Our understanding of the role chirality plays in the activity of drugs has been steadily growing in recent decades. Although we cannot always explain mechanistically why different enantiomers can manifest strikingly diverging pharmacological behaviors, we can often measure significant differences in their binding affinity, selectivity and ADME properties. Even for drugs that are currently marketed in racemic mixtures there is often evidence that one of the enantiomers dominates the pharmacology of the drug. It is not surprising therefore, that stereo-selective methods and chiral starting materials have become pivotal to synthesis in this domain.
Including stereochemistry into our synthesis planning tool, ARChem, has been a major undertaking at SimBioSys. The development encompassed many layers, from algorithmic perception of the full spectrum of stereogenic types, through representation of stereochemical reactions, to the proper depiction of molecules. We are very excited to release the first version of ARChem to address stereochemistry. It offers the following capabilities:
Full perception of stereochemistry in the target molecule.
Matching of literature precedents with proper chirality during the retrosynthetic analysis.
Matching proper enantiomers from the collection of starting materials.
The synthesis for Azalanstat below demonstrates the utility of these features. The synthetic route suggested by ARChem, generates one of the chiral centers of the target molecule using an enantioselective reaction step taken from a specific literature example, whereas the other chiral center is introduced using a chiral starting material.
All steps in the plan are supported by literature examples, and all starting materials are found in catalogs of commercial suppliers.
While we hope you share our satisfaction with this accomplishment, our work on stereochemistry is far from complete. The next few months will be dedicated to developing the capability of generating enantioselective reaction rules. This will allow ARChem to provide the novelty and robustness it achieves in the synthesis design of achiral compounds, and will further enhance its usefulness as a synthetic idea generator.