Microwave-assisted multicomponent diastereoselective 1,3-dipolar cycloaddition of ethyl glyoxylate derived azomethine ylides

Article abstract of DOI:10.1039/c2ob27072b

The thermal multicomponent 1,3-dipolar cycloaddition (1,3-DC) of diethyl aminomalonate or α-amino esters (derived from glycine, alanine, phenylalanine, and phenylglycine) with ethyl glyoxylate and the corresponding dipolarophile such as maleimides, methyl acrylate, methyl fumarate, (E)-1,2-bis(phenylsulfonyl)ethylene, and electron deficient alkynes allows the diastereoselective synthesis of new polysubstituted pyrrolidine derivatives. Microwave-assisted heating processes give better results than conventional heating ones, affording endo-cycloadducts as major stereoisomers. In general, 2,5-cis-cycloadducts are preferentially formed according to the previous formation of the W-shaped dipole. Only in the 1,3-DC of the disulfone with phenylglycine and ethyl glyoxylate the corresponding exo-trans-cycloadduct was isolated. The compound endo-cis-4b, derived from phenylalanine, ethyl glyoxylate and N-benzylmaleimide, has been further transformed into a very complex diazabicyclo[2.2.1]octane skeleton with potential biological activity.

Full text of DOI:10.1039/c2ob27072b

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Microwave-assisted multicomponent diastereoselective
1,3-dipolar cycloaddition of ethyl glyoxylate derived
azomethine ylides†‡
Cite this: Org. Biomol. Chem., 2013, 11,
662
Juan Mancebo-Aracil, Carmen Nájera* and José M. Sansano*
The thermal multicomponent 1,3-dipolar cycloaddition (1,3-DC) of diethyl aminomalonate or α-amino
esters (derived from glycine, alanine, phenylalanine, and phenylglycine) with ethyl glyoxylate and the
corresponding dipolarophile such as maleimides, methyl acrylate, methyl fumarate, (E)-1,2-bis(phenyl-
sulfonyl)ethylene, and electron deficient alkynes allows the diastereoselective synthesis of new polysub-
stituted pyrrolidine derivatives. Microwave-assisted heating processes give better results than
conventional heating ones, affording endo-cycloadducts as major stereoisomers. In general, 2,5-cis-
cycloadducts are preferentially formed according to the previous formation of the W-shaped dipole. Only
in the 1,3-DC of the disulfone with phenylglycine and ethyl glyoxylate the corresponding exo-trans-cyclo-
adduct was isolated. The compound endo-cis-4b, derived from phenylalanine, ethyl glyoxylate and N-
benzylmaleimide, has been further transformed into a very complex diazabicyclo[2.2.1]octane skeleton
with potential biological activity.
Received 24th October 2012,
Accepted 23rd November 2012
DOI: 10.1039/c2ob27072b
www.rsc.org/obc
Introduction
The use of multicomponent reactions (MCRs)1 in organic syn-
thesis allows the efficient preparation of a wide range of
complex molecules in an economically favourable way by using
simple processes. In the case of 1,3-dipolar cycloadditions
(1,3-DC)2 of azomethine ylides and dipolarophiles, generally,
the corresponding imino esters have to be prepared previously
from the carbonyl compound and the α-amino acid to yield
highly substituted prolines.3–5 This core heterocyclic structure
is readily involved in diversity-oriented synthesis (DOS)6 allow-
ing the preparation of different small structures in a reduced
number of synthetic steps.
However, few examples of 1,3-DC of azomethine ylides have
been described using MCR.7 In all of these examples, aromatic
carbonyl compounds and amino esters have been combined
affording the corresponding prolines bearing at the 5-position
an aromatic or heteroaromatic ring. Alternatively, the use of
ethyl glyoxylate as the aldehyde component would allow the
synthesis of 2,5-bis(alkoxycarbonyl)-substituted pyrrolidines I
by means of 1,3-DC (Scheme 1). In this particular situation,
Scheme 1 Retrosynthetic analysis for the synthesis of I.
the preparation and isolation of imino esters is very difficult
due to their instability. Therefore, in the only described contri-
bution using ethyl glyoxylate and ethyl N-(1-phenylethyl)glyc-
inate, the 1,3-DC had to be performed in a multicomponent
process affording a mixture of pyrrolidines II–V with very low
diastereoselection (Scheme 2).8
In this work, we describe for the first time the employment
of the very reactive ethyl glyoxylate as the aldehyde component
in a general domino-MCR, involving in situ generation of the
imino esters, followed by a [1,2]-prototropy shift, and further
thermal 1,3-DC with electrophilic alkenes or alkynes, for the
general synthesis of prolines I.
Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Facultad
Results and discussion
de Ciencias, Universidad de Alicante, 03080-Alicante, Spain. E-mail: cnajera@ua.es,
jmsansano@ua.es; Fax: +34-965903549
†Dedicated to the memory of Prof. Balbino Mancheño.
For initial studies, diethyl aminomalonate was chosen as an
appropriate and more reactive candidate to undergo this type
of multicomponent 1,3-DC.7a–d The model reaction between
commercially available ethyl glyoxylate (50% solution in
‡Electronic supplementary information (ESI) available. CCDC 906384. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob27072b
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Scheme 2 Published example using ethyl glyoxylate in a multicomponent 1,3-
DC.
Fig. 1 1,3-DC of ethyl glyoxylate and diethyl aminomalonate in toluene.
fumarate furnished endo-1d in relatively good yield (57%
regardless of the selected heating mode). (E)-1,2-Bis(phenyl-
sulfonyl)ethylene, a synthetic equivalent of acetylene, was also
assessed giving disulfone endo-1e in higher yield (67%) when
the reaction took place under microwave irradiation. In the
case of methyl acrylate an excess (10 equiv.) was required
affording, under both heating conditions (MW and CH), a
mixture of two endo-1f, and exo-1f stereoisomers and regio-
isomer endo-1f′ (3 : 3 : 1) in moderate yields (Fig. 1).
Scheme 3 1,3-DC involving diethyl aminomalonate.
Then acetylenic dipolarophiles were assayed. Symmetrical
toluene) diethyl aminomalonate hydrochloride and N-methyl- diethyl acetylenedicarboxylate afforded Δ3-pyrroline 1g (Fig. 1)
maleimide, in the presence of triethylamine (1.1 equiv.), was in moderate yield (57%). An unexpected result was obtained in
tested using several solvents under conventional heating (CH) the thermal multicomponent reaction involving methyl propio-
or through microwave (MW)-assisted heating.9 Good conver- late. The reaction occurred in the presence of 3 equiv. of the
sions and stereoselections of cycloadducts 1 were achieved by dipolarophile in 61 and 44% overall yields under microwave-
using toluene as the pure solvent by heating at 110 °C for 24 h assisted and conventional heating, respectively. The corre-
(Scheme 3). Moreover, the multicomponent microwave-assisted sponding products were isolated as a mixture of two regio-
transformation afforded a cleaner crude reaction mixture prob- isomers 1h and 1i in equal proportions (Fig. 1).
ably due to the faster reaction (1 h) of the in situ generated azo-
The relative configuration of products 1 was determined
methine ylide with the dipolarophile.
employing bidimensional NMR experiments (NOESY, COSY,
The scope of this 1,3-DC was studied with several dipolaro- HSMC, etc.) and by comparison of the experimental coupling
philes (Scheme 3 and Fig. 1). In the case of maleimides such constants with those reported in the literature for related struc-
as N-methyl, N-benzyl, and N-phenyl maleimides (NMM, NBM, tures.10 For example, positive NOESY experiments and coup-
and NPM, respectively) pure endo-cycloadducts 1a–c were iso- ling constants of 8.5 Hz for the cis-arrangements H3–H3a and
lated in very good yields and diastereoselectivity. Dimethyl H3a–H6a supported the skeleton represented by endo-1a, 1b
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and 1c structures. The higher chemical shift observed for H6a
(4.1–4.4 ppm, in cis-position with respect to an ester group)
versus a range of 3.85–4.00 ppm for H6a supported this
arrangement. For the cases of endo-cycloadducts 1d and 1e,
derived from 1,2-trans-disubstituted alkenes, both of the cis-
and trans-coupling constants are very similar. NOESY experi-
ments did not clarify the relationship of hydrogen atoms
bonded at positions 3, 4 and 5 of the heterocycle of compound
1d, but the chemical shifts of H3 and H5 matched with the
structure represented in Fig. 1 according to the previous
comment (see above). This assignment was also confirmed by
the structural analysis of the molecule endo-1e, which dis-
played a very important positive nOe between cis-H4–H5. The
observed coupling constant [J(H4–H5) = 4.7 Hz] was slightly
higher than the corresponding trans-H3–H4 (3.7 Hz), although
with a lower absolute value than the analogous one observed
for maleimide derivatives. Chemical shifts 4.64 ppm (H4 in
trans-position with respect to CO2Et) and 5.15 ppm (H3 in cis-
position with respect to CO2Et) were considered as definitive
parameters to resolve the relative configuration.
