Transannular rearrangement of activated 2,5-diketopiperazines: A key route to original scaffolds

Article abstract of DOI:10.1039/b810352f

An efficient and original stereocontrolled transannular rearrangement starting from activated 2,5-diketopiperazines has been developed, an opportunity for the medicinal chemistry field, which requests access to novel biological scaffolds. This powerful ri

Full text of DOI:10.1039/b810352f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Transannular rearrangement of activated 2,5-diketopiperazines:
a key route to original scaffolds†
Daniel Farran,a Isabelle Parrot,a Lo¨ıc Toupet,b Jean Martineza and Georges Dewynter*a
Received 18th June 2008, Accepted 24th July 2008
First published as an Advance Article on the web 3rd September 2008
DOI: 10.1039/b810352f
An efficient and original stereocontrolled transannular rearrangement starting from activated
2,5-diketopiperazines has been developed, an opportunity for the medicinal chemistry field, which
requests access to novel biological scaffolds. This powerful ring contraction, which can be related to a
stereoselective aza-version of the Chan rearrangement, allows for example the one-step synthesis of
various tetramic acids, access to 2-disubstituted statins, or the synthesis of relevant lactam-constrained
dipeptide mimetics using a TRAL–RCM sequence.
substituted pyrrolidine-2,4-diones or tetramic acids, key patterns
Introduction
founded in several biological compounds.4 Moreover, the first
successful application of the TRAL leads to a highly selective
synthesis of various novel 2-disubstituted statins 4.5,6
Access to new therapeutic entities depends greatly on the discovery
of original and pertinent scaffolds, connected with the develop-
ment of innovative synthetic reactions. In the perpetual quest for
pioneering compounds, we recently described an unprecedented
ring contraction reaction. The transannular rearrangement of
activated lactams (TRAL) leads to 4-hydroxy-3-pyrrolin-2-ones
2 starting from suitable Boc-activated 2,5-diketopiperazines 1
(Scheme 1).1 This powerful rearrangement could be seen as a new
intramolecular N→C acyl migration reaction of cyclic imides. It
can be related to a highly stereocontrolled aza-version of the Chan
rearrangement,2 or to the interesting reaction of acyclic imides
described by Hamada et al.3
After a full account of our results on the TRAL/TRAL-
alkylation, including a debate on various activating groups of the
2,5-diketopiperazines (DKPs), we will extend the discussion to the
postulated mechanism and then report on original applications
of TRAL, such as the asymmetric synthesis of original lactam-
constrained dipeptide mimetics as a key route to promising
heterocyclic scaffolds.
Results and discussion
The transannular rearrangement of activated lactams (TRAL):
a serendipitous finding
Stereoselective ring contraction of DKPs into 3-aminotetramates
While our efforts were initially devoted to the stereoselective 3-
or 6-alkylation of bis-(N-tert-butoxycarbonyl)-DKPs (bis-Boc-
DKPs), by taking advantage of the electrophilicity of such
substituted lactams, we made an unexpected observation. Instead
of displaying a predictable protecting group character, under
certain basic conditions, the two Boc moieties acted as electron
withdrawing activators, allowing the unusual transformation of
symmetrical and unsymmetrical bis-Boc-DKPs 1 into the corre-
sponding 3-aminopyrrolidine-2,4-diones 2 (Scheme 1).
Scheme 1 TRAL and TRAL-alkylation. Access to statins.
By adding an alkylating agent during the course of the
TRAL, bis-Boc cyclo-[Gly-X] 1 can be easily converted into its
dialkylated pyrrolidine-2,4-dione 3 in an exceptionally diastereos-
elective manner (TRAL-alkylation, Scheme 1). This regioselective
ring contraction allows then the one-step synthesis of various
A preliminary study has concentrated on the reaction with
diprotected bis-Boc-DKPs 5a–f, in the presence of t-BuOK
(Table 1).
Contradictorily to the few examples described in the literature
concerning the reactions on Boc-protected DKPs under basic
conditions,7,8 we highlighted a new kind of reactivity. According
to chiral HPLC analyses, 1H NMR and 13C NMR studies, we ob-
served that the keto–enolic equilibrium of pyrrolidine-2,4-diones
was always shifted towards the enol formation. We noticed a totally
regioselective ring contraction which allows the exclusion from the
ring system of the Boc-N1 of the DKPs, leading to the formation
of the corresponding aminotetramates 6a–f in good yields with
aInstitut des Biomole´cules Max Mousseron, UMR CNRS 5247, Universite´
Montpellier 1, Universite´ Montpellier 2, Place Euge`ne Bataillon, 34095
Montpellier Cedex 5, France. E-mail: dewynter@univ-montp2.fr
bGroupe Matie`re Condense´e et Mate´riaux, UMR 6626, Universite´ de Rennes
1, Campus de Beaulieu, 35042 Rennes Cedex, France
† CCDC reference number 643845. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b810352f
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3989–3996 | 3989
©

View Article Online
Table 1 Stereocontrolled ring contraction of activated DKPs
Table 2 TRAL on symmetrical DKPs
Entry
9
R
10
Yielda (%)
deb (%)
1
2
3
9a
9b
9c
Me (S)
10a
10b
10c
66
68
29
67
>95
>95
iPr (S)
MeO2C(CH2) (S)
a Yield of product isolated by flash chromatography. b The de values were
determined by HPLC of the crude product.
Entry
5
R1
R2
6/7
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
Boc
Boc
Boc
Boc
Boc
Boc
Z
Bz
Bz
Bz
Ac
6a
6b
6c
6d
6e
6f
6g
6h
6i
72
60
64
82
84
71
0
69
98
98
37
—
Me (S)
Me (R)
iPr (S)
iPr (R)
sBu (S)
iPr (S)
H
iPr (S)
iPr (R)
H
>99
>99
>99
>99
>95
—
—
87
87
—
Claisen-like rearrangement applied to the TRAL products
(obtained from unsymmetrical DKPs)
With the scope of the TRAL on unsymmetrical DKPs established,
the synthetic value of the tetramate adducts was then investigated.
The asymmetric Claisen-like rearrangement described for 3-O-
allyl(isopropylidene)ascorbate10 was successfully transposed to the
bis-Bz-pyrrolidine-2,4-dione 6j and to the bis-Boc-pyrrolidine-2,4-
dione 6e. After an appropriate O-allylation, derivatives 11j and
11e followed a sigmatropic rearrangement to yield 12j and 12e in
a stereocontrolled manner (Scheme 2).
