Fundamentals of Medicinal Chemistry

(b)The placement of the isocyanate building blocks Y1 to Y8

1 2 3 4 5 6 7 8 9

10

11

12

A X1 X1 X1 X1 X1 X1 X1 X1 X1 X1 X1 X1

B X2 X2 X2 X2 X2 X2 X2 X2 X2 X2 X2 X2

C X3 X3 X3 X3 X3 X3 X3 X3 X3 X3 X3 X3

D X4 X4 X4 X4 X4 X4 X4 X4 X4 X4 X4 X4

E X5 X5 X5 X5 X5 X5 X5 X5 X5 X5 X5 X5

F X6 X6 X6 X6 X6 X6 X6 X6 X6 X6 X6 X6

G X7 X7 X7 X7 X7 X7 X7 X7 X7 X7 X7 X7

H X8 X8 X8 X8 X8 X8 X8 X8 X8 X8 X8 X8

A B C D E F G H 1 X1−Y1 X2−Y1 X3−Y1 X4−Y1 X5−Y1 X6−Y1 X7−Y1 X8−Y1 2 X1−Y2 X2−Y2 X3−Y2 X4−Y2 X5−Y2 X6−Y2 X7−Y2 X8−Y2 3 X1−Y3 X2−Y3 X3−Y3 X4−Y3 X5−Y3 X6−Y3 X7−Y3 X8−Y3 4 X1−Y4 X2−Y4 X3−Y4 X4−Y4 X5−Y4 X6−Y4 X7−Y4 X8−Y4 5 X1−Y5 X2−Y5 X3−Y5 X4−Y5 X5−Y5 X6−Y5 X7−Y5 X8−Y5 6 X1−Y6 X2−Y6 X3−Y6 X4−Y6 X5−Y6 X6−Y6 X7−Y6 X8−Y6 7 X1−Y7 X2−Y7 X3−Y7 X4−Y7 X5−Y7 X6−Y7 X7−Y7 X8−Y7 8 X1−Y8 X2−Y8 X3−Y8 X4−Y8 X5−Y8 X6−Y8 X7−Y8 X8−Y8 9 X1−Y9 X2−Y9 X3−Y9 X4−Y9 X5−Y9 X6−Y9 X7−Y9 X8−Y9 10 X1−Y10 X2−Y10 X3−Y10X4−Y10 X5−Y10 X6−Y10 X7−Y10X8−Y10 11 X1−Y11 X2−Y11 X3−Y11X4−Y11 X5−Y11 X6−Y11 X7−Y11X8−Y11 12 X1−Y12 X2−Y12 X3−Y12X4−Y12 X5−Y12 X6−Y12 X7−Y12X8−Y12

Deprotection of the amino acid

(a)The placement of the first building blocks, the BOC protected amino acids X1 to X12 and their attachment to the resin

(c)Reaction, by placing the array in a suitable eaction environment, to form the substituted urea and subsequent treatment with hot 6M hydrochloric acid to form the hydantoins Z1 to Z96

The hydantoins Z1 to Z96

1 2 3 4 5 6 7 8 9

10 11 12

A Z1 Z9 Z17 Z25 Z33 Z41 Z49 Z57 Z65 Z73 Z81 Z89

B Z2 Z10 Z18 Z26 Z34 Z42 Z50 Z58 Z66 Z74 Z82 Z90

C Z3 Z11 Z19 Z27 Z35 Z43 Z51 Z59 Z67 Z75 Z83 Z91

D Z4 Z12 Z20 Z28 Z36 Z44 Z52 Z60 Z68 Z76 Z84 Z92

E Z5 Z13 Z21 Z29 Z37 Z45 Z53 Z61 Z69 Z77 Z85 Z93

F Z6 Z14 Z22 Z30 Z38 Z46 Z54 Z62 Z70 Z78 Z86 Z94

G Z7 Z15 Z23 Z31 Z39 Z47 Z55 Z63 Z71 Z79 Z87 Z95

H Z8 Z16 Z24 Z32 Z40 Z48 Z56 Z64 Z72 Z80 Z88 Z96

Figure 6.8 The pattern of well loading for the formation of a combinatorial library of 96 hydantoins

are attached to the beads via the linker. The array is washed with suitable

reagents to purify the ureas. Each well is treated with 6 M hydrochloric acid

and the whole array heated to simultaneously form the hydantoins and release

them from the resin. Although it is possible to simultaneously synthesize a total

of 96 different hydantoins (Z1–Z96, Figure 6.8(c) ) by this technique, in practice

it is likely that some of the reactions will be unsuccessful and a somewhat

smaller library of compounds would normally be obtained.

A well array combinatorial synthesis can consist of any number of stages.

Each stage is carried out in the general manner described for the previous

example. However, at each stage only either the numbered or lettered rows are

used, not both, unless a library of mixtures is required. Finally, the products are

liberatedfromtheresinbytheappropriatelinkercleavagereaction(seeFigure6.5)

120 COMBINATORIAL CHEMISTRY