Adaptation of a retrosynthetic tool to project-specific chemistry: oligomer synthesis case study
- 1Laboratory of Chemoinformatics, UMR 7140 CNRS, University of Strasbourg, 4, rue B. Pascal, Strasbourg, France, 67000
- 2Chemistry Solutions, Life Science Solutions, Elsevier, Nielsen House, John Smith Drive, Oxford, United Kingdom, OX4 2WB
- 3Institute for Chemical Reaction Design and Discovery (WPI-ICReDD, Hokkaido University, Kita 21 Nishi 10, Kita-ku, Sapporo, Japan, 001-0021
Abstract
Retrosynthetic planning for discrete oligomers presents challenges that differ from those encountered for conventional small molecules because their synthesis often relies on repeated transformations applied at multiple related sites within a multistep route. In conventional template-based search, each application of a single-center reaction rule is represented as an independent action, causing repeated chemistry to consume additional search depth and potentially generating order-equivalent trajectories. Here, we showcase the adaptation of the SynPlanner retrosynthetic platform to oligomeric chemistry through the introduction of project-specific priority rules and a newly implemented Rule Multi-Application (RMA) mechanism. RMA enables repeated applications of the same single-center rule to be represented within a single search expansion, with the multiplicity determined dynamically from the molecular structure. Composite rules were additionally used to provide sequence-level guidance for selected ordered transformations. The approach was evaluated on two literature-derived targets: a linear oligoacetylacetone-derived oligomer and a macrocyclic calix[3]pyrrole. For the linear target, baseline planning generated 161 complete routes across 20 strategic-bond-pattern (SBP) clusters but did not reproduce the literature strategy. Combining priority-rule guidance, RMA, and sequence-level abstraction enabled exact recovery of the reported pathway. For the macrocyclic target, baseline planning failed to identify a complete route even after increasing the search budget to 10,000 iterations, whereas the RMA-enabled guided configuration generated 65 complete routes across three SBP clusters, including routes reproducing the strategic-bond pattern of the literature synthesis. These results demonstrate that adapting a retrosynthetic planner to oligomeric chemistry requires not only access to relevant reaction knowledge but also an appropriate representation of repeated transformations during multistep search.
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BibTeX
@misc{gilmullin2026adaptation,
title = {{Adaptation of a retrosynthetic tool to project-specific chemistry: oligomer synthesis case study}},
author = {Almaz Gilmullin and Tagir Akhmetshin and Olga Klimchuk and Dragos Horvath and Timur Madzhidov and Yuki Ide and Ruben Staub and Yasuhide Inokuma and Alexandre Varnek},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010108/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010108/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Adaptation of a retrosynthetic tool to project-specific chemistry: oligomer synthesis case study
AU - Almaz Gilmullin
AU - Tagir Akhmetshin
AU - Olga Klimchuk
AU - Dragos Horvath
AU - Timur Madzhidov
AU - Yuki Ide
AU - Ruben Staub
AU - Yasuhide Inokuma
AU - Alexandre Varnek
PY - 2026
DA - 2026/10/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010108/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010108/v1
AB - Retrosynthetic planning for discrete oligomers presents challenges that differ from those encountered for conventional small molecules because their synthesis often relies on repeated transformations applied at multiple related sites within a multistep route. In conventional template-based search, each application of a single-center reaction rule is represented as an independent action, causing repeated chemistry to consume additional search depth and potentially generating order-equivalent trajectories. Here, we showcase the adaptation of the SynPlanner retrosynthetic platform to oligomeric chemistry through the introduction of project-specific priority rules and a newly implemented Rule Multi-Application (RMA) mechanism. RMA enables repeated applications of the same single-center rule to be represented within a single search expansion, with the multiplicity determined dynamically from the molecular structure. Composite rules were additionally used to provide sequence-level guidance for selected ordered transformations. The approach was evaluated on two literature-derived targets: a linear oligoacetylacetone-derived oligomer and a macrocyclic calix[3]pyrrole. For the linear target, baseline planning generated 161 complete routes across 20 strategic-bond-pattern (SBP) clusters but did not reproduce the literature strategy. Combining priority-rule guidance, RMA, and sequence-level abstraction enabled exact recovery of the reported pathway. For the macrocyclic target, baseline planning failed to identify a complete route even after increasing the search budget to 10,000 iterations, whereas the RMA-enabled guided configuration generated 65 complete routes across three SBP clusters, including routes reproducing the strategic-bond pattern of the literature synthesis. These results demonstrate that adapting a retrosynthetic planner to oligomeric chemistry requires not only access to relevant reaction knowledge but also an appropriate representation of repeated transformations during multistep search.
ER -