is a technique for solving problems in the planning of organic syntheses
. This is achieved by transforming a target molecule into simpler precursor structures without assumptions regarding starting materials. Each precursor material is examined using the same method. This procedure is repeated until simple or commercially available structures are reached. E.J. Corey
formalized this concept in his book The Logic of Chemical Synthesis
The power of retrosynthetic analysis becomes evident in the design of a synthesis. The goal of retrosynthetic analysis is structural simplification. Often, a synthesis will have more than one possible synthetic routes. Retrosynthesis is well suited for discovering different synthetic routes and comparing them in a logical and straightfoward fashion.
Disconnection: A retrosynthetic step involving the breaking of a bond to form two (or more) synthons.Retron: A minimal molecular substructure that enables certain transformations.Retrosynthetic tree: A directed acyclic graph
of several (or all) possible retrosyntheses of a single target.Synthon
: An idealized molecular fragment. A synthon and the corresponding commercially available synthetic equivalent
are shown below:
Target: The desired final compound.Transform: The exact reverse of a synthetic reaction; the formation of starting materials from a single product.
An example will allow the concept of retrosynthetic analysis to be easily understood.
In planning the synthesis of phenylacetic acid, two synthons are identified. A nucleophilic "-COOH" group, and an electrophilic "PhCH2+" group. Of course, both synthons do not exist per se; synthetic equivalents corresponding to the synthons are reacted to produce the desired product. In this case, the cyanide anion is the synthetic equivalent for the -COOH synthon, while benzyl bromide is the synthetic equivalent for the benzyl synthon.
The synthesis of phenylacetic acid determined by retrosynthetic analysis is thus:
- PhCH2Br + NaCN → PhCH2CN + NaBr
- PhCH2CN + 2 H2O → PhCH2COOH + NH3
Manipulation of functional groups can lead to significant reductions in molecular complexity.
Numerous chemical targets have distinct stereochemical demands. Stereochemical transformations (such as the Claisen rearrangement
and Mitsunobu reaction
) can remove or transfer the desired chirality thus simplifying the target.
Directing a synthesis toward a desirable intermediate can greatly narrow the focus of an analysis. This allows bidirectional search techniques.
The application of transformations to retrosynthetic analysis can lead to powerful reductions in molecular complexity. Unfortunately, powerful transform-based retrons are rarely present in complex molecules, and additional synthetic steps are often needed to establish their presence.
The identification one or more key bond disconnections may lead to the identification of key substructures or difficult to identify rearrangement transformations.
- Disconnections that preserve ring structures are encouraged.
- Disconnections that create rings larger than 7 members are discouraged.