10
11
5j
5k
6j
7
a Yield of product isolated by flash chromatography. b The ee values were
determined by HPLC on a chiral phase.
excellent enantioselectivities and with absolute retention of the
initial configuration.
The examination of the feasibility of this serendipitous rear-
rangement was then extended to other conventional N-protecting
groups that could be perceived as lactamic activators of the
TRAL. While no reaction was detected with a bis-Z-DKP (entry
7, Table 1), the reaction of bis-Bz-DKPs occurred with higher
yields but lower stereoselectivity, contrasting with the exceptional
enantioselectivity described for the bis-Boc-DKPs (entries 8–10,
Table 1). This tiny fall in stereoselectivity could be explained by the
increased facility of racemisation of the bis-Bz-DKPs in alkaline
media.
Interestingly, when we investigated the switch to bis-Ac-DKP
5k, the tris-acetylated DKP 7 was produced in moderate yield
with no trace of the corresponding tetramate (entry 11, Ta-
ble 1). Ascribing this to an intermolecular acetyl migration,
since unprotected DKP was simultaneously generated, we then
exploited this peculiarity for the synthesis of an interesting
scaffold. The reduction of the DKP 7 using LiAlH(OtBu)3 allowed
us access to the dehydro product 8, in good yield, in a Perkin-like
elimination with concomitant cleavage of the neighboring acetyl
group. The Z-stereochemistry of this compound was established
using 1H NMR spectra by comparison with previously described
analyses.9
Scheme 2 Claisen-like rearrangement. Reagents and conditions: (a) KOH,
=
DMSO, CH2 CHCH2Br; (b) microwave irradiation, toluene–DMSO,
170 ◦C, 30 min.
The stereochemistry of this Claisen-like rearrangement was
unambiguously determined by X-ray diffraction crystal analysis
of the major compound 12j enantioenriched by recrystallization
(Scheme 3).‡
The high diastereoselectivity of this sigmatropic rearrangement
could be easily explained by the structural parameters of the
Zimmermann–Traxler chair transition state, as illustrated by
Scheme 4.
In agreement with our preliminary studies on TRAL, benzoyl
groups also appear to be a suitable alternative to Boc activating
groups here.
Further applications of the TRAL to other symmetrical DKPs,
such as di-protected cyclo-[X-X] (X = Ala, Val, Glu(OMe)),
provide original substituted pyrrolidine-2,4-diones, in which the
two alkyl chains belong to the same half-space of the heterocyclic
moiety (Table 2).
‡ C24H24O4N2, Mr = 404.45, orthorhombic, P212121, a = 10.4911(5),
3
˚
˚
b = 12.2289(6), c = 16.1319(7) A, V = 2069.6(2) A , Z = 4, DX
=
-3
-1
˚
1.298 Mg.m , l(Mo Ka) = 0.71073 A, m = 0.89 cm , F(000) =
856, T = 110(1) K. CCDC 643845. These data can also be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.uk/data_request/cif.
3990 | Org. Biomol. Chem., 2008, 6, 3989–3996
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Towards a plausible mechanism to explain the stereoselectivity of
the TRAL
The transannular rearrangement of activated lactams (TRAL), an
intramolecular acylation of an imide enolate, could be related
to the Dieckmann and Gabriel–Colman reactions or to the
early step of the Dakin–West reaction. However, a better match
could be made with the Chan reaction,2 a rearrangement of an
acyloxyacetate to a 2-hydroxy-3-keto-ester in the presence of a
strong base (Scheme 5). Its aza-version has been developed on
acyclic imides by Hamada et al.3 and extended to biological hits
by Wipf and Methot,11 and White et al.,12,13 as illustrated by the
Holton Taxol total synthesis.14
Scheme 3 X-Ray analysis of (3S,5R)-12j.
Scheme 5 The Chan rearrangement.
As suggested by Wipf and co-workers, only the s-cis conforma-
tion of the ester and the tertiary amide of the incriminated imide
moiety is able to undergo the Chan rearrangement. A transposi-
tion of this interpretation could allow us to connect the success of
the TRAL to the unique presence of the s-cis conformation, since
bis-Boc-DKPs could be likened to constrained cyclic systems of
two imides.
Scheme 4 Zimmermann–Traxler chair transition state.
Stereoselective ring contraction of DKPs in the presence of an
alkylating agent: the TRAL-alkylation
To improve the access to more functionalized tetramates, we have
already described a viable route for the relevant regioselective
and stereoselective ring contraction of DKPs into pyrrolidine-2,4-
diones in the presence of an alkylating agent. By using symmetrical
or unsymmetrical DKPs, we could obtain a range of derivatives
bearing the two side chains R1 and R2 on the same face of the
heterocyclic ring (Table 3).
Concerning the mechanism of the TRAL, we anticipated that
the TRAL of activated DKPs could sensibly follow the Chan–
Hamada reaction (Scheme 6). We proposed that after a suitable
deprotonation of the activated DKP under basic conditions, the
kinetic enolate would be formed. The transannular attack of
the enolate, and nucleophilic acyl substitution with the adjacent
carbonyl of the imide group could afford an aziridine intermediate,
Table 3 TRAL-alkylation of unsymmetrical and symmetrical DKPs
Entry
5
R1
R2X
R
13
Yielda (%)
deb (%)
= R2
= R2
= R1
= R1
= R1
= R1
= R1
= R1
13a
13b
13c
13d
13e
13f
13g
13h
62
57
60
72
69
76
84
68
>95
>95
>95
>95
>95
>99
>95
>95
=
1
2
3
4
5
6
7
8
5a
5a
5e
5e
5e
5e
5e
5f
H
H
CH2 CHCH2Br
BnBr
iPr (R)
iPr (R)
iPr (R)
iPr (R)
iPr (R)
iBu (S)
CH3I
BnBr
EtO2CCH2I
=
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.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3989–3996 | 3991
©

View Article Online
Scheme 7 Lactam-constrained dipeptide mimetics.
Scheme 6 Postulated mechanism for the TRAL, by analogy with the
Chan reaction.
