One-pot synthesis of poly-substituted tetramic acids for the preparation of putative turn mimics

Article abstract of DOI:10.1016/j.tet.2011.11.006

A one-pot synthesis of poly-substituted tetramic acids and of their six-membered ring analogs have been obtained in one step by reaction of N-Boc dipeptides, activated as their O-succinimidyl esters (Boc-AA-AA-OSu), with the sodium anion of dibenzyl malonate. The adducts spontaneously cyclize to form five or six-member rings. To check whether this class of compounds may be used to promote reverse-turn conformations, one adduct was further derivatized. The formation of a hydrogen bond between the NH-Boc and the carbonyl at C2 of the heterocycle is highlighted, upon analysis of the product by IR, ¹H NMR, and MD techniques, thus suggesting that these compounds are good candidates to promote reverse-turn conformations or other secondary structures and may be used for the formation of new foldamers.

Full text of DOI:10.1016/j.tet.2011.11.006

Tetrahedron 68 (2012) 4506e4512
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of poly-substituted tetramic acids for the preparation
of putative turn mimics
*
Nicola Castellucci, Luca Gentilucci, Claudia Tomasini
ꢀ
Dipartimento di Chimica ‘G. Ciamician’, Alma Mater Studiorum Universita di Bologna, Via Selmi 2, Ie40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2011
Received in revised form 6 October 2011
Accepted 3 November 2011
Available online 11 November 2011
A one-pot synthesis of poly-substituted tetramic acids and of their six-membered ring analogs have been
obtained in one step by reaction of N-Boc dipeptides, activated as their O-succinimidyl esters (Boc-AA-
AA-OSu), with the sodium anion of dibenzyl malonate. The adducts spontaneously cyclize to form five or
six-member rings. To check whether this class of compounds may be used to promote reverse-turn
conformations, one adduct was further derivatized. The formation of a hydrogen bond between the
NHeBoc and the carbonyl at C2 of the heterocycle is highlighted, upon analysis of the product by IR, 1H
NMR, and MD techniques, thus suggesting that these compounds are good candidates to promote
reverse-turn conformations or other secondary structures and may be used for the formation of new
foldamers.
Keywords:
Tetramic acids
Reverse-turn mimics
Conformational analysis
One-pot synthesis
Foldamers
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
thefirstnaturalproducts reportedtoselectivelyblock transactivation
of the N terminus of the androgen receptor in prostate cancer cells.8
Naturally occurring tetramic acids (pyrrolidin-2,4-dione) have
attracted a great deal of interest because many natural compounds
containing these heterocycles exhibit interesting biological activi-
ties,1 such as dolastatin 152 and althiomycin.3 HSAF (Fig. 1) was iso-
lated fromLysobacterenzymogenes, a bacteriumused inthebiological
control of fungal diseases of plants.4 Furthermore the natural prod-
ucts tenuazonic acid,5 melophlins,6 and reutericyclin7 are represen-
tative examples of the structurally diverse family of acyl-tetramic
acids. Finally sintokamides AeE,1,5-disubstituted tetramic acids, are
Tetramic acids are very polar and scarcely reactive and may be
prepared with several methods. The most simple one is the acti-
vation of a Boc-protected amino acid with EDC, condensation with
Meldrum’s acid, and finally cyclization to give the Boc-protected
pyrrolidine-2,4-diones. The following N-deprotection may be ac-
complished with TFA treatment giving the parent pyrrolidine-2,4-
diones.9 Another straightforward method is the condensation of
methyl (E)-4-chloro-3-methoxy-2-butenoate with a 2-amino al-
cohol in the presence of triethylamine.10
The functionalization of these heterocycles is often a difficult
task, due to their low reactivity and to the equilibrium between the
ketonic and enolic form, although they may react with several
classes of compounds. In many natural compounds, the tetramic
acid moiety is present as a 3-acyl derivative or, less commonly, as
a 4-O-alkyl ether derivative (Fig. 2).
Fig. 1. Chemical structure of HSAF, the tetramic acid moiety is highlighted in red.
Fig. 2. Chemical structure of tetramic acid. The equilibrium between the two forms is
shown.
