Catalytic asymmetric one-pot synthesis of α-methylene-γ-lactams

Article abstract of DOI:10.1016/j.tet.2013.11.028

An organocatalytic enantioselective synthesis of α-methylene-γ- lactams has been developed. The reaction between protected 2-aminomalonates and Morita-Baylis-Hillman carbonates is catalyzed by chiral Lewis bases to afford the corresponding lactams in exce

Full text of DOI:10.1016/j.tet.2013.11.028

Tetrahedron 70 (2014) 75e82
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic asymmetric one-pot synthesis of
a-methylene-
g
-lactams
c
b
a
ꢀ a
Xavier Companyo , Pierre-Yves Geant , Andrea Mazzanti , Albert Moyano ,
,c,
Ramon Rios a
*
a
ꢁ
ꢀ
Universitat de Barcelona, Departament de Química Organica, Facultat de Química, c/Martí i Franques 1-11, 08028 Barcelona, Catalonia, Spain
b Department of Industrial Chemistry “Toso Montanari”, School of Science, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
c School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2013
Received in revised form 29 October 2013
Accepted 12 November 2013
Available online 16 November 2013
An organocatalytic enantioselective synthesis of
a-methylene-g-lactams has been developed. The re-
action between protected 2-aminomalonates and MoritaeBayliseHillman carbonates is catalyzed by
chiral Lewis bases to afford the corresponding lactams in excellent yields and moderate to good enan-
tioselectivities, after work-up.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Lactams
Asymmetric synthesis
One-pot reaction
MoritaeBayliseHillman
1. Introduction
a
-Methylene-
and hence, their synthesis has attracted much attention from the
chemical community. The aforementioned interest in -methylene-
-lactams relies in the fact that these compounds show bio-
activities similar to those of -methylene- -lactones but with much
lower toxic side effects. However, -methylene- -lactams are less
abundant in nature than are -methyl-
-lactones.1
-Methylene- -lactams found in plants are often used in tra-
g-lactams show interesting biological properties,
a
g
a
g
Fig. 1. Natural compounds with an a-methylene-g-lactam moiety.
a
g
a
g
a
g
inhibitory properties, and the consequent allergenic, phytotoxic,
cytotoxic, and antimicrobial properties of -methylene- -lactams
make them potential drug candidates.3 However, an important
drawback of -methylene- -lactams is their multitarget nature
resulting from their chemical properties, which can lead to di-
minished therapeutic value.
More importantly, in recent years, the abovementioned type of
compounds have been extensively studied because of their anti-
cancer properties.4 Some of the mechanisms involved in the anti-
ditional medicine for the treatment of inflammatory diseases. Ex-
amples of a few naturally occurring compounds having this
structure include pukeleimid E, isolated from Lyngbya majuscula,1b
and two imidazole alkaloids, anatin and isoanatin, found in the
leaves of Cynometra (Fig. 1), and they show a broad spectrum of
biological activities.1d
a
g
a
g
The high bioactivity of these compounds is most often due to the
presence of the highly electrophilic
a-exo-methylene-g-lactam
moiety, which can react with nucleophilic sites on enzyme targets
(for instance with mercapto groups in cysteine residues) via Mi-
chael addition. a-Methylene-g-lactams have been found to be ac-
cancer activity of a-methylene-g-lactams are as follows: inhibition
of transcription factors and gene expression, inhibition of the MAPK
signaling pathway, microtubule-interfering activity, modulation of
DNA methylation, induction of apoptosis, cell cycle arrest, and in-
hibition of proliferation and suppression of metastasis.
tive as cellular steroidal inhibitors, blockers of tumor necrosis
factor-a production, DNA polymerase inhibitors, etc.2 These
In spite of the interest in the synthesis of these privileged
compounds, only a few methodologies allowing for their prepara-
tion in optically active form have been reported. There are some
* Corresponding author. Tel.: þ44 (023) 8059 4137; fax: þ44 (023) 8059 4137;
e-mail addresses: R.Rios-Torres@southampton.ac.uk, riosramon@yahoo.com (R.
Rios).
organometallic asymmetric synthesis methods for a-methylene-g-
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.028

ꢀ
X. Companyo et al. / Tetrahedron 70 (2014) 75e82
76
lactams, but all of them rely on the use of chiral auxiliaries.5 Re-
cently, Wang and co-workers reported the asymmetric construc-
acted as a nucleophile, and subsequent in situ deprotection of the
nitrogen substitution adduct 5a (TFA) or 5b (piperidine/DMF)
tion of a couple of spirocyclic
a
-methylene-
g-lactams through
afforded the desired a-methylene-g-lactam 6a (Scheme 2).
sequential reactions of cyclic iminoesters with Mor-
itaeBayliseHillman (MBH) bromides, catalyzed by chiral copper
complexes.6
In the field of organocatalysis, in 2008, Jørgensen and co-
workers reported an elegant multistep asymmetric approach to
a
-methylene-
lective Michael addition of aldehydes to
acrylates.7 In 2012, Liao and co-workers reported the racemic
syntheses of -methylene- -lactams via both a tandem allylic al-
kylation/amination protocol8 and
multicomponent tandem
d
-lactones and
d
-lactams, based on the enantiose-
a
-(diethoxyphosphoryl)
a
g
a
organocatalytic reaction.9 In 2013, Zhu and co-workers reported
the addition of diazo compounds to MBH carbonates promoted by
chiral Lewis bases. After further functionalization they reported
Scheme 2. Modified strategy for the synthesis of a-methylene-g-lactams.
a single example of the synthesis of an
good yield and enantioselectivity.10 Almost at the same time
Krawczyk and co-workers reported the racemic synthesis of
methylene- -lactams via conjugate addition of acetamido malo-
nates to unsaturated phosphonates.11
Very recently, our research group has disclosed the direct
asymmetric synthesis of -methylene- -lactones by the base-
a-methylene-g-lactam with
Next, we proceeded to evaluate different chiral Lewis bases as
a
-
catalysts. As shown in Table 1, the best results with N-Boc-protected
g
malonate 3a were obtained when using b-isocupreidine (b
-ICPD)16
as the catalyst, and the final product was obtained in full conversion
and with 75% ee after 14 h of stirring at room temperature in tol-
uene (entry 1). Cinchona alkaloids or dimeric catalysts, such as
Sharpless ligands resulted in lower reaction rates and enantiose-
lectivities (entries 2e6). Use of additives, such as FeCl2 or Ti(iOPr)4,
which had been previously used by Shibata and co-workers17 in the
substitution of MBH carbonates by fluorobis(phenylsulfonyl)
methane with excellent results, did not improve the previous
a
g
catalyzed substitution of MBH carbonates with 2-hydroxy
malonates, with good yields and enantioselectivities.12
Remarkably, a general catalytic asymmetric strategy for the
synthesis of
lenge in organocatalysis.13 Herein, we report the first enantiose-
lective organocatalytic one-pot synthesis of -methylene-
a-exo-methylene-g-lactams remains an unmet chal-
a
g-
lactams, which can be achieved directly from the substitution of
MBH carbonates14 by 2-aminomalonates.
