Amides, solution-phase combinatorial libraries

The earliest report of a solution-phase combinatorial library of small drug-like molecules was by Smith et al. [2], The reaction of 40 individual acid chlorides with an equimolar mixture of 40 nucleophiles (alcohols or amines) and of the individual nucleophiles with an equimolar mixture of the acid chlorides produced a library of 1600 amides and esters as pools of 40 compounds. The orthogonal design strategy determined that each possible product should appear in a unique pair of samples to allow the rapid identification of lead compounds after screening. 

Some recent reviews that thoroughly cover solution-phase combinatorial libraries are provided in references 2 and 38-45. Two examples will be described in details in the following sections and only a few recent reports will be cited here. Stewart et al. (46) have reported the preparation of a focused, 48-member phenothiazine amide... 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

Boger DL, Goldberg J, Satoh S, Ambroise Y, Cohen SB, Vogt PK, Non-amide based combinatorial libraries derived from N-Boc iminodiacetic acid Solution-phase synthesis of piperazinone libraries with activity against LEF-l//l-catenin-mediated transcription, Helv. Chim. Acta, 83 1825-1845, 2000. 

The reaction of an a-haloketone with thiourea gives rise to the 2-aminothiazole. This reaction has been used in a combinatorial approach for the synthesis of libraries of 2-aminothiazoles in excellent yields and purities first in the solution phase <1996BML1409> and then on a solid support using Rink amide MBHA, glycyl-Rink amide MBHA, and reductively aminated ArgoGel MB-CHO resins (Scheme 55) <1998JOG196>. 

This inexpensive scavenger can be prepared on a large scale and effectively eliminates excess acyl chlorides by simple aqueous extraction (Scheme 8.58). The desired compounds were isolated in high yield and purity, making this a versatile reagent for combinatorial solution-phase synthesis of amide libraries. 

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