Fundamentals of Medicinal Chemistry

Wells contain the

reagent

Pin

(b) Pin and well grid arrays

The grid consists of

an array of wells

sunk in a plastic plate

Beads and

reagents

(a) Simple well grid array

Crown, to which

are attached the

linkers

Figure 6.6 Examples of the arrays used in combinatorial chemical synthesis

plastic ‘crowns’ pushed on to the tops of the pins, the building blocks being

attached to these crowns by linkers similar to those found on the resin beads.

The position of each synthetic pathway in the array and hence the structure of

the product of that pathway is usually identified by a grid code.

The technique of parallel synthesis is best illustrated by means of an example.

Consider the general theoretical steps that would be necessary for the prepar-

ation of a combinatorial library of hydantoins by the reaction of isocyanates

with amino acids (Figure 6.7) using a 96 well array.

Eight N-protected amino acids (X1, X2,... X8) are placed in the well array so

that only one type of amino acid occupies a row, that is row A will only contain

amino acid X1, row B will only contain amino acid X2 and so on (Figure

6.8(a) ). Beads are added to each well and the array placed in a reaction environ-

ment that will join the X compound to the linker of the bead. The amino acids

are deprotected by hydrogenolysis and 12 isocyanates (Y1, Y2,... , Y8) added

to the wells so that each numbered row at right angles to the lettered rows

contains only one type of isocyanate. In other words, compound Y1 is only

added to row one, compound Y2 is only added to row two and so on (Figure

6.8(b) ). The isocyanates are allowed to react to form substituted ureas, which

R^1 R^1 R^1

R^2 R^2 R^2

TFA

or

Piperidine

OCOCNH 2

R^3 NCO

OCOCNHCONHR^3

HCl

Heat

OCOCNHBOC

R^1

R^2

R^3

O N O

H

N

Resin

bead

Key: BOC = PhCH 2 OCO−

A substituted urea Hydantoins

Figure 6.7 The reaction of amino acids with isocyanates to form hydantoins

THE SOLID SUPPORT METHOD 119