Reactor latest

ChemAxon User Group Meeting Budapest 2007

György Pirok

Content

Elements of the Virtual Synthesis

Encoding Synthetic Knowledge in Reactions

Applications

New Features

Summary

Elements of the Virtual Synthesis Technology

• A language for describing chemical rules

– Chemical Terms

• A library of selective reactions „knowing”

chemistry

– Chemaxon Reaction Library

• A reaction engine with high capacity and

performance

– Reactor

• Virtual reaction applications

– Reactor GUI, Metabolizer

Calculator Plugins

acceptor acceptorCount acceptorSiteCount acidicpKa acidicpKaLargeModel aliphaticAtom aliphaticAtomCount aliphaticBondCount aliphaticRingCount angle aromaticAtom aromaticAtomCount aromaticBondCount aromaticElectrophilicityOrder aromaticNucleophilicityOrder aromaticRingCount array asymmetricAtom asymmetricAtomCount atno atomCount atomicPolarizability averagePolarizability balabanIndex basicpKa basicpKaLargeModel BCUT bond bondCount bondType canonicalResonant canonicalTautomer carboaromaticRingCount carboRingCount chainAtom chainAtomCount chainBond chainBondCount charge chiralCenter chiralCenterCount composition conformer conformerCount conformers connected connectedGraph connections count cxsmarts cxsmiles cyclomaticNumber dihedral dissimilarity distance distanceDegree donor donorCount donorSiteCount dotDisconnectedFormula doubleBondStereoisomer doubleBondStereoisomerCount doubleBondStereoisomers dreidingEnergy eccentricity electrophilicLocalizationEnergy enumeration enumerationCount enumerations exactMass field filter formalCharge formula fusedAliphaticRingCount fusedAromaticRingCount fusedRingCount hararyIndex hasValidConformer hydrogenCount heavy heteroaromaticRingCount heteroRingCount hyperWienerIndex isoelectricPoint isotopeComposition isotopeFormula largestAtomRingSize largestRingSize logD logP logPIncrement logS logSMicro logSNeutral logSTrue lowestEnergyConformer majorMicrospecies majorMs map mass match matchCount max maxAtom maxValue microspecies microspeciesCount microspeciesDistribution min minAtom minValue molBinFormat molecularPolarizability molFormat molImage name nucleophilicLocalizationEnergy pair piChargeDensity piEnergy piOrbitalElctronegativity pKa plattIndex polarizability property randicIndex refractivity refractivityIncrements resonant resonantCount resonants ringAtom ringAtomCount ringBond ringBondCount ringCount ringCountOfAtom rotatableBond rotatableBondCount shortestPath sigmaOrbitalElectronegativity smallestAtomRingSize smallestRingSize smarts smiles solubility solubilityAtIsoelectricPoint solubilityOfMicroSpecies solubilityOfNeutral solventAccessibleSurfaceArea sortAsc sortDesc stereoisomer stereoisomerCount stereoisomers stericEffectIndex stericHindrance sum szegedIndex tautomer tautomerCount tautomers tetrahedralStereoisomer tetrahedralStereoisomerCount tetrahedralStereoisomers topologicalPolarSurfaceArea totalChargeDensity traditionalName uniqueSmiles valence vanDerWaalsSurfaceArea wienerIndex wienerPolarity

Encoding Synthetic Knowledge in ReactionsThe Baeyer-Villiger carbonyl oxidation

Victor Villiger1868-1934

Johann Friedrich Wilhelm

Adolf Ritter von Baeyer 1835-1917

Reaction Processing from Command Line

react -r '[C:2][C:1](=O)C>>[C:2][O:3][C:1](=O)C' 'CC(=O)C1CCCCC1'CC(=O)OC1CCCCC1COC(=O)C1CCCCC1

reactionreactant

products

Batch Reaction Processing from Command Line

react -r Baeyer-Villiger oxidation.mrv carbonyls.sdf CCc1oc2ccccc2c1OC(=O)c3ccc(O)cc3OC(OC(=O)c1ccccc1)c2ccccc2C[NH2+]C1(CCCCC(=O)O1)c2ccccc2ClCOc1ccc(OC(=O)c2ccc(C)cc2)c(O)c1O=C(OCC[NH+]1CCC(C1)c2ccccc2)c3ccc4OCCOc4c3Oc1cccc2Cc3cccc(O)c3C(=O)Oc12C[NH+](C)CCOc1cc2oc(=O)c3ccccc3c2c4ccccc14Oc1c(oc(=O)c2ccccc12)-c3ccc(Br)cc3CC([NH3+])OC(=O)c1ccccc1Oc1c(oc(=O)c2ccccc12)-c3ccc(Cl)cc3...