Table 1
Reaction screeninga
2. Results and discussion
Based on our previous research in organocatalysis15 and taking
into account the excellent results obtained in our MBH carbonate
substitution approach to
an easy protocol for the asymmetric synthesis of
a
-methylene-
g
-lactones,12 we envisioned
-methylene-g-
a
Entry
3
Catalyst
-ICPD
Quinine
Cinchonine
(DHQ)2AQN
(DHQD)2PHAL
T
[3] (M)
Conv.b
eec
lactams via the nucleophilic substitution of MBH carbonates by 2-
aminomalonates, followed by intramolecular lactamization
(Scheme 1). Notably, the possible intramolecular Michael reaction
between the amine with the conjugated double bond would be
disfavored (5-endo-trig cyclization according to Baldwin rules) in
preference to the lactamization (5-exo-trig cyclization).
1
2
3
4
5
6
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
b
rt
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
100%
Traces
Traces
Traces
Traces
Traces
n.r.
þ75%
d
50 ꢀC
50 ꢀC
50 ꢀC
50 ꢀC
50 ꢀC
rt
d
þ16%
ꢁ65%
þ48%
Nd
þ60%
þ74%
d
b-ICPD
b-ICPD
b-ICPD
b-ICPD
b-ICPD
7d
8e
9
10
11
12
13
14
15d
16g
17
rt
4
92%
ꢀC
78%f
ꢁ5 ꢀC
n.r.f
(DHQ)2PYR
(DHQ)2AQN
(DHQD)2PHAL
rt
13%
25%
17%
100%
Traces
100%
100%
þ65%
þ50%
ꢁ88%
þ86%
d
rt
rt
rt
rt
rt
4
b-ICPD
b-ICPD
b-ICPD
b-ICPD
þ50%
þ81%
ꢀC
a
In a vial equipped with a magnetic stirring bar, the MBH carbonate 2a (0.1 mmol,
2 equiv), N-Boc-aminomalonate (0.05 mmol, 1 equiv) and catalyst (0.01 mmol,
0.2 equiv) were added in toluene and the reaction was stirred at room temperature
for 14 h (for 3a) or 24 h (for 3b). Next, the reaction crude was diluted with 1.0 mL of
CH2Cl2, 0.1 mL of TFA was added in one portion and the mixture was stirred over-
night (with compound 3a) or 1.0 mL of DMF/piperidine (20% w/w) was added in one
portion and the mixture was stirred overnight (with compound 3b). Then, 1.0 mL
H2O was added at the reaction crude and neutralized until pH¼7, extracted three
times with EtOAc.
Scheme 1. Proposed reaction pathway for the catalytic asymmetric synthesis of
methylene- -lactams.
a-
g
In preliminary experiments, the reaction of 2-amino-diethyl
malonate 1 with MBH carbonate 2a was explored using DABCO as
catalyst. Unfortunately, all of the reactions resulted in substitution
of the MBH carbonate by the amine, affording the allylic aminoester
4. For this reason, we turned our attention to the use of N-protected
malonates (3a and 3b). This time, the C2 carbon of the malonate
b
Conversion of product 6a determined by 1H NMR analysis of the reaction crude.
c
Enantiomeric excess of 6a, determined by chiral HPLC.
d
0.2 equiv of FeCl2 were used as catalyst additive in the substitution step.
e
0.2 equiv of Ti(OiPr)4 were used as catalyst additive in the substitution step.
f
Conversion after 3 days.
g
0.1 equiv of Schreiner thiourea were used as additive.

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X. Companyo et al. / Tetrahedron 70 (2014) 75e82
77
Table 2
results (entries 7, 8). Decreasing the temperature did not increase
the ee of the reaction (entries 9, 10). Then, we turned our attention
Reaction scopea
to Fmoc-protected aminomalonates 3b; in this case, both the yield
and enantioselectivity of the product
were improved, albeit with longer reaction times (entries 11e17).
Again, the best catalyst was -ICPD, affording 6a with full conver-
a-methylene-g-lactam 6a
b
sion and in 86% ee after 14 h (entry 14). When Sharpless ligands
were tested with 3b, the reaction proceeded with very low con-
versions (entries 11e13). The use of additives or decreasing the
temperature did not improve the outcome of the reaction (entries
14e16). Other solvents, such as dichloromethane, xylene, THF, and
CF3ePh were also investigated, but the yields and enantiose-
lectivities were not better than those obtained with toluene.
With the optimized conditions on hand, we proceeded to study
Entry
Ar
2
tb
6:7 ratioc
1:0
Yieldd
79%
eee
1
2a
14 h
73%
83%
the scope of the reaction. Unfortunately the b-ICPD-catalyzed re-
action of N-Fmoc-protected malonate 3b with MBH carbonate 2b,
having a p-bromophenyl substituent, gave a 1:4 nonseparable
mixture of products 6b and 7b in 55% global yield (Scheme 3).
When the same reaction was run with the N-Boc-protected malo-
nate 3a, the formation of 7b was diminished, and hence, we de-
cided to use 3a in the b-ICPD-catalyzed reaction with a series of
MBH carbonates 2aei, although the enantioselectivity was poorer
than that with 3b in our screening experiments.
2
3
2b
2c
2 d
3 d
2:1
0:1
76%
97%
d
4
5
2d
2e
2 d
3 d
1:0
3:1
90%
83%
53%
74%
6
2f
3 d
0:1
83%
d
7
8
2g
2h
2i
3 d
2 d
3 d
1:0
7:1
1:0
87%
95%
90%
61%
58%
78%
Scheme 3. Reaction of 2b with 3a and 3b.
9
a
In a vial equipped with a magnetic stirring bar, the corresponding MBH car-
bonate (0.05 mmol, 2 equiv), N-Boc-aminomalonate (0.025 mmol, 1 equiv) and
catalyst (0.001 mmol, 20 mol %) were added in 1.0 mL of toluene (C¼0.1 M) and the
reaction was stirred at room temperature for 14 h. Next, the reaction crude was
diluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in one portion and the
mixture was stirred overnight. Then, 1.0 mL H2O was added at the reaction crude
and neutralized until pH¼7 with Na2CO3, extracted three times with EtOAc.
