A new benzotriazole-mediated stereoflexible gateway to hetero-2,5- diketopiperazines

Article abstract of DOI:10.1002/chem.201103143

Open chain Cbz-L-aa¹-L-Pro-Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans- or cis-fused 2,5- diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans-DKPs (69-75%). Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65-72%). A representative set of proline-containing cis- and trans-DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results. Stereoflexible route to DKPs: A convenient, versatile, and flexible benzotriazole-mediated methodology for the synthesis of proline-containing hetero-2,5-diketopiperazines (DKPs) is reported. Depending on the reaction conditions, either cis- or trans-configured DKPs were obtained starting from the same inexpensive l,l-dipeptidoyl benzotriazole key intermediate (see scheme). Kinetics, chiral HPLC, and computational studies forged a background for mechanistic rationalization. Copyright

Full text of DOI:10.1002/chem.201103143

DOI: 10.1002/chem.201103143
A New Benzotriazole-Mediated Stereoflexible Gateway to Hetero-2,5-
diketopiperazines
Jean-Christophe M. Monbaliu,[a, b] Finn K. Hansen,[a] Lucas K. Beagle,[a]
Matthew J. Panzner,[c] Peter J. Steel,[d] Ekaterina Todadze,[a] Christian V. Stevens,[b] and
Alan R. Katritzky*[a, e]
Abstract: Open chain Cbz-l-aa1-l-Pro-Bt (Bt=benzotriazole) sequences were con-
verted into either the corresponding trans- or cis-fused 2,5-diketopiperazines
(DKPs) depending on the reaction conditions. Thermodynamic tandem cycliza-
tion/epimerization afforded selectively the corresponding trans-DKPs (69–75%).
Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65–72%).
A representative set of proline-containing cis- and trans-DKPs has been prepared.
A mechanistic investigation, based on chiral HPLC, kinetics, and computational
studies enabled a rationalization of the results.
Keywords: diketopiperazines · den-
sity functional calculations · pep-
tides
· stereoflexible · synthetic
methods
Introduction
Among the wide variety of peptidic structures, small cyclic
peptides form a fascinating subgroup. The broad range of
available natural or synthetic amino acids generates a nearly
infinite combination of cyclic structures with intrinsically
specific behavior.
The smallest cyclic peptidoyl sequence, that is, the 2,5-di-
ketopiperazine (DKP) backbone, is a prominent fragment in
a plethora of naturally occurring molecules (Scheme 1).[1]
Among the proteinogenic amino acids that could be includ-
ed in such a sequence, proline which plays an important role
in protein folding also confers to proline-containing DKPsꢀ
useful properties to mimic specific protein domains such as
[a] Dr. J.-C. M. Monbaliu, Dr. F. K. Hansen, L. K. Beagle,
Dr. E. Todadze, Prof. Dr. A. R. Katritzky
Center for Heterocyclic Compounds
Department of Chemistry, University of Florida
Gainesville, FL 32611-7200 (USA)
E-mail: katritzky@chem.ufl.edu
Scheme 1. Naturally occurring molecules with the smallest cyclic peptido-
yl sequence.
[b] Dr. J.-C. M. Monbaliu, Prof. Dr. C. V. Stevens
Dept. of Sustainable Organic Chemistry and
Technology Faculty of Bioscience Engineering
Ghent University, 9000 Ghent (Belgium)
b-turns or loop motifs.[2] The cyclic and constrained nature
of these DKPs improves bioavailability and resistance to en-
zymatic degradation in comparison to their linear analogues.
Lipophilicity of the lateral chains can be easily tuned simply
by adapting their nature.[3] The DKP backbone favors mo-
lecular diversity with up to six positions capable of function-
alization, two being stereogenic centers.[4]
A wide range of biological activity has been reported so
far: antibiotic,[5] insecticidal,[6] antimitotic,[7] chemosensitiz-
ing,[8] anti-HIV,[9] and so forth.[10,11] All these properties
[c] Dr. M. J. Panzner
Department of Chemistry, University of Akron
Akron, OH 44325 (USA)
[d] Prof. Dr. P. J. Steel
Department of Chemistry, University of Canterbury
Christchurch 8020 (New Zealand)
[e] Prof. Dr. A. R. Katritzky
Chemistry Department, King Abdulaziz University
Jeddah, 21589 (Saudi Arabia)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103143.
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FULL PAPER
make DKPs substantial building blocks for the discovery of
new leads and therapeutic agents.
As a consequence of their predominant biosynthetic
origin from l-a-amino acids, most naturally occurring fused
DKPs are cis-configured, and considerable research atten-
tion has been given to their synthesis.[2,10,11] cis-Cyclic dipep-
tide synthesis usually starts from appropriately protected
amino acids/peptidic subunits either in solution or on solid
phase.[10–12] Literature synthetic methods can be classified
into three main strategies: 1) head-to-tail condensation be-
tween the N- and C-termini of the corresponding linear di-
peptides;[13] 2) dimerization of two peptidic subunits;[14] and
3) formally non-peptidic coupling reactions.[15] Despite the
apparent hegemony of cis-DKPs, an increasing number of
reports of trans-configured DKPs with non-proteinogenic d-
a-amino acids have appeared over recent years.[13c] Promis-
ing anticancer,[7] anti-HIV,[9] and antibiotic activities[16] have
already been reported. Recently, trans-DKPs were reported
as building blocks for foldamers.[17] Studies have shown that
a trans-DKP backbone, especially when d-proline is includ-
ed, may retard metabolism and provide potent drugs with
increased half-life[18] or selectivity by mimicry of specific
substrates.[19] The thermodynamically more stable trans-
DKPs are usually synthesized either directly from the more
expensive d-Pro-containing sequence[9,18,20] or by epimeriza-
tion of the corresponding cis-DKP.[5b,21] Epimerization was
often reported as a side reaction upon cyclization[22] or upon
further functionalization[5b,23] leading to cis/trans-DKP mix-
tures in various ratios, thus decreasing reaction efficiency.
Despite the considerable exploration to date, there is still
a need for further development of alternative, flexible, and
cost-effective synthetic strategies. Our longstanding involve-
ment in benzotriazole (Bt)-mediated oligopeptide chemistry
prompted us to design a new, versatile, and flexible strategy
able to provide either cis- or trans-configured DKPs starting
from the same inexpensive l,l-dipeptidoyl benzotriazoles.
