Piperazinediones by Acid Cyclative Cleavage Method A, including Reductive Alkylation

Piperazinediones by Acid Cyclative Cleavage Method A, including Reductive Alkylation 

This method has been used for the preparation of a prototype combinatorial Hbrary of 1000 piperazinediones [118]. The key step of the experimental procedure is a reductive alkylation with sodium triacetoxyborohydride, which has been thoroughly validated for the solid-phase reaction format. 

Coupling A solution of the Boc-amino acid component (0.2 mmol, 1.1 equiv.) in CH2CI2 (0.5 mL, plus DMF as needed for solubilization) was added to the resin 92 obtained as described above (previously resuspended in CH2CI2 (3 mL)). A solution of PyBrOP (0.2 mmol, 1.1 equiv.) in CH2CI2 (0.5 mL) was added, followed by DIPEA (0.4 mmol, 2.2 equiv). The reaction mixture was stirred for 24 h and then filtered the resin was washed (DMF, H2O, THF) and dried, and the coupling process was repeated. 

Cleavage from the resin Resin 93 was suspended in TFA (1 mL) for 3 h with occasional agitation, then filtered off and washed with CH2CI2 (5 mL). The filtrate was concentrated, and the residue was redissolved in toluene and concentrated once more to remove any residual TFA. 

In this reaction, partial racemization of some homochiral amino acids was observed. In addition, the combination of a hindered amino acid and an electronically deactivated aldehyde may lead to low yields. Bis-alkylation side reactions of aliphatic aldehydes may generate 1-10% of tertiary amines. 

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