Tutorial A: The Application of WODCA to the Design of a Synthesis for a Single Compound

Introduction

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.

1. Start WODCA by calling the WODCA start script wodca.sh.
2. 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.
3. 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.
4. Perform an identity search to check whether the target compound is contained in the catalog of chemicals or not.
5. Perform a similarity search to search for suitable starting materials contained in the catalog of chemicals.
6. Choose a disconnection strategy and perform a strategic bonds search to dissect the target compound into suitable synthesis precursors.
7. Cut a strategic bond that has a high rating to generate suitable synthesis precursors.
8. Attach the precursors generated by WODCA to the synthesis tree in the CACTVS Synthesis Planner.

9. 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 "2-methoxycarbonyl-3-phenylcyclopentanone"

The Synthesis Planning Study of 2-methoxycarbonyl-3-phenylcyclopentanone

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 icon.

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 Structure Browser

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 Strategic Bonds

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 synthesis tree

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 3-phenyl-cyclopentanone

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)

Figure 15: Evaluation of strategic bonds in 3-phenyl-cyclopentanone

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 synthetic direction.

Figure 16: The disconnection of 3-phenyl-cyclopentanone

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

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