Centre for Molecular and Biomolecular Informatics Radboud University Nijmegen

Retrosynthetic analysis or retrosynthesis is a technique for solving problems in synthesis planning, especially those presented by complex structures. The retrosynthetic approach to synthesis planning was formulated explicitly for the first time by Corey. The purpose of retrosynthetic analysis (RA) is to transform the structure of a synthetic target molecule to simpler molecules. Hence, in RA reactions are viewed in the retrosynthetic direction, starting with the product of the reaction and going backwards to the reactants. The terminology used with RA, as opposed to synthesis, is summarized below.

Transforms or retro-reactions, are the imaginary counterparts of reactions. Each transform corresponds to a reaction, and vice versa, but of course it cannot be carried out in the laboratory; it is purely a thought process:

A transform, in this case the retrosynthetic counterpart of the aldol condensation.

Each reaction generates a characteristic structural element in the product, such as the enone resulting from the above Aldol condensation. This substructure, called the retron, must be present in a target to be able to apply the corresponding transform to that target.

Retrosynthetic analysis, then, consists of applying transforms to a given target, thereby generating all precursors from which that target can be made in a single step. The analysis can be repeated for each precursor, generating a second level of precursors:

Schematic depiction of a retrosynthetic tree.

It is possible that a transform generates a precursor actually consisting of two or more fragments, as in the case of a convergent step; these fragments can each be treated in the same way as single precursors. For clarity, multiple fragments are not showm. Further analysis can generate deeper levels of precursors. Each precursor generated can then be checked for availability, thus defining an endpoint for that line of analysis. The final result, a complete retrosynthetic tree, will contain all possible syntheses of the given target, reasonable and unreasonable, efficient and cumbersome ones. Of course, such a tree would be unmanageably large both for man and computer, even when the number of precursor levels is limited. The `combinatorial explosion', as this phenomenon is called, effectively prohibits the use of retrosynthetic analysis in such an unconstrained way. To keep the size of the retrosynthetic tree under control, a selection of transforms to be considered must be made. The guiding principles for this selection are called strategies.

Other topics:

• Analysis of Complex Synthetic Problems
• Terminology
• Retrosynthetic Strategies
• Goals and Subgoals
• Computer-Assisted Retrosynthetic Analysis

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