Furthermore, the presence of a quaternary stereogenic carbon
center enhances the significance of these bicyclic derivatives,
regarding the fact that aza-cyclic a-aminoacids with quaternary
stereocenters are part of biologically active natural products
with therapeutic potential,33–35 and are useful building blocks for
natural product synthesis and enantioselective syntheses.36–40
In order to add more constraints on the pyrrolidine-2,4-dione
moieties, we first imagined linking the side chains of the dipeptide
mimetic, taking the opportunity given by the TRAL to choose
their spatial arrangement. First of all, as we already demonstrated,
the bis-Boc cyclo-[Gly-Gly] 5a can be easily converted into
its dialkylated pyrrolidine-2,4-dione 13a in a diastereoselective
manner (Scheme 8). With both allyl chains being in the same
half-space and properly positioned for cyclization, the use of a
Grubbs’ catalyst II in the second step leads to the over-constrained
derivative 14a in good yield.
in accordance with the oxirane formation described for the Chan
reaction.
To explain the exceptional stereoselectivity of the TRAL, we
could postulate that the aziridine ring would be positioned on
the less bulky half-space rather than on the face containing the
side chain R1. Prototropy on the oxanion could lead to the
anionic intermediate shown. In the presence of an alkylating
reagent such as R2–X, we have anticipated that the constrained
ring system could hinder the attack of the sp3 carbanion on the
face where the Boc-aziridine moiety is located. The electrophile
could then only add to the open half-space of the heterocycle,
where the R1 group is pointed away from the Boc-aziridine
moiety. In the last step, the opening of the aziridine affords the
resulting bis-Boc 3-aminopyrrolidine-2,4-dione or its enolic form.
The possibility of immediate ring opening of the in situ formed
aziridine intermediate could be also considered. This opening
could be induced by the alkoxide anion, followed by prototropy
to the nitrogen anion, affording an anionic intermediate which
could attack the electrophile R2–X. Taking into account the high
reactivity of 2-oxyaziridines, the ring opening of the proposed 2-
hydroxyaziridine intermediate in a final stage of the process is less
likely.15
Scheme 8 Synthesis of bicyclo-compound 14a starting from bis-Boc
cyclo-[Gly-Gly]. Reagents and conditions: (a) (i) LiHMDS, -78 ◦C, THF
(ii) CH2 CHCH2Br, 62%; (b) 2% mol Grubbs’ catalyst II, CH2Cl2, r.t.,
84%. About 14a: the 13C NMR spectrum of the crude material gave only
TRAL: a key route to promising scaffolds
=
Besides the first described application of the TRAL leading to
the synthesis of statin analogues, we describe here an original
access to promising heterocyclic scaffolds, using a tandem TRAL–
metathesis approach.
one set of peaks.
In the quest for novel heterocyclic scaffolds and encouraged
by the efficiency of this pioneering ring-closing metathesis on
pyrrolidine-2,4-dione derivatives, we decided to expand our strat-
egy to the synthesis of spiro-derivatives.
Asymmetric synthesis of original lactam-constrained dipeptide
mimetics
The concept of conformational constraint has emerged as the
favourite method in medicinal chemistry of “freezing” the bioac-
tive conformation of the initial peptide in order to optimize its ac-
tivity, its receptor selectivity or the duration of its action.16–26 Since
the lactam-bridged dipeptides described by Freidinger et al. have
been well recognized to be a significant type of conformational
constraint in peptides27,28 and since the ring-closing metathesis
reaction has been shown to be a powerful method of accessing
rigidified dipeptides of biological interest,29–32 we chose to design
a new and efficient method leading to original lactam-constrained
dipeptide mimetics.
By taking advantage of the potential for high stereoselectivity of
one of our previously reported synthetic sequences, the TRAL and
O-allylation followed by a Claisen-like rearrangement, we already
knew how to access 3-allyl-3-aminopyrrolidine-2,4-dione 12e from
bis-Boc cyclo-[Gly-D-Val] 5e (Scheme 2).
Taking a bet on this totally diastereoselective sequence, we were
then able to transpose it to the O,N-diallyl derivative 17, which
could be accessed from the same aminotetramate intermediate
6e by using two equivalents of base and allyl bromide. The
sigmatropic rearrangement provided the new C,N-diallyl 18 in
good yield in a stereocontrolled manner. This reaction was carried
out under microwave conditions, which appeared to be more
efficient than thermal conditions.
Using a highly stereoselective chemical sequence, TRAL fol-
lowed by a ring-closing metathesis reaction (RCM), we have
been able to access unprecedented heterocyclic scaffolds 14–
16 (Scheme 7), that could be received as dipeptide mimetics.
A suitable intramolecular cyclization by ring-closing metathesis
of the pyrrolidine-2,4-dione 18, allowed the new stereoselective
3992 | Org. Biomol. Chem., 2008, 6, 3989–3996
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Scheme 9 TRAL and O-allylation followed by a Claisen-like rearrangement. Reagents and conditions: (a) tBuOK, THF, r.t., 84%; (b) KOH (2.0 equiv.),
DMSO, CH2 CHCH2Br (2.0 equiv.), 76%; (c) microwave irradiation, toluene–DMSO, 170 ◦C, 30 min, 73%; (d) 2% mol Grubbs’ catalyst II, DCM, r.t.,
=
88%. About 15a: the 13C NMR spectrum of the crude material gave only one set of peaks.
construction of the innovative [5 + 6] spiro-derivative 15a in
excellent yield (Scheme 9).
allylic methylene protons on the nitrogen side possess anisochrony,
exhibited as a significant splitting of signals (Dd = 1.42 ppm).
This allowed us to conclude on a chair-like favorite conformation.
This observation was also confirmed by molecular modelling
studies on 16a (Scheme 11a).45 We then had to admit that the
boat-like conformer was critical for the transannular reaction
(Scheme 11b).
This unprecedented spiro-scaffold could be classified as a
significant lactam-constrained dipeptide mimetic. In addition it
could be also considered a more complex derivative of Baiki-
ain, a cyclic a-amino acid isolated from the heartwood of
Rhodesian teak (Baikiaea plurijuga).41 This interesting natural
compound is an unsaturated derivative of pipecolic acid, which
is a non-proteinogenic amino acid present in pharmacologi-
cally active molecules such as immunosupressors or antitumor
antibiotics.42
Finally, regarding the fact that using RCM to synthesize an
eight-membered cycle is still challenging,43,44 we performed the
cyclization starting from the intermediate compound 16a, to
build the [5 + 4] spiro-derivative 15b, another lactam-constrained
dipeptide mimetic (Scheme 10). We were delighted to observe
that the aminotetramate 17 was easily converted into the novel
bicyclo-derivative 16a, in good yield, probably helped by the steric
constraints induced by the N-Boc group. This optically active
compound 16a can be considered as an interesting bicyclo- and
dehydro- quaternary dipeptide mimetic.