The mixture of compounds 1f was more difficult to eluci-
date because crucial signals appeared in very narrow ranges of
ppm and also the stereoisomers could not be separated by
flash chromatography. Compound endo-1f was identified
according to the J(H4–H5) = 8.2 Hz by comparison with the
analogous data obtained for the cis-arrangement observed for
cycloadduct endo-1d, and by nOe experiments. In addition, the
other stereoisomer possesses a signal, with J(H4–H5) = 6.9 Hz,
which is appropriate for a trans-arrangement of those hydro-
gen atoms. Regioisomer endo-1f′, also observed in other
examples of cycloaddition performed with methyl acrylate (see
below), was identified in less proportion as the all-cis substitu-
ent pyrrolidine (confirmed by a small H3–H5 nOe) as a conse-
quence of the attack of the W-shaped dipole A through its
γ-position (Scheme 4).
Scheme 5 1,3-DC of ethyl glycinate and ethyl glyoxylate with maleimides.
Table 1 1,3-DC between ethyl glycinate, ethyl glyoxylate, and maleimides
Entry
R
Heatinga Con.b (%)
2
Yieldc (%) cis/transb,d
1
2
3
4
5
6
Me CH
Me MW
100
100
100
85
100
96
2a
2a
2b 64
2b 60
2c
2c
75
80
3 : 1 (2 : 1)
3 : 1 (2 : 1)
1 : 1 (2 : 1)
1 : 1 (2 : 1)
>20 : 1 (4 : 1)
>20 : 1 (4 : 1)
Bn
Bn
Ph
Ph
CH
MW
CH
71e
70e
MW
a Conventional heating (CH) takes 24
h for completion whilst
microwave-assisted heating (MW) needs 1 h. b Determined by 1H and
13C NMR analysis. c Isolated yield after flash chromatography. d In
brackets the diastereomeric ratio determined in the crude product.
e Yield for compound endo-cis-2c.
and faster reactions than the analogous processes performed
under conventional heating (24 h) (Table 1). Again, MW
1
heating afforded cleanest crude reaction mixtures by H NMR,
without signals of the corresponding polymer from ethyl gly-
oxylate. Symmetrical dipolarophiles such as N-methyl, N-benzyl,
and N-phenyl maleimides (NMM, NBM, and NPM, respecti-
vely) were evaluated affording cycloadducts 2 in moderate to
good yields (Table 1). Nevertheless, the cis/trans ratio (referred
to both CO2Et group arrangement) of the final bicycle 2 was
unexpectedly very different. Thus, NMM and NPM furnished
endo-cis-2a as the major stereoisomer (Table 1, entries 1, 2, 5
and 6). However, NBM afforded equimolar amounts of both
cis- and trans-isomers 2b. The relative stereochemistry of the
major endo-cis-2c was determined through NOESY experiments
and by comparison of its X-ray diffraction pattern11 with the
analogous one described for a similar compound to 2c (pre-
pared in a fullerene-sensitized 1,3-DC between maleimides
and iminodiacetic acid).12 As was described in this last contri-
bution the second order coupling constant did not confirm
the higher value for the cis-arrangement. However, for the
In this series, the microwave-assisted reaction was much
more advantageous. Surprisingly, when a freshly distilled ethyl
glyoxylate was employed in this MCR the crude reaction
mixture was extremely complex to analyze (1H NMR). It is
worth noting the importance of this multicomponent process
because attempts to prepare the imine derived from diethyl
aminomalonate and ethyl glyoxylate failed.
Encouraged by the good diastereoselection and simplicity
of these reactions, we decided to explore the analogous trans-
formation using α-amino esters. First, glycine ethyl ester was
used for the synthesis of cycloadducts 2 under the previously
described reaction conditions (Scheme 5). Microwave-assisted
heating (1 h) provided similar conversions, chemical yields
endo-trans-isomers
a cis-coupling constant was observed
(8.0–8.1 Hz) and smaller coupling constants in the correspond-
ing multiplet. The imine derived from ethyl glycinate and ethyl
glyoxylate could not be isolated in spite of testing several con-
ditions and dehydrating protocols. We assume that in the case
Scheme 4 Dipole conformations derived from ethyl glyoxylate and diethyl
aminomalonate.
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Scheme 6 Dipole conformations derived from glycine ethyl ester and ethyl
Scheme 8 Dipole conformations derived from α-substituted amino esters and
ethyl glyoxylate.
glyoxylate.
of NMM and NPM the W-shaped ylide B reacts preferentially
than the S-shaped one B affording mainly the 2,5-cis substi-
tuted pyrrolidine (Scheme 6).
mixture of endo-cis-regioisomers 3f and 3f′ together with the
stereomutated adduct endo-trans-3f (Scheme 7) originated by
means of the S1-dipole C (R2 = Me, Scheme 8). The presence of
an important amount of endo-cis-3f′ implies that the isomeriza-
tion of the imino ester occurred towards the formation of the
thermodynamically more substituted resonance form of
W-dipole C (R2 = Me, Scheme 8) allowing the attack of the dipole
by its γ-position. The analogous reaction with tert-butyl acr-
ylate gave a very poor yield of an unidentified mixture of pro-
ducts. In any case involving acrylates, the reaction carried out
under conventional heating afforded lower chemical yields
(34–37%). The relative configuration of compound endo-cis-3f
was determined according to H4–H5 nOe and very small nOe
between the methyl group and H5. The presence of this substi-
tuent in the ring reduced the cis-coupling constant to a 7.0 Hz
value, which was also observed for the endo-trans-3f. For the
last compound 3f′, NOESY experiments were very helpful
because intense nOe was shown between H3–H5 and also by
the methyl group with H3.
Lower LUMO-alkenes such as dimethyl fumarate and (E)-
1,2-bis(phenylsulfonyl)ethylene were next examined as dipolaro-
philes in this multicomponent transformation (Scheme 9). In
both examples, the reaction was highly diastereoselective
obtaining the corresponding endo-cis-cycloadducts 3d and 3e
in good yields after flash chromatography (70 and 66% yield,
respectively). Apparently, other different stereoisomers were
not detected either from the 1H NMR reaction crude or by
analysis of the purified compounds. The nature of substituents
in a small-size carbocycle can alter their cis- and trans-coupl-
ing constants, thus, the reaction employing fumarate, with
The described reaction involving maleimides and glycine
ethyl ester hydrochloride afforded symmetrical arrangement in
structures 2. In order to study the effect of a non-symmetrical
alkene, the MW-assisted reaction was performed, in toluene as
the solvent, with several dipolarophiles such as methyl acr-
ylate, dimethyl fumarate, (E)-1,2-bis(phenylsulfonyl)ethylene
or methyl propiolate. In all these examples, mixtures of uni-
dentified isomers were obtained in low yields presumably
due to epimerizations mainly at the 2- and/or 5-position of the
pyrrolidine ring.
