Retrosynthesis
Retrosynthesis
Retrosynthesis
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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?
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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
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Synthesis-Planning Tools
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Examples:
• LHASA, SECS / CASP ... (Corey, Wipke)
• WODCA, EROS ... (Gasteiger)
• SYNGEN ... (Hendrickson)
• AIPHOS ... (Sasaki)
• .....
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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
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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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CH3 CH3
HO OH O
O O O
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Definition of Transform
Template: 6
1
2 CH3 9
3 5
8
O 7
4
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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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⇒
Transform
⇒
Transform Rating c
RetroSyn
⇒
Transform Rating B
Rating A
Transform
Library
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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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Conclusions
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Thank you!
InfoChem GmbH © 2006 ICIC Nîmes, October 22-25, 2006 Dr. V. Eigner-Pitto