Upload
pramod-aryal
View
126
Download
4
Tags:
Embed Size (px)
DESCRIPTION
introduction
Citation preview
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
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?
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
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
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)
• .....
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
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
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
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::
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
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
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
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
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
15 / 20
InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006
Prototype: Query FormPrototype: Query Form
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“
17 / 20
InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006
Prototype: Prototype: Suggested PrecursorsSuggested Precursors
18 / 20
InfoChem GmbH © 2006 Dr. V. Eigner-PittoICIC Nîmes, October 22-25, 2006
Prototype: Synthesis Prototype: Synthesis TreeTree
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
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]