Some synthetic methods have been reported. For instance the 3-
acylation of tetramic acids was performed via O-acylation with
* Corresponding author. Tel.: þ39 051 2099596; fax: þ39 051 2099456; e-mail
address: claudia.tomasini@unibo.it (C. Tomasini).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.006

N. Castellucci et al. / Tetrahedron 68 (2012) 4506e4512
4507
carboxylic acids followed by acyl migration.11 Another approach is
the reaction of tetramic acids with the ylide Ph3PCCO, that affords
exclusively the corresponding 3-acylylidenetetramic acids. These
were amenable to Wittig olefinations with aliphatic, aromatic,
saturated and unsaturated aldehydes after deprotonation with
KOtBu.12 Very interesting are the studies reported by Tønder et al.13
who have developed a straightforward strategy for the synthesis of
N-acylates, O-alkylated pyrrolidin-2-ones by functionalization of
tetramic acids, that leads to the formation of dipeptidomimetics
comprising a pyrrolidinone and a protected amino acid. They have
also reported an optimized two-step reductive amination pro-
cedure, which provides a small library of pyrrolidinone-containing
dipeptide analogs. Another interesting approach to the synthesis of
N-Boc 5-substituted tetramic acids is the cyclization of N-hydrox-
Scheme 1. Reagents and conditions: (i) Naþ ꢀCH(CO2Bn)2 (1.5 equiv), dry THF, 30 min
ꢂ
at 0 ꢁC then 2h at rt; (ii) 2 M NaOH (166 equiv), BnOH, 2 h, rt.
ysuccinimide esters of Boc-protected
products have been obtained in two steps, by coupling of the
amino acid derivatives with an alkyl malonate in the presence of
NaH, with the formation of -amino- -oxoalkanoates, that in turn
a
-amino acids.14 The desired
a
-
As the final scope is the formation of a free carboxy unit, the
reaction was performed with benzyl malonate, as the benzyl unit
may be removed easily by hydrogenolysis. So benzyl malonate was
treated with NaH in dry THF, followed by the N-hydrox-
ysuccinimide esters, to afford the desired
esters 1aed in high yield. This reaction allows to obtain the desired
compound 1, starting from both - and -amino acids (Scheme 1).
The following cyclization was performed in benzyl alcohol and
aqueous 2 M NaOH. While satisfactory yields were obtained for the
synthesis of both 4-hydroxy-2-oxo-1H-pyrrole-1,3(2H,5H)-dicar-
boxylates 2a and 2b (60% and 52%, respectively), the synthesis of 4-
hydroxy-2-oxo-5,6-dihydropyridine-1,3(2H)-dicarboxylates 2c and
2d afforded very unsatisfactory results, as 2c was obtained only in
traces from 1c and 2d in 26% yield from 1d. No racemization oc-
curred in the formation of 2b (after analysis with HPLC equipped
with a chiral column AD, n-hexane/iso-propanol 8:2, flow: 0.5 mL/
min), probably due to the mild reaction conditions.
g
b
cyclize under basic conditions to give the desired compounds.
We have become interested in the synthesis and in the de-
rivatization of 1-acyl 3-carboxy tetramic acids, as they are con-
strained amino acid mimetics, contain an endocyclic carbonyl group
and may be functionalized in several ways, thus they be may applied
to the formation of pseudopeptide foldamers.15 We have studied
foldamers containing imide moieties, where the nitrogen atom is
connected to an endocyclic and an exocyclic carbonyl, which tend to
adopt always the trans conformation.16 As a consequence of this
locally constrained disposition effect, these imide-type oligomers
g-amino b-oxo benzyl
a
b
are forced to fold in ordered conformations, such as PPII helixes,17
band ribbon spirals,18 -sheets,19 and -turns.20
- or
1-Acyl 3-carboxy tetramic acids are constrained
b-
b
b
g
b
-amino acids,
where the carbonyl unit is placed between the two functions, thus
it forces the two carbonyls in the trans conformation, following the
same effect that we have observed for the 4-carboxy-oxazolidin-2-
ones (Fig. 3). As a consequence of this disposition, this scaffold may
behave as a reverse-turn mimic, if it is introduced in the middle of
a polypeptide chain, or it may promote the formation of new fol-
damers, if it is introduced in more complex structures. Although
many examples of nonpeptidic reverse-turn surrogates have been
reported, it is still challenging to find a new type of nonpeptidic
scaffold that can adopt a highly populated reverse-turn confor-
mation in solution21 and that may be regarded as constrained
Then 2a was deprotected from the Boc moiety by reaction
with trifluoroacetic acid in dry dichloromethane, for further
derivatizations. The desired product was obtained in high yield.
Unfortunately, the following N-acylation reaction, performed with
standard coupling conditions (HBTU or HATU, in the presence of
tertiary amines) was totally unsuccessful, as the heterocyclic
nitrogen of this compound is very unreactive. In effect, this reaction
has been previously reported only in hard conditions,13a by reaction
with a lithium base (n-BuLi or LiHMDS), followed by addition of an
activated ester (Fmoc-AA-OPfp) at ꢀ50 ꢁC.
pseudo-
b
-prolines.
To overcome this problem, we reversed the step order, making
the coupling before the cyclization (Scheme 2). Thus four di-
peptides were prepared containing both a- and b-amino acids, in
both positions. Then the carboxy moieties were activated as the
corresponding N-hydroxysuccinimide esters and treated with the
sodium anion of the benzyl malonate to obtain the corresponding
g-amino b-oxo acids, as previously reported in Scheme 1. Much to
our surprise, the expected products were not obtained, as the re-
action proceeded directly to the formation of the heterocyclic rings.