We now report that tandem triethylamine-catalyzed cycliza-
tion/epimerization leads to trans-DKPs, whereas a tandem
deprotection/cyclization affords the corresponding cis-DKPs.
A mechanistic investigation, based on chiral HPLC, kinetic
experiments, and computation afforded rationalization.
Scheme 2. Synthesis of Cbz-dipeptides 2a–g (for designation of a–g, see
Table 1).
Table 1. Synthesis of Cbz-l,l-dipeptides 2a–g.
2
R1
A[a]
Yield [%]
B[b]
Yield [%]
t [min]
t [min]
a
b
c
d
e
f
H
Me
PhSCH2
iPr
iBu
120
120
180
300
180
180
180
76
92
89
77
91
89
91
5
5
87
92
91
85
94
95
90
10
15
10
10
10
Bn
g
INDM[c]
[a] MeCN/water 3:1, 1 equiv Et3N, RT. [b] MeCN/water 3:1, 1 equiv
Et3N, MW, 50 8C. [c] 1H-Indol-3-ylmethyl.
Dipeptides 2a–g were then converted into their corre-
sponding benzotriazole derivatives 3a–g. When carried out
at À108C, the reaction of 2a–g with in situ generated
BtS(O)Bt[24] led cleanly, and without epimerization, to the
desired Cbz N-protected dipeptidoyl benzotriazoles 3a–g in
good to high yield (61–87%, Scheme 3), although at room
temperature, notable degradation of the dipeptidoyl com-
pounds 2a–g was observed.
Scheme 3. Preparation of benzotriazole derivatives 3a–g.
Preliminary investigation: Preparative conditions for cycliza-
tion were first optimized using compound 3a (R1 =H,
Scheme 4 and Table 2). Different co-reagents, solvents and
reaction conditions were assessed both under conventional
Results and Discussion
Synthesis of the starting materials: Dipeptides 2a–g were
obtained from the readily available and stable l-Cbz-N-pro-
tected (a-aminoacyl)benzotriazoles 1a–g and l-proline ac-
cording to the mild conditions of our previously reported
procedure (Scheme 2, conditions A).[24] At room tempera-
ture, the reaction was usually complete within 3 h in aque-
ous acetonitrile in the presence of triethylamine (Table 1,
conditions A). Significant improvements in reaction time
and yield were observed under microwave heating
(Scheme 2, conditions B), which led to the corresponding
enantiopure dipeptides 2a–g within 15 min in 85–95% yield
and high purity (Table 1, conditions B).
Scheme 4. Cyclization/racemization sequence to rac-4a.
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A. R. Katritzky et al.
Table 2. Optimization of the cyclization conditions for compound 3a
under MW heating.
Entry
Cpd
Solvent
Co-reagent (equiv)
t [min][a]
Isolated
rac-4a [%]
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a’
3a
3a
3a
3a
MeCN
MeCN
MeCN
MeCN
MeCN
THF
MeCN
MeCN
MeCN
none
60
60
60
20
20
40
25
40
20
0
0
0
83
80
83
75
72
0[b]
pyridine (1)
NaHCO3 (5)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (0.1)
Et3N (0.01)
DBU (1)
Scheme 5. Cyclization/racemization sequence to rac-4h.
observations seem to implicate the Cbz group in effecting
this stereochemical outcome.
[a] 808C, 70 W. [b] Complete degradation was observed.
Development of a novel tandem trans-selective cyclization/
epimerization sequence: Following this first set of observa-
tions, we postulated that with a stereogenic center present
in position 3, the cyclization of proline-containing Cbz-N-
protected dipeptidoyl benzotriazoles under thermodynamic
conditions would lead to the corresponding trans-DKPs. To
prove this concept, a series of chiral HPLC experiments was
designed (Table 3). A number of authentic stereomeric Cbz-
and microwave (MW) heating. No reaction was observed
when compound 3a was MW irradiated in acetonitrile with-
out additive for 60 min (Table 2, entry 1), whereas the con-
version reached just 14% after 18 h reflux in acetonitrile.
With pyridine or sodium bicarbonate in acetonitrile, no re-
action was observed and the starting material was recovered
without notable degradation (Table 2, entries 2 and 3).
When carried out in the presence of triethylamine (1 equiv),
the reaction led to the desired, but racemized, DKP rac-4a
(Table 2, entry 4). Compound 3a’ with a d-proline moiety
similarly led upon Et3N-induced cyclization to rac-4a
(Table 2, entry 5). Both batches gave a similar chiral HPLC
profile (see the Supporting Information). In THF, the reac-
tion required prolonged irradiation to reach a similar con-
version (Table 2, entry 6). In the presence of water, the hy-
drolysis of 3a was mainly observed. With substoichiometric
amounts of triethylamine (0.1 equiv or 0.01 equiv), the cycli-
zation, concomitant with racemization, proceeded as well
but required a prolonged reaction time (Table 2, entries 7
and 8). Addition of 1,8-diazabicycloundec-7-ene (DBU) led
to complete degradation of the dipeptidoyl benzotriazole 3a
(Table 2, entry 9). The reaction was significantly accelerated
under MW heating, as shown by the experimental pseudo-
Table 3. Chiral HPLC analysis.[a]
Entry
X,Y-3[b]
Yield 4 [%]
tR [min]
Stereochem. 4
1
2
3
4
5
6
7
8
9
ld,l-3b
l,l-3b
l,d-3b
d,l-3b
d,d-3b
l,l-3e
l,d-3e
d,l-3e
d,d-3e
70
69
72
71
63
75
77
79
69
42.0, 43.3
43.3
43.3
41.9
42.0
35.2
35.1
37.9
37.9
l,d+d,l-4b
l,d-4b
l,d-4b
d,l-4b
d,l-4b
l,d-4e
l,d-4e
d,l-4e
d,l-4e
[a] Chiral HPLC was performed using a Chirobiotic T column. Flow
rate=0.1 mLminÀ1; eluent=methanol. [b] X,Y-3 refer to the Cbz-dipeti-
doyl benzotriazole sequence with an alanine (3b) or leucine (3e) residue
of stereochemistry X and a proline residue of stereochemistry Y.