The microwave-assisted heating was next applied to the syn-
thesis of more substituted pyrrolidine derivatives 3, where
methyl alaninate was selected as the dipole precursor com-
bined with NMM and methyl acrylate as dipolarophiles
(Scheme 7). In the reaction involving NMM the product endo-
cis-3a was stereoselectively obtained in very good chemical
yield (85%). The coupling constants of the cyclic hydrogen
atoms were 8.0 Hz (cis-arrangement). Also, a small nOe
between the methyl group and the H3, H3a or H6a hydrogen
atoms was observed. The reaction carried out in the presence
of methyl acrylate was not so diastereoselective obtaining a
Scheme 7 1,3-DC involving ethyl alaninate, ethyl glyoxylate with NMM or
Scheme 9 1,3-DC of methyl alaninate and ethyl glyoxylate with dimethyl
fumarate or (E)-1,2-bis(phenylsulfonyl)ethylene.
methyl acrylate.
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Scheme 10 1,3-DC of ethyl phenylalaninate and ethyl glyoxylate with
maleimides.
JcisH4–H5= 8.0 Hz, is clearly lower than the JtransH3–H4= 10.0 Hz
for the compound endo-cis-3d (also observed in compounds
endo-cis-4d and endo-cis-5d, see below). Nevertheless, phenyl-
sulfonyl substituents maintained the higher coupling constant
for the cis-arrangement J(H4–H5) = 6.5 Hz versus a 4.5 Hz value
given by a trans-H3–H4 junction, such as occurred in every
cycloadduct of this work derived from this disulfone. A very
small nOe was detected between the methyl group and H5 and
a small one with the sulfonyl aromatic ring too (Scheme 9).
Similar behaviour was observed when the microwave-
assisted heating was employed in the cycloaddition of ethyl
phenylalaninate, ethyl glyoxylate and dipolarophiles. Male-
imides were suitable electrophilic alkenes, for example NMM,
NBM and NPM afforded exclusively, under the standard reac-
tion conditions, products endo-cis-4 in 96, 75, and 82% yield,
respectively (Scheme 10). The corresponding JcisH3–H3a coup-
ling constants were 8.4 Hz for endo-cis-4a, and 7.8 Hz for both
endo-cis-4b and c. The benzylic substituent is in a cis-position
with respect to H3–H3a–H6a according to NOESY experiments.
Dimethyl fumarate and phenylalaninate ethyl ester hydro-
chloride afforded cycloadduct endo-cis-4d in higher yield than
the corresponding one obtained in the reaction using the alan-
inate (Scheme 11). The JtransH3–H4 (10.1 Hz) and the JcisH4–H5
(8.5 Hz) were similar to those observed for compound endo-cis-
3d. A nOe was observed between benzylic protons and both H4
and H5. When disulfone (E)-1,2-bis(phenylsulfonyl)ethylene
was allowed to react with ethyl phenylalaninate and ethyl
glyoxylate, cycloadduct exo-cis-4e was obtained in 60% yield as
the major diastereoisomer (exo/endo > 20 : 1, Scheme 11). Its
relative configuration was determined by strong positive
benzylic hydrogen atoms – H3 nOe and a noticeable nOe
between this benzylic methylene and H5. In addition, a double
Jtrans = 5.2 Hz was observed in the H4 signal. This opposite dia-
stereoselectivity observed (in comparison with the diethyl amino-
malonate adduct 1e or endo-cis-3e) could be caused by steric
repulsions of the benzylic substituent with the sulfonyl group.
Scheme 11 1,3-DC of ethyl phenylalaninate and ethyl glyoxylate with
dimethyl fumarate or (E)-1,2-bis(phenylsulfonyl)ethylene.
Another interesting series of α-quaternized pyrrolidine
derivatives were isolated from the microwave assisted cyclo-
addition between methyl phenylglycinate hydrochloride, ethyl
glyoxylate and different dipolarophiles (Scheme 12). Firstly,
NMM afforded a 2 : 1 mixture of endo-cycloadducts, the
Scheme 12 1,3-DC of methyl phenylglycinate and ethyl glyoxylate with NMM
or methyl acrylate.
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stereomutated product being the minor isomer. The double and 0.5 ppm, respectively, with respect to the analogous shift
cis-coupling constants for H3–H3a and H3a–H6a (8.5 and 7.5 appearing when H3 and the phenyl group are in a cis-junction.
Hz, respectively), and the positive nOe of H3–H3a–H6a to each
With all this information, it was possible to elucidate the
other supported the structure drawn for endo-cis-5a in structure of cycloadduct exo-trans-5e, which was obtained, in
Scheme 12. In the case of the endo-trans-5a the same positive 68% yield, under standard reaction conditions employing (E)-
nOe of H3–H3a–H6a was detected (cis-coupling constants 1,2-bis(phenylsulfonyl)ethylene, ethyl glyoxylate and phenyl-
around 7.6 Hz) but the H3 chemical shift (4.25 ppm) appeared glycine methyl ester hydrochloride (Scheme 13). Again, all-
at lower fields than the corresponding H3 chemical shift trans coupling constants 5.3 and 5.0 Hz, and H3-CO2Me nOe
(3.96 ppm) of the product endo-cis-5a. In the reaction per- supported the drawn structure. However, the most relevant
formed with methyl acrylate the resulting regioselection was detail was the H3 chemical shift (4.86 ppm), which is around
very high, however, the diastereoselection was similar to that 0.35 ppm higher than, for example, the chemical shift of H3 in
described previously for NMM. The equimolar ratio of endo- disulfonylated cycloadducts exo-cis-4e or endo-cis-3e.
1
cis-5f/endo-trans-5f was identified by H NMR and the assign-
According to very simple MM3 force field free energy calcu-
ment of both relative configurations by NOESY experiments, lations13 the formation of the most energetically favoured
specially by the nOe exhibited by H3 with aromatic protons in stereoisomer exo-trans-5e was confirmed. Despite the apparent
cycloadduct endo-cis-5f. In both endo-cis-5f and endo-trans-5f a low difference in energy between the two resonance forms of
weak H3–H5 nOe was identified (Scheme 12). According to S1-dipole C (Scheme 8, R1 = Me, R2 = Ph) it seems that the
these results the S1-dipole C (Scheme 8, R1 = Me, R2 = Ph) bulky disulfone is better approached in an exo-manner due to
could be the precursor of endo-trans-cycloadducts. Due to possible hydrophobic interactions between a phenylsulfonyl
steric reasons this dipole S1-C reacted preferentially through ring and the phenyl group of the dipole.
its γ-position.
Cycloadditions involving electron poor alkynes deserve a
Dimethyl fumarate furnished an equimolecular mixture of special mention. Methyl propiolate and diethyl acetylenedicarb-
diastereoisomers endo-cis-5d and exo-cis-5d in 87% yield oxylate were appropriate dipolarophiles in the reaction per-
(Scheme 13). For the endo-cis-arrangement Jtrans was 10.1 Hz formed with diethyl aminomalonate (Fig. 1). However, when
and 8.5 Hz for Jcis, and also H3-CO2Me nOe data were valuable glycinate, alaninate, phenylalaninate, and phenylglycinate
to assign the final structure. The exo-cis-5d compound showed were used for the 1,3-DC with methyl propiolate, the reaction
all-trans coupling constants 6.7 and 6.9 Hz, and a clear H3-Ph mixture was extremely complex and no cycloadduct could be
nOe. From the analysis of chemical shifts of the H3 atom in isolated. However, when α-substituted amino esters were
compounds 5a, 5d and 5f, when this atom is in almost allowed to react with ethyl glyoxylate and diethyl acetylenedi-
eclipsed conformation (cis-relative position) with the methyl carboxylate, cycloadducts cis-3g, cis-4g and cis-5g were isolated
ester group (bonded to C2) it is deshielded by around 0.3, 0.4, after purification (flash chromatography) in moderate yields
and as pure cis-stereoisomers (Scheme 14). In these three
examples nOes between H5 and the corresponding substituent
(R1) were observed.