Complete conversion of the starting MBH carbonates 2aei to the
products 6aei and/or 7aei was achieved after 1e3 days (monitored
by 1H NMR) at room temperature. As shown in Table 2, the yield of
byproduct 7 depends on the nature of the aromatic moiety of 2, and
7 is observed to be the sole product when a substituent is present at
the ortho position (compound 2c, entry 3) and in the case of the a-
b
Allylic substitution reaction time.
naphthyl derivative 2f (entry 6). Remarkably, the racemic reactions
using DABCO as catalyst only rendered products 6aei with mod-
erate to good yields. Therefore, steric hindrance in the aryl moiety
c
Determined by 1H NMR of the crude reaction.
Isolated combined (6þ7) yield after column chromatography.
d
e
Determined by chiral HPLC.
of the MBH carbonate appears to be an important factor in the
ICPD catalyzed reaction. The enantioselectivity for the formation of
the chiral -methylene- -lactams 6 varies from moderate to good.
b-
a
g
Strongly electronegative substituents at the 4-position of the phe-
nyl ring (entries 4,7, and 8) decrease the enantioselectivity of the
reaction. On the other hand, the highest enantioselectivities were
obtained with the p-Br derivative 2b (entry 2) and the p-tolyl de-
rivative 2i (entry 9). The
sults as did 2a (entry 5).
b-naphthyl derivative 2e gave similar re-
In order to explain the formation of the achiral lactams 7, we
postulate that the reaction can take place via two possible com-
peting pathways: an SN20eSN20 pathway (Scheme 4, left) and an
SN20 pathway (Scheme 4, right).
In the SN20eSN20 pathway, the Lewis base catalyst first sub-
stitutes the carbonate to give a cationic chiral intermediate I that
undergoes enantioselective allylic substitution by the carbanion
derived from the N-protected malonate 3. In the SN20 pathway, the
malonate carbanion directly substitutes the MBH carbonate,
affording an achiral intermediate II that after N-deprotection, cy-
clizes to form lactam 7. Steric hindrance in the aryl substituent of
the MBH carbonate 2 will slow down the SN20eSN20 pathway,
driving the reaction toward the achiral SN20 pathway. The higher
Scheme 4. Mechanistic scheme for the competing formation of lactams 6 and 7.

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X. Companyo et al. / Tetrahedron 70 (2014) 75e82
78
steric bulk of the Fmoc moiety could also explain the predominance
of 7 when 3b was used. Finally, the nature of the Lewis base is also
a key factor in the process, since a sterically hindered Lewis base
theoretical levels provided consistent shapes of the simulated
spectra. Simulations were performed using BH&HLYP, M06-2X,
u
B97XD and CAM-B3LYP, together with the 6-311þþG(2d,p) or
(such as
b
-ICPD) would slow down the formation of intermediate I
the def2-TZVP basis sets. As shown in Fig. 2, the spectra calculated
and favor direct SN20 substitution of the MBH carbonate by the
malonate carbanion. To confirm this hypothesis (two possible re-
action pathways, one catalyzed by Brønsted base and another cat-
alyzed by Lewis base), we ran additional experiments (Scheme 5).
assuming the (R) configuration match very well the experimental
spectra of 6b (using b-ICPD as catalyst.) The full conformational
analysis and further details can be found in S.D.
€
When we used a tertiary hindered amine, such as Hunig’s base (a
rather poor Lewis base and a good Brønsted base) the only product
obtained from 2a and 3a was the achiral compound 7a in 90% yield.
When DABCO was used, the only product observed was 6a in 92%
yield.
Fig. 2. TD-DFT Simulations of the ECD spectrum of 6b (red and blue traces). The ex-
perimental spectrum (black trace) was obtained of acetonitrile solution (1.0 10ꢁ4 M,
0.2 cm path length).
D .
ε are expressed in mol Lꢁ1 cmꢁ1
Scheme 5. Influence in the base catalyst in the competing formation of products 6
and 7.
3. Conclusions
The synthetic usefulness of this methodology was exemplified
by the transformation of 6a into different products. For example, 6a
reacted with cyclopentadiene to afford a 3.5:1 mixture of the
DielseAlder adducts 8a/8b.18 The exo-methylene double bond of 6a
could be epoxidised by mCPBA in good yield and high diaster-
eoselectivity (9a/9b¼10:1) or hydrogenated by catalysis with Pd/C
to afford the reduced product 10 in satisfactory yields and as
a single diastereoisomer, to which a cis configuration was tenta-
tively assigned.19 Finally, 6a underwent sequential saponification
and decarboxylation to afford 11a/11b in good yields and moderate
diastereoselectivities (Scheme 6).
In summary, we have developed a new enantioselective one-pot
methodology for the synthesis of -methylene- -lactams. Starting
from MBH carbonates, the reaction affords -methylene- -lactams
in satisfactory yields and moderate to good enantioselectivities
when commercially available chiral Lewis bases are used as cata-
lysts. Remarkably, this is the first report on the asymmetric orga-
a
g
a
g
nocatalytic synthesis of a-exo-methylene-g-lactams by a one-pot
procedure. These results allow for more compounds to be synthe-
sized and evaluated, which could lead to the discovery of new drug
candidates.
4. Experimental section
4.1. General methods
Chemicals and solvents were either purchased puriss p.A. from
commercial suppliers or purified by standard techniques. For thin-
layer chromatography (TLC), silica gel plates Merck 60 F254 were
used and compounds were visualized by irradiation with UV light
and/or by treatment with a solution of phosphomolybdic acid
(25.0 g), Ce(SO4)2$H2O (10.0 g), concd H2SO4 (60.0 mL), and H2O
(940.0 mL) followed by heating or by treatment with a solution of
p-anisaldehyde (23.0 mL), concd H2SO4 (35.0 mL), acetic acid
(10.0 mL), and ethanol (900 mL) followed by heating. Flash chro-
matography was performed using silica gel Merck 60 (particle size
0.040e0.063 mm), 1H NMR, 19F NMR and 13C NMR spectra were
recorded on Varian AS 400. Chemical shifts are given in parts per
million relative to tetramethylsilane (TMS) and the coupling con-
stants J are given in Hertz. The spectra were recorded in CDCl3 as
solvent at room temperature. TMS served as internal standard
Scheme 6. Synthetic transformations of compound 6a.
The absolute configuration of
a
-methylene-
g-lactams 6 was
(d
¼0 ppm) for 1H NMR, CDCl3 was used as internal standard
assigned by means of TD-DFT calculations of the electronic circular
dichroism (ECD) spectra.20 Four different methods (functionals)
and two different basis sets were used to ascertain if different
(d
¼77.0 ppm) for 13C NMR and TFA was used as external standard
for 19F NMR. High-resolution mass spectra were recorded on
a Bruker MicroTOF spectrometer.

