Nonoligomeric library

Nonoligomeric libraries. Peptide and peptoid libraries are examples of oligomeric (polymeric) libraries made up of repeating monomers (a-amino acids, A-substitutcd glycines). Random libraries composed of nonoligomeric compounds have been extensively explored. One illustration comes from the former laboratories at Organon (Fig. 1.6) (16). Thirteen different secondary amino-phenol inputs were attached to solid support by reaction with REM resin yielding resin-bound b-amino propionates. Two-site derivatization was then used to drive library diversity. The free phenolic OH was subjected to O-alkylation,... 

O-acylation, O-sulfanylation, O-triflation/Suzuki coupling followed by N-quaternization (six inputs) and Hofmann elimination to release a 3,042-member library of tertiary amino aryls. One advantage of small-molecule nonoligomeric libraries... 

Fig. 1.6. Nonoligomeric library (reprinted ( adapted or in part ) with permission from Journal of the American Chemical Society. Copyright 2002 American Chemical Society).

Molecular tags overcome the chemical sensitivity and orthogonal protection required by both peptide and oligonucleotide encoding. Two such methods have been developed and applied to the synthesis of both peptide and nonoligomeric libraries. One of these [34] approaches uses chemically robust haloaromatic tags which are used in a binary encoding... 

Pirrung, M.C., Chau, J.H.-L., and Chen, J., Indexed combinatorial libraries nonoligomeric chemical diversity for the discovery of novel enzyme inhibitors, in Combinatorial Chemistry, Wilson, S.R. and Czarnik, A.W., Eds., Wiley, New York, 1997, pp. 191-206. 

Bartlett proposed some early guidelines for library synthesis (a) The sequence should involve a small number of steps, (b) no more than one variable should be introduced in any step, (c) starting materials should be readily obtained with a diverse selection of substituents, and (d) cyclic, nonoligomeric structures represent the most interesting targets [18]. Furthermore, Armstrong did some early work toward libraries composed of multiple scaffolds, derived from common synthetic intermediates [19, 20]. In one case, Ugi multicomponent coupling reaction products were converted to various linear and cyclic derivatives (Fig. 9.1-4(a)). In another, squaric acid was proposed as a precursor that could be converted to multiple cyclic and polycyclic products (Fig. 9.1-4(b)) and several such transformations were demonstrated. 

The selected example, by Baldwin et al. [36], showed the application of this technique to a small-molecule, nonoligomeric, large organic library of dihydrobenzopyrans (six steps over 85,000 members). The synthetic scheme for some among the prepared sublibraries is reported in Figure 10. The first monomer set (seven amines) was condensed in solution to a bromophotolinker, then the construct was hooked onto TentaGel amino resin (step A). After TFA deprotection, the resin-bound secondary amines were coupled to the second monomer set (two subsets, six carboxylic acids, step B), prepared by condensa-... 

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