Chemoenzymatic Multistep Retrosynthesis with Transformer Loops

12 April 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Integrating enzymatic reactions into computer-aided synthesis planning (CASP) should help devise more selective, economical, and greener synthetic routes. Herein we report the triple-transformer loop algorithm with biocatalysis (TTLAB) as a new CASP tool for chemo-enzymatic multistep retrosynthesis. Single-step retrosyntheses are performed using two triple transformer loops (TTL), one trained with chemical reactions from the US Patent Office (USPTO-TTL), the second one obtained by multitask transfer learning combining the USPTO dataset with preparative biotransformations from the literature (ENZR-TTL). Each TTL performs single-step retrosynthesis independently by tagging potential reactive sites in the product, predicting for each site possible starting materials (T1) and reagents or enzymes (T2), and validating the predictions via a forward transformer (T3). TTLAB combines predictions from both TTLs to explore multistep sequences using a heuristic best-first tree search and propose short routes from commercial building blocks including enantioselective biocatalytic steps. TTLAB can be used to assist chemoenzymatic route design.


computer-aided synthesis planning
chemoenzymatic synthesis
multi-step retrosynthesis

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