Introduction
Axial stereoisomerism (atropisomerism) representation in CDD Vault
Registering Pure Enantiomers with Unknown Absolute Configuration
Registering a Series of Duplicates with Unique Registration IDs
Instructions for creating Brackets within Chemical Drawing Packages
Mixture Registration
Introduction
In general, molecules registered into CDD Vault containing “up” or “down” bonds are interpreted "as drawn". You can, however, represent racemic mixtures, pure enantiomers (both known and unknown configurations) using the V3000 enhanced stereochemical notation.
This annotation allows for registration of a single entity to describe stereochemical mixtures. The alternative method to draw two or more enantiomers, leading to registration of multiple entities in a single record with properties reflecting the total number of all molecules. This may lead to confusion since the fully drawn mixture of two entities would double the molecular mass. Using AND/OR annotations to register a single entity, will lead to expected molecular mass of only the one compound.
Here we demonstrate some implementations of these "AND" and "OR" enhanced stereochemical labels/designations.
As pointed out elsewhere in our Knowledge Base, stereochemical information is best dealt with as MOL (alt. SDF) format, instead of SMILES format due to the limitations of SMILES, especially with regards to mixtures. Therefore, we recommend drawing and registering a Molecule using the V3000 Enhanced Stereochemistry. Use the "AND" enhanced stereo label to indicate that the Molecule represents an isomeric mixture and the “OR” label to indicate cases for absolute, but unknown stereochemical centers.
With the Structure Editor in CDD Vault, users can select the atom and use the Stereochemistry tool from the top toolbar to add the labels. Note: You may also use the Alt-E keyboard shortcut after selecting the atom.
Once you've chosen the Stereochemistry tool, the Enhanced Stereochemistry menu will display. Here, you may select which label you wish to apply, AND or OR.
Below we illustrate several examples to help users with visibility/understanding of registered compounds using these labels. This should also allow the otherwise difficult to achieve registration of sterically hindered amides, or other, non-tetrahedral chiral structures.
The following represents a mixture of 4 diastereoisomers
and represents a mixture of all of the following 4 diastereoisomers
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The following represents a mixture of 2 enantiomers
and represents a mixture of the following 2 enantiomers
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The following represents a mixture of 2 enantiomers
and represents a mixture of the following 2 enantiomers
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The following represents a pure sample of unknown configuration
but is one of these 4 diastereoisomers
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The following represents a pure sample of unknown absolute configuration
but is one of these 2 enantiomers
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The following represents a pure sample unknown configuration
but is one of these 2 enantiomers
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Axial stereoisomerism (atropisomerism) representation in CDD Vault
CDD Vault supports the registration of compounds containing Axial stereoisomerism (atropisomerism), which is a stereochemical assignment resulting from hindered rotation around a single bond when the isolation of individual conformer is possible.
Atropisomers can still be drawn with solid wedged and hashed wedged bonds within the aromatic rings and directly connected to the single bonds about which they rotate. However, the representation of atropisomers in CDD Chemistry requires additional information. The common atropisomer representation using wedged bonds in aromatic systems is stored and displayed to the user but this information is not used by the registration system for the purposes of duplicate detection. For example, these two molecules will be seen as the same by our registration system:
To distinguish between them, we have two special S-Groups, "atropisomer" and "override", that can be added to bonds or atoms.
Method
If I have registered this structure...
... and now want to register the other atropisomer, I should:
- open the Ketcher Structure Editor,
- draw or insert the structure,
- click on [S+] on the left toolbar, and
- click on the stereo bond.
In the S-Group Properties pop-up dialog box, I would then:
- fill in the "Field name" box with the term, "atropisomer", and
- fill in the "Field value" box with a unique value for this structure
The new structure now contains a bond that's annotated with the "atropisomer" label that contains the value provided, and will register into CDD Vault as a new, separate Molecule.
