Axial stereoisomerism - atropisomerism

Atropisomerism

Stereochemical assignment

Stereoisomerism resulting from hindered rotation around a single bond when the isolation of invidual conformer is possible. (from Greek, a= not and tropos= turn)

MarvinSketch assigns 'M' and 'P' stereodescriptors to biaryl structures with at least 3 ortho substituents.

images/download/attachments/1806265/atropisomerism_for_documentation.png

Representation of atropisomers in MarvinSketch

Atropisomers should always be drawn with solid wedged and hashed wedged bonds within the aromatic rings and directly connected to the single bonds about which they rotate.

One ring system of each pair should be drawn exclusively with plain bonds. The other ring can be drawn with two solid wedged bonds, one directly connected to the rotating bond and one opposite. In even-membered systems, the bond between the solid wedged bonds should be depicted as bold and unwedged if it does not itself participate in a ring fusion. It is acceptable to depict the aryl systems with only a single wedged bond, as long as it remains directly connected to the single bond about which the aryl system rotates.

images/download/attachments/1806265/atropisomer_drawing_examples.png

Limitations

MarvinSketch assigns M/P stereolabels exclusively to biaryl compounds having at least 3 (2+1) ortho substituents.

However, in many other structures atropisomerism can be observed, which are not supported:

  • bridged biaryl compounds where the ring involving the two substituents is less then 8 membered

images/download/thumbnails/1806265/7_bonds_example.png

  • some heterocyclic aromatic rings i.e. quinone derivatives, telenzepine

  • macrocyclic compounds i.e. lorlatinib

Dimension changing ( i.e. 3D/3D cleaning) does not preserve atropisomerism.

Axial stereocenters

If two stereoactive atoms (atoms with at least three different ligands) are connected by an even numbered chain of rigid parts then axial stereo information can be defined on the ligands of the stereactive atoms.

These ligands are the ones which are not in the chain of the rigid part.

images/download/thumbnails/1806265/allene_axuial_isomer.png

The following substructures are considered as rigid parts:

  • double bonds,

  • four- or six-membered ring,

  • odd membered rings having lower than eight members, connected to each other directly or connected by intermediate four or six membered rings. Connection of two rings means that they share exactly one common bond (all rings are fused). The intermediate even membered rings have to connect to other rings by bonds on the opposite sides.

    images/download/attachments/1806808/stereo-ringChains.png

You may find more information concerning stereochemistry in the query guide or in the developer guide.