The reaction yield was further optimized with the addition of
2.5 equiv of base. No epimerization of 3b was observed by 1H NMR
and HPLC analysis (chiral column AD, n-hexane/iso-propanol 8:2,
flow: 0.5 mL/min).
The different behavior between Boc-AA-OSu and Boc-AA-AA-
OSu may be ascribed to the secondary amide involved in the cy-
clization, that is, more acidic than the carbamate involved in the
cyclization of Boc-AA-OSu. The heterocycles 3aed are obtained in
good to high yield and can be further derivatized simply by re-
moving the Boc or benzyl ester protecting groups.
Fig. 3. (a) Preferential conformation of 4-carboxy-oxazolidin-2-ones and (b) possible
preferential conformation of 1-acyl 3-carboxy tetramic acids.
2. Results and discussion
2.1. Synthesis of the heterocycles
We report here a one-pot synthesis of poly-substituted tetramic
acids
(4-hydroxy-2-oxo-1H-pyrrole-1,3(2H,5H)-dicarboxylates)
and of the corresponding six-membered rings (4-hydroxy-2-oxo-
5,6-dihydropyridine-1,3(2H)-dicarboxylates) starting from benzyl
malonate and N-hydroxysuccinimide esters of Boc-protected amino
acids (Scheme 1). As a first attempt, we utilized the protocol de-
Finally, the achiral 3d was further derivatized to check if this
new class of compounds may be utilized to promote the formation
of reverse-turn mimics, as they may be considered as a mimic of the
scribed by Igglessi-Markopoulou et al.14a that allows to obtain
g-
b
-turn motifs.22 Thus
amino
b-oxo acids by reaction of N-hydroxysuccinimide esters of
Gly-Pro moiety, that is, often present in the
we replaced the OBn group with H-Ala-OMe that contains the small
Boc-protected amino acids with alkyl malonate.

4508
N. Castellucci et al. / Tetrahedron 68 (2012) 4506e4512
Scheme 2. Reagents and conditions: (i) Naþ ꢀCH(CO2Bn)2 (1.5 equiv), dry THF, 16 h, rt.
ꢂ
methyl ester. Of course, if a longer peptide chain has to be in-
troduced, benzyl-protected amino acids are preferred.
After hydrogenolysis of the benzyl ester with H2 and Pd/C, the
acid was coupled with H-Ala-OMe, but the coupling reaction pro-
duced only a mixture of products, probably due to the free hydroxyl
group, that was then protected by methylation of the Li anion with
(trimethylsilyl)diazomethane (Scheme 3).13a The product 4 was
obtained in good yield and the deprotected by reaction with H2 and
Pd/C to form the free acid 5, that was coupled with H-Ala-OMe in
the presence of HBTU and Et3N. The derivative 6 was obtained in
high yield after purification.
Fig. 4. FT-IR absorption spectrum in the NeH stretching region for 3 mM concentra-
tion samples of 6 in pure CH2Cl2 at room temperature.
The titration of the NH bonds shows that NHeAla is poorly bonded
(
Dd¼0.68 ppm), while the NHeBoc is an equilibrium between
a hydrogen-bonded and an open conformation (Dd¼0.48 ppm). A
strong hydrogen-bonded conformation would require a lower Dd
outcome (Ddꢃ0.15 ppm).
Some more information have been obtained, by recoding the 1H
NMR spectrum of a 10 mM sample of 6 in CDCl3 at different tem-
perature, to check the dependence of the NH proton from the
temperature (Fig. 5b).
Scheme 3. Reagents and conditions: (i) LiHMDS (1.1 equiv), dry THF, 10 min, rt (ii)
(trimethylsilyl)diazomethane (8 equiv), dry THF, 3 h, rt (iii) H2, Pd/C, MeOH, 6 h, rt; (iv)
HCl$H-Ala-OMe (1 equiv), HBTU (1.1 equiv), Et3N (3 equiv), CH3CN, 2 h, rt.
2.2. Conformational analysis of 6
This test points out the presence of hydrogen-bonded amide
protons, as in CDCl3 a small temperature coefficient (ꢃ3 ppb/K in
absolute value) indicates the presence of a hydrogen-bonded
amide proton,24 while protons, which participate to an equilib-
rium between hydrogen-bonded and non-hydrogen-bonded state
show a larger temperature coefficient. In DMSO-d6 the temper-
ature coefficients can be bigger, so that a hydrogen-bonded am-
ide proton can have a value of ꢀ4 ppb/K or smaller in absolute
value. The analysis of the variation of the NH chemical shift with
the temperature furnish a result, that is, in agreement both with
the titration and with the IR spectrum, because a Dd of ꢀ6.0 ppb/
K for NHeAla shows that no hydrogen bond is formed, while
ꢀ3.0 ppb/K for NHeBoc suggests the formation of a weak hy-
drogen bond.
