Strategic Bonds

Organic chemists have developed a rich set of reactions for the construction of chemical compounds. The disconnection approach is a useful method for the development of a synthesis plan for a target molecule. Corey's synthon concept is well established for the generation of a synthesis plan in a retrosynthetic direction. The starting point of such a procedure is the target compound. The main task is to find strategic bonds for the disconnection of the target into synthons. After generation of these - usually charged - synthons they are converted into precursors by addition or removal of charged atoms or groups. WODCA is able to handle these three tasks automatically:

• the perception of strategic bond
• the cutting of strategic bonds on demand
• the conversion of synthons into precursors.

What is a Strategic Bond?

Strategic bonds are bonds within the target molecule which are qualified to be disconnected. Whether a bond is a strategic one depends on whether the bond cut leads to structural simplification in the precursors (topological criteria), and on whether the resultant precursors can easily be converted into the target by chemical reactions that have a broad scope.

Principle of a Strategic Bond Search: The Disconnection Strategies

WODCA offers four different disconnection strategies to perceive strategic bonds within the target compound:

• Aliphatic Bonds
• Aromatic Substitution
• Carbon-Heteroatom Bonds

• Polycyclic Compounds

In each strategy, different rules are used to evaluate strategic bonds. The maximum rating for a strategic bond is 100, the lowest one is 0. It is important to realize that these values are not absolute but relative to the compound actually loaded. As can be seen in Table 4, a nitro bond to an aromatic ring system is rated in one compound with 100, in another compound with 2, and in a third compound it is not strategic at all. The rating of a strategic bond always depends on the chemical environment of the bond.

The different approaches to the disconnection of a target compound are now discussed in the following.

Aliphatic Bonds

Only non-aromatic C-C-bonds are analyzed here. Aliphatic bonds to aromatic rings are not considered in this disconnection strategy but are handled in the strategy for Aromatic Substitution. An aliphatic bond can be either in a non-aromatic ring or in a carbon chain. Both single and multiple bonds are considered. For the rating of strategic C-C-bonds WODCA considers topological criteria and calculated physicochemical properties for the aliphatic bond being analyzed. Topological criteria are whether the bond is endocyclic or exocyclic to a ring system, whether it is a bond at a branching point, and whether it is a bond to a chiral carbon atom.

WODCA calculates for each atom and bond within a molecule a set of empirical physicochemical properties which are listed in the scheme on Figure 1. The results of these calculations and the topological criteria of a bond are analyzed by WODCA and are used to rate the strategic bonds.

Figure 1: Physicochemical parameters for the evaluation of strategic C-C-bonds
(click on the image to obtain an enlarged view)

Aromatic Substitution

This disconnection strategy is still in development but large improvements have been made recently. WODCA calculates a set of physicochemical properties to reflect the mesomeric and inductive effects of substituents on the aromatic ring system. Additionally, the substitution pattern on the aromatic ring is considered to perceive activated ring positions. In aromatic compounds with more than one substituent only bonds on activated positions can be strategic. In order to decide whether a bond to a substituent is activated or not the directing influence of the other substituents is considered.

The rating for a strategic bond to an aromatic ring system depends on the properties of the bond from the aromatic ring system to the substituent. This bond is defined by the atoms labels 1 and 2. At this stage of development the strategy is limited to six-membered aromatic ring systems.

The following table gives an overview about the physicochemical properties considered for the rating of strategic bonds linked to benzene ring systems.

Table 3: Physicochemical properties for the evaluation of strategic bonds to aromatic ring systems.

In Table 4 the disconnection strategy Aromatic Substitution is applied to different aromatic compounds. The first column show the rating of strategic bonds evaluated by WODCA. The second column shows the precursors automatically generated by WODCA after cutting the bond marked with 100.

Table 4: Some examples for the rating of strategic bonds in different aromatic compounds and the generation of precursors.

