2,5-Piperazinediones dipeptide esters

It is well known that derivatives of a-amino acids, especially the esters, can undergo cyclodimerization to form piperazine-2,5-diones. The stereochemistry of such self-condensation of initial stages but increasing amounts of the trans product were formed later. The results have been interpreted as reflecting the difference in the rates of cyclization of the two diastereomeric dipeptide esters. 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

JC Purdie, NL Benoiton. Piperazinedione formation from esters of dipeptides containing glycine, alanine and sarcosine the kinetics in aqueous solution. J Chem Soc Perk Trans 2, 1845, 1973. 

Cyclization of the dipeptide and cyclol formation can be carried out in a single step (90MI1). The substrate in this case was the p-nitrophenyl ester (-ONp) of A-salicyloylphenylalanylproline. Treatment of this active ester (55) in benzene solution with DBU gave the oxacyclol (56) in 40% yield. It has been shown that this involves cyclization to the piperazinedione, epimerization of the proline C—aH and then cyclol formation. The l3C-NMR spectrum of the product shows only two carbonyl signals in addition, there is a signal at 102.38 ascribed to the quaternary carbon... 

Sterically pure piperazinediones have been prepared from formate salts of dipeptide methyl esters (1622). The conformation of piperazine-2,5-diones has been reviewed (1623). 

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