Helpful Hints:
- Using the S-Group Field Name of "atropisomer" is highly encouraged as it will facilitate easy recognition of these compounds in your Vault in the future (when a more formal support mechanism is in place)
- We also have another data s-group called "override" (without quotes) that can be used for a similar purpose and is meant to be used for cases beyond atropisomerism.
Registering Pure Enantiomers with Unknown Absolute Configuration
To register pairs of enantiomers when the absolute configuration is unknown:
1) For the first isomer:
- Draw a wedge (up) bond for the stereocenter .
- Select the stereocenter and click the stereo tool from the top toolbar (or click Alt-E).
- In the dialog box, select “Create new OR Group".
- Click the Apply button.
2) For a second isomer, repeat the process for the first isomer with a hash bond at the stereocenter.
3) When you register the second isomer, you will get the message below at the top the page. Scroll down below the Strip and Stoichiometry radio buttons and select New molecule. A new molecule ID will be assigned.
This allows you to register the racemate, both unknown configurations and both known configurations of this molecule as separate entities:
Registering a Series of Duplicates with Unique Registration IDs
CDD Vault supports additional functionality within external drawing programs like ChemDraw to help with structure registrations that are problematic.
To register when using external applications, either save as MDL SDfile (V3000 will be created automatically) or copy/paste via “Copy as” and choose “MDL MOL file” and paste this into the text portion of the "Structure" section of the manual registration page (not into the built-in Ketcher Structure Editor present in CDD Vault). Similarly, in ChemDraw, users would select the option Edit - Copy As - MOL V3000 Text and paste the contents into the "Structure" section of the manual registration page.
You will likely see a warning in the banner section stating that the new molecule is a duplicate. This is expected behavior and can help for faster identification of related stereoisomers.
Example: Non-tetrahedral chiral compounds
Non-tetrahedral compounds are more complex to register, but it is possible to register with brackets (sterically hindered amide or axially chiral compounds are an example):
The procedure is the same as described in the previous section, for additional clarity you can add the “ABS” feature to the Nitrogen (select the N and click Stereochemistry tool.
Example: Axial chirality (non-tetrahedral chiral compound)
In the case of axial chirality, you will have to group each enantiomer, and you will have to group each in a different way. We suggest using “monomer” in one case and “repeating unit…. = 1” in the other.
For helicene type of compounds you would register them in the same way.
The important feature to remember for this type of registration is the usage of the “Group…” functionality. By choosing a different type of group each time, the registration system keeps entities apart, despite seeing them as potential duplicates.
Instructions for creating Brackets within Chemical Drawing Packages
If you are in need of generating duplicate registrations for 2 to 4 molecules, users can create the molecules using CDD Vault's built in chemistry editor, Ketcher. Here are the steps:
1) Draw the first molecule in Ketcher and Register the structure.
2) For the first duplicate (molecule 2), draw the molecule again in Ketcher. Select the portion of the molecule where the Repeating Group should appear. Click the "S Group" icon on the left toolbar.
Fill in the details in the S-Group Properties dialog box.
3) For the 2nd duplicate (molecule 3), Repeat Step 2 and change the top pull down box to "Head-to-head". Register the molecule.
4) For the 3rd duplicate (molecule 4), Repeat Step 3 and change the top pull down box to "Either unknown". Register the molecule.
** Note - Most chemical properties will not be calculated with the structure created using this S-Group Properties menu.
If you are in need of generating more that 4 duplicate registrations, you will need to use a 3rd party chemical editor (like ChemDraw).
For ChemDraw v18, here are the steps to create molecules with different bracket combinations:
1) Draw the molecule
2) Click the "Brackets" icon on the main toolbar. Extend the bracket so the entire molecule is within the bracket.
3) Mouse over the bracket and right click. Select Bracket Usage, then "Monomer". Right click again and select Repeat Pattern then "Head to Tail"
Our current testing should allow users to register up to 32 copies (duplicates) of the same molecule using the following combinations of Bracket Usage and Repeat Pattern.