Carbon-Heteroatom Bonds

The evaluation of strategic carbon-heteroatom bonds is restricted to bonds between carbon and those heteroatoms, which are embedded in a larger carbon framework, such as when the heteroatom has two bonds to carbon atoms. Bonds between carbon and heteroatoms of terminal substituents such as to halogen atoms or NH₂ or OH groups are not considered as strategic. The rating of the strategic carbon heteroatom bonds depends on the functionality of the compound which is investigated. WODCA is able to perceive C-X-bonds and bonds in -position to these bonds within the following organic compounds listed in Table 5.

Table 5: Functional groups, derived C-X-bonds and bonds in alpha-position to the C-X-bonds considered for the evaluation of strategic C-X-bonds

This list of organic compounds is not yet complete and will gradually be extended. WODCA distinguishes between - and - C-X-bonds and furthermore considers bonds which are in a -position to a functional group. Often, these -bonds are strategic, too. The assignment of a bond to a functional group is always clear. It is not possible that, for example, WODCA evaluates a carbon nitrogen double bond as an imine bond and as a part of an amidine group, simultaneously. Only one of both assignments is made, because WODCA checks not only the isolated bond but the framework in which the bond is embedded in. The scheme in Figure 2 shows an organic compound with its functionality perceived by WODCA.

Figure 2: Example for the classification of C-X-bonds

It is important to realize that the bonds 7, 9 and 10 are part of an amide group. These bonds are not classified as amine bonds. Bond 4 is a carboxylic acid single bond, not a bond in an alcohol. Bonds 3 and 6 are classified as carbonyl bonds of a carboxylic acid or an amide, respectively, and thus distinguished from a carbonyl bond of an ester.

Polycyclic Compounds

The method of searching for strategic bonds in polycyclic compounds is only useful for molecules with large condensed ring systems. A set of topological criteria based on Corey's rules for the treatment of complex ring systems is applied to the query structure. The rules are:

• strategic bonds have to be in a primary ring with four to seven ring atoms.

• strategic bonds have to be in exo position to another ring system with more than three ring atoms.

• strategic bonds have to be in the ring with the maximum number of bridgehead atoms.

• core bonds are not strategic. Core bonds are bonds, whose disconnection will lead to the formation of primary rings with more than seven ring atoms.

• ring bonds between two chiral carbons are not strategic.

All this topological criteria are analyzed by WODCA and lead to a rating for strategic bonds in polycyclic compounds. The maximum rating is 100, the lowest one is a value of 0.

The Strategic Bonds Window

If the user clicks with the left mouse button on the entry Strategic Bonds... in the disconnection menu the window for the evaluation of strategic bonds appears. The Strategic Bonds window is shown in Figure 3.

Figure 3: Window for the application of a disconnection strategy

The Strategic Bonds window contains three different window elements, which are now explained in detail. The left hand area is called strategic bond display, the right hand area is called disconnection strategy list box and the lower part of the window with the button bar is called action area.

Strategic Bond Display

The strategic bond display is used to display a chemical structure that is analyzed for strategic bonds. Furthermore, all strategic bonds perceived by WODCA in a query structure and the precursors generated by WODCA after cutting a strategic bond are shown in this display area.

Figure 4: Example for the tautomerization of precursors generated by WODCA

Functional Group Interconversion (FGI)

Functional group interconversions are often used in synthetic chemistry to change functional groups into others which can be easily disconnected. Many FGIs are performed during the synthesis of aromatic compounds, e.g., aromatic acids can be made by oxidation of methyl or aldehyde groups and amino groups can be obtained by reduction of nitro groups. WODCA is able to handle these tasks. FGIs can be directly applied to the precursor compound displayed in the strategic bond display. Often, it is a good idea to apply a FGI to a precursor before WODCA is searching for strategic bonds. The result of a strategic bond search depends on the molecular structure of a query. Therefore, if a nitro bond is changed to an amine bond, this will affect the rating and the order of a strategic bond within the query compound.

The FGI Panel (see Figure 5) is reachable from the context menu of the strategic bond display. It is organized in four sections: Oxidation, Reduction, Organometallic, and Others. Each section can be entered while the right mouse button is pressed.

