Fundamentals of Medicinal Chemistry

The Wang linker for

carboxylic acids

O

C

O

Cl Amines O

C

O

Amine

TFA Final product

A benzyloxycarbonyl chloride

linker for amines

O ROH O O OR TFA

O Final product

The tetrahydropyranyl (THP)

linker for alcohols

O O O

R

OH C

O

RCOOH TFA Final

product

Figure 6.5 Examples of linkers that use trifluoroacetic acid (TFA) to detach the final product

carried out by placing the bags in solutions containing the appropriate reagents.

The use of the bag makes it easy to purify the resin beads by washing with the

appropriate solutions. Furthermore, the method has considerable flexibility and

has been partly automated.

Combinatorial synthesis on solid supports is usually carried out by using

either the parallel synthesis (see section 6.2.1) or the Furka split and mix

procedures (see section 6.2.2). The precise method and approach adopted

when using these methods will depend on the nature of the combinatorial library

being produced and also the objectives of the investigating team. However, in all

cases it is necessary to determine the structures of the components of the library

by either keeping a detailed record of the steps involved in the synthesis or

giving beads a label that can be decoded to give the structure of the compound

attached to that bead (see section 6.3). The method adopted to identify the

components of the library will depend on the nature of the synthesis.

6.2.1 Parallel synthesis

In parallel synthesis the compounds are prepared in separate reaction vessels but

at the same time, that is, in parallel. The array of individual reaction vessels

often takes the form of either a grid of wells in a plastic plate or a grid of plastic

rods called pins attached to a plastic base plate (Figure 6.6) that fits into a

corresponding set of wells. In the former case the synthesis is carried out on

beads placed in the wells whilst in the latter case it takes place on so called

118 COMBINATORIAL CHEMISTRY