Retro Synthesis

20
1 / 20 InfoChem GmbH © 2006 Dr. V. Eigner-Pitto ICIC Nîmes, October 22-25, 2006 Novel Approach to Retrosynthesis Novel Approach to Retrosynthesis Automatic Generation of Automatic Generation of Transform Libraries Transform Libraries V. Eigner-Pitto , J. Eiblmaier, H. Kraut, H. Saller and P. Loew. InfoChem GmbH, Landsberger Strasse 408, Munich, 81241, Germany

description

introduction

Transcript of Retro Synthesis

Page 1: Retro Synthesis

1 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Novel Approach to RetrosynthesisNovel Approach to RetrosynthesisAutomatic Generation ofAutomatic Generation of

Transform Libraries Transform Libraries

V. Eigner-Pitto, J. Eiblmaier, H. Kraut, H. Saller and P. Loew.InfoChem GmbH, Landsberger Strasse 408, Munich, 81241, Germany

Page 2: Retro Synthesis

2 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

WhyWhy Retrosynthesis?Retrosynthesis?

How can I synthesize

this compound?

Is there a shorter

synthesis path to my target?

Can we increase the yield of this

process by choosing another

synthesis strategy?

Page 3: Retro Synthesis

3 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

1. Evaluation of Alternative Synthesis PathwaysSorting criteria are necessary for broad representations with many expanding paths: • Yield• Type of transformation (e.g. ring-closures or construction reactions preferred, etc.)

Retrosynthesis: Retrosynthesis: ExpectedExpected FeaturesFeatures

2. Support of Multistep SynthesisNecessary to guide the synthesis from the target to all existing precursors that can be obtained from commercially available substances

3. Organized VisualizationAllows a broad view over the different strategies. A tree view, i.e., gives an organized representation of the synthesis paths to the target

Main Challenge: Automatic generation of chemically meaningfulprecursors and their reasonable validation

Page 4: Retro Synthesis

4 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

SynthesisSynthesis--PlanningPlanning ToolsTools

1. Use of known compounds and published reactionsi.e. MDL (CrossFire Commander), Symyx (Reaction Pathfinder), InfoChem (STS)

!! Handle multistep synthesis

!! Order in synthesis paths - Sorting criteria

!! Shows synthesis options in your database (tree representation)

"" Structure and corresponding reaction(s) must be in database

2. „Intellectual“ retrosynthesis systems!! New molecules (not in the database)

!! Alternative routes to known molecules

!! Reaction transformation / Synthesis strategy to specify

!! Transform based

Page 5: Retro Synthesis

5 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

„„IntellectualIntellectual“ Retrosynthesis “ Retrosynthesis ApproachesApproaches

2a. Transforms compiled manually from literature

!! accurate, highly specific"" tedious, expensive, restrictive

2b. Transforms based on enumerated bond changes

!! fully automated

"" unspecific, combinatorial explosion

Examples:

• LHASA, SECS / CASP ... (Corey, Wipke)

• WODCA, EROS ... (Gasteiger)

• SYNGEN ... (Hendrickson)

• AIPHOS ... (Sasaki)

• .....

Page 6: Retro Synthesis

6 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

RetroSynthesis RetroSynthesis Concept OverviewConcept Overview

1. Pre-processing

2. RetroSynthesis

Automatic transform extraction(ICMAP/CLASSIFY)

TransformTransformLibraryLibrary

RetroSynRetroSyn

N

R e m o v e b o n d 1 - 3

M a k e n e w s in g le b o n d b e tw e e n a t o m s 3 a n d 5R em ov e b ond 1 -2

M a k e ne w s in g le bond be t w e en a tom s 3 an d 4

12

3

O4

5

6

7 8

91 0

R111

R21 2

13

14

Template (2 levels):

Transform:

Make new single bond between atoms 2 and 6.

Decrease bond order of double bond 2=4 by 1.

Add group to atom 3: -OH

Remove bond between atoms 3 and 6.

Transform x

Transform y

Transform z

Lookupstored

examples

Reaction database

e. g.SPRESI

proprietary databasescommercial databases

Target molecule

O

O

H

H

Precursor(s) 1

Precursor(s) 2

Precursor(s) n

Reaction 1:

Reaction 2:

Reaction n:

Transform x

Transform y

Transform z

...

Target molecule

O

O

H

H

Page 7: Retro Synthesis

7 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Reaction Reaction Database Database RequirementsRequirements

2. Reaction Classification

Automatic identification of the structural environment around the reacting centers⇒ Determination of unique identifiers (ClassCodes)

.1..2.

O

O.3.

N.4.

.5.

.1..2.

N.4.

.5.

O.3.

