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LETTER
letter
From Diketopiperazines to Hydantoins: An Unprecedented Rearrangement
Diketopiperazine–Hydantoin Rearrangement
Guilhem Chaubet, Guillaume Cazals, Aurélien Lebrun, Jean Martinez, Isabelle Parrot*
Institut des Biomolécules Max Mousseron IBMM UMR 5247 CNRS-Université Montpellier I-Université Montpellier II, Pl. E. Bataillon,
34095 Montpellier Cedex 5, France
Fax (+33)467144866; E-mail: isabelle.parrot@um2.fr
Received: 08.11.2013; Accepted after revision: 15.12.2013
from piperazine-tetrones (H. Wamhoff, 1981)11
Abstract: Bis-Boc-activated 2,5-diketopiperazines on reaction
with potassium hydroxide or sodium methoxide in dry tetrahydro-
furan led to Boc-protected hydantoins through an unprecedented
ring contraction. This rearrangement was applied to several mono-
substituted 2,5-diketopiperazines with good yields and regioselec-
tivity.
Me
N
Me
O
O
O
O
O
O
N
hν
O
THF–H2O
N
N
Me
Me
Key words: ring contraction, rearrangement, heterocycles, lac-
tams, amino acids
from dihydroorotic acid (M. Gütschow, 2003)12
O
R3
N
R1
R1
EtOH
R2
O
EtONa
R2HN
R3HN
N
Δ
NH
O
In the field of bioorganic chemistry, considerable atten-
tion has been paid to diketopiperazines (DKP)1,2 and
hydantoins3 as biologically active scaffolds, targets in
combinatorial chemistry for the discovery of lead struc-
tures, or motifs for building foldamers.4 Hydantoin and
DKP skeletons are used for adding or suppressing a meth-
ylene unit in analogues to affect their pharmacological
recognition and biological properties.5–7 The literature re-
veals a plethora of studies emphasizing the strong chemi-
cal and biological impact of both aza-heterocycles, raising
them to the status of ‘privileged scaffolds’ in medicinal
chemistry.8,9 Furthermore, Menéndez et al. recently clas-
sified DKP moieties as ‘privileged scaffolds in synthesis’
as critical starting materials for other heterocyclic sys-
tems.2 However, to the best of our knowledge, no mention
has been made of direct hydantoin synthesis from DKP re-
arrangement.
O
N
O
O
O
H
from aminobarbituric acid (I. G. Pojarlieff, 2004)13
O
O
R
HN
N
NH
HCl (aq)
O
O
N
OH
OH
O
Δ
R
OH
from DKPs (this work)
Boc
O
R
O
N
R
R
KOH
THF
N
N
O
R
N
O
Boc
O
Boc
Scheme 1 Six-to-five-membered ring rearrangements: access to hy-
dantoin skeletons
Hence, the N-tert-butoxycarbamate is no longer acting as
a protecting group but as an electrophilic activator of the
lactam function.18–20 More generally, it is well-known that
conversion of an amide moiety into its N-Boc derivative
leads selectively to the hydrolysis of the amide, with pres-
ervation of the N-Boc group, in the presence of a hydrox-
ide source.21,22
So far, the closest reactions described in literature are the
photorearrangement of 1,4-dimethylpiperazine-2,3,5,6-
tetrones to dimethylimidazolidinetriones,10 the aminobar-
bituric acid–hydantoin rearrangement11 and the transfor-
mation of dihydroorotic acid to hydantoinic acid12
(Scheme 1). We present in this study a simple and yet un-
precedented rearrangement allowing the synthesis of
functionalized hydantoins from suitable Boc-activated
2,5-diketopiperazines. The regio- and stereocontrol of the
reaction is also discussed.
While the weakly nucleophilic potassium tert-butoxide
acted on bis-Boc cyclo[Gly-Val] (1) as a strong base lead-
ing to the TRAL product, the use of a KOH suspension
initiated a different rearrangement, smoothly providing
the hydantoin 8.23 The ring-contracted product was isolat-
ed with an excellent yield and total regioselectively, but as
a mixture of enantiomers (S)-8 and (R)-8 with a modest
enantiomeric ratio (Table 1, entry 1).24
Boc-activated DKP were rarely considered as starting ma-
terials. They were essentially described as precursors of
peptidic pyrrolidines or as ring-contraction substrates
leading to pyrrolidine-2,4-dione systems via a transannu-
lar rearrangement of activated lactams (TRAL).13–17 The
reactivity of Boc-DKP centers around the conversion of a
lactam group into a more activated pseudo-imide moiety.
A simple acid–base extraction of the crude reaction mix-
ture allowed the clean separation of hydantoins 8 from the
unreacted DKP 1 which can then be recycled to provide a
quantitative yield.
SYNLETT 2014, 25, 0574–0578
Advanced online publication: 29.01.2014
DOI: 10.1055/s-0033-1340622; Art ID: ST-2013-D1040-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
As expected, reproducible results were observed with the
enantiomer 2 (Table 1, entry 2), which permitted us to de-
Chaubet, Guilhem
