of WODCA to the Design
of a Synthesis for a Single
- The following example demonstrates the application of WODCA to a
simple target compound - a disubstituted cyclopentanone derivative.
Before we start the synthesis planning process the individual steps
to build a synthesis plan with WODCA are collected here. The order
of events is mostly the same for any synthesis problem, although it
can be varied by the chemist.
Start WODCA by calling the WODCA start script
Define a new target compound by starting the CACTVS
Molecule Editor from the context menu of WODCA's structure
display and export it into WODCA.
Build a new synthesis tree by exporting the target compound to the
CACTVS Synthesis Planner. This can
be also performed within the context
menu of the structure display.
Perform an identity search to
check whether the target compound is contained in the catalog of
chemicals or not.
Perform a similarity search to
search for suitable starting materials contained in the catalog of
Choose a disconnection strategy
and perform a strategic bonds search to
dissect the target compound into suitable synthesis precursors.
Cut a strategic bond that has a high rating to generate
suitable synthesis precursors.
Attach the precursors generated by WODCA to the synthesis tree in
the CACTVS Synthesis Planner.
Search for a synthesis of the precursor compounds. That means:
Repeat step 4 to 8 with the precursor compounds until a promising
synthesis plan has been developed which is based on available
starting materials from the catalog of chemicals.
Figure 1: The target compound
The Synthesis Planning Study of
- The following screenshots demonstrate the individual steps which
are necessary to build a synthesis plan for the target compound. The
numbered headlines correspond to the individual steps which are
described in the introduction to this chapter.
1. Starting WODCA
- Call the start script
wodca.sh from a UNIX shell.
This provides the starting screen of WODCA (Figure 2).
Figure 2: WODCA's starting screen
2. Input the Target Compound
- To define a new target compound you have to launch the CACTVS
Molecule Editor. In order to start this editor click on the
entry Tools in WODCA's menu bar, pull it down and click on
Launch Molecule Editor. Another possibility results from the
use of the context menu in WODCA's
structure display. Select the command Define New Target ....
. After a few seconds the CACTVS
Molecule Editor window appears. It allows the drawing of a new
structure just with the mouse. It is not necessary to draw hydrogen
atoms into your target structure since they will be added
automatically to open valences. Once the target structure has been
drawn it has to be transferred into the structure display of WODCA's
main window. In order to achieve this, click on the File
entry in the menu bar of the CACTVS Molecule Editor (Figure 3: (1)),
pull it down and click on the Export entry (Figure 3: (2)).
The chemical structure is now automatically transferred into WODCA
and the molecule editor window will be automatically minimized to an
Figure 3: Export of a molecule from the CACTVS
Molecule Editor into WODCA
3. Build a Synthesis Tree
- In order to create a graphical scheme of the synthesis plan
generated in this session you have to export the target compound to
the CACTVS Synthesis Planner. This
can be performed with the context menu in WODCA's
structure display (Figure 4: (1)).
The context menu appears after pressing the right mouse button in
WODCA's structure display.
Select the entry Start New Synthesis Plan ... (Figure 4: (2))
to perform the export of the target compound into the CACTVS
Synthesis Planner. It is not necessary to separately start the
CACTVS Synthesis Planner, because it is started automatically after
calling the menu command.
Figure 4: Transfer of the target compound into
the CACTVS Synthesis Planner
The target compound is displayed in the CACTVS Synthesis Planner as
the top of the synthesis tree (Figure 5).
Figure 5: Display of the target compound in the
CACTVS Synthesis Planner
4. Perform an Identity Search
- An identity search (Figure 6: (1))
is useful if you want to check whether the target compound is
contained in the catalog of available chemicals. The message in the
WODCA console ("No matches.") and the Match List
icon (which is hidden by the pull down menu) indicates that the
target compound is not available from FLUKA (see Figure 6).
Figure 6: Performing an identity search
5. Perform a Similarity Search
- Since the target compound is not contained in the catalog of
chemicals we continue our study with a similarity search to find
suitable starting materials contained in the catalog of chemicals.
To initiate a similarity search we have to click on the menu item
Searches in WODCA's menu bar and select the entry Similar
Compounds ... (Figure 7: (1)).
A new window for the application of similarity searches pops up
(Figure 7: (2)). We choose the
similarity criterion Ring Substitution Positions (Figure 7:
(3)) since we are interested in
available starting materials containing the trisubstituted
cyclopentane ring of our target compound. After pressing the Search
button (Figure 7: (4)) the
similarity search is started.
Figure 7: Performing a similarity search
Four hits are obtained from the FLUKA catalog that contains 16,769
compounds. This is indicated by the Match List icon and the
message in the WODCA console (Figure 8). To view the hits
click on the Match List icon in WODCA'S icon bar with
the left mouse button.
Figure 8: Result of the similarity search "Ring
Substitution Positions" displayed in WODCA
The CACTVS Structure Browser is
used to display the result of a similarity search (Figure 9).
