Fundamentals of Medicinal Chemistry

Synthesis site Linker Primer (P) Tag site

(1) Gly Divide into two aliquots

(2) CACATG

Gly

(1) Met

(2) ACGGTA

(P)-CACATG Met (P)-ACGGTA

Mix and split into two aliquots

(P)-ACGGTAACGGTA

(P)-CACATGACGGTA

(1) Met

(2) ACGGTA

(1) Gly

(2) CACATG

Met-Met

Met-Gly

(P)-ACGGTACACATG

(P)-CACATGCACATG

Gly-Met

Gly-Gly

Mix and split into two aliquots and

repeat the previous processes until

the required library is obtained.

Figure 6.11 The use of oligonucleotides to encode a peptide combinatorial synthesis for a library

based on two building blocks

CH 2 O−C

O

Cl

B^1 NH NHCOOCH 2 OCH 3

B^1 NH NHP^1

Repeat this sequence of deprotecting and

coupling as appropriate in the mix and split

procedure

CH 2 OCONH NHCOOCH 2 OCH 3

C OCH 2 OCH 3

O

Cl

9-fluorenylmethoxy

chloroformate Acid labile Moz protecting group

(1) Acidic Moz cleavage.

(2) Peptide tag (P^1 ) coupling.

P^1 is suitably protected.

Base labile Fmoc protecting group

(1) Basic Fmoc cleavage.

(2) Building block (B^1 ) coupling.

B^1 is suitably protected, if

necessary.

4-methoxybenzyloxy

chloroformate

NH 2 −

−NH 2

Figure 6.12 An outline of the Zuckermann approach using peptides for encoding

the synthesis all the tags are detached from the linker and are detected by GC.

The gas chromatogram is read like a bar code to account for the history of the

bead. Suppose, for example, that the formation of a tripeptide using six aryl

ENCODING METHODS 125