Problem

Chemical reactions are selective!

Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: generic scheme

The Baeyer-Villiger oxidation is an organic reaction in which a ketone or aldehyde is oxidized to an ester by treatment with peroxy acids or hydrogen peroxide. The stereo configuration remains intact during the reactions.

Ret retention

L[H,C] carbon or hydrogen

Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: excluding compounds giving side

reactions, destroying the catalyst

EXCLUDE: match(reactant(0), "[H][#5,#14,#15,#16]") || match(reactant(0), "C=S") ||match(reactant(0), "[H]OC=O") || match(reactant(0), "[O-]C=O")

Exclude reagents containing BH, SiH, PH, SH or thiocarbonyl or carboxyl and carboxylate groups.

Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: finding reactive sites

REACTIVITY: !match(ratom(2), "[H][C:1](C=O)C=O", 1)

Beta diketones are able to enolize, they do not react on the carbon between the two carbonyl groups.

Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: finding the most reactive sites

SELECTIVITY: -charge(ratom(2), "sigma")

The oxygen goes between the carbonyl carbon and its neighbour having the lowest sigma charge value.

δ⊕ δ⊖

Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation as a selective reaction

REACTIVITY: !match(ratom(2), "[H][C:1](C=O)C=O", 1)

SELECTIVITY: -charge(ratom(2), "sigma")

EXCLUDE: match(reactant(0), "[H][#5,#14,#15,#16]") || match(reactant(0), "C=S") ||match(reactant(0), "[H]OC=O") || match(reactant(0), "[O-]C=O")

Reactor, the engine

REACTOR

ChemAxon Reaction Library

...Angeli-Rimini hydroxamic acid synthesisBaeyer-Villiger carbonyl oxidationBaylis-Hillman vinyl alkylationBeckmann rearrangementBischler-Napieralski isoquinoline synthesisFriedel-Crafts acylation...

Reactants Products

Reactor the Application

The Reaction EditorBuilt in Reaction Library Editor

The Reaction Editor Chemical Terms Editor for Rule Design

The Reaction Editor Internal Example and Property Editors

The Reaction EditorBuilt-in Reactant Standardizer and Reaction Tester

What's new in Reactor

• Automapping reaction results

• Aromaticity is automatically detected (no standardization needed)

• Synthesis code generation for the products

Bromination(Acylation(AMINE12, ACID37):1):2

• New and enhanced reactions in the library

• Separate example reaction properties

• Reaction testing with the internal examples

• Rule Editor

• Automatic reactant standardization can be built-in the virtual reaction

• Product standardization is a runtime option

• The Reactor license will contain about 10 sample reactions

• The new reaction library and reaction capabilities in Cartridge will be included in the Reactor Pro license

Future Features

• Reactor module in Instant JChem working in database tables (new, simplifed interface)

• Processing multistep reactions

• Transition states and intermedier based calculations

• Simplified rules– simplified Chemical Terms language– new plugin functions for reactivity and selectivity predictions– named functional groups (SMARTS-less rules)

• Reaction library can be classified by several aspects

• Functional group name based reaction definition

amine>>amide

Summary

• What is Reactor?– Reactor is an effective and selective virtual synthesis tool

transforming molecules to products according to given reaction schemes.

• What is it good for?– combichem library enumeration– reaction prediction– other transformation based applications (xenobiotic

biotransformation, bacterial biodegradation, random synthesis, generating chlick chemistry universe, etc.)

• How can I use it?– Off the shelf (Reactor Application)– Integrate into applications (Java/.NET API, Oracle Cartridge)– Reaction Library option with predefined synthetic reactions– FREE for Academics

Acknowledgements

Nóra Máté, Zsolt MohácsiPlugin system, Chemical Terms Evaluator, Reactor

Jenő Varga, Erzsébet CzinegeReaction Library, Reactor

József Szegezdi, Ferenc CsizmadiaProperty predictions, calculations

István Cseh, Attila SzabóReactor Application, Chemical Terms Editor

Szilárd Dóránt, Szabolcs CsepregiSubstructure searching functions, Pipeline Pilot integration

Péter KovácsJChem Cartridge integration

Miklós VargyasChemical Terms Evaluator