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X. Companyo et al. / Tetrahedron 70 (2014) 75e82
79
4.2. Procedure for the preparation of the MBH-alcohols
of CH2Cl2, 0.1 mL of TFA were added in one portion and the mixture
was stirred overnight. Then, the solution was diluted with 1.0 mL
H2O and neutralized until pH¼7 with solid Na2CO3. The reaction
mixture was extracted three times with EtOAc, the combined or-
ganic layers were dried over anhydrous MgSO4 and the organic
solvent eliminated at reduced pressure. Finally, the crude product
was purified by flash column chromatography to afford the desired
To a round bottom flask charged with MeOH (0.75 equiv) was
added the arylaldehyde (1.0 equiv) and methyl acrylate (1.2 equiv).
After was added 1,4-diaza-bicyclo[2.2.2]octane (0.5 equiv) and the
solution was stirred for 48e96 h until consumption of the starting
material. The crude reaction mixture was purified directly by flash
column chromatography (Hexane/EtOAc mixtures).
a-methylene-g-lactam in racemic form. Spectral data for racemic
compounds 6g, 6h, 6i coincided with those reported in Ref. 11.
4.3. Procedure for the preparation of MBH-carbonates
4.5. General procedure for the asymmetric synthesis of
To a solution of 1.0 equiv of the MoritaeBayliseHillman alcohol
in CH2Cl2 (0.5 M), 1.05 equiv of (Boc)2O and 0.1 equiv of 4-
dimethylaminopyridine were added. The solution was stirred un-
til consumption of starting material, the solvent was removed by
rotary evaporation and the reaction mixture was purified directly
by flash column chromatography (Hexane/EtOAc mixtures).
a-methylene-g-lactams from diethyl 2-(tert-butoxycarbonyl
amino)malonate (N-Boc-aminomalonate)
In a vial equipped with a magnetic stirring bar, 0.2 mmol of the
corresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Boc-
aminomalonate 3a (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)
were dissolved in 1.0 mL of toluene (C¼0.1 M) and the reaction was
stirred at room temperature over 1e5 days. After consumption of
starting material (monitored by 1H NMR) the reaction crude was
diluted with 1.0 mL of CH2Cl2, 0.1 mL of TFA was added in one
portion and the mixture was stirred overnight. Then, the solution
was diluted with 1.0 mL H2O and neutralized until pH¼7 with solid
Na2CO3. The reaction mixture was extracted three times with
EtOAc, the combined organic layers were dried with MgSO4 anhyd
and the organic solvent eliminated at reduced pressure. Finally, the
crude product was purified by flash column chromatography to
4.3.1. Diethyl 2-(tert-butoxycarbonylamino)malonate (3a). This
compound was synthetized according to the procedure described
by Berner and co-workers.21 To a solution of 10.0 g of diethyl
aminomalonate hydrochloride (47.3 mmol, 1.008 equiv) in 80.0 mL
of dioxane, 1.89 g of NaOH in water (1.01 equiv, 47.4 mmol, 1.0 M)
were added. After complete dissolution of the salt, a solution of
10.3 g of (Boc)2O (1.0 equiv, 46.8 mmol) in 20.0 mL of dioxane was
added dropwise and reacted overnight. Once the reaction was
finished the solvents were removed at reduced pressure, the crude
solid was redissolved with EtOAc, washed with solutions of 1 N HCl
and saturated NaCl, dried over MgSO4 anhyd and the solvent of the
combined organic phases was removed at reduced pressure. Fi-
nally, the crude product was purified by flash column chromatog-
raphy (Hexane/EtOAc 3:1) to afford the desired product as a white
afford the desired a-methylene-g-lactam.
4.6. General procedure for the asymmetric synthesis of
a-
methylene- -lactams from diethyl 2-(((9H-fluoren-9-yl)me-
g
thoxy)carbonylamino) malonate (N-Fmoc-aminomalonate)
solid in 91% yield. 1H NMR (400 MHz, CDCl3)
d
¼5.54 (br s, 1H), 4.93
(d, J¼7.8 Hz, 1H), 4.35e4.15 (m, 4H), 1.44 (s, 9H), 1.29 (t, J¼7.1 Hz,
In a vial equipped with a magnetic stirring bar, 0.2 mmol of the
corresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Fmoc-
6H).
aminomalonate 3b (1.0 equiv) and 0.02 mmol of b-ICPD (0.2 equiv)
4.3.2. Diethyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)malo-
nate (3b). 8.0 g of diethyl aminomalonate hydrochloride (1.0 equiv,
18.9 mmol) were dissolved in 30.0 mL of THF and 50.0 mL of
NaHCO3 10% (w/v). After the complete dissolution of the salt, a so-
lution of 5.4 g of Fmoc-Cl (1.1 equiv, 20.8 mmol) in 60.0 mL of THF
was added dropwise and reacted overnight. After complete con-
sumption of the starting material, the solution was extracted three
times with EtOAc, dried over anhydrous MgSO4 and the solvent was
removed at reduced pressure. Finally, the crude product was pu-
rified by flash column chromatography (Hexane/EtOAc 3:1) to af-
ford the desired product as a white solid in 83% yield: 1H NMR
were added in 1.0 mL of toluene (C¼0.1 M) and the reaction was
stirred at room temperature over 1e5 days. After consumption of
starting material (monitored by 1H NMR) 1.0 mL of DMF/piperidine
(20% w/w) was added in one portion and the mixture was stirred
overnight. Then, the reaction was quenched with 1.0 mL H2O,
treated with HCl 1 M until pH¼6 and extracted three times with
EtOAc. The combined organic layers were dried with MgSO4 and
the organic solvent eliminated to afford the crude product that was
purified by flash column chromatography to afford the desired
methylene- -lactam.