This type of 1,3-DC permits the generation of pyrrolidine
rings incorporating two alkoxycarbonyl groups, in many cases,
with a cis-2,5-arrangement which is very valuable from the syn-
thetic point of view because it is not a very easy task. As a poss-
ible application, we were interested in the synthesis of the
bicyclic system 8, which can be employed for the elaboration
of large series of biologically active compounds.14 For this
Scheme 13 1,3-DC of methyl phenylglycinate and ethyl glyoxylate with
dimethyl fumarate or (E)-1,2-bis(phenylsulfonyl)ethylene.
Scheme 14 1,3-DC of amino esters and ethyl glyoxylate with diethyl
acetylenedicarboxylate.
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According to the dipolarophiles, maleimides afforded exclu-
sively endo-cycloadducts as well as dimethyl fumarate and
methyl acrylate. Nevertheless, (E)-1,2-bis(phenylsulfonyl)ethyl-
ene reacted in a different manner depending on the amino
ester. Thus, the endo-approach prevailed for less hindered R2
substituents (amino malonate and alanine derivatives), mean-
while the exo-type interaction was favoured by phenylalanine
and phenylglycine surrogates.
Finally, diethyl acetylenedicarboxylate afforded just one
stereoisomer always operating under a W-shaped type A or C
1,3-dipole geometry. Methyl propiolate could only be tested in
the reaction with diethyl aminomalonate affording an equi-
molar mixture of regioisomers as a consequence of the compe-
tition of the attack of the W-shaped type A dipole through its
γ-position (Scheme 4).
Further studies to improve both regio- and diastereoselec-
tion by lowering the temperature of the reaction by means of
an efficient catalyst are currently underway.
Scheme 15 Synthesis of the biologically active compound 8.
Experimental
purpose, cycloadduct endo-4b was allowed to react with
benzoyl chloride15 and the resulting amide immediately General
reduced in the presence of lithium aluminum hydride obtain-
The structurally most important peaks of the IR spectra
ing a 2 : 1 mixture of the desired diol 6a and the debenzylated
bicycle 7a in 65% combined yield (Scheme 15). The latter was
successfully transformed to 6a in 78% yield by alkylation with
benzyl bromide in DMF at 100 °C. The final diazabicyclo[2.2.1]-
octane skeleton of 8 was achieved by a known methodology16
employing a double mesylation followed by a ring closing
nucleophilic substitution performed by benzylamine after 19 h
under refluxing acetonitrile. The all-cis-8 compound was iso-
lated as a unique diastereoisomer in 53% yield, and a 34%
overall yield from cycloadduct endo-4b (Scheme 15).
In conclusion, commercially available toluene solutions of
reactive ethyl glyoxylate could be incorporated into the multi-
component 1,3-DC of azomethine ylides with dipolarophiles.
Microwave-assisted heating was much more effective than the
conventional heating affording total conversions in 1 h and
cleaner reaction products in all the examples described across
the text. If we analyze the effect of the 1,3-dipole nature, the
normal trend of aminomalonate derived heterocycles is to
react as its W-shaped type A, B or C 1,3-dipole (Schemes 4, 6
and 8) finding an exception when methyl acrylate was used as
(recorded using a Nicolet 510 P-FT and a Jasco FTIR 4100) are
listed. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
obtained using a Bruker AC-300 with CDCl3 as the solvent and
TMS as the internal standard unless otherwise stated. Low-res-
olution electron impact (GC-EI) mass spectra were obtained at
70 eV using a Shimadzu QP-5000, and high-resolution mass
spectra were obtained using a Finnigan VG Platform. HRMS
(GC-EI) were recorded using a Finnigan MAT 95S instrument.
Analytical TLC was performed using Schleicher & Schuell
F1400/LS silica gel plates, and the spots were visualized under
UV light (λ = 254 nm). Melting points were determined with a
Reichert Thermovar hot plate apparatus and are uncorrected.
For flash chromatography, we employed Merck silica gel 60
(0.040–0.063 mm). CEM Discover and Explorer-Coolmate acces-
sories were employed in the microwave-assisted reactions for
the generation of imino esters.
General procedure for the microwave-assisted synthesis of
cycloadducts
the dipolarophile. W-Shaped 1,3-dipole B (Scheme 6) is the Ethyl glyoxylate (100 μL, 0.5 mmol, 50% in toluene), diethyl
most abundant intermediate when glycine ethyl ester was aminomalonate hydrochloride or the amino acid ethyl ester
involved in the cycloaddition, although the existence of the S- hydrochloride (0.5 mmol), the corresponding dipolarophile
shaped-B (Scheme 6) 1,3-dipole is noticeable. α-Substituted (0.5 mmol) and triethylamine (90 μL, 0.55 mmol) were dis-
amino esters such as alanine methyl ester or phenylalanine solved in toluene (4 mL). The reaction vessel was sealed and
ethyl ester overwhelmingly reacted through their W-shaped irradiated in a CEM-discover microwave reactor at 110 °C and a
type C 1,3-dipoles. However, in the reactions dealing with the maximum power of 60 W for 1 h. Alternatively, the reaction
more sterically hindered phenylglycine derivative a compe- can be refluxed for 19 h. The solvent was evaporated under
tition of the attack through both α- and γ-positions of S1- reduced pressure and the residue was dissolved in ethyl
dipole C (Scheme 8) was inferred. In fact, S1-dipole C precursor acetate, washed with brine and dried over MgSO4. After evapor-
exclusively reacted by its γ-position when the ethylenic disulf- ation the residue was purified by flash chromatography (silica
one was employed.
gel) to afford the corresponding product.
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(3R*,3aS*,6aR*)-Triethyl
5-methyl-4,6-dioxo
hexahydro- 61.9, 62.7, 62.7 (3 × CO2CH2CH3), 74.6 [C(CO2Et)2], 168.7,
pyrrolo[3,4-c]pyrrole-1,1,3(2H)-tricarboxylate
endo-1a. Sticky 168.9, 170.3, 171.0, 171.2 (5 × CO2CH3); MS (EI-GC) m/z: 403
pale yellow oil; Rf 0.24 (n-hexane–ethyl acetate 7 : 3); IR (neat) (M+ + 1, <1%), 299 (15), 298 (100), 198 (23), 166 (47), 152 (15),
1
νmax 2983, 1701, 1731 cm−1; H NMR δH: 1.28–1.37 (m, 9H, 3 × 138 (10), 119 (10), 94 (11); HRMS calculated for C17H25NO10:
CO2CH2CH3), 2.93 (s, 3H, NCH3), 3.42 (d, J = 10.5 Hz, 1H, NH), 403.1478, found: 403.1490.
