a synthesis design system as a window to a reaction … · 2005-07-07 · © gasteiger et al....
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© Gasteiger et al.C3
PhD with Prof. Rolf HuisgenUniversity of Munich (1967 – 1971)
mechanism of reactions of cyclooctatetraenecis - halogenation
Cl
Cl
H
H
Cl2+
homotropylium ion
© Gasteiger et al.C3
Postdoc with Prof. Andrew Streitwieser Jr.University of California, Berkeley (1971/1972)
acidity of hydrocarbonsab initio calculations of carbanionsuranocene chemistry C O
H
HH
C O
H
HHH
C O
HHH
. .
- H
- H
© Gasteiger et al.C3
CICLOPS
Computers in Chemistry, Logic Oriented Planning of Syntheses
Ivar Ugi, Janet Blair, Johann Gasteiger,Carol Gillespie, Paul D. Gillespie
presented at NATO/ASI, June 1973, Noordwijkerhout, NL
© Gasteiger et al.C3
CICLOPSmolecule representation
BE – matrices• by connection tables• all atoms: hydrogen atoms explicitly• free electrons
⇔ Wiswesser Line Notation (WLN)
reaction representationR – matrices
• as bond breaking and making and electron shifting patterns
⇔ lists of known reactions
© Gasteiger et al.C3
EROS:Elaboration of Reactions for Organic Synthesis
J. Gasteiger, C. JochumTopics Curr. Chem., 1978, 74, 93 -126
J. Gasteiger, M.G. Hutchings, B. Christoph, L. Gann, C. Hiller,P. Löw, M. Marsili, H. Saller, K. YukiTopics Curr. Chem., 1987, 137, 19 - 73
© Gasteiger et al.C3
Important Reaction Generators in EROS
nucleophilic aliphatic substitutionelectrophilic aromatic substitutionsadditions to multiple bondseliminations
Diels – Alder reactionCope rearrangementFavorskii rearrangement
oxidation reactions
K L
I J I
K L
JRG 22:
JI
N ML
K
NI
KJ
MLRG 33:
I
JX
J
IXRG 12:
© Gasteiger et al.C3
Factors Influencing Chemical Reactivityeffect measure
CHH
HCl polarity ∆qtot
CHH
HBr polarizability αb
CClCl
ClH CCl
Cl
Cl+ H
inductiveeffect ∆χσ
© Gasteiger et al.C3
Calculation of Chemical Effects
charge distributionJ. Gasteiger, M. Marsili, Tetrahedron 36, 3219 (1980)
inductive effectJ. Gasteiger, M. G. Hutchings, Tetrah. Lett. 24, 2541 (1983)
resonance effectJ. Gasteiger, H. Saller, Angew. Chem. Int. Ed. Engl. 24, 687 (1985)
polarizability effectJ. Gasteiger, M. G. Hutchings, J. Chem. Soc. Perkin 2, 559 (1984)
bond dissociation energyJ. Gasteiger, Comp. Chem. 2, 85 (1978)
© Gasteiger et al.C3
Charge Calculation in σ-Bonded Systems
( )
><
><><
><
+><
+=
∆=
∆+∆=∆
⋅−=∆
++=
∑nAAA
nAB
nA
nABABAB
iBiAiAnAB
AiAiiiA
qqqqq
qqqq
qcqbanαχχχ
χ 2
A
i = orbital of atom Aα = attenuation factorn = iteration number
J. Gasteiger, M. Marsili, Tetrahedron 36, 3219 (1980)
© Gasteiger et al.C3J. Gasteiger, M.G. Hutchings J. Chem. Soc. Perkin 2, 1984, 559-64
Polarizability Effect
∑=atoms
ii
njeff αα ij5.0,
© Gasteiger et al.C3
Calculation of Proton Affinities (PA)
• alkyl amines only (49 cpds)PA(kJ/mol) = 205.6 + 2.82 αd,N
J. Gasteiger, M.G. Hutchings, J. Chem. Soc. Perkin 2, 1984, 559
• alkyl amines + heteroatom substituted alkyl amines (80 cpds)PA(kJ/mol) = 1435.5 + 12.5 αd,N - 116.3 χr,N
J. Gasteiger, M.G. Hutchings, Tetrahedron Lett. 1983, 2541
N N H+ H
© Gasteiger et al.C3
Prediction of pKa Values
dpoa cNcccpK αχ 32121 +++=
45 alcohols, R2 = 0.98, s = 0.49
M.G. Hutchings, J. Gasteiger, J. Chem. Soc. Perkin 2, 1986, 455-462
σσ α qccAcQccpK dtota 43210 ++++=
77 alcohols, R2 = 0.95, s = 0.74, Q2 = 0.94, s = 0.78
725 aliphatic carboxylic acids, R2 = 0.82, s = 0.39, Q2 = 0.82, s = 0.39
J. Zhang, 2005, unpublished results
© Gasteiger et al.C3
ChemInform Reaction Database
1987 - 1991
Partners: FIZ Chemie BerlinBayer AG, LeverkusenChemoData, MunichGTS-Gral, Darmstadt
Project Manager: J. Gasteiger
funded by BMFT
© Gasteiger et al.C3
The Program System WODCA: A Set of Tools
SubstructureSearches
StrategicBonds
SimilaritySearches
MoleculeViewer
SynthesisTree
MoleculeEditor
WODCA
ReactionDatabase
© Gasteiger et al.C3
100O
HO
Cl
NCl
HCl
03855 Fluka 23065
O OCH3
ON 88
O OCH3
HO
75
O
HO
O
OCH3
100
OCH3
O
10208 Fluka 64710
COOH
COOH
08142 Fluka 53580
OCl
Cl
Design of a Synthesis
HO
12674 Fluka 77609
+
+
+
CX
CC
CC
CAr
Trioxifene
similaritysearch:
ring withskeleton
© Gasteiger et al.C3
Size of Database
structure and reaction input by ISISDraw
additional information through attribute editor
– 1,533 structures
– 2,175 reactions
/slides/Biochemical_Pathways/Folien/CCC/roche_2.ppt© Gasteiger et al.C3
© Gasteiger et al.C3
Structure Search
# reactionsas starting material 19as product 23as cofactor 1
© Gasteiger et al.C3 /
© Gasteiger et al.C3
Inhibitors of Enzymes as Transition State Analogs
N
N
N
NP O O
O O
OO
OHH
H H
HO N
H H
H H H
N
NP O O
O O
OO
OHH
H H
H H
N
N
O H
H
H
transition state coformycin
© Gasteiger et al.C3
Descriptors for Each Reacting Bond
A -- B → A+ + :B-
• difference in π-electronegativities• difference in σ-electronegativities• difference in total charges• mean of effective atom polarizabilities• delocalization stabilization of a negative charge• delocalization stabilization of a positive charge
© Gasteiger et al.C3
lactones
OO
HO
S R
RO
S R
alkyl O PO
OO cephaline
triaglyceride O PO
OO choline
triaglyceride O PO
OO cephaline
usual esters
formyl-thioester
thioesters
R: disaccharide, alkyl, nucleotides, triaglyceride,...
