Retrosynthetic Search

Structure-goal strategies—directed at the structure of a potential intermediate or potential starting material. Such a goal greatly narrows a retrosynthetic search and allows the application of bidirectional search techniques. 

Structure-goal Strategy. The use of a particular structure corresponding to a potentially available starting material or synthetic intermediate as a guide for retrosynthetic search. 

Fig. 10. Forward and retrosynthetic search by formal reaction generators...

The values of reaction enthalpies in a forward search can be of use in predicting the products of a reaction the more exothermic a reaction, the more it should be preferred. The situation will be different in a retrosynthetic search where retroreactions should be calculated to be endothermic to some degree. This underlines the point previously made (Sect. 2, Fig. 9) that the differences between a forward and a retrosynthetic search do not reside in the way reactions are generated — in both cases in EROS by the formal reaction schemes — but in the way they are evaluated. 

Diels-Alder disconnection will have been eliminated, and the retrosynthetic search becomes highly focused. Having selected both the transform and the mapping onto the TGT, it is possible to sharpen the analysis in terms of potentially available dienophile or diene components, variants on the structure of the intermediate for Diels-Alder disconnection, tactics for ensuring stereocontrol and/or position control in the Diels-Alder addition, possible chiral control elements for enantioselective Diels-Alder reaction, etc. 

Up to version 3.2 of the EROS system the selection of the chemically interesting reactions was based on heuristic rules for finding the appropriate bonds that were to be submitted to the reaction schemes. Furthermore, for each reaction the enthalpy was calculated and this value was used for selecting the best pathways. Clearly, in the selection process a distinction has to be made between a forward and a retrosynthetic search. Thus, the value of the heat of reaction is used with different sign and weight in the selection process for the two types of search strategies. 

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