a-
g
(400 MHz, CDCl3)
d
(ppm)¼7.76 (d, J¼7.6 Hz, 2H), 7.61 (d, J¼7.2 Hz,
4.6.1. Diethyl 2-(2-(methoxycarbonyl)-1-phenylallylamino)malonate
(4). White foam. 1H NMR (400 MHz, CDCl3):
2H), 7.41 (t, J¼7.2 Hz, 2H), 7.31 (t, J¼7.3 Hz, 2H), 5.85 (br s, 1H), 5.03
d
(ppm)¼7.32e7.15 (m,
(d, J¼8.3 Hz, 1H), 4.40 (d, J¼7.8 Hz, 2H), 4.34e4.20 (m, 4H), 1.31 (t,
5H), 6.33 (s, 1H), 6.08 (s, 1H), 4.69 (s, 1H), 4.20e4.10 (m, 4H), 3.87 (s,
J¼7.3 Hz, 6 Hz). 13C NMR (100 MHz, CDCl3):
(ppm)¼166.3, 155.4,
d
1H), 3.59 (s, 3H), 1.22e1.15 (m, 6H). 13C NMR (100 MHz, CDCl3):
143.6, 141.2, 127.7, 127.0, 125.0, 119.9, 67.5, 62.6, 57.7, 46.9, 13.9. IR
d
(ppm)¼168.5, 168.3, 166.4, 141.1, 140.1, 127.9, 128.4, 127.7, 125.6,
(
nmax, cmꢁ1): 539, 585, 620, 759, 1023, 1053, 1087, 1176, 1224, 1282,
62.9, 61.8, 60.3, 61.7, 51.7, 14.1, 14.0. IR (nmax, cmꢁ1): 668, 966, 1080,
1447, 1464, 1687, 1737, 2976, 3309. HRMS (ESI) calcd for C22H24NO6
1219, 1263, 1462, 1721, 1747, 2858, 2961 HRMS (ESI): calcd for
C
(MþH)þ 398.1598, found 398.1600.
18H24NO6 (MþH)þ 350.1598, found 350.1600.
4.4. General procedure for the synthesis of racemic
a
-meth-
4.6.2. (R)-Diethyl 4-methylene-5-oxo-3-phenylpyrrolidine-2,2-
ylene- -lactams 6 from diethyl 2-(tert-butoxycarbonylamino)
g
dicarboxylate (6a). White foam (25 mg, 79%). 1H NMR (400 MHz,
malonate (N-Boc-aminomalonate) catalyzed by DABCO
CDCl3):
d
(ppm)¼7.29e7.26 (m, 5H), 6.68 (br s,1H), 6.27 (d, J¼2.7 Hz,
1H), 5.34 (d, J¼2.7 Hz, 1H), 5.0 (t, J¼2.7 Hz, 1H), 4.31e4.21 (m, 2H),
In a vial equipped with a magnetic stirring bar, 0.2 mmol of the
corresponding MBH carbonate (2.0 equiv), 0.1 mmol of N-Boc-
aminomalonate 3a (1.0 equiv) and 0.02 mmol of DABCO (0.2 equiv)
were dissolved in 1.0 mL of toluene (C¼0.1 M) and the reaction was
stirred at room temperature. After consumption of starting material
(monitored by 1H NMR) the reaction crude was diluted with 1.0 mL
3.81e3.69 (m, 1H), 3.58e3.47 (m, 1H), 1.28 (t, J¼7.1 Hz, 3H), 0.79 (t,
J¼7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3):
(ppm)¼168.2, 167.7,
d
167.3, 140.9, 137.7, 129.5, 128.4, 128.0, 120.5, 71.2, 62.8, 62.3, 49.9,
13.9, 13.4. IR (nmax, cmꢁ1): 668, 966, 1081, 1209, 1263, 1461, 1725,
1742, 2852, 2956. HRMS (ESI) calcd for C17H20NO5 (MþH)þ
318.1336, found 318.1340. [
a]
þ40.6 (c 0.8, CHCl3). HPLC (Daicel
D

ꢀ
X. Companyo et al. / Tetrahedron 70 (2014) 75e82
80
Chiralpak IA, i-PrOH/Hexane¼20:80, 220 nm, 1 mL/min): major
J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
(ppm)¼167.9, 167.2,
d
7.3 min, minor 8.8 min. Enantiomeric excess: 73%.
166.9, 143.0, 139.9, 132.2, 130.4, 121.2, 118.3, 112.1, 70.8, 63.2, 62.6,
49.7, 13.9, 13.5. IR (nmax, cmꢁ1): 599, 748, 845, 1023, 1037, 1065,
1245, 1396, 1613, 1723, 1754, 2982, 3045, 3170. HRMS (ESI) calcd for
4.6.3. (R)-Diethyl 3-(4-bromophenyl)-4-methylene-5-oxopyrroli
dine-2,2-dicarboxylate (6b). Yellowish foam. 1H NMR (400 MHz,
C
21H22NO5 (MþH)þ 368.1492, found 368.1492.
CDCl3):
d
(ppm)¼7.43 (d, J¼8.6 Hz, 2H), 7.17 (d, J¼8.6 Hz, 2H), 6.65
(br s, 1H), 6.28 (d, J¼2.9 Hz, 1H), 5.33 (dd, J¼0.9 Hz, 2.5 Hz, 1H), 4.96
(t, 2.9 Hz, 1H), 4.35e4.25 (m, 2H), 3.86e3.77 (m, 1H), 3.65e3.57 (m,
1H), 1.30 (t, J¼7.4 Hz, 3H), 0.87 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz,
4.6.8. (R)-Diethyl 3-(4-methoxyphenyl)-4-methylene-5-oxopyrroli
dine-2,2-dicarboxylate (6g). Colorless crystals mp 140e143 ꢀC
(30 mg, 87%) 1H NMR (400 MHz, CDCl3):
d(ppm)¼7.19 (d, J¼9.2 Hz,
CDCl3):
d
(ppm)¼168.3, 167.5, 167.1, 140.4, 136.6, 132.2, 131.5, 131.3,
2H), 6.81 (d, J¼9.2 Hz, 2H), 6.63 (br s, 1H), 6.26 (d, J¼2.9 Hz, 1H),
5.33 (dd, J¼0.9 Hz, 2.5 Hz, 1H), 4.95 (t, J¼2.9 Hz, 1H), 4.34e4.22 (m,
2H), 3.84e3.75 (m, 1H), 3.77 (s, 3H), 3.64e3.54 (m, 1H), 1.29 (t,
J¼7.0 Hz, 3H), 0.86 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
131.2, 122.2, 120.7, 70.9, 63.0, 62.5, 49.4, 13.9, 13.4. IR (nmax, cmꢁ1):
672, 829, 891, 940, 1009, 1149, 1189, 1205, 1406, 1709, 1736, 2850,
2923, 2979, 3085, 3177. HRMS (ESI) calcd for C17H19BrNO5 (MþH)þ
396.0441, found 396.0437. HPLC (Daicel Chiralpak IC, i-PrOH/
Hexane¼10:90, 220 nm, 1 mL/min): major 65.9 min, minor 39.3.
