Mixture-based synthetic combinatorial resin mixtures

Two major techniques are generally employed in solid-phase chemistry to generate mixture-based synthetic combinatorial libraries (SCL) of millions of compounds. Multiple functionalities at diverse positions within the library are incorporated either by mixing multiple resins or by using mixtures of incoming reagents. 

The synthetic utility of ion exchange resins in combinatorial chemistry has been demonstrated by the use of a basic polymeric base PTBD (l,5,7-triazabicydo[4.4.0]dec-5-ene) 26 in a series of O- and N-alkylation experiments (Scheme 7) [15]. For example, deprotonation of the phenol 27 with this polymeric base PTBD 26 gave the ionic polymeric species 28 which contained the more nucleophilic phenolate. Addition of the 2-bromo aryl ketone 29 gave the aryl ether 30 in reasonable yield and in high purity (Scheme 7). The basic polymeric scavenger PTBD 26 removed all the unwanted HBr produced within the reaction mixture (in the form of 31) and advantageously eliminated the need for an aqueous extractive work-up procedure. 

If combinatorial libraries consist of compound mixtures (e.g., after cleavage from the resin beads), a reliable analytical characterization is difficult. In this case the utilization of mass spectrometry for analysis is based on the prediction of mass distribution of the library. Computer-generated distribution profiles can be compared with the actual profile obtained from the compound library [93,94]. Evaluation of mass distribution detects synthetic problems based on incomplete coupling (shift toward lower molecular masses), incomplete deprotection, or unwanted library modification, such as oxidation, acylation, or alkylation (shift toward higher molecular masses). However, for a larger library of compound mixtures many different compounds will have the same molecular mass. This greatly complicates structural determination and even makes it impossible at a certain mixture complexity. 

Some of the early examples of libraries yielding receptor agonists and antagonists were peptide-based. Houghten, Dooley and co-workers introduced synthetic peptide combinatorial libraries (SPCLs) in which defined mixtures of peptides were synthesized, cleaved from resin and assayed free in solution against either soluble (enzyme) or membrane associated (re-... 

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