH
2CH
2NH
2)2
Hugo Kubinyi, www.kubinyi.de
Resin capture strategy
A + BX
X-A-B A-BA-B + C +side product D
reagentC cleavage
Resin capture with an ion exchange resin
H2N-R
SO3
-
(Amberlite ion exchange resin)
H3N+-RSO
3
-NH3/MeOH
H2N-R
Catch and release strategy
B1 + B2X-A
X-A-B A-BB + C +side product D
reagentC
[ ]
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
12/15
Hugo Kubinyi, www.kubinyi.de
Catch and release strategy, using a traceless linker
B
R3
R1
R2 O O
R3
R1
R2
Si
MeMe
ONH
Susukicoupling release
R3
R1
R2
Hugo Kubinyi, www.kubinyi.de
Milestones in the History of Multicomponent Reactions
A. Strecker (1850)
A. R. Hantzsch (1890)
P. Biginelli (1893)
C. Mannich (1912)
NH3 + HCN + RCHO R NH2
C N
NH3 + R1
Cl
O
R2+ H
O
OR
O N
H
R1
R2 COOR
R1-CHO +
O
NH2
NH2+ R2
O
R3NH
NH
O
R2 R3
R1
CH2O + R1R2NH +H
O
R3
R4
NR1
R3 R4H
O
R2
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
13/15
Hugo Kubinyi, www.kubinyi.de
M. Passerini (1921)
H. T. Bucherer (1934)
F. Asinger (1958)
I. Ugi (1959)
R1NC + R2CHO + R3COOH
HCN + NH3 + CO2 + RCHO
+
R1NH2 + R2CHO+ R3NC + R4COOH
O
R3 O
R2
O
NH
R1
NHNH
O
O R
NH3 +
O
R1 R2
O
R3R4
SHN
SR4
R3
R1
R2
O
R4 N
R1
NH
O
R2
R3
Hugo Kubinyi, www.kubinyi.de
Complex Molecules from MulticomponentReactions
OSi(iPr)3
NH2
+O CHO+ +
NCAr
NH
O
HOOC
4 steps e.g. NN
ON
OH H
O
OH
BrHH
O
S. L. Schreiber, Science 287, 1964-1969 (2000)L. Weber, Drug
Discov. today 7, 143-147 (2002)
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
14/15
Hugo Kubinyi, www.kubinyi.de
The Generation of Scaffold Diversity
O
NH2
(Me)2N
OMeO
NC
COSH
CHO
NCOMe
H2NHN
N
NH2OHO
NH
N
O
O
O
OMe
NNH
NH
N N
NH
L. Weber, Drug Discov. today 7, 143-147 (2002)
Hugo Kubinyi, www.kubinyi.de
R1 N+
C R2 O R3 NH2
N
N
R
RNH
NHR
R
NH
N
O NHR
N
R
R
NHRO
N
NNN
N
R
R
COOEt
N
NH
R
MeOOC O
R
N
O NO
RHN
R
R
RNH
O
NH
R
R
+ +
N
NH R
ONHR
N
NHRO
R
O
R
NH
O
O
NHR
C
N
RN
N
NHR
ONHR
Three componentUgi reaction
L. Weber, QSAR Comb. Sci. 24, 809-823 (2005)
The Generation of Scaffold Diversity
-
8/14/2019 Hugo Kubinyi, Www.kubinyi.de
15/15
Hugo Kubinyi, www.kubinyi.de
Increasing Diversity of Combinatorial Libraries
NH
O
F
NO2
NH2
O
N
S
R2O
N
H
R1NH
2
OS
N
OR2NH
R1
NH2
O
N
N
R3O
R2
R1
NH2
O
N
N
R2
R1 O
R3
NH2
O
N
S
OR1 O
R3 NH2
O
N
NR1
O
R2
NH2
O
N
N
R1
NHR2
NH2
O
N
N
R1
S
R2
N
S
R2
O
NH
R1SNH2
O
courtesy of Drs.M. Mann, W. Sauer,Serono, Geneva
Hugo Kubinyi, www.kubinyi.de
References
Bunin BA, The Combinatorial Index, Academic Press, San
Diego,1998. 350 pp, $ 80.
Terrett NK, Combinatorial Chemistry. Oxford University Press,New
York, 1998. 186 pp, $ 29 (in German 264 pp, EUR 29).
Jung G, Combinatorial Chemistry, Wiley-VCH, Weinheim, 1999.601
pp, EUR 149.
Beck-Sickinger AG and Weber P, Combinatorial Strategies
inBiology and Chemistry, Wiley, 2002. 179 pp, $ 35 (in German EUR
20).Bannwarth W and Felder E, Combinatorial Chemistry,
Wiley-VCH,
Weinheim, 2000. 430 pp, EUR 149.Seneci P, Solid-Phase Synthesis
and Combinatorial Technologies,
Wiley-Interscience, New York, 2000. 637 pp, $ 115.Ghose AK and
Viswanadhan VN, Combinatorial Library Design and
Evaluation: Principles. Software Tools, and Applications in
DrugDiscovery, Marcel Dekker, New York, 2001. 631 pp, $ 195.
Nicolaou KC, Hanko R and Hartwig W, Handbook of
CombinatorialChemistry. Drugs, Catalysts, Materials, Wiley-VCH,
Weinheim,2002. 1114 pp, EUR 389.