3.60 [deform. dd, J = 8.5, 8.5 Hz, 1H, CHCH(CO2Et)NH], 3.85
[dd, J = 10.5, 8.5 Hz, 1H, CHC(CO2Et)NH], 4.15–4.45 [m, 7H, 3 2,2,5-tricarboxylate endo-1e. Pale yellow prisms, mp
CO2CH2CH3 and CH(CO2Et)2NH]; 13C NMR δC: 13.8 49–51 °C (from hexane–ethyl acetate); Rf 0.11 (n-hexane–ethyl
(3R*,4R*,5S*)-Triethyl
3,4-bis(phenylsulfonyl)pyrrolidine-
=
×
(CHCO2CH2CH3), 13.9 (2 × CO2CH2CH3), 25.3 (NCH3), 49.1 acetate 7 : 3); IR (neat) νmax 3105, 2360, 2341, 1747, 1265,
1
[CHCH(CO2Et)NH], 51.6 [CHC(CO2Et)2NH], 61.2 [CH(CO2Et) 1153 cm−1; H NMR δH: 1.10 (t, J = 7.1 Hz, 3H, CO2CH2CH3),
NH], 61.3, 61.9 (2 × CO2CH2CH3), 62.9(CO2CH2CH3), 75.3 1.27 (t, J = 7.1 Hz, 3H, CO2CH2CH3), 1.34 (t, J = 7.1 Hz, 3H,
[C(CO2Et)2], 166.1, 168.5, 168.6 (3 × CO2CH2CH3), 174.4, 174.6 CO2CH2CH3), 4.04 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 4.16 [d, J =
(2 × CON); MS (EI-GC) m/z: 370 (M+ + 1, <1%), 298 (15), 297 (100), 4.7 Hz, 1H, CH (CO2Et)NH], 4.29–4.40 (m, 4H,
2 ×
166 (56), 138 (11), 94 (15), 93 (10); HRMS calculated for CO2CH2CH3), 4.64 [dd, J = 4.7, 3.7 Hz, 1H, CHCH(CO2Et)NH],
C16H22N2O8: 370.1336, found: 370.1337. 5.15 [d, J = 3.7 Hz, 1H, CH(CO2Et)2NH], 7.45–7.74 (m, 8H,
(3R*,3aS*,6aR*)-Triethyl
5-benzyl-4,6-dioxohexahydropyr- ArH), 7.84–7.96 (m, 2H, ArH), NH nd; 13C NMR δC: 13.6
rolo-[3,4-c]pyrrole-1,1,3(2H)-tricarboxylate endo-1b. Sticky pale (CHCO2CH2CH3), 13.8, 13.9 (2 × CO2CH2CH3), 60.4 [CHCH-
yellow oil; Rf 0.39 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax (CO2Et)NH], 62.2, 63.3, 63.4 (3 × CO2CH2CH3), 63.5 [CHC-
2939, 2984, 2341, 2360, 1734, 1708 cm−1
;
1H NMR δH: (CO2Et)2NH], 68.3 [CH(CO2Et)NH], 76.1 [C(CO2Et)2], 128.7,
1.24–1.34 (m, 9H, 3 × CO2CH2CH3), 3.62 [deform. dd, J = 8.5 129.0, 129.2, 129.3, 134.2, 134.3, 137.5, 138.2 (ArC), 165.4,
and 8.5 Hz, 1H, CHCH(CO2Et)NH], 3.88 [d, J = 8.5 Hz, 1H, 167.5, 168.7 (3 × CO2CH2CH3); MS (EI-GC) m/z: 567 (M+ + 1,
CHC(CO2Et) NH], 4.14–4.43 [m, 7H, 3 × CO2CH2CH3 and CH <1%), 495 (10), 494 (35), 353 (14), 352 (73), 306 (41), 280 (50),
(CO2Et)2NH], 4.59 (s, 2H, CH2Ph), 7.32–7.26 (m, 5H, ArH), NH 235 (13), 234 (100), 212 (19), 166 (17), 141 (16), 140 (20), 125
nd; 13C NMR δC: 14.0 (CHCO2CH2CH3), 14.1 (2 × CO2CH2CH3), (18), 120 (11), 112 (22), 94 (32), 77 (42), 68 (16); HRMS calcu-
43.1 (CH2Ph), 49.3 [CHCH(CO2Et)NH], 51.8 [CHC(CO2Et)2NH], lated for C25H29NO10S2–C3H5O2: 494.0943, found: 494.0929.
61.7 [CH(CO2Et)NH], 62.2, 63.0, 63.1 (3 × CO2CH2CH3), 75.7
(4S*,5R*)-2,2,5-Triethyl
4-methylpyrrolidine-2,2,4,5-tetra-
[C(CO2Et)2], 128.1, 128.6, 128.7, 135.2 (ArC), 166.2, 168.6, 168.7 carboxylate endo-1f and compound exo-1f. Pale yellow oil; Rf
(3 × CO2CH2CH3), 174.2, 174.4 (2 × CON); MS (EI-GC) m/z: 446 0.41 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2985,
1
(M+ + 1, <1%), 374 (21), 373 (100), 227 (11), 166 (33), 94 (11), 1735 cm−1; H NMR δH: 1.20–1.29 (m, 2 × 9H, 3 × CO2CH2CH3
91 (42); HRMS calculated for C22H26N2O8: 446.1689, found: endo + exo), 2.31–2.83 [m, 2 × 2H, CH2C(CO2Et)2 endo + exo],
446.1688.
3.10 (br. s, 1H, NH), 3.64, 3.65 (2 × s, 2 × 3H, CO2CH3 endo +
(3R*,3aS*,6aR*)-Triethyl 4,6-dioxo-5-phenylhexahydropyrrolo- exo), 3.76 [deform. dd, J = 7.4, 7.2 Hz, 1H, CHCH(CO2Et)NH
[3,4-c]pyrrole-1,1,3(2H)-tricarboxylate endo-1c. Sticky pale exo], 3.88 [dd, 1H, J = 8.2, 6.9 Hz, CHCH(CO2Et)NH endo], 4.09
yellow oil; Rf 0.29 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax [d, J = 8.2 Hz, 1H, CH(CO2Et)NH endo], 4.12–4.30 [m, 13H, 6 ×
1
2983, 2939, 2906, 1714 cm−1; H NMR δH: 1.25–1.37 (m, 9H, 3 CO2CH2CH3 endo + exo CH(CO2Et)NH exo]; 13C NMR δC: 14.0,
× CO2CH2CH3), 3.64 (d, J = 10.0 Hz, 1H, NH), 3.78 [dd, J = 8.4, 14.1, 14.1, 14.2, 14.2, 14.3 (6 × CO2CH2CH3 endo + exo), 33.5,
7.9 Hz, 1H, CHCH(CO2Et)NH], 4.00 [dd, J = 10.0, 8.4 Hz, 1H, 34.6 [2 × CH2C(CO2Et)2NH endo + exo], 46.8, 49.5 [2 × CH-
CHC(CO2Et)NH], 4.16–4.45 [m, 7H, 3 × CO2CH2CH3 and CH- (CO2Et)NH endo + exo], 52.2, 52.3 [2 × CHCH(CO2Et)NH endo +
(CO2Et)2NH], 7.15–7.23 (m, 2H, ArH), 7.47–7.33 (m, 3H, ArH), exo], 59.1, 62.7 (2 × CO2CH3 endo + exo), 61.5, 61.6, 62.3, 62.5,
NH nd; 13C NMR δC: 14.0 (CHCO2CH2CH3), 14.1 (2
×
62.5, 62.6 (6 × CO2CH2CH3 endo + exo), 71.6, 75.31 [2 ×
CO2CH2CH3), 49.6 [CHCH(CO2Et)NH], 52.1 [CHC(CO2Et)2NH], C(CO2Et)2 endo + exo], 168.9, 169.7, 170.3, 171.0, 171.3, 171.5,
62.1 [CH(CO2Et)NH], 62.3, 63.1, 63.2 (3 × CO2CH2CH3), 76.2 171.9, 172.4 (8 × CO2 endo + exo); MS (EI-GC) m/z: 345 (M+ + 1,
[C(CO2Et)2], 126.7, 129.1, 129.4, 131.5 (ArC), 166.4, 168.7, 169.0 <1%), 273 (14), 272 (100), 140 (10), 170 (12), 94 (10), 68 (14);
(3 × CO2CH2CH3), 173.8, 174.0 (2 × CON); MS (EI-GC) m/z: 432 HRMS calculated for C15H23NO8: 345.1434, found: 345.1441.
(M+ + 1, <1%), 360 (20), 359 (100), 166 (58), 138 (12), 94 (19);
HRMS calculated for C21H24N2O8: 432.1533, found: 432.1544.
