Diketopiperazines via Backbone Amide Linker BAL

Linker attachment An amino-functionalized polystyrene or PEG-polystyrene resin may be used as starting material. First, 5-(4-formyl-3,5-dimethoxyphe-noxy)valeric acid (PALdehyde) [122] (4equiv.) and HATU [123] (4equiv.) were dissolved in DMF, DIEA (8 equiv.) was then added, and, after 1 min of pre-activation, this solution was added to the resin (1 equiv.). Coupling was allowed to proceed at 25 °C for 2 h, after which the Kaiser ninhydrin test [81] was negative. 

General procedure A mixture of the requisite amino acid methyl ester hydrochloride (10 equiv.) and NaBHsCN (10 equiv.) in DMF was added to the PALdehyde resin 88 (1 equiv.). The reaction was allowed to proceed for 1 h at 25 °C, after which the resin was washed with CH2CI2 and MeOH, and finally 

The trisubstituted diketopiperazine 91 was cleaved and released into solution by treatment with TFA/H2O (9 1) for 2 h and then isolated from the eluate and the combined washes by using appropriate solvents to solubilize the product 

Ertketopiperazine libraries prepared according to the above scheme are suitable for both on- and off-resin screening. The heterocycle formation occurs while the product is grafted on the soHd support, whereas alternative schemes described in the literature [118, 119] involve cyclative cleavage, with ring formation leading to concomitant release of the product into solution. 

The described chemistry has also been successfully applied for amino acid esters other than methyl esters. Ring formation rates and yields with methyl, aUyl, and benzyl esters were shown to be very similar. 

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