Compound libraries substitutional diversity

One type of oligoamide that can readily be prepared on supports without the need for any partially protected monomers (which are often tedious and expensive to synthesize) are N-substituted oligoglycines (Figure 16.21). These compounds are prepared by a sequence of acylation of a support-bound amine with bromoacetic acid, displacement of the bromide with a primary aliphatic or aromatic amine, and repeated acylation with bromoacetic acid. Because primary amines are cheap and available in large number, this approach enables the cost-efficient production of large, diverse compound libraries. Alternatively, protected N-substituted glycines can also be prepared in solution and then assembled on insoluble supports (Entry 5, Table 16.2). 

Scheme 3.22 Fluorous synthesis of a library of substituted quinazoline-2,4-diones (46) [22]. The key to this approach is a fluorous benzyloxycarbonyl group on which the target molecules are stepwise constructed and which keeps the different synthetic intermediates bound to fluorous reversed-phase silica gel (FRPSG) during the purification cycles. The structural diversity of the target compound library (46) is introduced by the different anthranilic acid derivatives and primary amines in boxes) (TBTU = 0-(benzotriazol-1-yl)-N,/ /,N, N -tetramethyluronium tetrafluoroborate).

The diversity of chemical libraries may derive from the high substitutional, stereochemical and scaffold diversity of its members. Combinatorial chemistry is focused on the synthesis of chemical libraries with only high substitutional diversity. In general, combinatorial syntheses exploit a rather limited palette of chemical transformations to vary the substitution of library members. The synthesis of compound libraries with high substitutional diversity is described in Section 1.2.1. 

Varying the configuration of library members is more challenging, but has been hugely facilitated by the many reliable asymmetric transformations that have been developed in the past 30 years. In many cases, the high enantio-selectivity of these transformations can dominate over substrate-based dia-stereoselectivity, and allow the configuration of compounds to be varied systematically. The synthesis of a compound library with both high substitutional and stereochemical diversity is described in Section 1.2.2. 

Synthesis of Compound Libraries with High Substitutional Diversity... 

The decoration of a central scaffold is illustrated by the triazine library Lll reported by Gustafson et al. (46) where trichlorotriazine was sequentially substituted with anilines (Ar), primary aliphatic amines (Ri), and secondary aliphatic amines (R2,3). The library, made up of 20 x 16 x 20 = 12,800 compounds, was prepared as discretes (Fig. 4.12) and used as a primary library to be screened on various assays. The introduction of sugars, dipeptides, and a-ketoamides among other amine substituents in Lll created diversity in the components even though each of them shares a common 2,4,6-triaminotriazine scaffold. Examples of individuals from LI 1 are provided in Fig. 4.12. Such a decoration library can be made when a suitable scaffold is available in large amounts, either commercially or through a simple synthetic route. Constrained... 

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