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Mar 25-29, 2012
San Diego, CA
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ARChem route designer: The application of automated retrosynthetic rule generation to synthesis analysis

A. Cook¹, A.Johnson¹, J. Law², M. Mirzazadeh², O. Ravitz², A. Simon²

¹ School of Chemistry, University of Leeds, Leeds, UK
²SimBioSys Inc., Toronto, Canada

Abstract

The 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 transformations.

In 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.

The systems that chose to use formal methods to automatically generate reactions from first principles^3,4 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.

In 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 decades.^5-8

Novel 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.

The 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 discussed.

References:

1. 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 press, 2011.
2. Corey, E.; Long, A.; Rubenstein, S. Computer-assisted analysis in organic synthesis. Science, 1985, 228, 408-418.
3. 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.
4. Hendrickson, J. B.; Braun-Keller, E. Systematic synthesis design. 8. Generation of reaction sequences., Journal of Computational Chemistry. 1980, 1, 323-333.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. FDA'S policy statement for the development of new stereoisomeric drugs. Chirality, 1992, 4, 338-34.
11. Corey, E. J. The logic of chemical synthesis. John Wiley: New York, 1989.

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