2,5-Diketopiperazines are typically prepared by one of three methods:
amide bond formation,
N-
alkylation and
C-
acylation.
Amide bond formation Most commonly 2,5-diketopiperazines are generated by cyclisation of dipeptides. In addition to the many methods of
peptide synthesis, the
Ugi reaction can be applied.
Dipeptides with an ester terminus spontaneously cyclize often.
Racemization can be problematic. The Ugi reaction using an isonitrile, amino acid,
aldehyde and amine, can produce a dipeptide in equally high yield and optical purity, to that formed by standard peptide couplings. Commonly, an isonitrile is chosen to give a labile terminal amide to enable cyclization. For example, the direct 2,5-DKP ring formation via such an activated leaving group using the stable, easily accessible and versatile convertible isonitrile 1-isocyano-2-(2,2-dimethoxyethyl)-benzene
4 gave a one-pot synthesis of N-substituted 2,5-diketopiperazine's
7. The mild acidic and
chemoselective post Ugi activation of
5 involving simultaneous indolamide formation and tert-butoxycarbonyl (Boc) removal gives the active amide
6 which allows cyclization to
7 without affecting other peptidic or even ester moieties and with
stereochemical retention of the
chiral centers.
N-Alkylation Intramolecular amide
N-alkylation of
alpha-haloacetamide amides
8 with ethanolic
potassium hydroxide using
ultrasonication gave the 2,5-diketopiperazines
9, where
8 was obtained by an Ugi reaction between amines, aldehydes, isocyanides, and
chloroacetic acid. However this route is limited by epimerization at the stereogenic centre and failure to obtain the 2,5-diketopiperazine ring if R1 = Alkyl.
C-Acylation Formation of the 2,5-diketopiperazine ring by
enolate acylation was used in the construction of the 2,5-diketopiperazine ring in
11 by intramolecular cyclization of the enolate of
10 onto the carbonyl of the phenyl
carbamate to give
11 in 90% yield. ==Reactions==