Table 6.1 A comparison of the advantages and disadvantages of the solid support and in solution
techniques of combinatorial chemistry
On a solid support In solution
Reagents can be used in excess in order to drive
the reaction to completion
Reagents cannot be used in excess, unless
addition purification is carried outPurification is easy: simply wash the support Purification can be difficult
Automation is easy Automation is difficult
Fewer suitable reactions In theory any organic reaction can be used
Scale-up relatively expensive Scale-up is easy and relatively inexpensive
Not well documented and time will be required
to find a suitable support and linker for a
specific synthesis
Only requires time for the development of the
chemistry6.2 The solid support method
The solid support method originated with Merrifields solid support peptide syn-
thesis.Itusesresinbeadsthathavealargenumberoffunctionalgroupsattachedto
the surface by a variety of structures known as either ahandleor alinker(Figure
6.4). Each of these functional groups acts as the starting point for the synthesis of
one molecule of a product. Since a bead will possess in the order of 6 103
functional groups of the same type the amount of the product formed on one
beadisoftensufficientforstructuredeterminationandhighthroughputscreening.
Resin
beadLinkerFunctional
group Synthesis is carried
out at this siteFigure 6.4 A schematic representation of the resin beads used in combinatorial synthesisThe linker moves the point of substrate attachment away from the surface of
the bead. This has the effect of reducing steric hindrance, thereby making reaction
easier. The choice of linker will depend on the nature of the reactions used in the
proposed synthetic pathway (Figure 6.5). For example, an acid labile linker, such
as HMP (hydroxymethylphenoxy resin), would not be suitable if the reaction
pathway contained reactions that were conducted under strongly acidic condi-
tions. Consideration must also be given to the ease of detaching the product from
the linker at the end of the synthesis. The method employed must not damage the
required product but must also lend itself to automation.
In 1985 Houghton introduced histea bagmethod for the rapid solid phase
multiple peptide synthesis. In this technique the beads are contained within a
porous polypropylene bag. All the reactions, including deprotections, are
THE SOLID SUPPORT METHOD 117