Enantiomeric excess: 82%.
d
(ppm)¼168.7, 167.7, 167.4, 159.3, 141.1, 130.7, 129.5, 120.3, 113.7,
71.2, 62.8, 62.3, 55.3, 49.4, 13.9, 13.5. IR (nmax, cmꢁ1): 553, 656, 808,
834, 892, 1032, 1144, 1464, 1511, 1583, 1610, 1658, 1734, 1756, 2838,
2935, 2980, 3074, 3183. HRMS (ESI) calcd for C18H22NO6 (MþH)þ
4.6.4. Diethyl
3-(2-bromophenyl)-4-methylene-5-oxopyrrolidine-
348.1442, found 348.1449. [
a]
þ41.0 (c 0.2, CHCl3) HPLC (Daicel
D
2,2-dicarboxylate (6c). White foam. 1H NMR (400 MHz, CDCl3):
Chiralpak IA, i-PrOH/Hexane¼10:90, 220 nm, 1 mL/min): major
d
(ppm)¼7.56 (dd, J¼1.2 Hz, J0¼8.0 Hz 1H), 7.20 (td, J¼1.1 Hz, 7.6 Hz,
15.0 min, minor 16.3 min. Enantiomeric excess: 61%.
1H), 7.13e7.03 (m, 2H), 6.70 (br s, 1H), 6.22 (d, J¼2.7 Hz, 1H), 5.76 (t,
J¼2.1 Hz, 1H), 5.40 (dd, J¼1.1 Hz, 2.1 Hz, 1H), 4.35e4.24 (m, 2H),
3.86e3.77 (m, 1H), 3.66e3.60 (m, 1H), 1.29 (t, J¼7.0 Hz, 3H), 0.86 (t,
4.6.9. (R)-Diethyl 3-(4-chlorophenyl)-4-methylene-5-oxopyrroli
dine-2,2-dicarboxylate (6h). Colorless crystals mp 154e156 ꢀC. 1H
J¼7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d(ppm)¼168.0, 167.2,
NMR (400 MHz, CDCl3):
d
(ppm)¼7.30e7.12 (m, 4H), 6.73 (br s, 1H),
166.6, 141.7, 139.6, 132.7, 129.4, 129.2, 127.9, 125.4, 121.2, 70.7, 63.1,
62.3, 47.7, 13.9, 13.4. IR (nmax, cmꢁ1): 685, 832, 878, 940, 1013, 1167,
1213, 1376, 1422, 1717, 1735, 2856, 2974, 3087, 3188. HRMS (ESI)
calcd for C17H19BrNO5 (MþH)þ 396.0441, found 396.0442.
6.29 (d, J¼2.9 Hz, 1H), 5.34e5.32 (m, 1H), 4.98 (t, J¼2.7 Hz, 1H),
4.36e4.22 (m, 2H), 3.87e3.78 (m, 1H), 3.66e3.58 (m, 1H), 1.29 (t,
J¼7.0 Hz, 3H), 0.87 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
(ppm)¼168.4, 167.5, 167.2, 140.5, 136.1, 134.0, 130.9, 128.6, 120.7,
71.0, 62.9, 62.4, 49.3, 13.9, 13.4. IR (nmax, cmꢁ1): 645, 709, 833, 1014,
1090, 1148, 1209, 1260, 1410, 1445, 1491, 1655, 1725, 1756, 2982,
3197. HRMS (ESI) calcd for C17H19ClNO5 (MþH)þ 352.0946, found
352.0943. HPLC (Daicel Chiralpak IC, i-PrOH/Hexane¼20:80,
220 nm, 1 mL/min): major 58.7 min, minor 36.9 min. Enantiomeric
excess: 58%.
4.6.5. (R)-Diethyl 3-(4-fluorophenyl)-4-methylene-5-oxopyrrolidine-
2,2-dicarboxylate (6d). White foam (30 mg, 90%). 1H NMR
(400 MHz, CDCl3):
d
(ppm)¼7.30e7.25 (m, 2H), 7.01 (t, J¼8.5 Hz,
2H), 6.66 (br s, 1H), 6.29 (d, J¼2.9 Hz, 1H), 5.34 (dd, J¼1.0 Hz, 2.9 Hz,
1H), 5.00 (t, J¼2.9 Hz), 4.37e4.23 (m, 2H), 3.86e3.76 (m, 1H),
3.64e3.55 (m, 1H), 1.30 (t, J¼6.8 Hz, 3H), 0.91 (t, J¼7.4 Hz, 3H). 13
C
NMR (100 MHz, CDCl3):
d
(ppm)¼168.4, 167.6, 167.2, 162.4 (d,
4.6.10. (R)-Diethyl 3-(4-methylphenyl)-4-methylene-5-oxopyrroli
dine-2,2-dicarboxylate (6i). Colorless crystals mp 109e113 ꢀC
J¼256 Hz), 140.7, 133.3, 131.3, 131.2, 120.6, 115.4, 115.2, 71.1, 62.9,
62.4, 49.2, 13.9, 13.5. 19F NMR (376 MHz, CDCl3):
(ppm)¼ꢁ113.8. IR
nmax, cmꢁ1): 546, 738, 818, 845, 1014, 1079, 1209, 1195, 1299, 1419,
d
(30 mg, 90%). 1H NMR (400 MHz, CDCl3):
d
(ppm)¼7.18e7.06 (m,
(
4H), 6.48 (br s, 1H), 6.26 (d, J¼2.9 Hz, 1H), 5.34 (dd, J¼0.9 Hz, 2.5 Hz,
1H), 4.96 (t, J¼2.9 Hz, 1H), 4.34e4.22 (m, 2H), 3.83e3.74 (m, 1H),
3.62e3.54 (m, 1H), 2.31 (s, 3H),1.28 (t, J¼7.0 Hz, 3H), 0.83 (t,
1507, 1713, 1745, 2983, 3080, 3183. HRMS (ESI) calcd for C17H19FNO5
(MþH)þ 336.1214, found 336.1245. [
a
]
þ29.7 (c 1, CHCl3) HPLC
D
(Daicel Chiralpak IA, i-PrOH/Hexane¼10:90, 250 nm, 1 mL/min):
J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
(ppm)¼168.6, 167.7,
d
major 12.6 min, minor 13.7 min. Enantiomeric excess: 53%.
167.3, 141.0, 137.8, 137.7, 128.7, 128.2, 126.5, 71.2, 62.8, 62.3, 49.7,
21.0, 13.9, 13.3. IR (nmax, cmꢁ1): 717, 808, 935, 1012, 1040, 1113, 1145,
1207, 1261, 1391, 1444, 1514, 1659, 1709, 1740, 2924, 3081. HRMS
4.6.6. (R)-Diethyl 4-methylene-3-(naphthalen-2-yl)-5-oxopyrroli
dine-2,2-dicarboxylate (6e). White foam. 1H NMR (400 MHz,
(ESI) calcd for C18H22NO5 (MþH)þ 332.1492, found 332.1495. [
a]
D
CDCl3):
d
(ppm)¼7.82e7.74 (m, 4H), 7.50e7.45 (m, 2H), 7.38e7.35
þ42.1 (c 0.5, CHCl3) HPLC (Daicel Chiralpak IA, i-PrOH/
Hexane¼10:90, 220 nm, 1 mL/min): major 11.8 min, minor
13.5 min. Enantiomeric excess: 78%.