Scheme 11 (a) The predicted lower energy conformation of 16a: the
chair-like favorite conformation observed by molecular modelling studies
and 1H NMR; (b) the boat-like conformer probably crucial for the
transannular Claisen rearrangement reaction.
Conclusions
In conclusion, we have devised a powerful method for accessing
new lactam-constrained dipeptide mimetics, new chemical entities
that could be of broad interest in the quest for original scaf-
folds for drug discovery. The success of this strategy is closely
linked to the access to suitable building blocks for the ring-
closing metathesis, which can only be obtained by the highly
stereocontrolled TRAL. The association of the TRAL and an
unprecedented ring-closing metathesis on pyrrolidine-2,4-dione
derivatives provided lactam-constrained dipeptide mimetics in
good yields with remarkable stereoselectivity. We believe that this
study will offer a strong incentive for the construction of larger
or structurally modified dipeptide mimetics and potentially novel
biological hits.
Scheme 10 Synthesis of a [5 + 4] spiro-derivative. Reagents and conditions:
(a) 2% mol Grubbs’ catalyst II, CH2Cl2, r.t., 78%; (b) microwave
irradiation, toluene–DMSO, 170 ◦C, 30 min.
Interestingly, under microwaves or thermal conditions, the
sigmatropic rearrangement of 16a was unsuccesful, leading to
a partial cleavage of the Boc protecting group. In order to
give an explanation, we first postulated two ring-conformations
for 16a, the chair-like and boat-like conformations. A careful
1
examination of the H NMR spectrum of the eight-membered
ring part of the cyclic system, showed unambiguously that the
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3989–3996 | 3993
©

View Article Online
solution was stirred for 12 hours under an argon atmosphere. The
medium was then diluted with AcOEt (10 mL), washed with a
solution of 0.1 N HCl (20 mL), and dried over anhydrous MgSO4.
The solvent was removed in vacuo and the desired compound was
Experimental
General procedures
All solvents were dried and freshly distilled prior to use. TLC was
performed with Merck-Kieselgel 60 F254 plates, and spots were
visualized with UV light and/or by staining with ninhydrin solu-
tion followed by heating. Flash chromatography was performed on
Merck-Kieselgel 60 (230–400 mesh). Melting points were recorded
on Buchi 510 melting apparatus. Optical rotations were measured
with a 1 cm cell (concentration c given in g 100mL-1solvent) on
a Perkin Elmer Polarimeter at 20 ◦C with a sodium lamp (589
nm). HPLC analyses were performed on a Waters-Millennium
(column 250 ¥ 4.6 mm Nucleosil C18 5 m, detection UV). High
resolution mass spectra (HRMS) were obtained on a JEOL JMS-
1
obtained (0.054 g, 69% yield) as a yellow oil. H NMR (CDCl3,
300 MHz): d 4.44 (s, 2H), 7.21–8.05 (m, 11H), 12.50 (m, 1H);
13C NMR (CDCl3, 75 MHz): d 46.8, 104.2, 127.4 to 133.4, 131.0,
134.3, 156.5, 165.3, 167.2, 168.3; HRMS (FAB+) m/z calcd for
C18H14N2O4 [M + H+] 323.1032, found 323.1026.
(5R)-1-(Benzoyl)-3-[(benzoyl)amino]-4-hydroxy-5-isopropyl-3-
pyrrolin-2-one 6j
Mp = 94 ◦C; [a]D20 = -137.3 (c = 1.02, CH2Cl2); 1H NMR (CDCl3,
300 MHz): d 0.96 (d, 3H, J = 7.0 Hz), 1.16 (d, 3H, J = 7.1 Hz),
2.39–2.55 (m, 1H), 4.89 (d, 1H, J = 2.8 Hz), 7.29–8.02 (m, 11H),
12.57 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 16.6, 18.0, 29.3,
61.4, 103.9, 127.4 to 133.2, 131.0, 134.9, 160.1, 165.8, 167.2, 168.7;
HRMS (FAB+) m/z calcd for C21H20N2O4 [M + H+] 365.1501,
found 365.1495.
1
SX-102 high resolution magnetic sector mass spectrometer. H
NMR and 13C NMR spectra were recorded with Bruker 200 MHz,
Bruker AC250 MHz, Bruker Advance 300 MHz or Bruker A DRX
400 MHz spectrometers. Chemicals shifts are reported in d relative
1
to an internal standard of residual chloroform (d = 7.26 for H
NMR and 77.16 for 13C NMR) or DMSO-d6 (d = 2.50 for H
1
NMR and 39.52 for 13C NMR). The reported H NMR signals
1
1,4-Di(acetyl)-piperazine-2,5-dione 5k
were assigned using standard 2D NMR techniques or by direct
comparison to the 1H NMR spectra of the corresponding starting
materials. The reported 13C NMR signals were assigned using
DEPT-135 and HMQC techniques or by direct comparison of the
13C NMR spectra of the corresponding starting materials.
A solution of piperazine-2,5-dione (0.424 g, 3.72 mmol) in acetic
anhydride (2 mL) was irradiated for 26 min at 180 ◦C (Biotage
Initiator apparatus). The medium was then concentrated in
vacuo and purified by column chromatography (CH2Cl2–AcOEt
(100 : 0 → 90 : 10)), providing 1,4-diacetyl-piperazine-2,5-dione
◦
1
in 76% yield (0.560 g) as white crystals. Mp = 97 C; H NMR
(CDCl3, 400 MHz): d 2.52 (s, 6H), 4.55 (s, 4H); 13C NMR (CDCl3,
100 MHz): d 26.7, 47.1, 166.0, 170.8; HRMS (FAB+) m/z calcd
for C8H10N2O4 [M + H+] 199.0719, found 199.0730.