1) Base Molecule
2) Ketcher - Repeating Groups - ht, n=1 OR ChemDraw 18 - Bracket Usage = SRU, n=1 - Repeat Pattern = Head to Tail (default)
3) Ketcher - Repeating Group - hh - n=1 OR ChemDraw 18 - Bracket Usage = SRU, n=1 - Repeat Pattern = Head to Head
4) Ketcher - Repeating Group - eu - n=1 OR ChemDraw 18 - Bracket Usage = SRU, n=1 - Repeat Pattern = Either/Unknown
** Note - Most chemical properties will not be calculated with the structure created via these workflows.
5) ChemDraw 18 - Bracket Usage = Monomer - Repeat Pattern = Head to Tail (default)
6) ChemDraw 18 - Bracket Usage = Monomer - Repeat Pattern = Head to Head
7) ChemDraw 18 - Bracket Usage = Monomer - Repeat Pattern = Either/Unknown
8) ChemDraw 18 - Bracket Usage = Component - Repeat Pattern = any
9) ChemDraw 18 - Bracket Usage = Co Polymer - Repeat Pattern = Head to Tail (default)
10) ChemDraw 18 - Bracket Usage = Co Polymer - Repeat Pattern = Head to Head
11) ChemDraw 18 - Bracket Usage = Co Polymer - Repeat Pattern = Either/Unknown
12) ChemDraw 18 - Bracket Usage = Copolymer Alternating - Repeat Pattern = Head to Tail (default)
13) ChemDraw 18 - Bracket Usage = Copolymer Alternating - Repeat Pattern = Head to Head
14) ChemDraw 18 - Bracket Usage = Copolymer Alternating - Repeat Pattern = Either/Unknown
15) ChemDraw 18 - Bracket Usage = Copolymer Block - Repeat Pattern = Head to Tail (default)
16) ChemDraw 18 - Bracket Usage = Copolymer Block - Repeat Pattern = Head to Head
17) ChemDraw 18 - Bracket Usage = Copolymer Block - Repeat Pattern = Either/Unknown
18) ChemDraw 18 - Bracket Usage = Copolymer Random - Repeat Pattern = Head to Tail (default)
19) ChemDraw 18 - Bracket Usage = Copolymer Random - Repeat Pattern = Head to Head
20) ChemDraw 18 - Bracket Usage = Copolymer Random - Repeat Pattern = Either/Unknown
21) ChemDraw 18 - Bracket Usage = Crosslink - Repeat Pattern = Head to Tail (default)
22) ChemDraw 18 - Bracket Usage = Crosslink - Repeat Pattern = Head to Head
23) ChemDraw 18 - Bracket Usage = Crosslink - Repeat Pattern = Either/Unknown
24) ChemDraw 18 - Bracket Usage = Generic - Repeat Pattern = Head to Tail (default)
25) ChemDraw 18 - Bracket Usage = Generic - Repeat Pattern = Head to Head
26) ChemDraw 18 - Bracket Usage = Generic - Repeat Pattern = Either/Unknown
27) ChemDraw 18 - Bracket Usage = Graft - Repeat Pattern = Head to Tail (default)
28) ChemDraw 18 - Bracket Usage = Graft - Repeat Pattern = Head to Head
29) ChemDraw 18 - Bracket Usage = Graft - Repeat Pattern = Either/Unknown
30) ChemDraw 18 - Bracket Usage = Modification - Repeat Pattern = Head to Tail (default)
31) ChemDraw 18 - Bracket Usage = Modification - Repeat Pattern = Head to Head
32) ChemDraw 18 - Bracket Usage = Modification - Repeat Pattern = Either/Unknown
Other bracket notations may be available in ChemDraw that has not be tested and could result in even more duplicate molecules.
Mixture Registration
For registration of mixtures (multi-compound) structures, please visit these articles
Single Registration of Chemical Entities
Is it possible to add structures to structureless molecules