N-dipetidoyl benzotriazole sequences containing Ala-Pro or
Leu-Pro residues were synthesized according to our proce-
dure and subjected to thermodynamic tandem cyclization/
epimerization using the optimized conditions described
above (sequences 3b and 3e, Cbz-N-Ala-Pro-Bt and Cbz-N-
Leu-Pro-Bt, respectively; see Table 3 for designation and
stereochemistry assignments). After reaction, the crude mix-
tures were purified by column chromatography, and subse-
quently analyzed by chiral HPLC affording the expected
DKPs.
The results gathered from Table 3 provided clear evidence
for the postulated epimerization. Firstly, the cyclization of
compound ld,l-3b led to a racemic mixture of the trans-
DKPs l,d-4b and d,l-4b (Table 3, entry 1). The two enan-
tiomers were co-crystallized and the relative (trans) configu-
ration was unambiguously assigned by X-ray diffraction
(Figure 1). The cyclized DKPs obtained either from l,l-3b
and l,d-3b gave the same HPLC profile, with a unique re-
tention time of 43.3 min (Table 3, entries 2 and 3). Similar
HPLC profiles were later obtained for the cyclized DKPs
obtained either from d,l-3b and d,d-3b (Table 3, entries 4
first-order kobs rate constants: k =0.31 sÀ1 and k
=
conv
obs
MW
obs
0.59 sÀ1, at 658C under conventional and microwave heating
respectively. At 808C, under microwave irradiation, the re-
action reached completion within 20 min with 1 equiv of
triethylamine in acetonitrile.
The unexpected racemization of DKP 4a probably arose
by base-induced enolization of the primary DKP
(Scheme 4). In the absence of any stereocenter in position 3
to act as a chiral memory, the racemate was obtained. The
literature data emphasize that proline-containing DKPs are
more inclined to acid- or base-induced prototropy than non-
proline ones,[21] nevertheless, racemization was also observed
(Scheme 5) upon cyclization of Cbz-N-glycyl-l-leucyl benzo-
triazole (3h). The racemate rac-4h was isolated in modest
yield after a prolonged reaction time, highlighting the turn-
inducer effect of a proline residue.[25] Interestingly, a recent
report from Simpkins et al.,[23a] in which p-methoxybenzyl-
N-protected proline-containing DKPs were cyclized under
harsh conditions, did not mention any epimerization. Our
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Benzotriazole-Mediated Gateway to Hetero-2,5-diketopiperazines
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trans-DKP 4e was then subjected to N-deprotection
under a hydrogen atmosphere in the presence of Pd/C for
24 h at room temperature. After recrystallization, the corre-
sponding free trans-2,5-diketopiperazine 5e was obtained in
87% yield.
Development of the cis-selective tandem deprotection/cycli-
zation sequence: As a complementary route to the one dis-
cussed for the preparation of trans-2,5-diketopiperazines but
leading to unprotected cis-2,5-diketopiperazines, a one-pot
two-step condensation–deprotection procedure was devel-
oped from the intermediate Cbz-dipeptidoyl benzotriazoles
3a, 3b, and 3e (Scheme 7). Compound 3a was stirred under
Figure 1. X-ray crystal structures of the racemic l,d+d,l-4b (left, d,l-
enantiomer shown) and l,d-4e (right). Both pictures show clearly the
trans configuration of the DKPs.
and 5), showing a single signal at about 42.0 min. These re-
sults were supported by measurement of the optical rotation
(see the Experimental Section). These data allowed us to
unambiguously assign a trans-configuration for all synthe-
sized DKPs regardless of the initial configuration. Similarly,
results gained for the Leu-Pro series (Table 3, entries 6–9)
were consistent with a trans-configuration for all DKPs syn-
thesized. In the case of l,d-4e, the absolute configuration
was determined by anomalous dispersion using a CuKa X-
ray source. These results were confirmed by X-ray crystal
structures of the DKPs from Table 3, entries 6 and 7
(Figure 1).
Under the conditions optimized by this initial screening, a
library of representative proline-containing trans-2,5-diketo-
piperazine (4b–g) was obtained from the corresponding
Cbz-l-aa1-l-Pro-Bt sequence (3b–g), with complete and se-
lective epimerization at position 6, in high yields (69–75%,
Scheme 6 and Table 4). 2D Homo- and heteronuclear NMR
correlation confirmed the structures. All condensations were
carried out with 1 equivalent Et3N to ensure short reaction
times. The crude mixtures were purified by column chroma-
tography to afford directly the corresponding pure trans-2,5-
diketopiperazines 4b–g.
Scheme 7. Tandem deprotection/cyclization to DKPs 5a,b and 5e.
a hydrogen atmosphere in the presence of Pd/C (10 wt%) at
room temperature for 18 h. After filtration through Celite
and recrystallization from ethanol/hexanes, compound 5a
was obtained in high yield (72%) as a single enantiomer.
Comparison of the optical rotation measured for compound
5a was consistent with the reported value,[13c] confirming
that this tandem deprotection/cyclization proceeded without
epimerization.
The same conditions were applied to Cbz-dipeptidoyl
benzotriazoles 3b and 3e, leading to the corresponding cis-
DKPs cis-5b and cis-5e in 65–69% yield, respectively. Their
[a]D values were consistent with the values reported in the
literature. Notably, a negative [a]D was obtained for cis-5e,
whereas a positive value was measured for trans-5e. As a
further structural proof, the NMR spectra of compounds
were found to be in total agreement with a recent report
(see the Supporting Information).[13c]
Mechanistic investigation: Kinetic and computational stud-
ies afforded a mechanistic rationalization. Pseudo-first-order
kinetics were observed for the base-catalyzed head-to-tail
condensation of compound 3a. The apparent rate constants,
kobs, for the formation of DKP 4a in CD3CN with 1 equiva-
lent Et3N were obtained at 35, 45, 55, and 658C by linear re-
gression of semi logarithmic first-order plots (see the Sup-
porting Information). A plot of the temperature dependence
of kobs allowed determination of the Arrhenius activation
energy (Ea =39.7 kJmolÀ1) and activation parameters
(DH° =37.0 kJmolÀ1 and DS° =À146.2 JKÀ1 molÀ1). The
negative activation entropy value is characteristic of the ex-
pected, highly ordered (cyclic) transition state.
Scheme 6. Tandem cyclization/epimerization of Cbz-dipeptidoyl benzo-
triazoles 3b–g and further deprotection.
Table 4. Optimal conditions for the tandem cyclization/epimerization of
3b–g.