1,4-Di(benzoyl)-piperazine-2,5-dione 5h
Typical procedure for the benzoylation of DKP. A solution of
piperazine-2,5-dione (0.198 g, 1.74 mmol) and benzoic anhydride
(1.572 g, 6.95 mmol) in toluene (2 mL) was irradiated for
20 min at 180 ◦C (Biotage Initiator apparatus). The medium
was then concentrated in vacuo and 10 mL of CH2Cl2 were
added. The organic layer was washed with a saturated solution
of NaHCO3, dried over MgSO4 and concentrated in vacuo. The
crude residue was purified by column chromatography (CH2Cl2–
AcOEt (100 : 0 → 90 : 10)), providing 1,4-di(benzoyl)-piperazine-
2,5-dione 5h in 56% ◦yield (0.318 g) as a white powder. Mp
1,2,4-Tri(acetyl)-piperazine-2,5-dione 7
To a solution of 1,4-di(acetyl)-piperazine-2,5-dione 5k (0.070 g,
0.35 mmol) in dry THF (5 mL) was added tBuOK (0.044 g,
0.39 mmol) at r.t. The solution was stirred for 12 hours under
an argon atmosphere. The medium was then diluted with AcOEt
(10 mL), washed with a solution of 0.1 N HCl (20 mL), dried
over anhydrous MgSO4 and concentrated in vacuo. The crude
residue was purified by column chromatography (CH2Cl2–AcOEt,
100 : 0 → 96 : 4). The desired compound was obtained (0.031 g,
37% yield) as a colorless oil. 1H NMR (CDCl3, 400 MHz): d 2.41 (s,
3H), 2.52 (s, 3H), 2.55 (s, 3H), 3.82 (d, 1H, JAB = 18.1 Hz), 4.95 (d,
1H, JAB = 18.1 Hz), 6.08 (s, 1H); 13C NMR (CDCl3, 100 MHz):
d 26.6, 26.9, 27.4, 46.5, 68.5, 162.3, 165.0, 170.6, 171.2, 197.5;
HRMS (FAB+) m/z calcd for C10H12N2O5 [M + H+] 241.0824,
found 241.0825.
1
(decomposed) = 207 C; H NMR (CDCl3, 400 MHz): d 4.54
(s, 4H), 7.39–7.65 (m, 10H); 13C NMR (CDCl3, 100 MHz): d 48.8,
128.5, 128.9, 133.1, 133.8, 166.6, 170.9; HRMS (FAB+) m/z calcd
for C18H14N2O4 [M + H+] 323.1032, found 323.1042.
(3R)-1,4-Di(benzoyl)-3-isopropylpiperazine-2,5-dione 5j
Mp = 77 ◦C; [a]D20 = -17.6 (c = 1.08, CH2Cl2); 1H NMR (CDCl3,
300 MHz): d 1.18 (t, 6H), 2.22–2.41 (m, 1H), 4.48 (d, 1H, JAB
=
18.8 Hz), 4.88 (d, 1H, JAB = 18.8 Hz), 4.94 (d, 1H, J = 8.4 Hz),
7.40–7.71 (m, 10H); 13C NMR (CDCl3, 75 MHz):d 19.5, 19.7, 32.6,
48.5, 64.2, 128.3 to 132.9, 134.1, 134.3, 167.0, 167.9, 171.1, 171.6;
HRMS (FAB+) m/z calcd for C21H20N2O4 [M + H+] 365.1501,
found 365.1514.
(Z)-1-Acetyl-3-ethylene-piperazine-2,5-dione 8
To a solution of 1,2,4-tri(acetyl)-piperazine-2,5-dione 7 (0.162 g,
0.68 mmol) in 10 mL of dry THF was added LiAlH(OtBu)3
(1.01 mmol) at r.t. under stirring and an argon atmosphere.
After 2 hours, AcOEt (30 mL) was added. The organic layer was
washed with 0.1 N HCl, dried over MgSO4 and concentrated in
vacuo. The crude residue was then purified by silica gel column
chromatography (CH2Cl2–MeOH (100 : 0 → 96 : 4)). The desired
compound was obtained (0.103 g, 83% yield) as a white powder.
1-(Benzoyl)-3-[(benzoyl)amino]-4-hydroxy-3-pyrrolin-2-one 6h
Typical procedure for the rearrangement. To a solution of 1,4-
di(benzoyl)-piperazine-2,5-dione 5h (0.077 g, 0.24 mmol) in dry
THF (5 mL) was added tBuOK (0.030 g, 0.26 mmol) at r.t. The
3994 | Org. Biomol. Chem., 2008, 6, 3989–3996
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Mp = 145 ◦C; 1H NMR (CDCl3, 300 MHz): d 1.80 (d, 3H, J = 7.6
Hz), 2.54 (s, 3H), 4.37 (s, 2H), 6.34 (q, J = 7.6 Hz), 8.66 (br s, 1H);
13C NMR (CDCl3, 75 MHz): d 11.7, 27.1, 45.9, 119.4, 127.3, 159.7,
163.9, 172.6; HRMS (FAB+) m/z calcd for C8H10N2O3 [M + H+]
183.0770, found 183.0775.
NMR (CDCl3, 200 MHz): d 1.35 (s, 9H), 1.54 (s, 9H), 2.22–2.33
(m, 1H), 2.55–2.68 (m, 1H), 2.36–2.48 (m, 1H), 2.80–2.92 (m, 1H),
4.70 (m, 1H), 5.40 (s, 1H), 5.46–5.61 (m, 2H); 13C NMR (CDCl3,
100 MHz): d 28.0, 28.2, 30.3, 33.7, 62.0, 64.4, 81.6, 84.2, 121.9,
124.5, 148.4, 154.6, 170.3, 204.7. HRMS (FAB+) m/z calcd for
C18H26N2O6 [M + H+] 367.4092, found 367.4101.