+

O

O

NN

O

+

N

OFF

F

Cl

N

O O

FF

F

Cl

O

O

+

Reaction Type Amination:

1. Correct Reaction Mapping

Description of the transformation occuring during the reaction ⇒ Determination of reaction centers

Page 8: Retro Synthesis

8 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Definition of Definition of Template Template ((RetronRetron))

SPRESI Reaction Reg-No.: 3179546Kita Yasuyuki, Yoshida Yutaka, Mihara Sachiko, Fang Dai-Fei, Higuchi Kazuhiro, Furukawa Akihiro, Fujioka HiromichiEfficient pinacol rearrangement mediated by trimethyl orthoformateTetrahedron Lett., 38 (1997) 48, 8315-8318

CH3

OH OH

CH3

O

Template (level 2)

CH3

O

Template (level 3)

CH3

O

Template (level 4)

CH3

O

Page 9: Retro Synthesis

9 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Definition of Definition of TransformTransform

3 5

CH3

6

8

9

7

2

O4

1

Template:

• Remove bond between atom 5 and 6• Decrease bond order of double bond 3=4 by 1• Make new single bond between atoms 3 and 6• Add group to atom 5: -OH

IndicationsIndications::

Page 10: Retro Synthesis

10 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

PrePre--processing Stepprocessing Step ((TransformTransform Library Library BuildingBuilding))

Transform Transform GeneratorGenerator

Template Index

Transform Library

N

R e m o v e b o n d 1 - 3

M a k e n e w s in g le b o n d b e tw e e n a to m s 3 a n d 5

R e m o ve b on d 1 -2

M a k e ne w s ing le bo nd b e tw ee n a tom s 3 a nd 4

1

23

O4

5

6

7 8

910

R111

R212

13

14

Template (2 levels):

Transform:

Make new single bond between atoms 2 and 6.

Decrease bond order of double bond 2=4 by 1.

Add group to atom 3: -OH

Remove bond between atoms 3 and 6.

Reaction Database

O

O

NN

O

+

O

O

N

O O

N

O

+

N

OFF

F

Cl

N

O O

FF

F

Cl

O

O

+

Generation of substructure index

Page 11: Retro Synthesis

11 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Templates SearchTemplates Search

Target Molecule

Rated Templates

Strategy ParametersRating A

Rating B

Rating C

ICICFSEFSE

Template Index

Page 12: Retro Synthesis

12 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Strategy Strategy Parameters and Parameters and Precursors RatingPrecursors Rating

These criteria are weighted depending on the chosen configuration:

• sets of pre-defined strategy parameters are available• sets may be defined from user

Strategy parameters for precursor-rating consider the following criteria:

• formation of a new carbon-carbon bond• bond change within a functional group• formation of a new ring/aromatic bond

• formation of a new bond between two symmetric fragments• formation of a new bond near the center of the molecule• number of generated precursors

Page 13: Retro Synthesis

13 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Precursors Precursors Generation Generation from Targetfrom Target

Rated Templates

RetroSynRetroSyn

TransformLibrary

Target Precursors

⇒Transform

⇒Transform

⇒Transform

Rating A

Rating B

Rating c

Page 14: Retro Synthesis

14 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Multistep SynthesisMultistep Synthesis

O O

O

Catalog

O

ON

OH

O

O

NH2

OH

Target

Limits:steps

prec

urso

rs

O

O

Br

O

OH

O

O

OH

Precursors Step 1

Rating A

Rating B

OMg

Br

O

O

N+

N

O

ON

Precursors Step 2

Rating AA

Rating AB

Rating BA

Best First Search

OH

O

O

ON

Page 15: Retro Synthesis

15 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Prototype: Query FormPrototype: Query Form

Page 16: Retro Synthesis

16 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

ReactionReaction Databases Used Databases Used in Prototype in Prototype

• SPRESI Synthesis 2.5 mio reactions from SPRESIreactions with 50% minimum yield

• Name Reactions 140.000 reactions from SPRESI

all examples for a large set of Name Reactions

• EROS 68.000 reactions from J. Wileys„Encylopedia of Reagents for Organic Synthesis“

• SOS 120.000 reactions from Thiemes „Science of Synthesis“

• CAC 6.600 reactions from Springers „Comprehensive Asymmetric Catalysis“

Page 17: Retro Synthesis

17 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Prototype: Prototype: Suggested PrecursorsSuggested Precursors

Page 18: Retro Synthesis

18 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

Prototype: Synthesis Prototype: Synthesis TreeTree

Page 19: Retro Synthesis

19 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

ConclusionsConclusions

• Very large pool of data available (SPRESI 4 million reactions)

• Automatic transform generation from reaction databases

• Suggestions based on real (analogous) reactions

• Verification of suggested synthesis reactions, through link to reaction database / literature

• Availability-check of precursors in catalogs

• System will be integrated in a retrieval system providing common search tools

Page 20: Retro Synthesis

20 / 20

InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006

ThankThank youyou!!

InfoChem GmbH:InfoChem GmbH: www.infochem.de [email protected]