Once the structure of a lead has been decided it is necessary to design a synthetic pathway to produce that lead. These pathways may be broadly classified as either partial or full synthetic routes.
- The partial synthetic pathways use biochemical and other methods to produce the initial starting materials and traditional organic synthesis to convert these compounds to the target structure.
- The full synthetic routes start with readily available compounds, both synthetic and naturally occurring, but only utilize the standard methods of organic synthesis to produce the desired product.
The chemical reactions selected for the proposed synthetic pathway will obviously depend on the structure of the target compound. However, a number of general considerations need to be borne in mind when selecting these reactions:
- The yields of reactions should be high. This is particularly important when the synthetic pathway involves a large number of steps.
- The products should be relatively easy to isolate purify and identify.
- Reactions should be stereospecific, as it is often difficult and expensive to separate enantiomers. This is a condition that is often difficult to satisfy.
- The reactions used in the research stage of the synthesis should be adaptable to large scale production methods.
Ideally, the chosen route should be such that it is relatively easy to modify the structure of the lead compound either directly or during the course of its synthesis. This is an economic way of producing a greater range of analogues for testing and hence increasing the chance of discovering an active compound.
Asymmetry in syntheses
The presence of asymmetric center or centers in a target structure means that its synthesis requires either the use of non-stereoselective reactions and the separation of the resulting stereoisomers or the use of stereoselective reactions that mainly produce one of the possible enantiomers. This section introduces some of the general methods used to incorporate stereospecific centers into a target molecule.
Designing organic syntheses
The synthetic pathway for a drug or analogue must start with readily available materials and convert them by a series of inexpensive reactions into the target compound. There are no obvious routes as each compound will present a different challenge. The usual approach is to work back from the target structure in a series of steps until cheap commercially available materials are found. In all cases the final pathway should contain a minimum of stages, in order to keep costs to a minimum and overall yields to a maximum.
This approach starts with the target structure and then works backwards by artificially cutting the target structure into sections known as synthons. Each of these backward steps is represented by a double shafted arrow (¼)) whilst is drawn through the disconnected bond of the target structure. Each of the possible synthons is converted on paper into a real compound known as a reagent, whose structure is similar to that of the synthon.
All the possible disconnection routes must be considered. The disconnection selected for a step in the pathway is the one that gives rise to the best reagents for a reconnection reaction. This analysis is repeated with the reagents of each disconnection step until readily available starting materials are obtained. The selection of the reagents and the reactions for their reconnection may require extensive literature searches.
In the disconnection approach, bonds are usually disconnected by either homolytic or heterolytic fission. However, some bonds may be disconnected by a reverse pericyclic mechanism.