(5R)-4-Allyloxy-1-benzoyl-3-[(benzoyl)amino]-5-isopropyl-3-
pyrrolin-2-one 11j
(5R)-4-Allyloxy-3-[allyl-(tert-butoxycarbonyl)amino]-1-(tert-
butoxycarbonyl)-5-isopropyl-3-pyrrolin-2-one 17
To a solution of (5R)-1-(benzoyl)-3-[(benzoyl)amino]-4-hydroxy-
5-isopropyl-3-pyrrolin-2-one 6j (0.152 g, 0.42 mmol) in dry DMSO
(5 mL) was added KOH in powder form (0.021 g, 0.37 mmol)
with stirring. Gentle warming was necessary for dissolution. The
mixture changed color from pink to deep violet. Allyl bromide
(0.03 mL, 0.38 mmol) was then added and the medium was
allowed to stir under an argon atmosphere for 6 h. AcOEt (10 mL)
was then added. The organic layer was washed with 0.1 N HCl
(10 mL), dried over MgSO4 and concentrated in vacuo. The crude
residue was purified by column chromatography (CH2Cl2–AcOEt,
100 : 0 → 80 : 20), providing the derivative 11j (0.120 g) as a
To a stirred solution of (5R)-1-(tert-butoxycarbonyl)-3-[(tert-
butoxycarbonyl)amino]-4-hydroxy-5-isopropyl-3-pyrrolin-2-one
6e (0.713 g, 2.00 mmol) in dry DMSO (8 mL) was added KOH
powder (0.280 g, 5.01 mmol). Gentle warming was necessary for
total dissolution. The mixture turned from pink to deep violet.
Allyl bromide (0.44 mL, 5.01 mmol) was then added and the
medium was stirred under an argon atmosphere for 12 hours.
The reaction mixture was diluted with AcOEt (16 mL) and then
washed with 0.1 N HCl (16 mL). The organic layer was dried over
anhydrous MgSO4 and concentrated in vacuo. The crude residue
was purified by flash chromatography on silica gel (CH2Cl2–
AcOEt, 100 : 0 → 80 : 20), providing the derivative 17 (0.665 g) as
a colorless oil in 76% yield. [a]2D0= -46.0 (c = 2.20, CH2Cl2); tr =
14.549 min; 1H NMR (CDCl3, 400 MHz): d 0.79 (d, 3H, J = 6.9
Hz), 1.10 (d, 3H, J = 7.2 Hz), 1.41 (s, 9H), 1.53 (s, 9H), 2.38–2.50
(m, 1H), 3.79–4.34 (m, 2H), 4.28 (s, 1H), 4.68–4.87 (m, 2H), 5.10–
5.40 (m, 4H), 5.81–6.00 (m, 2H); 13C NMR (CDCl3, 100 MHz): d
16.4, 18.9, 28.2, 28.4, 29.5, 52.1, 62.2, 71.5, 81.1, 82.8, 109.3, 119.0,
131.7, 133.2, 149.3, 154.9, 166.9, 167.9; HRMS (FAB+) m/z calcd
for C23H36N2O6 [M + H+] 437.2652, found 437.2627.
1
colorless oil in 71% yield. [a]2D0 = -160.4 (c = 1.11, CH2Cl2); H
NMR (CDCl3, 300 MHz): d 1.10 (d, 3H, J = 7.0 Hz), 1.23 (d,
3H, J = 7.1 Hz), 2.45–2.59 (m, 1H), 4.77–4.92 (m, 2H), 5.00 (d,
1H, J = 2.5 Hz), 5.24–5.39 (m, 2H), 5.85–6.02 (m, 1H), 7.33–
7.82 (m, 11H); 13C NMR (CDCl3, 75 MHz): d 17.3, 18.0, 29.7,
61.8, 71.5, 103.1, 119.1, 127.4 to 132.3, 132.7, 134.9, 168.1, 168.2,
168.3, 169.0; HRMS (FAB+) m/z calcd for C24H24N2O4 [M + H+]
405.1814, found 405.1819.
(3S,5R)-3-Allyl-1-(benzoyl)-3-[(benzoyl)amino]-5-
isopropylpyrrolidine-2,4-dione 12j
(3S,5R)-3-Allyl-3-[allyl-(tert-butoxycarbonyl)amino]-1-(tert-
butoxycarbonyl)-5-isopropylpyrrolidine-2,4-dione 18
A solution of (5R)-4-allyloxy-1-benzoyl-3-[(benzoyl)amino]-5-
isopropyl-3-pyrrolin-2-one 11j (0.020 g, 0.05 mmol) in toluene
(3 mL) with some drops of DMSO was irradiated for 30 min
at 170 ◦C (Biotage Initiator apparatus). The medium was then
concentrated in vacuo and the crude residue was purified by
column chromatography (CH2Cl2–AcOEt, 100 : 0 → 95 : 5),
A
solution of (5R)-4-allyloxy-3-[allyl-(tert-butoxycarbonyl)-
amino]-1-(tert-butoxycarbonyl)-5-isopropyl-3-pyrrolin-2-one 17
(0.180 g, 0.45 mmol) in toluene (3 mL) containing some drops
of DMSO, was irradiated for 30 min at 170 ◦C (Biotage Initiator
apparatus). The medium was then concentrated in vacuo and the
crude residue was purified by column chromatography on silica
gel (CH2Cl2–AcOEt, 100 : 0 → 95 : 5), providing compound 18
as a colorless oil (0.143 g, 73% yield). [a]2D0 = -98.0 (c = 1.48,
CH2Cl2); tr = 15.413 min; 1H NMR (CDCl3, 300 MHz): d 1.06 (d,
3H, J = 7.1 Hz), 1.18 (d, 3H, J = 6.9 Hz), 1.40 (s, 9H), 1.55 (s, 9H),
2.39–2.52 (m, 1H), 2.39–2.67 (m, 2H), 3.93 (d, 1H, J = 5.9 Hz),
4.01 (br s, 2H), 5.10–5.23 (m, 2H), 5.10–5.40 (m, 2H), 5.48–5.62
(m, 1H), 5.81–5.98 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 18.6,
21.4, 28.0, 28.1, 31.4, 37.4, 46.3, 68.4, 69.4, 81.8, 83.4, 115.8, 122.1,
128.4, 135.6, 150.0, 155.3, 171.8, 206.8; HRMS (FAB+) m/z calcd
for C23H36N2O6 [M + H+] 437.2652, found 437.2649.
1
providing 12j in 74% yield (0.015 g) as a colorless oil. H NMR
(CDCl3, 300 MHz): d 1.17 (d, 3H, J = 6.9 Hz), 1.19 (d, 3H, J =
6.6 Hz), 2.50–2.62 (m, 3H), 4.73 (d, 1H, J = 4.4 Hz), 5.20–5.36
(m, 2H), 5.64–5.81 (m, 1H), 6.51 (br s, 1H), 7.32–7.95 (m, 10H);
13C NMR (CDCl3, 75 MHz): d 18.9, 19.4, 29.8, 38.2, 62.6, 67.3,
123.0, 127.4 to 133.9, 166.7, 170.2, 171.0, 205.1.
