Multi-purpose functionality for the structural elaboration of the piperazine-2,5-dione motif

Article abstract of DOI:10.1016/S0040-4039(02)02571-6

Mild methods for controlled C- and N-alkylation of 3-benzyloxycarbonylpiperazine-2,5-diones are reported. The benzyloxylcarbonyl substituent can also serve as latent functionality for N-acyliminium ion formation and subsequent trapping enables installation of new carbon and/or heteroatom substituents.

Full text of DOI:10.1016/S0040-4039(02)02571-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 263–265
Multi-purpose functionality for the structural elaboration of the
piperazine-2,5-dione motif
Christina L. L. Chai,* John A. Elix and Paul B. Huleatt
Department of Chemistry, The Faculties, Australian National University, Canberra, ACT 0200, Australia
Received 14 October 2002; accepted 8 November 2002
Abstract—Mild methods for controlled C- and N-alkylation of 3-benzyloxycarbonylpiperazine-2,5-diones are reported. The
benzyloxylcarbonyl substituent can also serve as latent functionality for N-acyliminium ion formation and subsequent trapping
enables installation of new carbon and/or heteroatom substituents. © 2002 Elsevier Science Ltd. All rights reserved.
The piperazine-2,5-dione motif is found in a number of
biologically active natural products.1 The structural
complexities of these natural products range from sim-
with Boc-sarcosine under standard peptide coupling
procedures (DCC/HOBt). The Boc group of the dipep-
tide was then cleaved using trifluoroacetic acid and
following a basic workup procedure, cyclization of the
dipeptide was induced thermally to give the piperazine-
2,5-dione 1. With this key piperazinedione in hand,
chemoselective N- or C-alkylation can be effected
depending on the alkylating conditions employed
(Scheme 1, Table 1).† For example, selective N-methyl-
ple
derivatives
of
piperazine-2,5-diones,
e.g.
phenylahistin2 to highly complex functionalized deriva-
tives e.g. scabrosin esters.3 In recent years, our studies
have identified the need to develop rapid and efficient
routes for the selective functionalization of piperazine-
diones. The successful application of existing method-
ologies for a-carbon functionalization via the
corresponding bromides is highly dependent on the
systems to be synthesized due to the influence of steric
and electronic factors.4 Other methods for a-carbon
functionalization, e.g. alkylation, rely on the generation
of the a-anion and this frequently requires the use of
strong bases and harsh reaction conditions.5 Mindful of
these problems, we sought to develop an alternative
multi-directional approach to the a-functionalisation of
the piperazine-2,5-dione ring.
Scheme 1. Reagents and conditions: Route A: For R=Me (i)
K2CO3, Me2SO4 (ii) K2CO3 or NaH, R%X; Route B: (i)
K2CO3, R%X (ii) NaH, RX.
Our plan involved the use of an alkoxycarbonyl group
as a temporary multi-purpose appendage on the piper-
azine-2,5-dione ring. Specifically, the alkoxycarbonyl
group will serve (i) to enhance reactivity of the a-car-
bon center (ii) to direct regioselectivity and (iii) to
enable the installation of carbon and/or heteroatom
substituents where desired.
Table 1.
Compound
R
R%
Yields (%)
2a
2b
2c
2d
2e
2f
Me
H
H
H
H
Me
Me
Ac
H
Me
Et
Bn
Allyl
Me
Bn
H
89
Quantitative
90
Quantitative
82
88
85
91
Thus, benzyloxycarbonylpiperazine-2,5-dione
readily synthesized following modifications of literature
1
was
procedures.6 Dibenzyl aminomalonate was coupled
2g
2h
Keywords: N-acyliminium ions; alkylations; amino acids and deriva-
tives; trapping reactions.
* Corresponding
author.
Fax:
+61-2-6125
0760;
e-mail:
† All new compounds gave satisfactory spectroscopic and analytical
data.
christina.chai@anu.edu.au
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02571-6

