Page 1279 - Advanced Organic Chemistry Part B - Reactions & Synthesis

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SECTION 13.4
Combinatorial Synthesis

Fig. 13.2. Use of chemical tags to encode the sequence in a combinatorial synthesis
on a solid support. Reproduced from W. C. Still, Acc. Chem. Res., 29, 155 (1996),
by permission of the American Chemical Society.

as illustrated in Figure 13.2. 62 After each combinatorial step, a different chemical tag
is applied to each of the splits before they are recombined. The tags used for this
approach are a series of chlorinated aromatic ethers that can be detected and identified
by mass spectrometry. The tags are attached to the polymer support by a Rh-catalyzed
carbenoid insertion reaction. Detachment is done by oxidizing the methoxyphenyl
linker with CAN. Any bead that shows interesting biological activity can then be
identified by analyzing the code provided by the chemical tags for that particular bead.

Cl m
N CHC (CH ) O
2 n
2
n = 2–11
m = 2–5

Combinatorial approaches can be applied to the synthesis of any type of molecule
that can be built up from a sequence of individual components, for example, in reactions
forming heterocyclic rings. 63 The equations below represent an approach to preparing
differentially substituted indoles.

62 H. P. Nestler, P. A. Bartlett, and W. C. Still, J. Org. Chem., 59, 4723 (1994); C. Barnes, R. H. Scott,
and S. Babasubramanian, Recent Res. Develop. Org. Chem., 2, 367 (1998).
63
A. Netzi, J. M. Ostresh, and R. A. Houghten, Chem. Rev., 97, 449 (1997).