1-tert-Butoxycarbonylamino-8,9-dioxo-7-aza-bicyclo[4.2.1]non-3-
ene-7-carboxylic acid tert-butyl ester 14a
To a stirred solution of 3,5-trans-diallyl-1-(tert-butoxycarbonyl)-
3-[(tert-butoxycarbonyl)amino]pyrrolidine-2,4-dione 13a (0.226 g,
0.57 mmol) in dichloromethane (8 mL) was added Grubbs’
catalyst (2% mol of benzylidene-[1,3-bis-(2,4,6-trimethylphenyl)-
2-imidazolidinylidene]-dichloro (tricyclohexyl phosphane) ruthe-
nium, 0.010 g in 2 mL of dichloromethane, 0.0115 mmol). The
reaction mixture was stirred for 2 h. DMSO (0.04 mL, 0.48 mmol,
50 equiv. related to catalyst) was then added and the solution was
stirred for an additional 12 hours. After concentration in vacuo,
the residue was purified by flash chromatography on silica gel
(CH2Cl2–AcOEt, 100 : 0 → 85 : 15) to give the compound 14a
(0.176 g, 84% yield) as a solid. Mp = 104 ◦C; tr = 10.937 min; 1H
Baikiain spiro-derivative 15a
To a stirred solution of (3S,5R)-3-allyl-3-[allyl-(tert-butoxy-
carbonyl)amino]-1-(tert-butoxycarbonyl)-5-isopropylpyrrolidine-
2,4-dione 18 (0.105 g, 0.24 mmol) in dichloromethane (5 mL) was
added Grubbs’ catalyst (2% mol of benzylidene-[1,3-bis-(2,4,6-
trimethylphenyl)-2-imidazolidinylidene]-dichloro (tricyclohexyl
phosphane) ruthenium, 0.004 g, in 2 mL of dichloromethane,
0.0048 mmol). The reaction mixture was stirred for 2 hours.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3989–3996 | 3995
©

View Article Online
DMSO (0.02 mL, 0.24 mmol, 50 equiv. related to catalyst)
was then added and the solution was stirred for an additional
12 hours. After concentration in vacuo, the residue was purified
by flash chromatography on silica gel (CH2Cl2–AcOEt, 100 :
0 → 98 : 2) to produce the compound 15a (0.086 g, 88% yield) as
7 C. Alcaraz, M. Dolores Fernandez, M. Pilar de Frutos, J. L. Marco, M.
Bernabe´, C. Foces-Foces and F. H. Cano, Tetrahedron, 1994, 50, 12443.
8 M. Oba, T. Terauchi, Y. Owari, Y. Imai, I. Motoyama, and K.
Nishiyama, J. Chem. Soc., Perkin Trans. 1, 1998, 1275.
9 C. Gallina and A. Liberatori, Tetrahedron, 1974, 30, 667.
10 K. Wimalasena and M. P. D. Mahindaratne, J. Org. Chem., 1994, 59,
3427.
11 P. Wipf and J.-L. Methot, Org. Lett., 2001, 3, 1261.
12 J. D. White and S. C. Jeffrey, J. Org. Chem., 1996, 61, 2600.
13 J. D. White, M. A. Avery, S. C. Choudhry, O. P. Dhingra, B. D. Gray,
M. C. Kang, S. C. Kuo and A. J. Whittle, J. Am. Chem. Soc., 1989, 111,
790.
◦
a solid. Mp = 124 C; tr = 14.275 min; [a]2D0 = -89.0 (c = 1.90,
1
CH2Cl2); H NMR (CDCl3, 300 MHz): d 1.04 (d, 3H, J = 7.0
Hz), 1.08 (d, 3H, J = 7.2 Hz), 1.35 (s, 9H), 1.50 (s, 9H), 2.24–2.36
(m, 1H), 2.40–2.52 (m, 2H), 3.98–4.02 (m, 2H), 4.23 (d, 1H,
J = 4.5 Hz), 5.60–5.70 (m, 1H), 5.86–5.94 (m, 1H); 13C NMR
(CDCl3, 75 MHz): d 19.1, 19.2, 28.0, 28.2, 30.6, 30.9, 43.6, 62.8,
67.0, 81.7, 83.8, 118.5, 126.0, 150.0, 155.1, 171.1, 206.2; HRMS
(FAB+) m/z calcd for C21H32N2O6 [M + H+] 409.2339, found
409.2347.
14 R. A. Holton, C. Somoza, H. B. Kim, F. Liang, R. J. Biediger, D.
Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki,
C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthy, L. N. Gentile and J. H.
Liu, J. Am. Chem. Soc., 1994, 116, 1597.
15 G. S. Singh, M. D’hooghe and N. De Kimpe, Chem. Rev., 2007, 107,
2080.
16 M. Goodman and S. Ro, in Burger’s Medicinal Chemistry and Drug
Discovery Volume I: Principles and Practice, ed. M. E. Wolff, John
Wiley & Sons, New York, 5th edn,1995, vol. 1, pp. 833–838.
17 P. A. Hart, in The Practice of Medicinal Chemistry, ed. C. J. Wermuth,
Academic Press, London, 1996, pp. 393–412.
18 T. K. Sawyer, in Structure-Based Drug Design: Targets, Techniques and
Developments, ed. P. Veerapandian, Marcel Dekker, New York, 1997,
vol. 1, pp. 559–634.
19 V. J. Hruby and P. S. Hill, in Conformational Analysis of Medium-Sized
Heterocycles, ed. R. S. Glass, VCH, New York, 1998, pp. 217–260.
20 A. Fe´lix, in Houben-Weyl Methods in Organic Chemistry: Synthesis of
Peptides and Peptidomimetics, ed. M. Goodman, A. Fe´lix, L. Moroder
and C. Toniolo, Georg Thieme Verlag, Stuttgart, 2004, vol. E22c.
21 A. Giannis and T. Kolter, Ang. Chem., Int. Ed. Engl., 1993, 32, 1244.
22 J. Gante, Ang. Chem., Int. Ed. Engl., 1994, 33, 1699.
23 P. Gillespie, J. Cicariello and G. L. Olson, Biopolymers, 1997, 43, 191.
24 S. Hanessian, G. McNaughton-Smith, H.-G. Lombart and W. D.
Lubell, Tetrahedron, 1997, 53, 12789.