(m, 1H), 6.66 (br s, 1H), 6.32 (d, J¼2.7 Hz, 1H), 5.37 (dd, J¼0.9 Hz,
2.5 Hz, 1H), 5.19 (t, J¼2.7 Hz, 1H), 4.36e4.26 (m, 2H), 3.29e3.18 (m,
1H), 2.84e2.76 (m, 1H), 1.07 (t, J¼7.0 Hz, 3H), 0.60 (t, J¼7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3):
d(ppm)¼168.6, 168.0, 166.9, 142.6,
4.6.11. Diethyl 4-(2-bromobenzylidene)-5-oxopyrrolidine-2,2-
136.2, 133.4, 132.7, 128.6, 128.4, 127.1, 126.5, 125.8, 125.3, 123.8,
121.2, 71.3, 63.0, 61.9, 43.6, 13.9, 12.6. IR (nmax, cmꢁ1): 647, 744, 857,
1011, 1038, 1077, 1260, 1394, 1507, 1600, 1729, 1746, 2980, 3056,
3184. HRMS (ESI) calcd for C21H22NO5 (MþH)þ 368.1492, found
368.1496. HPLC (Daicel Chiralpak IA, i-PrOH/Hexane¼10:90,
220 nm, 1 mL/min): major 14.4 min, minor 18.2 min. Enantiomeric
excess: 74%.
dicarboxylate (7c). White foam (38 mg, 97%). 1H NMR (400 MHz,
CDCl3):
d
(ppm)¼7.65 (t, J¼2.7 Hz, 1H), 7.67e7.63 (m, 1H), 7.48e7.43
(m, 1H), 7.40e7.33 (m, 1H), 7.24e7.18 (m, 1H), 6.60 (br s, 1H),
4.32e4.23 (m, 4H), 3.53 (d, J¼2.7 Hz, 2H), 1.29 (t, J¼7.1 Hz, 6H). 13
C
NMR (100 MHz, CDCl3):
d
(ppm)¼169.3, 168.2, 133.4, 132.6, 131.6,
130.2, 129.3, 127.3, 121.1, 65.6, 63.0, 33.1, 13.9. IR (nmax, cmꢁ1): 756,
1026, 1095, 1162, 1188, 1466, 1707, 1745, 2853, 2924,m 2980, 3197.
HRMS (ESI) calcd for
396.0444.
C
17H19BrNO5 (MþH)þ 396.0441, found
4.6.7. Diethyl 4-methylene-3-(naphthalen-1-yl)-5-oxopyrrolidine-
2,2-dicarboxylate (6f). White foam 1H NMR (400 MHz, CDCl3):
d
(ppm)¼8.27 (d, J¼9.1 Hz, 1H), 7.62 (d, J¼8.4 Hz, 1H), 7.53 (d,
4.6.12. Diethyl 4-(naphthalen-1-ylmethylene)-5-oxopyrrolidine-2,2-
J¼8.4 Hz, 1H), 7.41e7.28 (m, 2H), 7.15 (t, J¼7.4 Hz, 1H), 6.98 (dd,
J¼7.4 Hz, 1.4 Hz 1H), 6.64 (br s, 1H), 6.08 (d, J¼2.5 Hz, 1H), 5.82 (t,
J¼2.3 Hz, 1H), 5.11 (dd, J¼0.9 Hz, J¼2.1 Hz, 1H), 4.14e4.01 (m, 2H),
3.70e3.66 (m, 1H), 3.45e3.35 (m, 1H), 1.30 (t, J¼7.0 Hz, 3H), 0.60 (t,
dicarboxylate (7f). White foam (31 mg, 83%). 1H NMR (400 MHz,
CDCl3):
d
(ppm)¼8.15e8.10 (m, 2H), 7.91e7.85 (m, 1H), 7.64e7.48
(m, 5H), 6.51 (br s, 1H), 4.27 (m, 4H), 3.57 (d, J¼2.5 Hz, 2H), 1.28 (t,
J¼7.0 Hz, 6H). 13C NMR (100 MHz, CDCl3):
(ppm)¼187.2, 169.7,
d

ꢀ
X. Companyo et al. / Tetrahedron 70 (2014) 75e82
81
168.4, 133.6, 131.8, 131.7, 130.0, 129.6, 128.9, 128.7, 126.7, 126.3,
126.2, 125.1, 124.0, 65.7, 62.9, 33.5, 13.9. IR (nmax, cmꢁ1): 631, 726,
777, 796, 1011, 1076, 1161, 1188, 1238, 1342, 1443, 1517, 1701, 1740,
2924, 2980. HRMS (ESI) calcd for C21H22NO5 (MþH)þ 368.1492,
found 368.1489.
crude product was suspended in toluene and heated at 80 ꢀC for
1 h. Finally, the solution was directly purified by flash column
chromatography (EtOAC/MeOH¼15:1) to furnish the desired
product as a mixture of diastereomers (25 mg, 78% yield, 2.5:1 d.r.).
11a (Major diastereoisomer) 1H NMR (400 MHz, DMSO-d6):
d
(ppm)¼8.51 (br s, 1H), 7.38e7.13 (m, 5H), 5.86 (d, J¼2.54 Hz, 1H),
4.6.13. Diethyl 20-oxo-40-phenylspiro[bicyclo[2.2.1]hept[5]ene-2,30-
pyrrolidine]-50,50-dicarboxylate (8a). A solution of 50.0 mg of com-
pound 6a (0.16 mmol, 1.0 equiv) and 100.0 mg of freshly distilled
cyclopentadiene (1.6 mmol, 10.0 equiv) in 5.0 mL of toluene was
refluxed overnight. Then, the organic solvent was removed at re-
duced pressure and the crude product was directly purified by flash
column chromatography (Hexane/EtOAc¼3:1) to afford the desired
product (35 mg, 58% yield, 3.5:1 d.r.). 1H NMR (400 MHz, CDCl3):
5.04 (d, J¼2.54 Hz, 1H), 4.52 (dt, J¼8.4 Hz, 2.5, 1H), 4.37 (dd,
J¼8.4 Hz, 0.97 Hz, 1H). 13C NMR (100 MHz, DMSO-d6):
(ppm)¼
d
171.9, 169.3, 143.7, 138.3, 129.0, 128.2, 127.2, 115.8, 58.7, 47.0. 11b
(Minor diastereomer) 1H NMR (400 MHz, DMSO-d6):
d(ppm)¼8.65
(br s,1H), 7.38e7.13 (m, 5H), 5.82 (d, J¼2.5 Hz,1H), 5.07 (d, J¼2.5 Hz,
1H),4.13e4.09 (m, 1H), 4.07 (dd, J¼4.2 Hz, 1.0 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6):
d
(ppm)¼172.9, 168.2, 144.2, 142.1, 128.8,
127.4, 127.0, 116.7, 60.3, 47.9. HRMS (ESI) calcd for C12H12NO3
d
(ppm)¼7.23e7.15 (m, 3H), 7.07e6.95 (m, 2H), 6.50 (br s, 1H),
(MþH)þ 218.0812, found 218.0814.