(R/S)-2,2,3,4,5-Pentaethyl
1H-pyrrole-2,2,3,4,5(5H)-penta-
carboxylate 1g. Yellow oil; Rf 0.10 (n-hexane–ethyl acetate
1
(3S*,4S*,5R*)-2,2,5-Triethyl
3,4-dimethyl
pyrrolidine- 7 : 3); IR (neat) νmax 2981, 2360, 2341, 1741 cm−1; H NMR δH
2,2,3,4,5-pentacarboxylate endo-1d. Yellow pale oil; Rf 0.34 (n- 1.33–1.24 (m, 15H, 5 × CO2CH2CH3), 4.14–4.32 (m, 10H, 5 ×
hexane–ethyl acetate 7 : 3); IR (neat) νmax 2984, 2956, 2910, CO2CH2CH3), 5.51 [s, 1H, CH(CO2Et)NH], NH nd; 13C NMR δC:
1732 cm−1 1H NMR δH: 1.20–1.30 (m, 9H, 3 × CO2CH2CH3), 13.9, 14.0, 14.1, 14.1, 14.3 (5 × CO2CH2CH3), 59.8, 62.1, 62.2,
;
3.56 [deform. dd, J = 9.0, 8.0 Hz, 1H, CHCH(CO2Et)NH], 62.5, 62.5 (5 × CO2CH2CH3), 77.24 [C(CO2Et)2], 92.91 [CHC-
3.68–3.75 [m with 2 × s, 7H, 2 × CO2CH3, CHC(CO2Et)NH], 4.08 (CO2Et)2NH], 146.9 [CCH(CO2Et)NH], 147.0 [CC(CO2Et)2NH],
[d, J = 9.0 Hz, 1H, CH(CO2Et)2], 4.10–4.32 (m, 6H, 3 × 163.4, 166.7, 166.7, 166.8, 169.3 (5 × CO2); MS (EI-GC) m/z: 429
CO2CH2CH3), NH nd; 13C NMR δC: 13.9 (CHCO2CH2CH3), 14.0, (M+ + 1, <1%), 345 (18), 300 (15), 299 (16), 273 (12), 272 (84),
14.2 (2 × CO2CH2CH3), 50.5 [CHCH(CO2Et)NH], 52.6 [CHC- 227 (29), 226 (100), 199 (10), 198 (79), 181 (20), 170 (33), 154
(CO2Et)2NH], 52.7, 53.4 (2 × CO2CH3), 61.8 [CH(CO2Et)NH], (11), 142 (14), 125 (10), 124 (19), 87 (16), 69 (13), 68 (12);
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microanalysis calculated for C19H27NO10: C, 53.1; H, 6.3; N,
3.4%; found: C, 53.0; H, 6.0; N, 3.4%.
(1R*,3S*,3aR*,6aS*)-Diethyl
pyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
5-benzyl-4,6-dioxooctahydro-
endo-cis-2b. Sticky
(R/S)-2,2,5-Triethyl 4-methyl 1H-pyrrole-2,2,4,5(5H)-tetracar- yellow oil; Rf 0.15 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax
1
boxylate 1h. Yellow oil; Rf 0.49 (n-hexane–ethyl acetate 7 : 3); 2984, 1740, 1705 cm−1; H NMR δH: 1.28 (t, J = 7.1 Hz, 6H, 2 ×
IR (neat) νmax 2981, 2914, 1734, 1608 cm−1 1H NMR δH: CO2CH2CH3), 3.54 [m, 2H, CHCH(CO2Et)NH], 3.94 [m, 2H, CH-
;
1.19–1.33 (m, 9H, 3 × CO2CH2CH3), 3.63 (s, 3H, CO2CH3), (CO2Et)NH], 4.24 (q, J = 7.1 Hz, 4H, 2 × CO2CH2CH3), 4.58 (s,
4.09–4.31 (m, 6H, 3 × CO2CH2CH3), 4.83 [d, J = 1.7 Hz, 1H, CH- 2H, CH2Ph), 7.18–7.38 (m, 5H, ArH); 13C NMR δC: 14.1 (2 ×
(CO2Et)NH], 6.86 [d, J = 1.7 Hz, 1H, CHC(CO2Et)2], NH nd; 13C CO2CH2CH3), 43.0 (CH2Ph), 49.8 [2 × CHCH(CO2Et)NH], 62.0
NMR δC: 13.9 (3 × CO2CH2CH3), 61.5 (CO2CH2CH3), 62.6 (2 × (2 × CO2CH2CH3), 63.0 [2 × CH(CO2Et)NH], 128.1, 128.6, 128.7,
CO2CH2CH3), 62.8 (CO2CH3), 67.0 [CH(CO2Et)NH], 79.0 [C- 135.2 (ArC), 168.8 (2 × CO2CH2CH3), 174.6 (CON); MS (EI-GC)
(CO2Et)2NH], 150.8 [CHC(CO2Et)2NH], 150.9 [CCH(CO2Et)NH], m/z: 374 (M+ + 1, 2%), 302 (18), 301 (100), 227 (50), 94 (23), 91
162.60, 168.1, 168.2, 170.5 (4 × CO2CH3); MS (EI-GC) m/z: 343 (47), 68 (11); HRMS calculated for C19H22N2O6: 374.1478,
(M+ + 1, <1%), 270 (25), 226 (10), 198 (100), 170 (30), 166 (30), found: 374.1470.
152 (60), 126 (19), 122 (13), 120 (54), 94 (14); HRMS calculated
for C15H21NO8–C3H5O2: 270.0980, found: 270.0995.
(1R*,3R*,3aR*,6aS*)-Diethyl 5-benzyl-4,6-dioxooctahydropyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate endo-trans-2b. Sticky
(R/S)-2,2,5-Triethyl 3-methyl 1H-pyrrole-2,2,3,5(5H)-tetracar- yellow oil; Rf 0.22 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax
boxylate 1i. Yellow oil; Rf 0.40 (n-hexane–ethyl acetate 7 : 3); IR 2990, 1740, 1700 cm−1
;
1H NMR δH: 1.23–1.38 (m, 6H, 2 ×
1
(neat) νmax 2953, 1730, 1608 cm−1; H NMR δH: 1.19–1.33 (m, CO2CH2CH3), 3.64 (dd, J = 8.0, 1.4 Hz, 1H, CHCH(CO2Et)NH),
9H, 3 × CO2CH2CH3), 3.74 (s, 3H, CO2CH3), 4.09–4.31 (m, 6H, 4.10–4.33 [m, 6H, CHCH(CO2Et)NH and CH(CO2Et)NH and 2 ×
3 × CO2CH2CH3), 4.54 [d, J = 13.0 Hz, 1H, CH(CO2Et)NH], 7.42 CO2CH2CH3], 4.52–4.69 (m, 3H, CH2Ph and CH(CO2Et)NH),
[d, J = 13.0 Hz, 1H, CHCH(CO2Et)NH], NH nd; 13C NMR 7.18–7.40 (m, 5H, ArH); 13C NMR δC: 14.2, 14.3 (2
×
δC: 13.9 (2
× CO2CH2CH3), 14.0 (CHCO2CH2CH3), 62.4 CO2CH2CH3), 43.1 (CH2Ph), 48.8 [CHCH(CO2Et)NH], 49.9
(CHCO2CH2CH3), 62.5 (2 × CO2CH2CH3), 62.8 (CO2CH3), 66.2 [CHCH(CO2Et)NH], 61.8, 62.0 (2 × CO2CH2CH3), 62.2 [CH-
[CH(CO2Et)NH], 83.0 [C(CO2Et)2NH], 136.8 [CHCH(CO2Et)NH], (CO2Et)NH], 62.5 [CH(CO2Et)NH], 128.1, 128.8, 129.1, 135.4
162.6 [CC(CO2Et)2NH], 168.2, 168.5, 168.6, 170.3 (4 × CO2); MS (ArC), 169.6, 171.7 (2 × CO2CH2CH3), 175.0, 176.3 (2 × CON);
(EI-GC) m/z: 343 (M+ + 1, <1%), 270 (20), 226 (10), 198 (100), 170 MS (EI-GC) m/z: 374 (M+ + 1, 2%), 302 (18), 301 (100), 227 (31),
(30), 166 (20), 152 (65), 126 (25), 122 (10), 120 (50), 94 (12); HRMS 94 (20), 91 (44), 68 (13); HRMS calculated for C19H22N2O6:
calculated for C15H21NO8–C3H5O2: 270.0980, found: 270.0995.