25 A. S. Ripka and D. H. Rich, Curr. Opin. Chem., 1998, 441.
26 O. Labbuda-Dawidowska, T. H. Wierzba, A. Prahl, W. Kowalczyk, L.
Gawinski, M. Plackova, J. Slaninova and B. Lammek, J. Med. Chem.,
2005, 48, 8055.
(3R)-3-isoPropyl-1-oxo-1,3,5,8-tetrahydro-4-oxa-2,9-diaza-
cyclopentacyclooctene-2,9-dicarboxylic acid di-tert-butyl ester 16a
To a stirred solution of (5R)-4-allyloxy-3-[allyl-(tert-butoxy-
carbonyl)amino]-1-(tert-butoxycarbonyl)-5-isopropyl-3-pyrrolin-
2-one 17 (0.403 g, 0.92 mmol) in dichloromethane (20 mL)
was added Grubbs’ catalyst (2% mol of benzylidene-[1,3-bis-
(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro (tricyclo-
hexyl phosphane) ruthenium, 0.016 g, in 2 mL of dichloromethane,
0.0185 mmol). The reaction mixture was stirred for 2 h. DMSO
(0.08 mL, 0.92 mmol, 50 equiv. related to catalyst) was then
added and the solution was stirred for an additional 12 hours.
After concentration in vacuo, the residue was purified by flash
chromatography on silica gel (CH2Cl2–AcOEt, 100 : 0 → 80 : 20)
to produce the compound16a (0.295g, 78%yield)as acolorless oil.
The 1H NMR spectrum of compound 16a gave two sets of peaks
for the methyl protons of one Boc and also two sets of peaks for the
isopropyl group. A high-temperature 1H NMR study in DMSO-d6
allowed us to correlate this observation with E/Z isomerisation
of the N1-Boc. Coalescence of the proton resonances occurred
at 120 ◦C. Once back at room temperature, the splitting of the
signals returned and the NMR spectrum was identical to the
initial spectrum, allowing us to prove that the compound was
not damaged. [a]2D0 = -66.9 (c = 1.45, CH2Cl2); tr = 13.428 min;
27 R. M. Freidinger, D. F. Veber, D. S. Perlow, J. R. Brooks and R.
Saperstein, Science, 1980, 210, 656.
28 R. M. Freidinger, D. S. Perlow and D. F. Veber, J. Org. Chem., 1982,
47, 104.
29 S. J. Miller, H. E. Blackwell and R. H. Grubbs, J. Am. Chem. Soc.,
1996, 118, 9606.
30 F. P. J. T. Rutjes and H. E. Schoemaker, Tetrahedron Lett., 1997, 38,
677.
31 A. J. Phillips and A. D. Abell, Aldrichimica Acta, 1999, 32, 75.
32 C. J. Creighton and A. B. Reitz, Org. Lett., 2001, 3, 893.
33 R. D. Long and K. D. Moeller, J. Am. Chem. Soc., 1997, 119, 12394.
34 D. Trancard, J. B. Tout, T. Giard, I. Chichaoui, D. Cahard and J.-C.
Plaquevent, Tetrahedron Lett., 2000, 41, 3843.
35 M. Gutie´rrez-Rodriguez, M. T. Garcia-Lopez and R. Herranz, Tetra-
hedron, 2004, 60, 5177.
36 C. Cativiela and M.-D. Diaz-de-Villegas, Tetrahedron: Asymmetry,
2000, 11, 645.
37 J. S. Clark and M. D. Middelton, Org. Lett., 2002, 4, 765.
38 K.-P. Park and M. J. Kurth, Tetrahedron, 2002, 58, 8629.
39 T. Kawabata, S. Kawakami and S. Majumdar, J. Am. Chem. Soc., 2003,
125, 13012.
◦
1H NMR (DMSO-d6, 400 MHz) at 25 C: d 0.60 (m, 1H), 0.72
(d, 2H, J = 7.0 Hz), 0.90 (m, 1H), 0.97 (d, 2H, J = 7.2 Hz), 1.28
(s, 3H), 1.34 (s, 6H), 1.53 (s, 9H), 2.18–2.37 (m, 1H), 3.39–3.61
(m, 1H), 4.17 (d, 1H, J = 2.5 Hz), 4.42–5.15 (m, 3H), 5.72–5.92
(m, 2H);13C NMR (CDCl3, 100 MHz) at 25 ◦C: d 16.0, 18.5,
18.8, 28.1, 28.3, 29.8, 30.2, 49.7, 62.2, 63.6, 81.2, 81.5, 82.6, 109.0,
121.2, 136.5, 149.3, 154.6, 166.3, 167.3; HRMS (FAB+) m/z calcd
for C21H32N2O6 [M + H+] 409.2339, found 409.2324.
40 T. Ooi, T. Miki and K. Maruoka, Org. Lett., 2005, 7, 191.
41 F. E. King, T. J. King, and A. J. Warwick, J. Chem. Soc., 1950,
3590.
42 L. A. Watanabe, S. Haranaka, B. Jose, M. Yoshida, T. Kato, M.
Moriguchi, K. Soda and N. Nishino, Tetrahedron: Asymmetry, 2005,
16, 903.
Notes and references
1 D. Farran, I. Parrot, J. Martinez and G. Dewynter, Angew. Chem., Int.
Ed., 2007, 46, 7488.
2 S. D. Lee, T. H. Chan and K. S. Kwon, Tetrahedron Lett., 1984, 25,
3399.
3 O. Hara, M. Ito and Y. Hamada, Tetrahedron Lett., 1998, 39, 5537.
4 B. J. L. Royles, Chem. Rev., 1995, 95, 1981.
5 D. Farran, L. Toupet, J. Martinez and G. Dewynter, Org. Lett., 2007,
9, 4833.
6 T. Coursindel, D. Farran, J. Martinez and G. Dewynter, Tetrahedron
Lett., 2008, 49, 906.
43 R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413.
44 S. J. Miller, S.-H. Kim, Z.-R. Chen and R. H. Grubbs, J. Am. Chem.
Soc., 1995, 117, 2108.
45 Experiments were performed on Silicon Graphics Indigo using Dis-
cover Molecular Simulation program, Biosym/MSI (Accelrys, San
Diego, USA).
3996 | Org. Biomol. Chem., 2008, 6, 3989–3996
This journal is
The Royal Society of Chemistry 2008
©