A Synthesis Design System as a Window to a Reaction … · structure and reaction input by ISISDraw ... Fructose 6-phosphate NADPH NADP+ H+ 1 3 4 5 6 2 5 9 4 2 7 8 ... Structure Elucidation

© Gasteiger et al.C3

Chemical Reactions


PhD with Prof. Rolf HuisgenUniversity of Munich (1967 – 1971)

mechanism of reactions of cyclooctatetraenecis - halogenation

Cl

Cl

H

H

Cl2+

homotropylium ion


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


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


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


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


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:


Factors Influencing Chemical Reactivityeffect measure

CHH

HCl polarity ∆qtot

CHH

HBr polarizability αb

CClCl

ClH CCl

Cl

Cl+ H

inductiveeffect ∆χσ


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)


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,


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


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


ChemInform Reaction Database

1987 - 1991

Partners: FIZ Chemie BerlinBayer AG, LeverkusenChemoData, MunichGTS-Gral, Darmstadt

Project Manager: J. Gasteiger

funded by BMFT


WODCA

orkbench for the

rganization of

ata for

hemical

pplications


The Program System WODCA: A Set of Tools

SubstructureSearches

StrategicBonds

SimilaritySearches

MoleculeViewer

SynthesisTree

MoleculeEditor

WODCA

ReactionDatabase


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



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


Structure Search

# reactionsas starting material 19as product 23as cofactor 1

© Gasteiger et al.C3 /


Pyruvate on ExPASy-Server

/© 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


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


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


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


1

23

4 6

8

10

12

12 13

14

1512

1[r4] 1[r6] 1[r8] 1[r10]

2 Ribu5P ---> E4P + F6P


Glucose6-phosphate

NADP+

NADPH H+



Ribulose5-phosphate

CO2

Xylulose5-phosphate

Ribose5-phosphate




Fructose6-phosphate

H+NADP+NADPH

1

3

45

6

2

5

9

24

7

8

10 11

14


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


Glucose6-phosphate

NADP+

NADPH H+



Ribulose5-phosphate

CO2

Xylulose5-phosphate

Ribose5-phosphate




Fructose6-phosphate

H+NADP+NADPH

1

3

45

6

2

5

9

24

7

8

10 11

14


1

23

4 6

8

10

12

12 13

14

1512

[r4] 1[r12]

Ribu5P + E4P ---> G3P + F6P

blocked !


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


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


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


Chemoinformatics - A Textbook -

J. Gasteiger, T. Engel(Editors)

650 pagesWiley-VCH, Weinheim, 2003

ISBN: 3-527-30681-1

Molecular Networks GmbHComputerchemie

Molecular Networks provides applications for ...

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Documents

A Synthesis Design System as a Window to a Reaction … · structure and reaction input by ISISDraw ... Fructose 6-phosphate NADPH NADP+ H+ 1 3 4 5 6 2 5 9 4 2 7 8 ... Structure Elucidation