(1R*,3S*,3aR*,6aS*)-Diethyl 5-methyl-4,6-dioxooctahydropyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate endo-cis-2a. Sticky yellow pyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
374.1478, found: 374.1470.
(1R*,3S*,3aR*,6aS*)-Diethyl
4,6-dioxo-5-phenyloctahydro-
endo-cis-2c. Colorless
oil; Rf 0.14 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2984, needles, mp = 123–125 °C (from hexane/CDCl3); Rf 0.11 (n-
1699, 1595 cm−1 1H NMR δH: 1.33 (t, J = 7.2 Hz, 6H, 2 × hexane–ethyl acetate 7 : 3); IR (neat) νmax 2980, 1741, 1732,
CO2CH2CH3), 2.94 (s, 3H, NCH3), 3.57 [m, 2H, 2 × CHCH 1708 cm−1 1H NMR δH: 1.32 (t, J = 7.2 Hz, 6H, 2 ×
;
;
(CO2Et)NH], 3.97 [m, 2H, 2 × CH(CO2Et)NH], 4.30 (q, J = 7.2 CO2CH2CH3), 3.05 (t, J = 12.7 Hz, 1H, NH), 3.71 [m, 2H, 2 ×
Hz, 4H, 2 × CO2CH2CH3), NH nd; 13C NMR δC: 14.2 (2 × CHCH(CO2Et)NH], 4.06 [m, 2H, CH(CO2Et)NH], 4.29 (q, J = 7.2
CO2CH2CH3), 25.5 (NCH3), 50.0 [2 × CHCH(CO2Et)NH], 61.9 (2 Hz, 4H, 2 × CO2CH2CH3), 7.19–7.22 (m, 2H, ArH), 7.37–7.46
×
CO2CH2CH3), 63.1 [2
×
CH(CO2Et)NH], 169.0 (2
×
(m, 3H, ArH); 13C NMR δC: 14.0 (2 × CO2CH2CH3), 49.9 [2 ×
CO2CH2CH3), 175.0 (2 × CON); MS (EI-GC) m/z: 298 (M+ + 1, CHCH(CO2Et)NH], 62.1 (2 × CO2CH2CH3), 63.4 [2 × CH(CO2Et)-
1%), 226 (12), 225 (100), 179 (32), 151 (53), 94 (44), 67 (12); NH], 126.5, 128.9, 129.2, 131.3 (ArC), 169.0 (2 × CO2CH2CH3),
HRMS calculated for C13H18N2O6: 298.1155, found: 298.1148.
(1R*,3R*,3aR*,6aS*)-Diethyl 5-methyl-4,6-dioxooctahydro- 287 (100), 94 (45), 68 (13), 67 (11); HRMS calculated for
pyrrolo[3,4-c]pyrrole-1,3-dicarboxylate endo-trans-2a. Sticky C18H20N2O6: 360.1301, found: 360.1291.
yellow oil; Rf 0.25 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax (1R*,3R*,3aR*,6aS*)-Diethyl 4,6-dioxo-5-phenyloctahydropyr-
2984, 1774, 1731, 1595 cm−1; H NMR δH: 1.33 (t, J = 7.2 Hz, rolo[3,4-c]pyrrole-1,3-dicarboxylate
endo-trans-2c. Colorless
174.1 (2 × CON); MS (EI-GC) 360 m/z (M+ + 1, 3%), 288 (19),
1
3H, CO2CH2CH3), 1.35 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.98 (s, needles, mp = 105–107 °C (from hexane/CDCl3); Rf 0.14 (n-
1
3H, NCH3), 3.56 [deform. dd, J = 8.0, 8.0 Hz, 1H, CHCH(CO2Et) hexane–ethyl acetate 7 : 3); IR (neat) νmax 2976, 1712 cm−1; H
NH], 3.64 [dd, J = 8.0, 1.2 Hz, 1H, CHCH(CO2Et)NH], 4.13 [d, J NMR δH: 1.20–1.32 (m, 6H, 2 × CO2CH2CH3), 2.85 (br. s, 1H,
= 8.0 Hz, 1H, CH(CO2Et)NH], 4.24 (q, J = 7.2 Hz, 2H, NH), 3.68 [deform. dd, J = 8.1, 8.1 Hz, 1H, CHCH(CO2Et)NH],
CO2CH2CH3), 4.27–4.35 [m, 3H, CO2CH2CH3 and CH(CO2Et)- 3.83 [d, J = 8.1, 1H, CHCH(CO2Et)NH], 4.25 [m, 5H, 2 ×
NH], NH nd; 13C NMR δC: 14.2, 14.3 (2 × CO2CH2CH3), 25.5 CO2CH2CH3 and CH(CO2Et)NH], 4.42 [s, 1H, CH(CO2Et)NH],
(NCH3), 47.6 [CHCH(CO2Et)NH], 48.8 [CHCH(CO2Et)NH], 61.8, 7.23–7.27 (m, 2H, ArH), 7.38–7.47 (m, 3H, ArH); 13C NMR δC:
62.0 (2 × CO2CH2CH3), 62.2 [CH(CO2Et)NH], 62.4 [CH(CO2Et)- 14.0, 14.1 (2 × CO2CH2CH3), 47.6 [CHCH(CO2Et)NH], 49.9
NH], 169.7, 171.7 (2 × CO2), 175.4, 176.6 (2 × CON); MS (EI-GC) [CHCH(CO2Et)NH], 61.9, 62.1 (2 × CO2CH2CH3), 62.3 [CH-
m/z: 298 (M+ + 1, 1%), 226 (12), 225 (100), 179 (17), 151 (40), 94 (CO2Et)NH], 62.9 [CH(CO2Et)NH], 126.4, 128.8, 129.1, 131.5
(40), 68 (10), 67 (13); HRMS calculated for C13H18N2O6: (ArC), 169.8, 171.4 (2 × CO2CH2CH3), 174.6, 175.6 (2 × CON);
298.1155, found: 298.1148.
MS (EI-GC) 360 m/z: (M+ + 1, 4%), 67 (10), 68 (13), 94 (40),
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287 (100), 288 (17); HRMS calculated for C18H20N2O6: 360.1301, 3.66 (2s, 3H, CO2CH3), 3.87 [dd, J = 8.6, 7.6 Hz, 1H, CH(CO2Et)
found: 360.1291.
NH], 4.15 (q, J = 7.1 Hz, 2H, CO2CH2CH3), NH nd; 13C NMR δC:
(1S*,3R*,3aS*,6aR*)-3-Ethyl 1-methyl 1,5-dimethyl-4,6-dio- 14.3 (CO2CH2CH3), 25.5 [CHC(CO2Me)CH3], 32.3 [CH2CH
xooctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate endo-cis- (CO2Et)NH], 52.0, 52.1 (2 × CO2CH3), 52.5 [CHC(CO2Me)Me],
3a. Sticky pale yellow oil; Rf 0.38 (n-hexane–ethyl acetate 6 : 4); 58.0 [CH(CO2Et)NH], 61.4 (CO2CH2CH3), 68.3 [C(CO2Me)Me],
1
IR (neat) νmax 2983, 2955, 1777, 1735, 1697 cm−1; H NMR δH: 171.6, 172.2, 174.3 (3 × CO2); MS (EI-GC) m/z: 273 (M+ + 1,
1.36 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 1.49 [s, 3H, C(CO2CH3) <2%), 215 (12), 214 (100), 200 (32), 140 (62), 108 (20), 99 (27),
CH3], 2.93 (s, 3H, NCH3), 3.25 [d, J = 8.0 Hz, 1H, CHC(CO2Me) 82 (23); HRMS calculated for C12H19NO6: 273.1212, found:
CH3], 3.37 (d, J = 12.5 Hz, 1H, NH), 3.63 [deform. dd, J = 8.0, 273.1214.