Cpd 4
R1
Conditions
Isolated yield [%]
b
c
d
e
f
Me
BnSCH2
iPr
70 W, 808C, 20 min
70 W, 808C, 35 min
70 W, 1208C, 35 min
70 W, 808C, 30 min
70 W, 808C, 35 min
70 W, 808C, 35 min
69
72
70
75
71
73
iBu
Bn
Computations at the B3LYP/6-31+G* level on model
compounds suggest two possible mechanisms for the DKPs
g
INDM[a]
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A. R. Katritzky et al.
formation: a unimolecular (unassisted) mechanism in which
the triazole leaving group also acts as a base and a bimolec-
ular assisted mechanism, in which Me3N (as a model for
Et3N) was introduced to induce cyclization by facilitating
the proton abstraction (Figure 2).
Figure 3. Relative energies (B3LYP/6-31+G*) of cis-DKPs and their cor-
responding enols.
Figure 2. Pictures of the transition states associated with the unimolecular
unassisted mechanism (TSuni, left) and with the bimolecular assisted
mechanism (TSbi, right). Cbz and benzotriazole groups are modeled by a
methyl carbamate and a triazole group, respectively.
Conclusion
We have provided a versatile, mild and efficient entry to
hetero-2,5-diketopiperazines from N-protected dipeptidoyl
benzotriazoles. Depending on the cyclization conditions, we
were able to obtain selectively trans- or cis-DKPs. This
methodology is compatible with a wide variety of amino
acids. Stereoselectivities and mechanism have been rational-
ized by chiral HPLC, kinetics and computational studies.
Computational and kinetic data allowed us to provide a
mechanistic interpretation and to emphasize the ambivalent
character of benzotriazole. By comparison to the previously
reported procedures, our methodology is endowed with a
strong utility: flexibility, cost- and atom-efficiencies. Given
that there are an increasing number of studies involving the
synthesis of trans- and cis-DKPs stereoisomers to compare
their biological activities, we believe this new approach rep-
resents a significant breakthrough in the field.
A conformation scan showed that the most stable confor-
mer for compound 3a is twisted in a ready-to-cyclize confor-
mation. The computed activation barrier (B3LYP/6-31+G*)
was significantly lower for the assisted bimolecular mecha-
nism (E° =43.6 kJmolÀ1 vs. 114.0 kJmolÀ1 for the unassisted
unimolecular mechanism), supporting the catalytic assis-
tance of triethylamine in this reaction, which is in agreement
with our experimental observations. A conformation scan
for a non-proline-containing model glycylalanoyl triazole
showed that the most stable conformer is completely linear.
Activation barriers were similarly computed for a non-pro-
line-containing model dipeptidoyl triazole; the higher acti-
vation energy (E° =175.7 kJmolÀ1) clearly emphasized the
positive impact of a proline residue for the cyclization of di-
peptides.
The difference in energy between the cis- and the trans-di-
ketopiperazines was calculated for model cyclo(Cbz-N-l-
Ala-l-Pro) and cyclo(Cbz-N-l-Ala-d-Pro) compounds. The
difference in energy was found to be 12.2 kJmolÀ1 in favor
of the thermodynamic trans-DKP (cyclo(Cbz-N-l-Ala-d-
Pro)). As illustrated in Scheme 4 and discussed above, the
formation of the trans-DKPs from the corresponding open
chain Cbz-l-aa1-l-Pro-Bt sequences is assumed to arise from
an enolization followed by a thermodynamic protonation on
the Si-face of the DKPs.[26] The Cbz group appears to play a
crucial role, as emphasized hereafter in Figure 2. Indeed,
energy differences computed for some N-protected cis-
DKPs (left in Figure 3) and the corresponding enols (right
in Figure 3) have showed that the presence of a Cbz protect-
ing group (modeled by a methyl carbamate) significantly
lowers (42.4 kJmolÀ1 for enol-4a versus 98.2 kJmolÀ1 for
enol-6a) the difference in energy between the cis-DKP and
its corresponding enol.
Experimental Section
General: 1H NMR spectra were recorded at 300 MHz and 13C NMR
spectra were recorded at 75 MHz on Gemini or Varian spectrometers at
room temperature. The chemical shifts are reported in ppm relative to
TMS as internal standard (1H NMR) or to the residual solvent peak
(13C NMR). The NMR experiments at variable temperatures (35, 45, 55,
and 658C) were recorded on a Varian Inova NMR spectrometer operat-
ing at 500 MHz. Chiral HPLC experiments were performed on a Chiro-
biotic-T column using methanol as mobile phase. Compounds were ana-
lyzed at a flow rate of 0.1 mLminÀ1 (detection wavelength=230 nm, sol-
vent=methanol). HRMS spectra were recorded on a LC TOF (ES) ap-
paratus. Elemental analysis was performed on a Carlo Erba-1106 instru-
ment. Melting points were determined on a capillary point apparatus
equipped with a digital thermometer and are uncorrected. [a]2D1 values
were recorded on a Perkin–Elmer polarimeter. [a]2D1 values are given in
degcm3 cmÀ1 gÀ1 and concentration are given in mg100 cmÀ3. CCDC-
844866, CCDC-844865, and CCDC-846343 contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Flash chromatography was per-
formed on silica gel 60 (230–400 mesh). All solvents were dried according
to standard procedures. Triethylamine was distilled prior to use. All com-
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Benzotriazole-Mediated Gateway to Hetero-2,5-diketopiperazines
FULL PAPER
mercially available substrates were used as received without further pu-
rification. All microwave-assisted reactions were carried out with a single
mode cavity Discover Microwave Synthesizer (CEM Corporation, NC).
The reaction mixtures were transferred into a 10 mL glass pressure mi-
crowave tube equipped with a magnetic stirrer bar. The tube was closed
with a silicon septum and the reaction mixture was subjected to micro-
wave irradiation (Discover mode; run time: 60 s; PowerMax-cooling
mode). Cbz N-protected amino acids were purchased from Chem-Impex
International.