6.41e6.36 (m, 1H), 6.31e6.26 (m, 1H), 4.38e4.28 (m, 2H), 4.03 (s,
1H), 3.76e3.64 (m, 2H), 2.79e2.72 (m, 2H), 2.08e1.98 (m, 2H), 1.34
(t, J¼7.8 Hz, 3H), 0.77 (t, J¼7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3):
Acknowledgements
d
(ppm)¼171.2, 167.2, 166.9, 140.7, 134.7, 130.9, 128.6, 127.5, 71.4,
Financial support from the University of Southampton (to R.R.)
and from the Universitat de Barcelona (to A.M.) is gratefully ac-
knowledged. X.C. is grateful to MICINN for a PFU pre-doctoral fel-
lowship. A.M. thanks the University of Bologna (RFO funds 2008).
This work has been done under the auspices of COST Action
CM0905 (ORCA). Financial support from European Regional De-
velopment Fund (ERDF) (AI-Chem & InterReg IVb) is gratefully ac-
knowledged (R.R.).
62.8, 62.1, 56.1, 55.6, 52.3, 46.3, 42.4, 35.0, 14.0, 13.3. HRMS (ESI)
calcd for C22H28NO5 (MþH)þ 386.1962, found 386.1966.
4.6.14. Diethyl 4-oxo-7-phenyl-1-oxa-5-azaspiro[2.4]heptane-6,6-
dicarboxylate (9a). To
a stirred solution of 0.1 mmol of 6a
(1.0 equiv) in 3 mL of CH2Cl2, were added 35.0 mg of mCPBA
(0.2 mmol, 2.0 equiv) and the solution was refluxed for 21 h. After
cooling the solution, the solvent was evaporated and the crude
product treated with 2.0 mL of acetone and 2.0 mL of a saturated
solution of NaHCO3 for 30 min. Then 5.0 mL of water were added
and the mixture was extracted three times with Et2O. The organic
layers were dried and evaporated and the crude product was pu-
rified by flash column chromatography (Hexane/EtOAC¼1:1) to
furnish the desired final product (26 mg, 79% yield, 10:1 d.r.). 1H
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.028.
References and notes
NMR (400 MHz, CDCl3):
d
(ppm)¼7.31e7.27 (m, 3H), 7.21e7.18 (m,
1. (a) Janecki, T.; Blaszczyk, E.; Studzian, K.; Janecka, A.; Krajewska, A.; Rosalski, M.
J. Med. Chem. 2005, 48, 3516e3521; (b) Cardellina, J. H.; Moore, R. E. Tetrahedron
Lett. 1979, 22, 2007e2010; (c) Duan, W. Z.; Zhang, J. T. Acta Chim. Sin. 1997, 32,
259e263; (d) Naito, T.; Honda, Y.; Miyata, O.; Ninomiya, I. Chem. Pharm. Bull.
1993, 41, 217e219; (e) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C.
A.; Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355e357.
2H), 4.40 (s, 1H), 4.37e4.24 (m, 2H), 3.89e3.79 (m, 1H), 3.68e3.60
(m, 1H), 3.29 (d, J¼5.6 Hz, 1H), 2.68 (d, J¼5.6 Hz, 1H), 1.30 (t,
J¼7.3 Hz, 3H), 0.81 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
(ppm)¼171.2, 167.2, 166.9, 135.5, 129.2, 128.6, 128.4, 128.3, 126.3,
63.2 62.6, 61.6, 50.6, 48.3, 29.6, 13.9, 13.3. HRMS (ESI) calcd for
C
2. (a) Lyss, G.; Knorre, A.; Schmidt, T. J.; Pahl, H. L.; Merfort, I. J. Biol. Chem. 1998,
273, 33508e33516; (b) Huang, P. R.; Yeh, Y. M.; Wang, T. C. Cancer Lett. 2005,
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d
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(m,1H),1.28 (t, J¼7.0 Hz, 3H),1.20 (d, J¼7.4 Hz, 3H), 0.81 (t, J¼7.0 Hz,
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3H). 13C NMR (100 MHz, DMSO-d6):
d(ppm)¼177.8, 168.7, 168.2,
136.4, 129.2, 128.7, 128.1, 71.4, 62.2, 61.9, 53.3, 14.5, 14.1, 13.7. HRMS
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acid
(11a/11b). This compound was synthetized adapting the procedure
reported by Rios and Cordova for a related compound.22 50 mg of
compound 4a (0.15 mmol, 1.0 equiv) was stirred for 21 h with
2.0 mL of NaOH 0.5 M at room temperature. Then, the solution was
extracted with 5.0 mL of EtOAc, the aqueous fraction was acidified
to pH¼2 with HCl, extracted three times with CH2Cl2, the combined
organic layers were dried over MgSO4 anhyd and the solvent was
eliminated at reduced pressure. Afterward, the corresponding
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2013, 1184e1186.

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X. Companyo et al. / Tetrahedron 70 (2014) 75e82
82
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been reported to produce exo adducts. We suppose that the addition of the
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stituent at the
previously reported DielseAlder reaction of
a substituent in the position, see: Bose, S.; Ghosh, M.; Ghosh, S. J. Org. Chem.
2012, 77, 6345e6350 We assume a similar behaviour in the case of -methy-
lene- -butyrolactams.
b
-position of the
a
-methylene lactone. This is in accordance with
a
-methylene lactones bearing
14. For a review about the organocatalytic methodologies based on MBH carbon-
ates see: Rios, R. Catal. Sci. Technol. 2012, 2, 267e278.
b
a
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g
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report Ref. 12.
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18. DielseAlder reaction of
a-methylene-g-butyrolactones with cyclic dienes has
been investigated in connection with the synthesis of natural products and has