Library piperazinediones

Gordon DW, Steele J, Reductive alkylation on a solid phase synthesis of a piperazinedione combinatorial library, Bioorg. Med. Chem. Lett., 5 47-50, 1995. 

Other recent repiorts of the automated synthesis of SP libraries of discretes include those of Wilson et al. (166), who prepared a library of more than 1000 aminohydantoins from a-hydrazino amino acids, amines, and aldehydes Perumattam et al. (167), who reported a 200-member library based on an anhydride template using anhydrides, primary amines, and a-amino acids Smith et al. (168), who described the synthesis of a library of more than 1000 piperazinediones from a-amino acids Crawshaw et al. (169), who presented a >200-member Ubrary of cyclohexanones from maleimides, nitrostyrenes, and aminobutadienes Shao et al. (170), who described a 96-member library of quina-zolinediones from anhydrides and amines Lebl et al. (21), presenting a 30,816-member... 

Werner S, Nielsen SD, Wipf P et al (2009) Eluorous parallel synthesis of a piperazinedione-fused tricyclic compound library. J Comb Chem 11 452-459... 

The method of piperazinedione synthesis [119] illustrated above (Scheme 22) is an example of scaffold proliferation by branching out from common intermediate structures ( divergent library design ). Resin-bound bromides such as 97 are suitable for bromine displacement with primary amines to obtain acyclic precursors of piperazinediones, but direct treatment with TFA also induces cycliza-tion, providing an efficient route to analogous morpholine derivatives. The intramolecular displacement of bromine by the carboxylate seems to occur in the cleavage solution, once the acyclic intermediate has been released from the solid support. 

Depending on the reaction conditions, a-iminodicarboxylic acid derivatives or 2,6-di-piperazinediones [120] are formed from a-amino acids, oxocompounds and isocyanides. The isomeric 2,4-piperazinediones can thus also be formed by some of the U-4CR of vicinal diamines, isocyanides, oxocompounds and glyoxylic monoesters [121,122],The libraries of highly substituted 2-piperazones were produced by the chemists of Merck Inc. from N-monosubstituted ethylenediamines, carboxylic acids, isocyanides and chloroacetalde-hyde. 

Figure 2 Generic piperazinedione library and fiiree specific molecules within the library that we might in principle wish to reject for various reasons...

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