41.1, 29.4, 24.9, 23.0, 22.8, 22.0 ppm; elemental analysis calcd (%) for
C19H24N2O4: C 66.26, H 7.02, N 8.13; found: C 66.18, H 7.25, N 8.07; crys-
tal data (CCDC-844866): C19H24N2O4; MW=344.40; colorless block;
monoclinic; P21; a=9.8826(6), b=8.7994(5), c=10.6857(6) ꢂ; b=
106.798(3)8; V=889.59(9) ꢂ3; Z=2; T=À1608C;
F
G
m
(MoKa)=0.091 mmÀ1, Dcalcd =1.286 gcmÀ3, 2qmax 508 (Bruker Apex II,
100% completeness), wR(F2)=0.0728 (all 3490 data), R=0.0310 (3148
data with I>2sI); crystal data (CCDC-846343) obtained using a CuKa X-
ray source: monoclinic; P21; a=9.8547 (5), b=8.7811 (4), c=
10.6717(6) ꢂ; b=106.843(3)8; V=883.86(9) ꢂ3; Z=2; T=À1608C; F-
General procedure for the tandem cyclization/epimerization sequence: A
solution of Cbz N-protected dipeptidoyl benzotriazole 3a–h (1 mmol)
and triethylamine (1 mmol) in dry acetonitrile (4 mL) was subjected to
microwave irradiation (for conditions, see Table 4). Upon completion,
the reaction mixture was concentrated under vacuum and the crude mix-
ture was directly purified by column chromatography (hexanes/ethyl ace-
tate gradient) to give the corresponding rac-diketopiperazines 4a,h or
trans-diketopiperazines 4b–g.
AHCTUNGTRE(GNUNN 000)=368; m ; D ; qmax 66.598
(CuKa)=0.744 mmÀ1 calcd =1.294 gcmÀ3
(Bruker Apex II, 100% completeness); wR(F2)=0.0612 (all 2926 data);
R=0.0234 (2907 data with I>2sI).
cyclo(Z-d-Leu-l-Pro) trans-d,l-4e: 79% yield (0.27 g), white solid. M.p.
1
118–1198C; [a]2D1 =À102.2 (c=0.2 in dichloromethane); H and 13C NMR
were identical to its enantiomer l,d-4e; elemental analysis calcd (%) for
C19H24N2O4: C 66.26, H 7.02, N 8.13; found: C 66.11, H 7.31, N 8.01.
cyclo(Z-Gly-d-Pro) rac-4a:[27] Yield: 83% (0.23 g), white microcrystals.
M.p. 110–1118C; [a]2D1 =0 (c=0.2 in dichloromethane); 1H NMR
(300 MHz, CDCl3): d=7.43–7.27 (m, 5H), 5.29 (d, J=12.3 Hz, 1H), 5.26
(d, J=12.3 Hz, 1H), 4.72 (d, J=16.5 Hz, 1H), 4.29–4.08 (m, 2H), 3.54
(dd, J=8.2, 5.8 Hz, 2H), 2.50–2.20 (m, 2H), 2.08–1.82 ppm (m, 2H);
13C NMR (75 MHz, CDCl3): d=167.4, 163.1, 151.9, 134.7, 128.8, 128.4,
69.5, 60.4, 50.0, 45.4, 28.2, 23.2 ppm; elemental analysis calcd (%) for
C15H16N2O4: C 62.49, H 5.59, N 9.72; found: C 62.09, H 5.61, N 9.64.
cyclo(Z-l-Phe-d-Pro) trans-4 f: 71% yield (0.27 g), colorless gel. [a]D21
=
79.89 (c=0.2 in dichloromethane); 1H NMR (300 MHz, CDCl3): d=
7.43–7.34 (m, 5H), 7.28–7.23 (m, 3H), 7.13–7.09 (m, 2H), 5.29 (d, J=
12.3 Hz, 1H), 5.23 (d, J=12.3 Hz, 1H), 5.09 (t, J=5.0 Hz, 1H), 3.58–3.48
(m, 1H), 3.44–3.36 (m, 1H), 3.31–3.18 (m, 2H), 2.60 (dd, J=9.8, 6.8 Hz,
1H), 2.18–2.04 (m, 1H), 1.92–1.77 (m, 2H), 1.70–1.56 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=167.4, 164.3, 152.1, 135.1, 134.8, 130.1,
128.8, 128.8, 128.4, 127.8, 69.3, 62.6, 58.9, 45.1, 38.5, 29.4, 22.1 ppm; ele-
mental analysis calcd (%) for C22H22N2O4·1/2H2O: C 68.20, H 5.98, N
7.23, found: C 68.30, H 6.01, N 6.92.
cyclo(Z-l-Ala-d-Pro) trans-l,d-4b: 69% yield (0.20 g), white microcrys-
tals. M.p. 149–1508C; [a]2D1 =101.0 (c=0.2 in dichloromethane); 1H NMR
(300 MHz, CDCl3): d=7.50–7.31 (m, 5H), 5.30 (s, 2H), 4.86 (q, J=
7.2 Hz, 1H), 4.20 (dd, J=9.3, 7.2 Hz, 1H), 3.62–3.52 (m, 2H), 2.49–2.39
(m, 1H), 2.25–1.85 (m, 3H), 1.53 ppm (d, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=167.4, 165.9, 151.9, 134.8, 128.8, 128.7, 128.3, 69.3,
59.4, 57.6, 45.6, 29.2, 22.8, 17.4 ppm; elemental analysis calcd (%) for
C16H18N2O4: C 63.56, H 6.00, N 9.27; found: C 63.92, H 6.08, N 9.29.
cyclo(Z-l-Trp-d-Pro) trans-4g:[28] 73% yield (0.27 g), white solid. M.p.
77–798C; [a]2D1 =135.5 (c=0.2 in dichloromethane); 1H NMR (300 MHz,
CDCl3): d=8.70 (sbr, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.43–7.28 (m, 6H),
7.20–7.04 (m, 2H), 6.86 (d, J=2.4 Hz, 1H), 5.31 (d, J=12.0, 1H), 5.20 (d,
J=12.3 Hz, 1H), 5.11 (dd, J=5.1, 3.6 Hz, 1H), 3.58 (dd, J=15.0, 3.6 Hz,
1H), 3.48–3.28 (m, 2H), 3.16–3.03 (m, 1H), 2.31–2.27 (m, 1H), 1.99–1.84
(m, 1H), 1.79–1.57 (m, 2H), 1.30–1.07 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): d=168.1, 165.1, 152.1, 136.3, 134.8, 128.8, 128.5, 127.2, 124.8,
122.6, 119.9, 118.9, 111.5, 109.0, 69.3, 62.2, 59.1, 45.1, 29.5, 28.6, 21.8 ppm;
elemental analysis calcd (%) for C24H23N3O4: C 69.05, H 5.55, N 10.07;
found: C 69.04, H 5.56, N 10.07.
cyclo(Z-d-Ala-l-Pro) trans-d,l-4b: 71% yield (0.21 g), white solid. M.p.