Information on the preferred conformation of the compound 6
in solution was obtained by FT-IR and 1H NMR techniques. The FT-
IR absorption spectrum of 6 was obtained as 3 mM solution in
methylene chloride, as at this concentration self-aggregation is
usually unimportant (Fig. 4). The IR spectrum of 6 shows the
presence of a non-hydrogen-bonded amide NeH bands (3438,
above 3400 cmꢀ1) and of a large band located at 3327 cmꢀ1, that
suggests that an equilibrium takes place, involving a hydrogen-
bonded amide protons bands.
The in-solution conformation of 6 was investigated also by 1H
NMR spectroscopy and MD simulations; NMR analyses were con-
ducted using standard techniques at 400 MHz in CDCl3. The 1H
NMR analysis of 6 revealed a single set of sharp resonances, in-
dicating conformational homogeneity or a fast equilibrium be-
tween conformers.
To verify the IR outcome and to check, which hydrogen-bonded
amide proton is involved in the equilibrium, some 1H NMR spectra
of 6 have been recorded, as a function of the addition of increasing
amounts of DMSO-d6, to check the dependence of NH proton
chemical shifts from DMSO-d6 (Fig. 5a);23 this solvent is a strong
hydrogen-bonding acceptor and, if it is bound to a free NH proton, it
will be expected to dramatically move its chemical shift downfield.
To have more information on the in-solution preferred confor-
mation, 6 was further analyzed by 2D ROESY experiments per-
formed on a 10 mM solution of 6 in CDCl3 (mixing time 0.500 s).
Several cross peaks were obtained (see Supplementary data), the
most interesting ones (Fig. 6, red arrows) are the cross peak be-
tween the b-AlaNH and the methylene at the C5 of the heterocycle,
and the cross peak between the CHaeAla and the Boc group. This
cross peak shows that one chain lays nearby to the other, thus
suggesting that this molecule is a good candidate for the formation
of a reverse-turn motif.

N. Castellucci et al. / Tetrahedron 68 (2012) 4506e4512
4509
Fig. 5. (a) Variation of NH proton chemical shift (ppm) of 6 as a function of increasing percentages of DMSO-d6 to the CDCl3 solution (v/v) (concentration: 3 mM); (b) variation of NH
proton chemical shift (ppm) of 6 as a function the temperature (ꢁC) for 10 mM samples measured in CDCl3.
Fig. 6. NOE enhancements as gathered from the ROESY analysis spectrum of 6 (10 mM
solution in CDCl3, mixing time 0.500 s).
Furthermore a strong signal was observed between the NHeAla
and the OMe heterocyclic group and two weaker signals between
CHaeAla and CO2Me and CHaeAla and OMe.
MD simulations25 furnished some more hints on the preferred in-
solution conformation of 6.26 Structures consistent with the spec-
troscopic analyses were obtained by restrained MD simulations, us-
ing the distances derived from ROESY as constraints, and minimized
with AMBER force field (see Supplementary data).27 To investigate
the dynamic behavior of 6, two structures a and b were analyzed by
unrestrained MD for 500 ns. The analysis of the trajectories did not
manifest the conversion of one conformation into the other.
The simulation of the more stable structure revealed a strong
propensity to maintain the folded conformations, with the occur-
Fig. 7. Representative low-energy structure of 6 obtained by unrestrained MD simu-
lation, performed on the lower-energy structure consistent with ROESY analysis, cal-
culated by restrained MD.
rence of an explicit H-bond between b-AlaNH and the heterocyclic
4. Experimental
C]O, in agreement to the IR and 1H NMR results (Fig. 7).
4.1. Materials and instrumentation
3. Conclusions
The melting points of the compounds under investigation were
determined in open capillaries and are uncorrected. High quality
infrared spectra (64 scans) were obtained at 2 cmꢀ1 resolution
using a 1 mm NaCl solution cell and an FT-infrared spectrometer. All
spectra were obtained in 3 mM solutions in dry CH2Cl2 at 297 K or
as 1% solid mixture with dry KBr. All compounds were dried in
vacuo and all the sample preparations were performed in a nitro-
gen atmosphere. Routine NMR spectra were recorded with spec-
trometers at 600, 400 or 300 MHz (1H NMR) and at 150, 100 or
75 MHz (13C NMR). The measurements were carried out in CDCl3
and in DMSO-d6. The proton signals were assigned by gCOSY
We have reported a one-pot synthesis of poly-substituted tet-
ramic acids and of their six-membered ring analogs. The key step is
the reaction of N-Boc dipeptides activated as their O-succinimidyl
esters (Boc-AA-AA-OSu) with the sodium anion of dibenzyl malo-
nate, that spontaneously cyclize to five or six-member rings. This
new class of compounds may be prepared in multigram scale.
