Transannular rearrangement of activated lactams: Stereoselective synthesis of substituted pyrrolidine-2,4-diones from diketopiperazines

Article abstract of DOI:10.1002/anie.200702132

(Chemical Equation Presented) The surprising reactivity under basic conditions of 2,5-diketopiperazines activated by N-Boc substituents provides a highly stereoselective pathway to pyrrolidine-2,4-diones. A wide range of valuable pharmaceutical scaffolds

Full text of DOI:10.1002/anie.200702132

Communications
DOI: 10.1002/anie.200702132
À
C C Activation
Transannular Rearrangement of Activated Lactams: Stereoselective
Synthesis of Substituted Pyrrolidine-2,4-diones from
Diketopiperazines**
Daniel Farran, Isabelle Parrot, Jean Martinez,* and Georges Dewynter*
A combination of two functional groups in a given molecule
often conveys a new reactivity that is not equivalent to that
expected if the two functionalities are considered independ-
ently. Such combinations can be seen as a unique function-
alities in their own right, and their presence could lead to
unexpected transformations during the course of otherwise
well known reactions. We describe herein the unprecedented
reactivity of N-carboxy derivatives of 2,5-diketopiperazines
(DKPs). The reaction of these derivatives under basic
conditions led to novel substituted pyrrolidine-2,4-diones.[1]
This serendipitous C aminoacylation of amino acids could
allow the straightforward synthesis of highly valuable phar-
macological scaffolds. Analogous structures to those of the
pyrrolidine-2,4-dione derivatives are present in various nat-
ural and synthetic compounds, such as ascorbic acid,[2,3] which
displays a broad range of well-known biological properties,
and tetramic acid,[4] which exhibits antibacterial and antiviral
activities. Furthermore, pyrrolidine-2,4-diones serve as sig-
nificant intermediates in the synthesis of statins,[5–11] a key
structural motif found in peptidomimetic inhibitors of pro-
teases, such as aspartic proteases.[13,14] Owing to the lack of a
general synthetic route to 3-amino, 3-alkyl derivatives of
pyrrolidine-2,4-diones, the absence of a stereoselective path-
way to these compounds,[15–18] and the significance of such
pharmacophore moieties, we became interested in developing
a stereoselective ring contraction of bis(N-tert-butoxycar-
bonyl)-DKPs (bis-Boc-DKPs) into pyrrolidine-2,4-diones.
DKPs, the smallest cyclic peptides, are not only of interest
because of their natural occurrence and pharmacological
properties,[19] but they have also been used widely as scaffolds
in asymmetric synthesis and combinatorial chemistry.[20]
However, they are generally not suitable as starting materials
in semisynthesis as a result of their high chemical stability and
their ready racemization in alkaline media.[21] We initially
planned to prepare bis-Boc derivatives of DKPs to carry out
ionic condensation reactions at the 3- and 6-positions by
enolate induction and to enhance the electrophilicity of such
substituted lactams. To the best of our knowledge, there are
few examples of reactions of Boc-DKPs under basic con-
ditions. In the synthesis of coronamic acid, BernabØ and co-
workers reported the opening of a mono-Boc-substituted
derivative of a Pro-containing DKP by alkaline hydrolysis,[22]
whereas Nishiyama and co-workers described a modified
Sasaki reaction in which a bis-Boc-DKP was alkylidenated
with an aldehyde in the presence of potassium tert-butoxide
with concomitant cleavage of one of the two protecting
groups.[23] We made the unexpected observation that instead
of displaying conventional protecting-group behavior, the two
Boc moieties on the nitrogen atoms of the heterocycle reacted
under certain basic conditions as electron-withdrawing acti-
vators to promote the unusual transformation of bis-Boc-
DKPs 1 into the corresponding 3-aminopyrrolidine-2,4-dione
derivatives 2 and/or 3 (Table 1 and Table 2).
We first examined the reaction with the diprotected 3-
alkyl piperazine-2,5-diones 1a–g (Table 1). Interestingly, in
the presence of tBuOK, the keto–enol equilibrium of unsym-
metrical DKPs was shifted towards enol formation in all
cases: A single product was detected and readily identified by
1H NMR and 13C NMR spectroscopy (see the Supporting
Information). The aminotetramates 2a–f were formed in
moderate to good yields with excellent enantioselectivities
and complete retention of configuration. According to chiral
HPLC analysis, the DKPs (3S)-1b, (3R)-1c, (3S)-1d, and
Table 1: Stereoselective ring contraction of unsymmetrical DKPs into 3-
aminotetramates.
Entry
1
R
2
Yield [%][a]
ee [%][b]
[*] D. Farran, Dr. I. Parrot, Prof. J. Martinez, Prof. G. Dewynter
Institut des BiomolØcules Max Mousseron, UMR 5247
UniversitØ Montpellier
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1 f
1g
H
2a
2b
2c
2d
2e
2 f
2g
72
60
64
82
84
71
16
–
Me (S)
Me (R)
iPr (S)
iPr (R)
sBu (S)
Bn (S)
>99
>99
>99
>99
>95
–
2, Place Eug›ne Bataillon, 34095 Montpellier Cedex 5 (France)
Fax: (+33)4-6714-4866
E-mail: martinez@univ-montp1.fr
georges.dewynter@univ-montp2.fr
[**] We thank Dr. Loïc Toupet of the Groupe Mati›re CondensØe et
MatØriaux (UMR 6626, UniversitØ Rennes 1) for X-ray analysis.
[a] Yield of product isolated by flash chromatography. [b] The ee values
were determined by HPLC on a chiral phase; see the Supporting
Information for details.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
7488
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Angew. Chem. Int. Ed. 2007, 46, 7488 –7490