1
153–1558C; [a]2D1 =À129.7 (c=0.2 in dichloromethane); H and 13C NMR
were identical to its enantiomer l,d-4b; elemental analysis calcd (%) for
C16H18N2O4: C 63.56, H 6.00, N 9.27; found: C 63.62, H 6.09, N 9.21; crys-
tal data (CCDC-844865): C16H18N2O4; MW=302.33; colorless block;
monoclinic; P21/n; a=10.075(2), b=11.009(2), c=2.972(2) ꢂ; b=
cyclo(Z-Gly-Leu) rac-4h: 42% yield (0.13 g), white solid. M.p. 96–988C;
[a]2D1 =0 (c=0.2 in dichloromethane); 1H NMR (300 MHz, CDCl3): d=
7.72 (sbr, 1H), 7.44–7.25 (m, 5H), 5.31 (s, 2H), 4.42 (d, J=17.4 Hz, 1H),
4.32 (d, J=17.4 Hz, 1H), 4.08–3.93 (m, 1H), 1.51–1.88 (m, 3H), 0.97 (d,
J=6.0 Hz, 3H), 0.94 ppm (d, J=5.7 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=167.2, 168.9, 152.2, 134.7, 128.8, 128.4, 69.5, 55.2, 48.0, 41.8,
24.4, 23.1, 21.4 ppm; elemental analysis calcd (%) for C16H20N2O4: C
63.14, H 6.65, N 9.20; found: C 62.81, H 6.65, N 9.25.
94.768(12)8; V=1433.8(4) ꢂ3; Z=4; T=À1608C;
F
(000)=640;
m
cycloACHTUNGTRENNUNG(Z-l-ACHTUNGTRENNUNG(BnS)-Cys-d-Pro) trans-4c: 72% yield (0.31 g), white solid.
M.p. 115–1168C; [a] 2D1 =79.8 (c=0.2 in dichloromethane); 1H NMR
(300 MHz, CDCl3): d=7.44–7.16 ( m, 10H), 5.29 (d, J=12.0, 1H), 5.26
(d, J=12.0, 1H), 5.01 (t, J=6.0 Hz, 1H), 4.41 (dd, J=10.5, 7.5 Hz, 1H),
3.71–3.43 (m, 4H), 2.96 (t, J=6.0 Hz, 2H), 2.46–2.29 (m, 1H), 2.14–
1.74 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=167.4, 164.0, 152.3,
137.1, 134.7, 129.2, 128.8, 128.5, 127.5, 69.6, 61.0, 60.2, 45.7, 37.0, 33.6,
29.7, 22.5 ppm; HRMS (ESI): m/z calcd for C23H24N2O4S+Na+: 447.1354
[M+Na+]; found: 447.1356.
Deprotection of compound 4e and characterization of compound trans-
5e: A solution of (3S,8aS)-benzyl-3-isobutyl-1,4-dioxohexahydropyrrolo-
AHCTUNGERTG[NNUN 1,2-a]pyrazine-2(1H)-carboxylate (4e) (5.8 mmol) in dry ethanol
(40 mL) in the presence of Pd-C (10 wt%) was stirred for 24 h at room
temperature under an atmosphere of hydrogen. Upon completion, the
crude mixture was filtered on Celite and concentrated under reduced
pressure. (3S,8aR)-3-isobutyl-hexahydropyrroloACTHNUTRGNEUG[N 1,2-a]pyrazine-1,4-dione
(trans-5e) was recrystallized from an ethyl acetate/hexanes mixture.
cyclo(Z-l-Val-d-Pro) trans-4d: 70% yield (0.23 g), white microcrystals.
M.p. 117–1198C; [a]2D1 =108.9 (c=0.2 in dichloromethane); 1H NMR
(300 MHz, CDCl3): d=7.50–7.16 (m, 5H), 5.29 (s, 2H), 4.62 (d, J=
9.6 Hz, 1H), 4.26 (t, J=8.1 Hz, 1H), 3.68–3.45 (m, 2H), 2.51–2.36 (m,
1H), 2.22–1.81 (m, 4H), 1.08 (d, J=6.9 Hz, 3H), 0.99 ppm (d, J=6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=168.1, 164.9, 152.4, 134.7, 128.6,
128.5, 128.3, 69.2, 66.6, 59.8, 45.6, 31.4, 29.6, 22.7, 19.5, 19.4 ppm; elemen-
tal analysis calcd (%) for C18H22N2O4: C65.44, H 6.71, N 8.48; found: C
65.15, H 6.77, N 8.18.
cyclo(l-Leu-d-Pro) trans-5e: 87% yield (1.06 g), white solid. M.p. 142–
1458C (lit. 146–1498C);[5] [a]D21 =88.6 (c=0.2 in ethanol) (lit. [a]2D1 =98.9,
c=0.9 in ethanol);[13c] 1H NMR (300 MHz, [D6]DMSO): d=8.36 (dbr,
J=4.1 Hz, 1H), 4.17 (dd, J=8.8, 6.8 Hz, 1H), 3.65–3.57 (m, 1H), 3.48–
3.24 (m, 2H), 2.19–2.06 (m, 1H), 1.90–1.62 (m, 4H), 1.60–1.49 (m, 1H),
1.47–1.35 (m, 1H), 0.91 (d, J=6.6 Hz, 3H), 0.87 ppm (d, J=6.3 Hz, 3H);
13C NMR (75 MHz, [D6]DMSO): d=168.7, 166.0, 57.3, 55.2, 45.0, 42.1,
28.4, 23.8, 22.8, 21.8, 21.5 ppm; elemental analysis calcd (%) for
C11H18N2O2: C 62.83, H 8.63, N 13.32; found: C 62.63, H 8.96, N 13.09.
cyclo(Z-l-Leu-d-Pro) trans-l,d-4e: 75% yield (0.26 g), white microcrys-
tals. M.p. 114–1158C; [a]2D1 =109.0 (c=0.2 in dichloromethane); 1H NMR
(300 MHz, CDCl3): d=7.44–7.28 (m, 5H), 5.28 (s, 2H), 4.85 (dd, J=8.9,
6.5 Hz, 1H), 4.22 (dd, J=9.0, 7.2 Hz, 1H), 3.64–3.45 (m, 2H), 2.50–2.30
(m, 1H), 2.26–2.09 (m, 1H), 2.06–1.81 (m, 2H), 1.77–1.54 (m, 3H), 0.95
(d, J=6.1 Hz, 3H), 0.90 ppm (d, J=6.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=167.9, 165.4, 152.1, 134.7, 128.7, 128.5, 69.3, 60.0, 59.6, 45.7,
General procedure for the tandem deprotection/cyclization sequence: A
solution of Cbz N-protected l,l-dipeptidoyl benzotriazole 3a,b or 3e
(5 mmol) in dry ethanol (50 mL) was stirred for 18 h at room tempera-
ture in the presence of Pd-C (10 wt%) under an atmosphere of hydrogen.
