The ubiquity of the piperazine-2,5-dione core (2,5-diketopiperazine, DKP) in
natural products and the preponderance of this heterocyclic framework in many bioactive
compounds have encouraged the development of methods for the selective functionalization
of readily available piperazine-2,5-dione substrates. C-functionalization using DKPs as
electrophilic glycine templates is generally mediated by N-acyliminium ions. These
intermediates show highly versatile reactivities, which are reflected in an impressive number
of synthetic applications. However, even in some highly comprehensive treatments of Nacyliminium
ions, references to the construction of these species on piperazine-2,5-dione
frameworks are scarce. The present review aims at filling this gap, placing emphasis upon the
construction of endocyclic and exocyclic acyliminium ions derived from piperazine-2,5-
diones and their synthetic applications. More complex structures that include this framework
as a structural fragment, such as pyrazino[1,2-b]isoquinoline-1,4-diones or pyrazino[2,1-
b]quinazoline-3,6-diones, are also overviewed.
Keywords: Piperazine-2, 5-dione, 2, 5-diketopiperazine, DKP, N-acyliminium
ions, privileged structures, dipeptide dimer, electrophilic glycine templates,
protein β-turn mimics, natural products, pyrazino[2, 1-b]quinazoline-3, 6-diones,
1, 5-imino-3-benzazocins, N-acetylardeemin, bicyclomycin, dragmacidin B,
phthalascidin analogs, antitumor tetrahydroisoquinoline alkaloids, trabectedin,
saframycins A and B, quinocarcin, meta- and para-2, 6- diazacyclophanes,
fumiquinazoline C, alantrypinone.
