Finding Relevant Retrosynthetic Disconnections for Stereocontrolled Reactions.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Organic Synthesis

Background:

• Computer-aided synthesis planning (CASP) tools are vital for designing complex molecules.
• Current CASP tools often neglect crucial stereochemical details.
• Accurate stereochemical representation is essential for drug discovery and development.

Purpose of the Study:

• To develop an automated method for extracting synthesis templates with stereochemical information.
• To implement these templates into the AiZynthFinder software for enhanced CASP.
• To evaluate the performance of stereochemically aware CASP for complex molecule synthesis.

Main Methods:

• Automated extraction of reaction templates from USPTO and AstraZeneca databases, including stereochemical data.
• Integration of extracted templates into the AiZynthFinder software.
• Performance evaluation of multistep CASP using the enhanced templates on ChEMBL and internal datasets.

Main Results:

• Successfully extracted 367 stereochemically relevant templates from USPTO and 20,724 from AstraZeneca.
• Demonstrated the utility of stereochemically informed templates in multistep CASP for 936 ChEMBL targets and 791 internal designs.
• Identified potential and limitations through case studies including FDA-approved drugs.

Conclusions:

• The novel approach enhances CASP by incorporating stereochemical information, improving synthetic route design.
• AiZynthFinder, with its expanded template library, offers a powerful tool for chemists.
• This advancement facilitates more accurate and efficient planning of complex molecule synthesis.