To check if they may be used to promote reverse-turn confor-
mations, achiral 3d was further derivatized at the C-terminal po-
sition with the small H-
analyzed by means of IR, 1H NMR, and MD techniques that all
suggest the formation of a hydrogen bond between the -AlaNH
L-Ala-OMe group. The product 6 was
b
spectra. Chemical shifts are reported in d values relative to the
and the carbonyl at C2 of the heterocycle. Further studies are cur-
rently ongoing on more complex structures containing poly-
substituted tetramic acids or their six-membered ring analogs to
check if they are able to promote the formation of new foldamers.
solvent (CDCl3 or DMSO-d6) peak. 2D spectra were recorded in the
phase sensitive mode and processed using a 90ꢁ-shifted, squared
sine-bell apodization. 2D ROESY experiments were recorded with
a 5000 ms mixing time with a proton spectral width of 4032.3 Hz.

4510
N. Castellucci et al. / Tetrahedron 68 (2012) 4506e4512
4.2. Synthesis and characterization
193.5. Anal. Calcd for C17H19NO6: C, 61.25; H, 5.75; N, 4.20. Found: C,
60.21; H, 5.79; N, 4.23.
4.2.1. General method for the derivatives 1. To a stirred solution of
NaH (60% in mineral oil, 1.4 mmol, 55 mg) in dry THF (3 mL) was
added benzyl malonate (1.05 mmol, 0.27 g) at 0 ꢁC and the mixture
was stirred 30 min. Then Boc-Xaa-O-Succinimide (0.7 mmol) was
added in one portion at 0 ꢁC and the mixture was stirred for 2 h at
room temperature. Then THF was removed under reduced pressure
and replaced with ethyl acetate. The mixture was washed with
water (2ꢄ30 mL), dried over sodium sulfate and concentrated in
vacuo. The product was obtained pure after silica gel chromatog-
raphy (cyclohexane/ethyl acetate 8:2 as eluant).
4.2.2.2. (S)-3-Benzyl 1-tert-butyl 5-benzyl-4-hydroxy-2-oxo-1H-
pyrrole-1,3(2H,5H)-dicarboxylates 2b. Yield: 52%; mp¼101 ꢁC; ½a D25
ꢅ
ꢀ32.0 (c 1.0, CH3OH); (CH2Cl2, 3 mM):
n
1736, 1677, 1640 cmꢀ1; 1H
NMR (400 MHz, CD3OD):
CH2ePh), 4.14 (s, 1H, CHCH2), 5.09 (s, 2H, OCH2ePh), 6.89e7.06 (m,
5H, Ph), 7.17e7.35 (m, 5H, Ph); 13C NMR (100 MHz, CD3OD):
24.2,
d
1.56 (s, 9H, tBu), 3.10e3.31 (m, 2H,
d
28.2, 28.5, 30.7, 36.0, 64.7, 126.2, 126.9, 127.5, 127.9, 129.6. Anal.
Calcd for C24H25NO6: C, 68.07; H, 5.95; N, 3.31. Found: C, 68.01; H,
5.92; N, 3.33.
4.2.1.1. Benzyl 1-tert-butoxycarbonylamino-2-benzoxycarbonyl-
4.2.2.3. (R)-3-Benzyl 1-tert-butyl 4-hydroxy-2-oxo-6-phenyl-5,6-
3-oxobutanoate 1a. Yield: 75%; mp¼99 ꢁC; IR (CH2Cl2, 3 mM):
n
dihydropyridine-1,3(2H)-dicarboxylate 2d. Yield: 26%; mp¼110 ꢁC;
3446, 1752, 1719 cmꢀ1
;
1H NMR (400 MHz, CDCl3; keto/enol,
½
a 2D5
ꢅ
ꢀ27.9 (c 0.4, CHCl3); IR (CH2Cl2, 3 mM):
n
3491, 3437, 3325,
t
t
50:50):
d
1.36 (s, 9H, Bu), 3.39 (s, 0.5H, CH(CO)3, keto), 4.07 (d,
1748, 1711 cmꢀ1
;
1H NMR (400 MHz, CD3OD):
d
1.29 (s, 9H, Bu),
J¼4.0 Hz, 1H, CH2, keto), 4.17 (d, J¼4.0 Hz, 1H, CH2, enol), 4.99 (br s,
2.56e2.62 (m, 2H, CH2CH), 4.87e4.98 (m, 1H, CH2CH), 5.08 (s, 2H,
1H, NH), 5.10e5.27 (m, 4H, 2ꢄ OCH2Ph), 7.16e7.32 (m, 10H, 2ꢄ Ph);
OCH2ePh), 7.06e7.32 (m, 10H, 2ꢄ Ph); 13C NMR (50 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
d
28.3, 41.5, 49.9, 67.2, 68.2,128.0,128.3,
d 26.9, 28.2, 29.7, 41.4, 51.2, 67.3, 80.0, 126.1, 127.3, 128.3, 128.6,
128.4, 128.5, 128.6, 134.5, 135.1, 168.8, 166.2.
