Page 1277 - Advanced Organic Chemistry Part B - Reactions & Synthesis

molecules by carrying out a synthetic sequence with several closely related starting 1253
materials and reactants. For example, if a linear three-step sequence is done with eight
related reactants at each step, a total of 4096 different products are obtained. The SECTION 13.4
product of each step is split into equal portions for the next series of reactions. Combinatorial Synthesis

Step 1 Step 2 Step 3
A (8) + B (8) A — B (64) A — B — C (512) A — B — C — D (4096)
C (8) D (8)

The objective of traditional multistep synthesis is the preparation of a single pure
compound, but combinatorial synthesis is designed to make many related molecules. 57
The purpose is often to have a large collection (library) of compounds for evaluation
of biological activity. A goal of combinatorial synthesis is structural diversity, that
is, systematic variation in subunits and substituents so as to explore the effect of a
range of structural entities. In this section, we consider examples of the application of
combinatorial methods to several kinds of compounds.
One approach to combinatorial synthesis is to carry out a series of conventional
reactions in parallel with one another. For example, a matrix of six starting materials,
each treated with eight different reactants will generate 48 reaction products. Splitting
each reaction mixture and using a different reactant for each portion can further
expand the number of final compounds. However, relatively little savings in effort is
achieved by running the reactions in parallel, since each product must be separately
isolated and purified. The reaction sequence below was used to create a 48-component
library by reacting six amines with each of eight epoxides. Several specific approaches
were used to improve the purity of the product and maximize the efficiency of the
process. First, the amines were monosilylated to minimize the potential for interference
from dialkylation of the amine. The purification process was also chosen to improve
efficiency. Since the desired products are basic, they are retained by acidic ion exchange
resins. The products were absorbed on the resin and nonbasic impurities were washed
out, followed by elution of the products by methanolic ammonia. 58
O purified by adsorption on 1
R 1 R 1 R 4 R OH
(CH 3 ) 3 SiX sulfonic acid ion exchange
R 2 C NHCH 2 CHR 4
R 2 C NH 2 R 2 C NHSi(CH 3 ) 3
resin, followed by elution
R 3 R 3 with methanolic ammonia R 3
A considerable improvement in efficiency can be achieved by solid phase
synthesis. 59 The first reactant is attached to a solid support through a linker group, as
was described for polypeptide and oligonucleotide synthesis. The individual reaction
steps are then conducted on the polymer-bound material. Use of solid phase method-
ology has several advantages. Excess reagents can be used to drive individual steps to
completion and obtain high yields. The purification after each step is also simplified,
since excess reagents and by-products are simply rinsed from the solid support. The
process can be automated, greatly reducing the manual effort required.
When solid phase synthesis is combined with sample splitting, there is a particu-
larly useful outcome. 60 The solid support can be used in the form of small beads, and
57
A. Furka, Drug Dev. Res., 36, 1 (1995).
58 A. J. Shuker, M. G. Siegel, D. P. Matthews, and L. O. Weigel, Tetrahedron Lett., 38, 6149 (1997).
59 A. R. Brown, P. H. H. Hermkens, H. C. J. Ottenheijm, and D. C. Rees, Synlett, 817 (1998).
60
A. Furka, F. Sebestyen, M. Asgedon, and G. Dibo, Int. J. Peptide Protein Res., 37, 487 (1991);
K. S. Lam, M. Lebl, and V. Krchnak, Chem. Rev., 97, 411 (1997).