Classification of EC 3.1.xO
O
pyranyl O PO3
furanyl O PO3
R O PO3
© Gasteiger et al.C3
Glucose6-phosphate
NADP+
NADPH H+
6-Phospho-gluconolactone
H2O6-Phospho-gluconate
Ribulose5-phosphate
CO2
Xylulose5-phosphate
Ribose5-phosphate
Glyceraldehyde3-phosphate
Sedoheptulose7-phosphate
Erythrose4-phosphate
Fructose6-phosphate
H+NADP+NADPH
1
3
45
6
2
5
9
24
7
8
10 11
14
Glyceraldehyde3-phosphate
1
23
4 6
8
10
12
12 13
14
1512
1[r4] 1[r6] 1[r8] 1[r10]
2 Ribu5P ---> E4P + F6P
© Gasteiger et al.C3
Glucose6-phosphate
NADP+
NADPH H+
6-Phospho-gluconolactone
H2O6-Phospho-gluconate
Ribulose5-phosphate
CO2
Xylulose5-phosphate
Ribose5-phosphate
Glyceraldehyde3-phosphate
Sedoheptulose7-phosphate
Erythrose4-phosphate
Fructose6-phosphate
H+NADP+NADPH
1
3
45
6
2
5
9
24
7
8
10 11
14
Glyceraldehyde3-phosphate
1
23
4 6
8
10
12
12 13
14
1512
2[r4] 1[r6] 1[r8] 1[r10] 1[r12]
3 Ribu5P ---> G3P + 2 F6P
© Gasteiger et al.C3
Glucose6-phosphate
NADP+
NADPH H+
6-Phospho-gluconolactone
H2O6-Phospho-gluconate
Ribulose5-phosphate
CO2
Xylulose5-phosphate
Ribose5-phosphate
Glyceraldehyde3-phosphate
Sedoheptulose7-phosphate
Erythrose4-phosphate
Fructose6-phosphate
H+NADP+NADPH
1
3
45
6
2
5
9
24
7
8
10 11
14
Glyceraldehyde3-phosphate
1
23
4 6
8
10
12
12 13
14
1512
[r4] 1[r12]
Ribu5P + E4P ---> G3P + F6P
blocked !
© Gasteiger et al.C3
Coworkers (1)1970´s Clemens Jochum
Mario Marsili Peter Röse1980´s M.Dolores Guillén Christine Rudolph
Michael Hutchings 1990`s Wolfgang HanebeckKazumi Yuki Klaus-Peter SchulzHeinz Saller Wolf-Dietrich IhlenfeldtBernd Christoph Markus WagenerLeopold Gann Vera SimonPeter Löw Ulrich HondelmannChristian Hiller Wolfgang Witzenbichler
© Gasteiger et al.C3
Coworkers (2)1990´s Jens Sadowski Bruno Bienfait
Angela Fröhlich Valentin SteinhauerKlaus Rafeiner Larissa SteinhauerXinzhi Li Giorgi LekishviliSusanne Bauerschmidt Lingran ChenRobert Höllering Ulrike BurkardRalf Fick Thomas KostkaMatthias Pförtner Sandra HandschuhPaul Selzer Andreas TeckentrupJan Schuur Dietrich TrümbachOliver Sacher Markus HemmerChristof Schwab
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Coworkers (3)2000´s Achim Herwig Martin Reitz
Markus Sitzmann Angelika Hofmann Jinhua Zhang Yongquan HanLothar Terfloth Jörg MarusczykAlexander von Homeyer Dimitar HristozovAixia YanFrank OellienJaroslaw Tomczak Visiting ScientistsThomas Kleinöder Jure ZupanAlexei Tarkhov Jarek Polanski Thomas Engel Joao Aires de SousaSimon Spycher Fernando B. Da Costa
© Gasteiger et al.C3
Chemoinformatics - A Textbook -
J. Gasteiger, T. Engel(Editors)
650 pagesWiley-VCH, Weinheim, 2003
ISBN: 3-527-30681-1
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