Computer‐aided synthesis design: 40 years on

Abstract

The discipline of retrosynthetic analysis is now just over 40 years old. From the earliest day, attempts were made to incorporate this approach into computer programs to test the extent in which chemical perception and synthetic thinking could be formalized. Despite pioneering research efforts, computer‐aided synthetic analysis failed to achieve widespread routine use by chemists, which can be attributed in part to the difficulty of building the required high‐quality retrosynthetic transform databases required for credible analyses. However, with the advent over the past 25 years of large comprehensive reaction databases, work on successfully automating the construction of reliable and comprehensive reaction rule databases is promising to revitalize research in this field. This review compares and contrasts the diverse approaches taken by selected programs in both the design and implementation of molecule feature perception and reaction rule representation, and we review the concepts of synthetic strategy selection, representation, and execution. In particular, we discuss the current work on automating the construction of reliable and comprehensive synthetic rule sets from available reaction databases in newer programs such as ARChem. We argue that the progress achieved in this aspect paves the way to a deeper exploration of computer approaches to applying strategy and control in the synthesis problem. © 2011 John Wiley & Sons, Ltd. This article is categorized under: Computer and Information Science > Chemoinformatics

Implementation of Stereochemistry in Automatic Kinetic Model Generation

“…Despite the lack of tools for the automated construction of kinetic models that account for stereochemistry, many of the key components and algorithms are readily available and used in fields such as cheminformatics and computer‐aided synthesis design . Indeed, the conceptual problem of the synthetic design of organic chemicals by starting from the target molecule and working backward toward potential starting materials bears many similarities with the current problem of automatic kinetic model generation.…”

“…As such, this field has provided many of the solutions for handling stereochemistry ranging from algorithmic formulations to ready‐to‐use open‐source implementations . However, despite the similarities, tools for computer‐aided retrosynthetic analysis cannot readily be used for automatic kinetic model generation for a number of reasons. First, whereas synthesis design is concerned with the network of target molecules, intermediates and starting materials, automatic kinetic model generation also requires the quantification of properties associated with species and reactions, in the form of thermodynamic and kinetic parameters.…”

“…Second, the notion of reactions is not completely aligned in both application domains. In tools such as ARChem , reactions are considered transformations between isolable molecules and may comprise a series of steps with nonisolable intermediates. On the other hand, tools for the automatic construction of kinetic models focus on microkinetic models, solely consisting of elementary reactions.…”

Vernetzt geplant — Synthesedesign ohne Chemiker?

“…Auch andere Chemiker wie Ivar Ugi träumten von computerunterstützen Lösungen für die Syntheseplanung 5,6. Nach großen Hoffnungen und vielen weiteren Projekten wurde es in den letzten Jahren jedoch ruhig um das “künstliche Chemikergehirn” 7,8. Ein Problem stellte besonders bei den frühen Versuchen die Überführung von graphischen chemischen Strukturen in computerlesbare Formate dar.…”

Modeling Organic Chemistry and Planning Organic Synthesis

“…It is known that CAOS is more challenging than chess due to a very high branching factor. The reviews [50], [8] and [9] provide a detailed analysis of CAOS research.…”