Upon completion, the crude mixture was filtered on Celite and concen-
Chem. Eur. J. 2012, 18, 2632 – 2638
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2637

A. R. Katritzky et al.
trated under reduced pressure. (S)-Hexahydropyrrolo
N
[7] H. D. Jain, C. Zhang, S. Zhou, H. Zhou, J. Ma, X. Liu, X. Liao,
A. M. Deveau, C. M. Dieckhaus, M. A. Johnson, K. S. Smith, T. L.
Macdonald, H. Kakeya, H. Osada, J. M. Cook, Bioorg. Med. Chem.
2008, 16, 4626–4651.
dione (5a),[13c] (3S,8aS)-3-methyl-hexahydropyrrolo
dione (cis-5b)[13c] and (3S,8aS)-3-isobutyl-hexahydropyrrolo
ACHTUNGTRENNUNG
zine-1,4-dione (cis-5e)[13c] were recrystallized from ethanol/hexanes mix-
tures.
[8] a) J. D. Allen, A. van Loevezijn, J. M. Lakhai, M. van der Valk, O.
van Tellingen, G. Reid, J. H. M. Schellens, G.-J. Koomen, A. H.
Schinkel, Mol. Cancer Ther. 2002, 1, 417–425; b) S. Nakatsuka, K.
Teranishi, T. Goto, Tetrahedron Lett. 1986, 27, 6361–6364.
[9] C. Pꢅrez-Balado, A. R. de Lera, Org. Biomol. Chem. 2010, 8, 5179–
5186.
[10] M. B. Martins, I. Carvalho, Tetrahedron 2007, 63, 9923–9932.
[11] C. J. Dinsmore, D. C. Beshore, Tetrahedron 2002, 58, 3297–3312.
[12] J. C. O’Neill, H. E. Blackwell, Comb. Chem. High Throughput
Screening 2007, 10, 857–876.
cyclo(Gly-l-Pro) 5a: 72% yield (0.55 g), white microcrystals. M.p. 218–
2218C (lit. m.p. 220–2238C);[13c] [a]2D1 =À194.2 (c=0.2 in ethanol) (lit.
[a]2D1 =À179.6, c=0.8 in ethanol);[5] 1H NMR (300 MHz, CDCl3): d=7.25
(s, 1H), 4.15–4.04 (m, 2H), 3.90 (dd, J=16.6, 4.4 Hz, 1H), 3.69–3.51 (m,
2H), 2.43–2.33 (m, 1H), 2.15–1.83 ppm (m, 3H); 13C NMR (75 MHz,
CDCl3): d=170.3, 163.7, 58.7, 46.8, 45.5, 28.6, 22.6; elemental analysis
calcd (%) for C7H10N2O2: C 54.54, H 6.54, N 18.17; found: C54.35, H
6.55, N 18.10.
cyclo(l-Leu-l-Pro) cis-5e: 69% yield (0.73 g), white microcrystals. M.p.
160–1638C (lit. m.p. 162–1688C);[13c] [a]D21 =À135.19 (c=0.2 in ethanol)
(lit. [a]2D1 =À134.3, c=1.1 in ethanol);[5] 1H NMR (300 MHz,
[D6]DMSO): d=8.02 (sbr, 1H), 4.19 (t, J=7.9 Hz, 1H), 4.00 (t, J=
6.3 Hz, 1H), 3.42–3.26 (m, 2H), 2.17–2.05 (m, 1H), 1.99–1.68 (m, 5H),
1.35 (ddd, J=13.6, 7.5, 5.7 Hz, 1H), 0.87 (d, J=2.4 Hz, 3H), 0.85 ppm (d,
J=2.7 Hz, 3H); 13C NMR (75 MHz, [D6]DMSO): d=170.2, 166.4, 58.4,
52.5, 44.8, 37.7, 27.4, 24.0, 22.8, 22.4, 21.8 ppm; elemental analysis calcd
(%) for C11H18N2O2: C 62.83, H 8.63, N 13.32; found: C 62.63, H 8.96, N
13.09.
[13] a) T. Yamakawa, E. Ideue, J. Shimokawa, T. Fukuyama, Angew.
Chem. 2010, 122, 9448–9451; Angew. Chem. Int. Ed. 2010, 49, 9262–
9265; b) H. Thajudeen, K. Park, S.-S. Moon, I. S. Hong, Tetrahedron
Lett. 2010, 51, 1303–1305; c) J. Campbell, Q. Lin, G. D. Geske,
H. E. Blackwell, ACS Chem. Biol. 2009, 4, 1051–1059; d) V. L.
Campo, M. B. Martins, C. H. T. P. da Silva, I. Carvalho, Tetrahedron
2009, 65, 5343–5349; e) M. Movassaghi, M. A. Schmidt, J. A. Ashen-
hurst, Angew. Chem. 2008, 120, 1507–1509; Angew. Chem. Int. Ed.
2008, 47, 1485–1487; f) M. Tullberg, K. Luthman, M. Grøtli, J.
Comb. Chem. 2006, 8, 915–922; g) M. Tullberg, M. Grøtli, K. Luth-
man, Tetrahedron 2006, 62, 7484–7491.
[14] a) D. Iannotta, N. Castellucci, M. Monari, C. Tomasini, Tetrahedron
Lett. 2010, 51, 4558–4559; b) M. Jainta, M. Nieger, S. Brꢇse, Eur. J.
Org. Chem. 2008, 5418–5424.
[15] a) R. Hili, V. Rai, A. K. Yudin, J. Am. Chem. Soc. 2010, 132, 2889–
2891; b) N. Deppermann, A. H. G. P. Prenzel, A. Beitat, W. Maison,
J. Org. Chem. 2009, 74, 4267–4271.
[16] O. S. Kwon, S. H. Park, B.-S. Yun, Y. R. Pyun, C.-J. Kim, J. Antibiot.