Angewandte
Chemie
(3R)-1e were converted with up to 99% ee into the isomers
(5S)-2b, (5R)-2c, (5S)-2d, and (5R)-2e, respectively
(Table 1, entries 2–5). We observed a totally regioselective
ring contraction. Thus, N1 of the DKP was excluded from the
ring system in each case, and the configuration at the C atom
bonded to the side chain R of the DKP was retained in the
product. In contrast, 2g was generated in poor yield from the
bis-Boc-substituted cyclo(Gly-Phe) 1g; instead, racemic 3-
benzyl-1-(tert-butoxycarbonyl)-3-(tert-
Scheme 1. Tandem rearrangement–alkylation of bis-Boc cyclo-(Gly-Gly).
HMDS=hexamethyldisilazide. Bn=Benzyl.
butoxycarbonylamino)pyrrolidine-2,4-dione, which results
from the more thermodynamically stable enolate, was the
major product (46%; see the Supporting Information).
Encouraged by these results, we decided to apply this
rearrangement to symmetrical DKPs (Table 2). We observed
the formation from substrates 1h–j of substituted pyrrolidine-
By starting from unsymmetrical DKPs, we were then able
to synthesize a range of derivatives 5 with the two side chains
R1 and R2 on the same face of the heterocycle (Table 3). The
Table 3: Tandem rearrangement–alkylation of unsymmetrical DKPs.
Table 2: Stereoselective ring contraction of symmetrical DKPs into
pyrrolidine-2,4-diones.
Entry
1
R2X
5
Yield [%][a]
de[b]
1
2
3
4
5
6
1e
1e
1e
1e
1e
1 f
MeI
BnBr
EtO2CCH2I
5a
5b
5c
5d
5e
5 f
60
72
69
76
84
68
>95
>95
>95
>99
>95
>95
Entry
1
R
3
Yield [%][a]
de[b]
1
2
3
1h
1i
1j
Me (S)
iPr (S)
MeO2C(CH2)2 (S)
3h
3i
3j
66
68
29
67
>95
>95
=
CH2 CHCH2Br
=
(CH3)2C CHCH2Br
=
CH2 CHCH2Br
[a] Yield of product isolated by flash chromatography. [b] The 13C NMR
spectra gave only one set of peaks; see the Supporting Information for
details.
[a] Yield of product isolated by flash chromatography. [b] The de values
were determined by HPLC of the crude product; see the Supporting
Information for details.
2,4-diones 3, in which the two alkyl chains are on the same
face of the heterocyclic ring, as shown by NOE experimental
data for 3h and the diastereoisomeric product (see the
Supporting Information). Compounds 3 were obtained with
good to excellent diastereoselectivity. Thus, the steric effect of
the substituents at C3 and C6 appears to be key to the high
diastereoselectivity observed. The occurrence of a retro-
Michael reaction at the 3-position of the pyrrolidine-2,4-dione
is a plausible explanation for the low yield and high
diastereoselectivity found for the formation of 2j from 1j
under basic conditions: A b elimination on the side chain of
the glutamate led to the elimination of methyl acrylate. The
resulting product with just one MeO2C(CH2)2 side chain was
obtained in 42% yield with > 95% ee.
tandem rearrangement/alkylation reaction occurred exclu-
sively on the Gly segment of the cyclic peptide. To the best of
our knowledge, all substitution patterns accessible by our
method have no precedent. Thus, this highly regioselective
and diastereoselective tandem rearrangement–alkylation
sequence allows the synthesis of highly valuable original
scaffolds.
On the basis of X-ray analysis of the DKP 1e,[24] the
observed strict conservation of the configuration of the
starting material during the rearrangement, and the high
stereoselectivity of the alkylation, we propose the following
mechanism (Scheme 2): Under basic conditions, the kinetic
enolate A is obtained in a first step from the activated DKP 1
To gain access to various functionalized pyrrolidine-2,4-
diones, we examined the rearrangement in the presence of an
