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Novel Approach to Retrosynthesis

Automatic Generation of
Transform Libraries

V. Eigner-Pitto, J. Eiblmaier, H. Kraut, H. Saller and P. Loew.

InfoChem GmbH, Landsberger Strasse 408, Munich, 81241, Germany

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Why Retrosynthesis?
How can I
Is there a synthesize
shorter this
synthesis path compound?
to my target?

Can we increase
the yield of this
process by
choosing another
synthesis
strategy?

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Retrosynthesis: Expected Features

Main Challenge: Automatic generation of chemically meaningful

precursors and their reasonable validation

1. Evaluation of Alternative Synthesis Pathways

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

2. Support of Multistep Synthesis

Necessary to guide the synthesis from the target to all existing precursors that can be
obtained from commercially available substances

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

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Synthesis-Planning Tools

1. Use of known compounds and published reactions

i.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

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„Intellectual“ Retrosynthesis Approaches

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)
• .....

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RetroSynthesis Concept Overview

N

1. Pre-processing R1
11

10
6
12
R2
9
Automatic transform extraction
(ICMAP/CLASSIFY)
Template (2 levels):
1 3 5
2
14 8
7
4
O 13

R e m o v e b o n d 1 -3
Transform: M a k e n eRemove
w s in bond
g le between
b ond b atoms
e t w 3eand
e n 6.a t o m s 3 a n d 5
R e m o v e b o n d 1 -2
Decrease bond order of double bond 2=4 by 1.
M a k e n e w s in g le b o n d b e t w e e n a to m s 3 a n d 4
Make new single bond between atoms 2 and 6.
Add group to atom 3: -OH

Reaction database
Transform
Library
e. g.
2. RetroSynthesis SPRESI
proprietary databases
commercial databases
O
H
H
O RetroSyn
Target molecule Lookup
stored
examples

Precursor(s) 1 Transform x
Reaction 1: Transform x
O
Transform y H
Reaction 2: Precursor(s) 2 Transform y
H
O
...
Transform z
Reaction n: Precursor(s) n Target molecule Transform z

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Reaction Database Requirements

1. Correct Reaction Mapping
Description of the transformation occuring during the reaction
⇒ Determination of reaction centers

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

O
O
Reaction Type Amination: O +
N
N
.3. .3.
O O
.5.
+ .5. F O F O O
.2. .4. N .2.
F F
O .1. N O
.1.
.4. F O F N
+
N

Cl Cl

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Definition of Template (Retron)

SPRESI Reaction Reg-No.: 3179546

Kita Yasuyuki, Yoshida Yutaka, Mihara Sachiko, Fang Dai-Fei, Higuchi Kazuhiro, Furukawa Akihiro, Fujioka Hiromichi
Efficient pinacol rearrangement mediated by trimethyl orthoformate
Tetrahedron Lett., 38 (1997) 48, 8315-8318

CH3 CH3

HO OH O

CH3 CH3 CH3

O O O

Template (level 2) Template (level 3) Template (level 4)

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Definition of Transform

Template: 6

1
2 CH3 9

3 5
8

O 7
4

Indications: • 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

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Pre-processing Step (Transform Library Building)

Reaction Database Transform Library

O
O
N
O +
N
N

11 12
R1 R2
10 9

Transform
6
Template (2 levels):
O
O O O 1
2
3 5

14
O + 4
7 8

N N O 13

Generator
R em ove bo nd 1-3
M a k e n e w s in g le b o n d b e t w e e n a t o m s 3 a n d 5
Transform: R e3mand
Remove bond between atoms o v6.e b on d 1-2
M a k e n e w sDecrease
in g le bbond
o n dorder
b eof
t wdouble
e e n bond
a t o2=4
m sby31.a n d 4
Make new single bond between atoms 2 and 6.
F O F O O Add group to atom 3: -OH
F O F
F O F N
+
N

Cl Cl

Generation of
substructure index

Template Index

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Templates Search

Rated Templates
Template Index

Target Molecule

ICFSE
Rating C

Rating B

Rating A
Strategy Parameters

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Strategy Parameters and Precursors Rating

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

These criteria are weighted depending on the chosen configuration:

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

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Precursors Generation from Target

Rated Templates Target Precursors

⇒
Transform

⇒
Transform Rating c
RetroSyn
⇒
Transform Rating B

Rating A

Transform
Library

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Multistep Synthesis
Best First Search Precursors Step 1 Precursors Step 2
Rating AA Catalog
Br
Rating A Mg
O O OH
Br
O
O

OH O
Target O

O O
O
O N NH2
O +
N
Rating AB

O OH

Limits: O
steps OH
Rating B O
O
precursors

N
N O
N O
Rating BA

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Prototype: Query Form

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Reaction Databases Used in Prototype

• SPRESI Synthesis 2.5 mio reactions from SPRESI

reactions 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“

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Prototype: Suggested Precursors

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Prototype: Synthesis Tree

InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto
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Conclusions

• 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

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Thank you!

InfoChem GmbH: www.infochem.de

www.spresi.de
info@infochem.de

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