141.4, 155.6, 176.0. Anal. Calcd for C24H25NO6: C, 68.07; H, 5.95; N,
3.31. Found: C, 68.10; H, 5.97; N, 3.29.
4.2.1.2. (S)-Benzyl 5-phenyl-4-tert-butoxycarbonylamino-2-
benzoxycarbonyl-2-benzoxycarbonyl-3-oxopentanoate
1b. Yield:
4.2.3. General method for the preparation of compounds 3. To
a stirred solution of NaH (60% in mineral oil, 1.75 mmol, 69 mg) in
dry THF (3 mL) was added benzyl malonate (1.05 mmol, 0.27 g) at
0 ꢁC and the mixture was stirred 30 min. Then Boc-AA-AA-O-Suc-
cinimide (0.7 mmol) was added in one portion at 0 ꢁC and the
mixture was stirred for 16 h at room temperature. Then THF was
removed under reduced pressure and replaced with ethyl acetate.
The mixture was washed with water (2ꢄ30 mL), dried over sodium
sulfate and concentrated in vacuo. The product was obtained pure
after silica gel chromatography (cyclohexane/ethyl acetate
1:9/pure ethyl acetate as eluant).
73%; mp¼167 ꢁC; ½a D25
ꢅ
þ23.4 (c 0.15, CHCl3); IR (CH2Cl2, 3 mM):
n
3436, 1761, 1720, 1650 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
1.35 (s,
t
9H, Bu), 2.97e3.06 (m, 1H, CHHCH), 3.07e3.17 (m, 1H, CHHCH),
3.40 (s, 1H, CH(CO)3), 4.46e4.59 (m, 1H, CHCH2), 4.98 (br s, 1H, NH),
5.10 (s, 4H, 2ꢄ OCH2Ph), 7.08e7.39 (m, 15H, 3ꢄ Ph); 13C NMR
(100 MHz, CDCl3):
d 24.7, 25.4, 28.3, 33.4, 49.8, 128.0, 128.3, 128.4,
128.6, 129.1, 129.2, 129.4, 135.2, 166.2.
4.2.1.3. Benzyl 4-tert-butoxycarbonylamino-2-benzoxycarbonyl-
3-oxopentanoate 1c. Yield: 80%; mp¼141 ꢁC; IR (CH2Cl2, 3 mM):
n
3514, 3451, 1816, 1787, 1744, 1713 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
1.46 (s, 9H, tBu), 2.71e2.87 (m, 2H, NHCH2CH2), 3.50 (s, 1H,
4.2.3.1. (S)-Benzyl 1-(2-((tert-butoxycarbonyl)amino)-3-
phenylpropanoyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-3-
CH(CO)3), 3.27e3.53 (m, 2H, NHCH2CH2), 4.96 (br s, 1H, NH),
5.10e5.35 (m, 4H, 2ꢄ OCH2Ph), 7.15e7.59 (m, 10H, 2ꢄ Ph); 13C NMR
carboxylate 3a. Yield: 63%; mp¼159 ꢁC; ½a D25
ꢅ
þ45.4 (c 0.6, CHCl3);
(100 MHz, CDCl3):
135.2, 166.2.
d
28.3, 30.9, 34.4, 41.5, 67.3, 128.3, 128.4, 128.6,
IR (CH2Cl2, 3 mM):
(400 MHz, CD3OD):
n
d
3427, 3364, 1702, 1675, 1645 cmꢀ1 1H NMR
;
1.23 (s, 9H, tBu), 2.49e2.67 (m, 1H, CHHePh),
3.06e3.16 (m, 1H, CHHePh), 3.73 (AB, 2H, J¼10.0 Hz, CH2), 5.16 (s,
4.2.1.4. (S)-Benzyl 5-phenyl-5-tert-butoxycarbonylamino-2-
2H, OCH2ePh), 6.95e7.50 (m, 10H, 2ꢄ Ph); 13C NMR (100 MHz,
benzoxycarbonyl-2-benzoxycarbonyl-3-oxopentanoate
1d. Yield:
CD3OD): d 24.6, 24.8, 27.0, 27.2, 37.9, 50.9, 55.4, 63.7, 79.0, 126.0,
76%; mp¼101 ꢁC; ½a D25
ꢅ
ꢀ19.4 (c 0.55, CHCl3); IR (CH2Cl2, 3 mM):
n
127.0, 127.2, 127.7, 127.8, 129.2, 137.3, 137.7. Anal. Calcd for
C26H28N2O7: C, 64.99; H, 5.87; N, 5.83. Found: C, 65.03; H, 5.89; N,
5.80.