alkylating agent added during the course of the reaction. With
two equivalents each of a base and an electrophilic reagent,
the bis-Boc cyclo(Gly-Gly) substrate 1a was converted
readily into the dialkylated pyrrolidine-2,5-diones 4a and
4b in a diastereoselective manner (Scheme 1). The positions
of the side chains were established by 1H NMR spectroscopic
analysis by comparison with reported data for the previously
described derivative 4b.[18] It was necessary to use LiHMDS
instead of tBuOK for this reaction.[24]
Scheme 2. Possible intermediates proposed to explain the observed
stereoselectivity of the reaction.
Angew. Chem. Int. Ed. 2007, 46, 7488 –7490
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Communications
without racemization. The transannular attack of A at the
the TRAL reaction to other heterocyclic substrates for the
synthesis of a broader range of pharmacological scaffolds, in
particular for the synthesis of statine derivatives.
activated lactam carbonyl group then provides the oxyanion
B, in which the aziridine moiety is located on the less bulky
face rather than on the face occupied by the side chain R1. In a
last step, the opening of the aziridine ring leads to the desired
Received: May 15, 2007
Revised: July 7, 2007
Published online: August 23, 2007
bis-Boc 3-aminopyrrolidine-2,4-dione or the corresponding
2
À
enol. In the presence of an alkylating reagent R X, the
constrained ring system may hinder the attack of B at the face
of the heterocycle with the Boc–aziridine moiety. The
electrophile can only approach the open face of the hetero-
cycle, and the R1 group is pointed away from the Boc–
aziridine moiety. This hypothesis is consistent with the
configuration established for compounds 5. The unexpected
rearrangement that we have described seems to be related to
well-known conventional transformations, such as the Die-
ckmann and Gabriel–Colman reactions and the first step of
the Dakin–West reaction. In accordance with the postulated
mechanism, we propose the name “transannular rearrange-
ment of activated lactams (TRAL)” for this reaction.
To expand the scope of the TRAL reaction, the asym-
metric Claisen-like rearrangement described for 3-O-allyl-
(isopropylidene) ascorbate[2] was applied to the pyrrolidine-
2,4-dione derivative 2e, following its conversion into 6 by
O allylation, to give compound 7 in a stereoselective manner
(Scheme 3). The TRAL/alkylation and Claisen-like rear-
À
Keywords: C C activation · diastereoselectivity ·
diketopiperazines · heterocycles · rearrangement
.
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Scheme 3. Claisen-like rearrangement: a) KOH, allyl bromide, DMSO,
60%; b) microwave, toluene/DMSO, 1708C, 30 min, 69%.[25] DMSO=
dimethyl sulfoxide.
rangement were both found to be completely diastereoselec-
tive reactions. The diastereoselectivity of the sigmatropic
rearrangement depends on the structural parameters of the
Zimmermann–Traxler chairlike transition state.
In summary, we have developed an efficient, mild, and
exceptionally stereoselective synthesis of dissymmetric pyr-
rolidine-2,4-diones from DKPs with a high potential for
structural diversity. The transannular rearrangement of
activated lactams, with or without concomitant alkylation, is
a rare tool for the preparation in a single step of a variety of
functionalized heterocyclic biomolecules with high stereo-
specificity. Further studies will be devoted to the extension of
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Angew. Chem. Int. Ed. 2007, 46, 7488 –7490