264
C. L. L. Chai et al. / Tetrahedron Letters 44 (2003) 263–265
Thus, in this manner, the benzyloxycarbonyl sub-
stituent activates the adjacent a-carbon position of the
piperazine-2,5-dione to alkylation and negates the use
of strong bases in proton abstraction. Efficient removal
of the benzyloxycarbonyl substituent via hydrogenoly-
sis then furnishes the corresponding 3-carboxypiper-
azine-2,5-dione 3. It should be noted that an
ethoxycarbonyl equivalent of 1 can be utilized in a
similar manner. In this case, saponification of the ethyl
ester gives access to the 3-carboxypiperazine-2,5-dione
3. With the 3-carboxypiperazine-2,5-dione 3 in hand,
thermal decarboxylation gives rise to the a-alkylated
piperazine-2,5-diones 4. This constitutes an overall syn-
thesis of N- and a-dialkylated piperazine-2,5-diones 4
from 3-benzyloxycarbonylpiperazine-2,5-dione 1.
Scheme 2. Reagents and conditions: (i) heat; (ii) for Y=OAc,
DIB, I2; for Y=OMe, DIB, I2 followed by MeOH; (iii) For
Z=SAc, AcSH; for Z=allyl, 1.1 equiv. BF3·OEt2, 5 equiv.
allylTMS; (iv) 1.1 equiv. BF3·OEt2.
The carboxy group of piperazine-2,5-dione 3 can also
serve as a masked functionality to other carbon and/or
heteroatom substituents. When carboxypiperazine-
diones of type 3 were treated with diacetoxyiodoben-
zene (DIB)/I2, acetoxy derivatives (5, Y=OAc) were
formed. Correspondingly reactions of piperazinedione 3
with DIB/I2 followed by addition of methanol led to
formation of the methoxy derivatives (5, Y=OMe)
(Scheme 2, Table 2). The formation of these oxygenated
derivatives under the reaction conditions above pre-
Table 2.
Compound
R
R%
Y
Z
Yields (%)
5a
5b
5c
5d
5e
6a
6b
6c
6d
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
Me
Me
Bn
H
H
Me
Me
OMe
OAc
OMe
OAc
OAc
–
–
–
–
–
–
–
–
76
83
77
55
74
74
68
80
66
sumably occurs via
a
DIB promoted radical
decarboxylation7 to give the intermediate a-carbon cen-
tered radical of the piperazinedione. In the presence of
DIB, the radical is oxidized to the N-acyliminium ion
which is then trapped by nucleophiles present in the
reaction mixture.
–
SAc
Allyl
SAc
Allyl
The oxygenated piperazine-2,5-dione derivatives 5 (Y=
OAc, OMe) can be readily converted to the N-
acyliminium ion. In trapping this highly reactive species
with a variety of nucleophiles the synthetic potential of
these systems is realized.8 For example, treatment of 5a
(R=Me, R%=H, Y=OMe) with BF3·OEt2, in the pres-
ence allyltrimethylsilane gave the corresponding allyl
compound 6b in 68% yield, Table 2. Alternatively, in
the absence of a nucleophile the N-acyliminium ion
undergoes rearrangement to the ylidenepiperazine-2,5-
dione. Treatment of 5e (R=Me, R%=Bn, Y=OAc)
with BF3·OEt2 in dichloromethane gave the 3-benzyli-
denepiperazine-2,5-dione 7 as a single diastereomer in
76% yield (Scheme 2). The spectroscopic data obtained
for piperazine-2,5-dione 7 was consistent with the Z-
isomer previously reported in the literature.9
Scheme 3.
In this manner, directed mono and dual functionaliza-
tion of piperazinediones can be achieved and the scope
of these reactions is summarized in Scheme 2. It should
be noted that the approach reported here leads to
compounds that cannot be readily synthesized using
previously reported literature procedures. Hence our
methods are orthogonal to and nicely complement
existing methodologies.
ation of 1 to give piperazinedione 2 (R=Me, R%=H)
can be achieved using potassium carbonate and
dimethyl sulfate. In contrast when piperazinedione 1
was treated with potassium carbonate and a variety of
alkyl halides, the C-alkylated piperazinediones of type
2 (R%=alkyl, R=H) were obtained in excellent yields.
The monoalkylated piperazinediones of type 2 can be
subsequently C- or N-alkylated. Alternatively, N-ace-
tyl-3-benzyloxycarbonylpiperazine-2,5-dione (2, R=Ac,
R%=H) can be synthesized from 3-benzyloxycar-
bonylpiperazine-2,5-dione 1 using acetic anhydride, in
the presence of DMAP.
To illustrate the versatility of alkoxycarbonylpiper-
azine-2,5-diones 1 in synthesis, conformationally con-
strained a-amino acid derivatives of pipecolic acid and
baikiain are targeted (Scheme 3). Thus, piperazine-2,5-

C. L. L. Chai et al. / Tetrahedron Letters 44 (2003) 263–265
265
dione 1 was converted to the diallylated piperazine-
dione 8 using sodium hydride and allyl iodide. Ring-
closing metathesis of the diallylated piperazinedione 8
using the first generation Grubb’s catalyst gave the
cyclic alkene 9 in 82% yield. When the alkene was
reacted with hydrogen in the presence of 10% Pd on C,
the saturated carboxylic acid 10 was obtained in quanti-
tative yield. With this compound in hand, the known10
pipecolic acid derivative 11 was accessed via thermal
decarboxylation of 10.
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Further work describing the applications of this strat-
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Acknowledgements
We thank the Australian Research Council for financial
support.
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