It is started automatically after clicking on the Match List
icon in WODCA'S icon bar.
Figure 9: Result of the similarity search
"Ring Substitution Positions" displayed in the CACTVS
We realize that the second compound "2-methyl-1,3-cyclopentanedione"
could be a suitable starting material for our target compound, since
it is symmetrical and allows the attachment of phenyllithium.
However, it is not quite clear how to oxidize the methyl group to a
carboxylic acid (Figure 9).
To explore additional synthesis routes and to demonstrate how
individual steps of a synthesis plan can be generated, we explore
the tools working on strategic bonds.
6. Choose a Disconnection Strategy and Perform a Search for
- Clearly, the synthesis of the cyclopentanone system is the most
interesting part of the problem. To initiate the disconnection of
the target compound we have to click on the menu item Disconnection
in WODCA's menu bar and select the entry Strategic Bonds ...
(Figure 10: (1)). A new window
for the evaluation of strategic bonds pops up (Figure 10: (2)).
We choose the disconnection strategy Aliphatic Bonds (Figure
10: (3)) since we are interested
in a disconnection of the carbon framework of the target compound.
After pressing the Search button in WODCA's strategic bond
window (Figure 10: (4))WODCA
perceives five strategic bonds (Figure 10: (5)).
One bond is rated at the maximum with "100", another one
with nearly the maximum rating of "97". It therefore seems
to be useful to follow both disconnections.
Figure 10: Evaluation of strategic bonds
7. Cut a Strategic Bond
- The disconnection of strategic bonds directly leads to
synthesis precursors, since WODCA automatically adds suitable atoms
to the open valences obtained on heterolysis of a bond. In a first
try, we have decided to cut the strategic bond with the maximum
rating of "100" which corresponds to rank 1 of all
strategic bonds (Figure 11: (1)).
After pressing the Cut Bond button WODCA generates two
synthesis precursors: 3-phenyl-cyclopentanone and methyl
chloroformate (Figure 11: (2)).
Figure 11: Dissection of the carbon skeleton
8. Export of precursors to the CACTVS Synthesis Planner
- Although we have realized that the reaction between both
precursors may not proceed in a regioselective manner we decide to
attach the precursors to our synthesis plan. This is performed with
the help of the context menu in WODCA's strategic bonds display
(Figure 12: (1)). Just click on
the entry Attach to Synthesis Plan to export the precursors
to the CACTVS Synthesis Planner
(Figure 12: (2)).
Figure 12: Adding synthesis precursors to the
It is important to realize that the compound shown in WODCA's
structure display is always synchronized with the compound which
is marked as active in the CACTVS
Synthesis Planner (Figure 13). Therefore, after the attachment
of the precursors to the synthesis tree, one compound - in our case
methyl chloroformate - is automatically exported back to the WODCA
main program and an identity search is automatically
performed by WODCA.
Figure 13: Building a synthesis tree
One of the precursor compounds - methyl chloroformate is found
directly by an identity search in the FLUKA catalog of
chemicals. The other precursor compound - 3-phenyl-cyclopentanone -
is exported by a single click with the left mouse button on the
structure icon in the synthesis tree to the WODCA main program.
3-Phenyl-cyclopentanone is contained neither in the FLUKA catalog
nor in the Acros catalog of chemicals.
9. The Similarity Search Ring Substitution Positions with
- After 3-phenyl-cyclopentanone is loaded into WODCA we perform
the similarity search Ring Substitution Positions.
Surprisingly, the FLUKA catalog of chemicals contains only two
1,3-disubstituted cyclopentane derivatives (Figure 14).
Figure 14: The result of the similarity search
Ring Substitution Positions with 3-phenyl-cyclopentanone as query
1,3-Cyclopentanedione is a suitable starting material for the
synthesis of 3-phenyl-cyclopentanone.
Another quite interesting synthesis route can be developed by
choosing initially the strategic bond that has been rated with the
value of "97" (see Figure 10). We leave it to the user to
explore this by himself. In the following, rather, we want to show
the merit of another disconnection strategy type.
10. The Disconnection Strategy Aromatic Substitution
- To develop an alternative route to 3-phenyl-cyclopentanone we
choose the disconnection strategy Aromatic Substitution.
WODCA perceives one strategic bond which is rated with "100"
Figure 15: Evaluation of strategic bonds in
After cutting the bond rated with "100" WODCA generates
phenyllithium and 2-cyclopentenone as suitable starting materials
(Figure 16). Both precursors correspond to a Michael addition in
Figure 16: The disconnection of
Both precursors are attached to the synthesis tree via the context
menu of the strategic bonds display (Figure 17).
Figure 17: Completion of the synthesis tree
After performing an identity search with both precursors in the
FLUKA catalog of chemicals we can see that both compounds are
available (Figure 18). Thus, we have completed our synthesis tree
for the target compound 2-methoxycarbonyl-3-phenylcyclopentanone.
Figure 18: Result of two identity searches with
both precursor compounds
- Last change: 2000-06-29