Library diketopiperazine

In another approach, 2,7,8-trisubstituted bicyclic diketopiperazine libraries were synthesized starting from piper-azinecarboxylic acid <2000TL4841, 2001W02001/046197>. 

Hulme C, Morrissette MM, Volz FA, Bums CJ (1998) The solution phase synthesis of diketopiperazine libraries via the Ugi reaction novel application of Armstrong s convertible isonitrile. Tetrahedron Lett 39(10) 1113-1116... 

Fig. 6. An early example of diketopiperazine library synthesis by Pfizer.

FIGURE 11.59 1,2,3,4-Tetrahydro-P-carboline-derived diketopiperazines library. (From Kundu, B., Solid-phase strategies for the design and synthesis of heterocyclic molecules of medicinal interest, Curr. Opin. Drug... 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

Szardenings AK, Antonenko V, Campbell DA, DeFrancisco N, Ida S, Shi L, Sharkov N, Tien D, Wang Y, Navre M (1999) Identification of highly selective inhibitors of collagenase-1 from combinatorial libraries of diketopiperazines. J Med Chem 42 1348-1357... 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

M. (1999) Identification of highly selective inhibitors of collagenase-1 from combinatorial libraries of diketopiperazines. / Med Cbem 42, 1348-1357. 

As illustrated by the examples in Table 15.30, diketopiperazines are amenable to many structural variations. These heterocycles thus seem to be well suited for the preparation of libraries for lead discovery, and have, for instance, been used for the identification of new enzyme inhibitors [368]. Libraries of diketopiperazines will, however, be sparsely diverse because the diketopiperazine ring itself is pharmacophore-rich , and will contribute significantly to the overall properties of all the members of the library (see Section 1.4). 

Among the six-membered ring heterocycles, diketopiperazines are most commonly prepared by cyclative cleavage. Indeed, diketopiperazine formation is often observed as an undesirable by-product during peptide synthesis20 and the facile nature of this cyclization makes it an obvious choice for library generation. In an early example from Pfizer,21 a set of 10 immobilized a-amino acids was reductively alkylated with 10 aldehydes, followed by acylation with 10 a-amino acids and cyclization (Fig. 6). By... 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

When the GC/MS analysis is done following a derivatization such as silylation, the differentiation of the two types of compounds is not simple because only a limited number of spectra for derivatized compounds is available. For example, in common mass spectral libraries (NBS, Wiley) only the spectrum of the TMS derivative of (non substituted) diketopiperazine is reported (see Figure 12.2.2) and not that of the corresponding imidazolindione. Therefore, not knowing the spectrum It is difficult to decide if certain imidazolindiones are present or not together with DKPs in the chromatograms of silylated pyrolysates of peptides. 

Different novel resin-bound isonitriles have been prepared in order to perform Ugi multicomponent reactions on the solid phase. Thus, Kennedy et al. [346] prepared a novel resin-bound carbonate convertible isonitrile (CCI) that was applied in the preparation of constrained 2,5-diketopiperazine and l,4-benzodiazepine-2,5-dione libraries in parallel 80-well format The first step of the synthetic strategy was a Ugi reaction with a wide variety of amines, aldehydes, and carboxylic acids. Further manipulations of the Ugi MCR products were achieved after basic cleavage from the resin. 

More recently, a novel resin-bound isonitrile has been reported to be suitable for synthesizing libraries of l,4-benzodiazepine-2,5-diones through Ugi multicomponent reactions [25]. The method produces solid-supported Ugi products, which are cleaved by base activation to form N-acyloxazolidone intermediates that can be further elaborated. The flexibility of the approach was demonstrated by an analogous preparation of 2,5-diketopiperazines by simply replacing the 2-aminobenzoyl building blocks with a-amino acids. 

Figure 1 Combinatorial libraries built around a benzodiazepine scaffold (left) and a diketopiperazine scaffold (right).

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