ARChem route designer: The application of automated retrosynthetic rule generation to synthesis analysis
A. Cook1, A.Johnson1, J.
Mirzazadeh2, O. Ravitz2, A. Simon2
School of Chemistry, University
of Leeds, Leeds, UK
2SimBioSys Inc., Toronto, Canada
discipline of computer-aided chemical synthesis design is now
approximately 40 years old.1
The original research programs of that period explored two approaches
to knowledge representation of retrosynthetic reaction
the original empirical rule based systems2
transforms were collated by hand from the primary literature and
distilled into coded reaction rules. This approach never acquired the
depth of knowledge of a skilled human chemist due to its laborious
and highly skilled nature. The rapid discovery of new reactions, new
methods and more selective reagents meant there was little hope of
ever catching up and the work of manually building the knowledge
bases eventually waned.
systems that chose to use formal methods to automatically generate
reactions from first principles3,4
conversely suffered from the need to
apply rigorous constraints to remove unlikely reactions. These
systems were capable of suggesting novel chemistry, but the lack of
hard precedents, with accompanying scope and limitations, was not
attractive for the end user.
recognition of these fundamental problems, research into a third
approach using automated production of transforms from curated
reaction databases has begun to make inroads over the last few
methodologies employed by the ARChem route designer program9
to generate reaction rules from available reaction
databases are discussed. The organization of the automatically
generated rules into hierarchies and their application to the
synthesis design problem is demonstrated. The need for augmenting key
reaction rules with manually curated data for improving the generated
routes is discussed.
requirement to produce enantiopure drugs10
poses significant challenges in planning an
enantioselective synthesis.11 A
new research project has been initiated at Leeds to study
computer-aided enantioselective chemical synthesis planning. Novel
algorithms for the recognition and treatment of stereochemistry in
targets molecules and transform rules are presented. Approaches for
goal directed strategy selection for stereocontrolled synthesis is
- Cook, A. P.; Johnson, A. P.; Law, J.; Mirzazadeh, M.; Ravitz, O.; Simon,
A. Computer-aided synthesis design: 40 years on. In Wiley
Interdisciplinary Reviews: Computational Molecular Science; in
- Corey, E.; Long, A.; Rubenstein, S. Computer-assisted analysis in organic
- Gasteiger, J.; Hutchings, M. G.; Christoph, B.; Gann, L.; Hiller, C.; Low, P.;
Marsili, M.; Saller, H.; Yuki, K. A New Treatment of Chemical
Reactivity: Development of EROS, an Expert System for Reaction
Prediction and Synthesis Design. Topics in Current
Chemistry. 1987, 137, 19-73.
- Hendrickson, J. B.; Braun-Keller, E. Systematic synthesis design. 8. Generation
of reaction sequences., Journal of Computational Chemistry.
1980, 1, 323-333.
- Röse, P.; Gasteiger, J. Automated derivation of reaction rules for the
EROS 6.0 system for reaction prediction. Analytica Chimica Acta,
1990, 235, 163-168.
- Blurock, E. S. Computer-aided synthesis design at RISC-Linz: automatic
extraction and use of reaction classes.
Journal of Chemical Information and Computer Sciences, 1990, 30, 505-510.
- Satoh, K.; Funatsu, K. A Novel Approach to Retrosynthetic Analysis Using
Knowledge Bases Derived from Reaction Databases. Journal of Chemical
Information and Computer Sciences, 1999,39,316-325.
- Wang, K.; Wang, L.; Yuan, Q.; Luo, S.; Yao, J.; Yuan, S.; Zheng, C.;
Brandt, J. Construction of a generic
reaction knowledge base by reaction data mining. Journal of Molecular
Graphics and Modelling, 2001, 19, 427-433.
- Law, J,; Zsoldos, Z.; Simon, A; Reid, D.; Liu, Y.; Khew, S. Y.; Johnson,
A. P.; Major, S; Wade, R. A.; Ando, H. Y. Route Designer: A
Retrosynthetic Analysis Tool Utilizing Automated Retrosynthetic Rule
Generation. Journal of Chemical Information and Modeling, 2009, 49, 593-602.
- FDA'S policy statement for the development of new stereoisomeric drugs.
Chirality, 1992, 4, 338-34.
- Corey, E. J. The logic of chemical synthesis. John Wiley: New York, 1989.