3436, 3362, 1761, 1708, 1646, 1601 cmꢀ1
;
1H NMR (200 MHz,
t
CDCl3):
d
1.44 (s, 9H, Bu), 2.83e3.09 (m, 1H, CHH), 3.10e3.32 (m,
1H, CHH), 4.97e5.34 (m, 5H, 2ꢄ OCH2PhþCHCH2), 5.74 (br s, 1H,
NH), 7.01e7.45 (m, 10H, 2ꢄ Ph); 13C NMR (50 MHz, CDCl3):
d
28.3,
4.2.3.2. (S)-Benzyl
5-benzyl-1-((S)-2-((tert-butoxycarbonyl)
40.9, 41.5, 67.3, 67.4, 100.9, 125.9, 126.1, 127.3, 128.1, 128.3, 128.3,
128.5, 135.2, 155.1, 166.1, 170.8, 180.9.
amino) propanoyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylate 3b. Yield: 50%; mp¼140 ꢁC; ½a D25
ꢀ54.5 (c 0.6, CHCl3);
ꢅ
IR (CH2Cl2, 3 mM):
n ;
3425, 3357, 1718, 1679, 1650 cmꢀ1 1H NMR
4.2.2. General method for the preparation of 4-hydroxy-2-oxo-1H-
pyrrole-1,3(2H,5H)-dicarboxylates or 4-hydroxy-2-oxo-5,6-
dihydropyridine-1,3(2H)-dicarboxylates 2. To a stirred solution of
compound 1aed (0.12 mmol) in benzyl alcohol (1 mL) was added
2 M NaOH (20 mmol, 1 mL) and the mixture was stirred at room
temperature for 2 h. Then water was removed under reduced
pressure and the product was obtained pure after silica gel chro-
matography (cyclohexane/ethyl acetate 1:9/pure ethyl acetate as
eluant) to remove benzyl alcohol and by-products.
(400 MHz, DMSO-d6):
d
1.11 (d, 1H, J¼8 Hz, CHCH3), 1.39 (s, 9H, tBu),
3.20e3.31 (m, 2H, CH2ePh), 3.40 (S, 1H, CHCH2), 5.00 (s, 2H,
OCH2ePh), 5.20e5.30 (m, 1H, CHCH3), 6.95e7.37 (m, 10H, 2ꢄ Ph);
13C NMR (100 MHz, DMSO-d6):
d 17.8, 28.2, 34.2, 49.5, 62.4, 77.7,
125.9, 126.8, 127.1, 127.5, 128.1, 128.3, 128.9, 129.7, 130.0, 136.1, 137.9,
155.0, 173.5. Anal. Calcd for C27H30N2O7: C, 65.57; H, 6.11; N, 5.66.
Found: C, 65.54; H, 6.08; N, 5.70.
4.2.3.3. (S)-Benzyl 1-(2-((tert-butoxycarbonyl)amino)-3-
phenylpropanoyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-
4.2.2.1. Benzyl
1-tert-butyl
4-hydroxy-2-oxo-1H-pyrrole-1,3
carboxylate 3c. Yield: 47%; mp¼119 ꢁC; ½a D25
ꢅ
þ4.9 (c 1.4, CHCl3); IR
(2H,5H)-dicarboxylates 2a. Yield: 60%; mp¼190 ꢁC; (CH2Cl2, 3 mM):
n
(CH2Cl2, 3 mM): n ;
3424, 3315, 1749, 1726, 1667 cmꢀ1 1H NMR
3595, 1752, 1650, 1605 cmꢀ1
;
1H NMR (400 MHz, CD3OD):
d
1.55 (s,
(400 MHz, CDCl3): d
1.31 (s, 9H, tBu), 1.82e1.91 (m, 1H, NCH2CHH),
9H, tBu), 3.83 (s, 2H, CH2), 5.27 (s, 2H, OCH2ePh), 7.22e7.49 (m, 5H,
Ph); 13C NMR (100 MHz, CD3OD):
30.9, 56.2, 67.6, 131.0, 131.1, 131.8,
2.19e2.31 (m, 1H, NCH2CHH), 2.92 (S, 2H, CH2ePh), 3.40 (S, 1H,
NCH2CH2), 4.51 (s, 1H, CHCH2), 5.09 (s, 2H, CH2ePh), 5.43 (br s, 1H,
d

N. Castellucci et al. / Tetrahedron 68 (2012) 4506e4512
4511
NH), 6.99e7.55 (m, 10H, 2ꢄ Ph); 13C NMR (100 MHz, DMSO-d6):
washed with water, dried over sodium sulfate and concentrated in
vacuo. The product 5 was obtained pure after silica gel chroma-
tography (cyclohexane/ethyl acetate 1:1/2:8 as eluant) in 70%
d
24.8, 25.5, 28.2, 33.6, 39.1, 41.6, 49.3, 67.3, 68.7, 126.9, 128.3, 128.4,
128.5, 128.6, 128.7, 129.3, 135.2, 136.6, 157.4, 161.2, 171.5. Anal. Calcd
for C27H30N2O7: C, 65.57; H, 6.11; N, 5.66. Found: C, 65.59; H, 6.14;
N, 5.68.