2001, 54, 179–181.
[17] S. Gupta, M. Macala, C. E. Schafmeister, J. Org. Chem. 2006, 71,
8691–8695.
[18] S. Zhao, K. S. Smith, A. M. Deveau, C. M. Dieckhaus, M. A. John-
son, T. L. Macdonald, J. M. Cook, J. Med. Chem. 2002, 45, 1559–
1562.
[19] a) D. R. Houston, B. Synstad, V. G. H. Eijsink, M. J. R. Stark, I. M.
Eggleston, D. M. F. van Aalten, J. Med. Chem. 2004, 47, 5713–5720;
b) D. R. Houston, I. Eggleston, B. Synstad, V. G. H. Eijsink, D. M. F.
van Aalten, Biochem. J. 2002, 368, 23–27.
Acknowledgements
This work was supported by the Belgian American Educational Founda-
tion, Inc. (B.A.E.F.), by the Research Foundation-Flanders (FWO-Vlaan-
deren, Belgium), by the Kenan Foundation (University of Florida) and
the King Abdulaziz University (Saudi Arabia). The authors are grateful
to Ms. Victoria Michler for her generous help with HPLC experiments,
Dr. Matthias Zeller (Youngstown State University) for his assistance
with X-ray analysis, Dr. C. D. Hall, Mr. Z. Wang, and Ms. Galina Vaku-
lenko for useful discussions. The National Science Foundation (CHE-
0840446) is acknowledged for funds used to purchase the Bruker
APEXII Duo CCD X-ray diffractometer at Akron University used in
this research.
[20] a) H. J. Lim, J. C. Gallucci, T. V. RajanBabu, Org. Lett. 2010, 12,
2162–2165; b) E. M. Moir, K. Yoshiizumi, J. Cairns, P. Cowley, M.
Ferguson, F. Jeremiah, T. Kiyoi, R. Morphy, J. Tierney, G. Wishart,
M. York, J. Baker, J. E. Cottney, A. K. Houghton, P. McPhail, A.
Osprey, G. Walker, J. M. Adam, Bioorg. Med. Chem. Lett. 2010, 20,
7327–7330.
[21] C. Eguchi, A. Kakuta, J. Am. Chem. Soc. 1974, 96, 3985–3989.
[22] a) M.-N. Cheng, H. Wang, L.-Z. Gong, Org. Lett. 2011, 13, 2418–
2421; b) A. Lꢄpez-CobeÇas, P. Cledera, J. D. Sꢆnchez, P. Lꢄpez-Al-
varado, M. T. Ramos, C. AvendaÇo, J. C. Menꢅndez, Synthesis 2005,
19, 3412–3422.
[1] a) P. Ruiz-Sanchis, S. A. Savina, F. Albericio, M. ꢃlvarez, Chem.
Eur. J. 2011, 17, 1388–1408; b) R. Raju, A. M. Piggott, X.-C. Huang,
R. J. Capon, Org. Lett. 2011, 13, 2770–2773; c) T. C. McMahon, S.
Stanley, E. Kazyanskaya, D. Hung, J. L. Wood, Tetrahedron Lett.
2011, 52, 2262–2264; d) R. R. King, L. A. Calhoun, Phytochemistry
2009, 70, 833–841.
[2] A. S. M. Ressurreiżo, R. Delatouche, C. Gennari, U. Piarulli, Eur.
J. Org. Chem. 2011, 217–228.
[3] M. Teixidꢄ, E. Zurita, M. Malakoutikhah, T. Tarragꢄ, E. Giralt, J.
Am. Chem. Soc. 2007, 129, 11802–11813.
[4] a) T. Coursindel, A. Restouin, G. Dewynter, J. Martinez, Y. Collette,
I. Parrot, Bioorg. Chem. 2010, 38, 210–217; b) D. Farran, D. Echa-
lier, J. Martinez, G. Dewynter, J. Pept. Sci. 2009, 15, 474–478; c) D.
Farran, I. Parrot, L. Toupet, J. Martinez, G. Dewynter, Org. Biomol.
Chem. 2008, 6, 3989–3996; d) T. Coursindel, D. Farran, J. Martinez,
G. Dewynter, Tetrahedron Lett. 2008, 49, 906–909; e) D. Farran, I.
Parrot, J. Martinez, G. Dewynter, Angew. Chem. 2007, 119, 7632–
7634; Angew. Chem. Int. Ed. 2007, 46, 7488–7490; f) M. Tullberg,
M. Grøtli, K. Luthman, J. Org. Chem. 2007, 72, 195–199.
[5] a) N. Shangguan, W. J. Hehre, W. S. Ohlinger, M. P. Beavers, M. M.
Jouillꢅ, J. Am. Chem. Soc. 2008, 130, 6281–6287; b) F. Fdhila, V.
Vꢆzquez, J. L. Sꢆnchez, R. Riguera, J. Nat. Prod. 2003, 66, 1299–
1301.
[23] a) M. Pichowicz, N. S. Simpkins, A. J. Blake, C. Wilson, Tetrahedron
2008, 64, 3713–3735; b) J. F. Sanz-Cervera, E. M. Stocking, T. Usui,
H. Osada, R. M. Williams, Bioorg. Med. Chem. 2000, 8, 2407–2415.
[24] A. R. Katritzky, P. Angrish, E. Todadze, Synlett 2009, 15, 2392–
2411.
[25] E. Alonso, F. Lꢄpez-Ortiz, C. del Pozo, E. Peralta, A. Macꢈas, J.
Gonzꢆlez, J. Org. Chem. 2001, 66, 6333–6338.
[26] S. Xiao, X.-X. Shi, F. Ni, J. Xing, J.-J. Yan, S.-L. Liu, Eur. J. Org.
Chem. 2010, 1711–1716.
[27] M. Goodman, K. C. Stueben, J. Am. Chem. Soc. 1962, 84, 1279–
1283.
[28] R. A. Moss, Y.-S. Lee, Tetrahedron Lett. 1981, 22, 2353–2356.
[6] T. Iizuka, S. Takiguchi, Y.-S. Kumakura, N. Tsukioka, K. Higuchi, T.
Kawasaki, Tetrahedron Lett. 2010, 51, 6003–6005.
Received: October 5, 2011
Published online: February 13, 2012
2638
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2632 – 2638