Fundamentals of Medicinal Chemistry

Resin beads

B C

B

A

A

D

The bonding of the

initial building blocks

to the resin beads.

Step ONE in the

synthetic pathway.

E F

A−D

B−D

C−D

G H

A−D−G

B−D−G

C−D−G

A−E−H

B−E−H

C−E−H

COMBINE, MIX and SPLIT into three new portions.

COMBINE, MIX and SPLIT into three new portions.

I

A−E−G

B−E−G

C−E−G

A−F−I

B−F−I

C−F−I

A−F−G

B−F−G

C−F−G

A−F−H

B−F−H

C−F−H

A−D−H

B−D−H

C−D−H

A−E−I

B−E−I

C−E−I

A−D−I

B−D−I

C−D−I

StepTWO in the

synthetic pathway.

C

A−E

B−E

C−E

A−F

B−F

C−F

Figure 6.9 An example of the Furka approach to combinatorial libraries using a two step

synthesis involving three building blocks at each stage

that can be synthesized for a given number of different building blocks (b)is

given by:

number of compounds¼b

x

(6:1)

wherexis the number of steps in the synthesis.

Unlike in parallel synthesis the history of the bead cannot be traced from a

grid reference; it has to be traced using a suitable encoding method (see section

6.3) or deconvolution (see section 6.5). Encoding methods use a code to indicate

what has happened at each step in the synthesis. They range from putting an

identifiable tag compound on to the bead at each step in the synthesis to using

computer readable silicon chips as the solid support. If sufficient compound is

produced its identity may also be confirmed using a combination of analytical

methods such as NMR, MS, HPLC and GC.

122 COMBINATORIAL CHEMISTRY