(21 mg) overall yield. ½a D25
ꢅ
ꢀ9.0 (c 0.1, CHCl3); IR (CH2Cl2, 3 mM):
n
3436, 3334, 1736, 1709, 1671 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
1.41 (s, 9H, tBu), 1.42 (d, 3H, J¼6.0 Hz, MeeAla), 2.37 (t, 2H,
4.2.3.4. Benzyl 1-(3-((tert-butoxycarbonyl)amino)propanoyl)-4-
J¼6.4 Hz, C5H2), 2.53 (t, 2H, J¼6.0 Hz, CaH2e
bAla), 3.37 (t, 2H,
bAla), 3.26 and 3.68 (s,
hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carboxylate 3d. Yield:
J¼6.4 Hz, C6H2), 3.51 (q, 2H, J¼6.0 Hz, CbH2e
80%; mp¼180 ꢁC; IR (CH2Cl2, 3 mM):
n
3441, 3314, 1750, 1734, 1704,
d
1H, OMe), 3.73 (s, 1H, COOMe), 4.55 (dq, 1H, J¼6.8 Hz, CaHeAla),
1670 cmꢀ1; 1H NMR (400 MHz, CDCl3):
1.34 (s, 9H, tBu), 2.16e2.33
6.35 (br s, 1H, NHe
b
Ala), 7.42 (d, 1H, J¼6.8 Hz, NHeAla); 13C NMR
(m, 2H, COCH2CH2), 2.44e2.49 (m, 1H, NCH2CHH), 2.71e2.76 (m,
1H, NCH2CHH), 3.22e3.35 (m, 2H, COCH2CH2), 3.36e3.49 (m, 2H,
NCH2CH2), 5.01e5.32 (m, 2H, OCH2ePh), 6.07e6.31 (m, 1H, NH),
(100 MHz, CDCl3): d 17.8, 28.4, 33.7, 34.9, 36.3, 42.3, 48.3, 51.8, 52.5,
112.5, 114.9, 156.2, 166.8, 171.6, 172.9, 173.0. Anal. Calcd for
C19H29N3O8: C, 53.39; H, 6.84; N, 9.83. Found: C, 53.42; H, 6.85; N,
9.85.
6.94e7.38 (m, 10H, 2ꢄ Ph); 13C NMR (100 MHz, CDCl3):
d 14.2, 21.0,
24.9, 28.3, 33.9, 36.2, 36.8, 41.5, 60.4, 67.4, 68.2, 79.2, 128.0, 128.3,
128.4, 128.5, 128.6, 128.7, 135.2, 156.0, 164.1, 166.2, 171.4. Anal. Calcd
for C21H26N2O7: C, 60.28; H, 6.26; N, 6.69. Found: C, 60.31; H, 6.74;
N, 6.66.
Acknowledgements
ꢀ
We are grateful to Ministero dell’Universita e della Ricerca Sci-
ꢀ
entifica (PRIN 2008), Universita di Bologna (Funds for selected
topics), to Fondazione del Monte di Bologna e di Ravenna and to
COST Action CM0803 for financial support.
4.2.3.5. Benzyl 1-(3-((tert-butoxycarbonyl)amino)propanoyl)-4-
methoxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carboxylate 4. To a so-
lution of compound 3d (0.2 mmol, 70 mg) in dry THF (10 mL) was
added LiHMDS (1 M solution in THF, 0.24 mmol, 0.24 mL) under
nitrogen atmosphere, then the mixture was stirred at room tem-
perature for 10 min and (trimethylsilyl)diazomethane (2 M solu-
tion in diethyl ether, 2.0 mmol, 1 mL) was added and the mixture
was further stirred for 3 h at room temperature. Then the volatiles
were removed under reduced pressure and replaced with ethyl
acetate. The mixture was washed with 1 N aqueous HCl, dried over
sodium sulfate and concentrated in vacuo. Cyclohexane was added
to the residue and the mixture was sonicated for 20 min. The
product 4 was obtained pure after concentration of the cyclohexane
mother liquid in 50% yield (37 mg) as a waxy solid. IR (CH2Cl2,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.11.006.
References and notes
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3444, 1749, 1733, 1708, 1672 cmꢀ1 1H NMR (400 MHz,
d
1.36 (s, 9H, tBu), 2.29 (t, 2H, J¼6.4 Hz,
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