Figure 5: Organization of the FGI panel for functional group interconversion

After selection of a FGI criterion from the submenu of the FGI Panel a functional group interconversion is performed to the precursor compound. The first functional group which matches the selected FGI criterion will be changed by WODCA. If all functional group of the same type should be changed, the procedure has to be repeated until the last functional group is modified. To prevent a functional group from changing it has to be protected by a protecitve group.

Protecting Groups (PG)

Protecting groups allow us to overcome simple problems of chemoselectivity. WODCA is able to handle PGs for amines, alcohols, aldehydes, ketones, and carboxylic acids. Protecting groups can be easily added to and also removed from the precursor compound shown in the strategic bond display.

The PG Panel (see Figure 6) appears within the context menu of the strategic bond display. It is divided into two parts. The upper part is used for protection of functional groups. The lower part is used for deprotection purposes.

Figure 6: Organization of the PG panel for the application of protecting groups.

To apply a PG to a functional group just select a suitable PG criterion from the PG Panel. All functional groups which matches the selected PG criterion will be protected.

List Box for Disconnection Strategies

Modification of Precursors

The dialog box in Figure 7 is displayed if the user presses the button Modify ... in the Strategic Bonds window (see Figure 3). It allows the modification of precursors. Often, it is a good idea to protect some functional groups before the target compound is disconnected. In other cases it can be useful to perform a functional group interconversion or a functional group addition. This dialog box enables the convenient application of protecting groups (PG), the removal of protecting groups (DPG), the functional group interconversion (FGI), and the addition of functional groups (FGA) to chemical compounds. At this stage of development the FGA is restricted to the addition of nitro groups to benzene derivatives.

Figure 7: Dialog box for the convenient application of PGs, DPGs, FGIs, and FGA to chemical compounds

Description of the Dialog Box: WODCA - Modify Precursor(s)

Figure 8: Perception of carboxylic groups marked with the bond label "6" and "18"

The Action Area

The action area is located in the lower part of the strategic bonds window (see Figure 8). It is divided into a larger left side and a smaller right side. The left side contains four buttons (Cut Bond, Undo Cut, Modify ..., Search), one option menu (Rank of Selected Bond), and one entry field (Set of Bonds). The right side contains two buttons (Options ... and Dismiss). The meaning of the different window elements and the implementation of a strategic bond search is explained in the following.

Description of the Window Elements

Implementation of a Strategic Bond Search

Manual Definition of Strategic Bonds

The manual definition of strategic bonds can be performed within a dialog box which is opened after selection of the corresponding menu command either from the context menu of the strategic bonds display or from the Disconnection menu in WODCA's menu bar. After the dialog box is opened the Precursor(s) display is automatically switched to atom labels instead of atom symbols. The entire procedure of manually defining a strategic bond is shown in Figure 9 and 10 and described in the following.

Figure 9: Dialog box for the manual definition of strategic bonds

The following steps are necessary to create the synthesis precursors of a Friedel-Crafts alkylation for the cyclopentanone derivative displayed in Figure 9.

1. Select a Strategic Bond Cut Mode or leave the default setting (Figure 9, (1)).
2. Enter both labels of the atoms which form the strategic bond (Figure 9, (2)). Both atom labels are highlighted in the Precursor(s) display of the Strategic Bonds window in Figure 9.
3. Enter the leaving groups which should be added to the open valences after disconnection of the strategic bond (Figure 9, (3)).
4. Press the Set button to define the strategic bond in the cyclopentane derivative (Figure 9, (4)) and close this dialog box. Afterwards, the strategic bond which is manually defined is displayed with a rating of 100 (Figure 10, (1)) and the Cut Bond button in the Strategic Bonds window is switched to active state (Figure 10, (2)).
5. After pressing the Cut Bond button, the strategic bond is disconnected and the corresponding precursors are generated by WODCA (Figure 10, (3)).

Figure 10: Disconnection of a strategic bond manually defined

Last change: 2000-08-22

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