8.0 Hz, 1H, CHCH(CO2Et)NH], 3.83 (s, 3H, CO2CH3), 4.14 [dd, J
(2S*,3S*,4S*,5R*)-5-Ethyl 2,3,4-trimethyl 2-methylpyrroli-
= 12.5, 8.0 Hz, 1H, CH(CO2Et)NH], 4.30 (q, J = 7.2 Hz, 2H, dine-2,3,4,5-tetracarboxylate endo-cis-3d. Pale yellow oil; Rf
CO2CH2CH3); 13C NMR δC: 14.2 (CO2CH2CH3), 24.6 0.20 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2986, 2954,
[C(CO2CH3)CH3], 25.4 (NCH3), 50.4 [CHCH(CO2Et)NH], 53.1 2907, 1730, 1729 cm−1 1H NMR δH: 1.27 (t, J = 7.1 Hz, 3H,
;
[CHC(CO2Me)CH3], 62.0 (CO2CH3), 62.1 (CO2CH2CH3), 69.4 CO2CH2CH3), 1.60 [s, 3H, C(CO2CH3)CH3], 3.24 [d, J = 10.0 Hz,
[CH(CO2Me)CH3], 169.5, 171.7 (2 × CO2), 175.0, 175.2 (2 × 1H, CHC(CO2Me)Me], 3.64, 3.68, 3.74 (3s, 3H, CO2CH3), 3.78
CON); MS (EI-GC) m/z: 298 (M+ + 1, <1%), 239 (67), 225 (39), [dd, J = 10.0, 8.1 Hz, 1H, CHCH(CO2Et)NH], 4.02 [d, J = 8.1 Hz,
165 (100), 108 (43), 81 (10), 80 (21); HRMS calculated for 1H, CH(CO2Et)NH], 4.15 (q, J = 7.1 Hz, 2H, CO2CH2CH3), NH
C13H18N2O6: 298.1165, found: 298.1163.
nd; 13C NMR δC: 14.2 (CO2CH2CH3), 24.9 [C(CO2CH3)CH3],
(2R*,3S*,5S*)-2-Ethyl 3,5-dimethyl 5-methylpyrrolidine-2,3,5- 49.6 [CHC(CO2Me)Me], 52.3, 52.6 52.7 (3 × CO2CH3), 56.8
tricarboxylate endo-cis-3f. Yellowish oil; Rf 0.41 (n-hexane– [CHCH(CO2Et)NH], 61.7 [CH(CO2Et)NH], 61.8 (CO2CH2CH3),
ethyl acetate 7 : 3); IR (neat) νmax 2983, 2954, 1731, 1725, 68.4 [C(CO2Me)Ph], 170.6, 172.3, 173.0, 173.8 (4 × CO2); MS
1
1700 cm−1; H NMR δH: 1.26 (t, J = 7.2 Hz, 3H, CO2CH2CH3), (EI-GC) m/z: 331 (M+ + 1, <2%), 272 (65), 258 (19), 262 (19), 241
1.49 [s, 3H, C(CO2CH3)CH3], 2.01 [dd, J = 12.9, 9.8 Hz, 1H, (10), 240 (82), 226 (99), 212 (80), 198 (60), 180 (10), 167 (11),
CHHC(CO2Me)CH3], 2.64 [dd, J = 12.9, 8.3 Hz, 1H, CHHC- 166 (100), 154 (25), 140 (72), 139 (10), 136 (10), 122 (10), 108
(CO2Me)CH3], 3.19 [ddd, J = 9.8, 8.3, 7.1 Hz, 1H, CH(CO2Me)], (58), 94 (11), 81 (22), 80 (27), 59 (24); HRMS calculated for
3.71, 3.73 (2s, 3H, CO2CH3), 3.77 [d, J = 7.1 Hz, 1H, CH(CO2Et) C14H21NO8: 331.1267, found: 331.1274.
NH], 4.16 (q, J = 7.2 Hz, 2H, CO2CH2CH3, NH nd; 13C NMR δC:
(2R*,3R*,4R*,5S*)-5-Ethyl 2-methyl 2-methyl-3,4-bis(phenyl-
14.3 (CO2CH2CH3), 25.9 [C(CO2CH3)CH3], 40.7 [CH2C(CO2Me)- sulfonyl)pyrrolidine-2,5-dicarboxylate endo-cis-3e. Orange oil;
CH3], 47.4 [CHCH(CO2Et)NH], 52.4, 52.7 (2 × CO2CH3), 61.6 Rf 0.11 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2985, 2956,
1
(CO2CH2CH3), 63.0 [CH(CO2Et)NH], 66.3 [C(CO2Me)CH3], 2905, 1735, 1710, 1308, 1146 cm−1; H NMR δH: 1.00 (t, J = 7.1
172.8, 173.5, 176.3 (3 × CO2); MS (EI-GC) m/z: 273 (M+ + 1, Hz, 3H, CO2CH2CH3), 1.72 [s, 3H, C(CO2CH3)CH3], 3.72 (s, 3H,
<2%), 215 (11), 214 (100), 200 (30), 168 (13), 140 (33), 108 (19), CO2CH3), 3.94 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 4.27 [d, J = 6.5
82 (21); HRMS calculated for C12H19NO6: 273.1212, found: Hz, 1H, CH(CO2Et)NH], 4.28 [d, J = 4.5 Hz, 1H, CHC(CO2Me)
273.1214.
Me], 5.01 [dd, J = 6.5, 4.5 Hz, 1H, CHCHCO2Et], 7.51–7.71 (m,
(2R*,3S*,5R*)-2-Ethyl 3,5-dimethyl 5-methylpyrrolidine- 6H, ArH), 7.81–8.02 (m, 4H, ArH), NH nd; 13C NMR δC: 14.0
2,3,5-tricarboxylate endo-trans-3f. Yellowish oil; Rf 0.22 (n- (CO2CH2CH3), 23.7 [CHC(CO2Me)CH3], 52.7 [CH(CO2Et)NH],
hexane–ethyl acetate 7 : 3); IR (neat) νmax 2983, 2953, 1732, 61.5 (CO2CH3), 62.2 (CO2CH2CH3), 69.4 [C(CO2Me)Me], 69.5
1725, 1703 cm−1 1H NMR δH: 1.25 (t, J = 7.2 Hz, 3H, [CHC(CO2Me)Me], 73.0 [CHCH(CO2Et)NH], 128.4, 128.9, 129.3,
;
CO2CH2CH3), 1.37 [s, 3H, C(CO2CH3)CH3], 2.01 [dd, J = 13.5, 129.4, 134.2, 134.4, 138.1, 140.4 (ArC), 170.1, 171.2 (2 × CO2);
8.0 Hz, 1H, CHHC(CO2Me)CH3], 2.68 [dd, J = 13.5, 7.2 Hz, 1H, MS (EI-GC) m/z: 495 (M+ + 1, <1%), 294 (32), 279 (21), 248 (39),
CHHC(CO2Me)CH3], 3.30 [ddd, J = 8.0, 7.2, 7.0 Hz, 1H, CHCH- 237 (14), 236 (100), 222 (26), 221 (10), 156 (11), 128 (17),
(CO2Et)], 3.62, 3.73 (2s, 3H, CO2CH3), 4.03 [d, J = 7.0 Hz, 1H, 125 (11), 108 (23), 96 (26), 95 (10), 94 (11), 81 (46), 80 (21),
CH(CO2Et)NH], 4.15 (q, J = 7.2 Hz, 2H, CO2CH2CH3), NH nd; 77 (14); HRMS calculated for C22H25NO8S2: 495.1022, found:
13C NMR δC: 14.2 (CO2CH2CH3), 28.3 [C(CO2CH3)CH3], 39.1 495.1015.
[CH2C(CO2Me)CH3], 47.1 [CHCH(CO2Et)NH], 53.3, 53.4 (2 ×
(1S*,3R*,3aS*,6aR*)-Diethyl 1-benzyl-5-methyl-4,6-dioxoocta-
CO2CH3), 61.4 (CO2CH2CH3), 62.8 [CH(CO2Et)NH], 65.4 hydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate endo-cis-4a. Sticky
[C(CO2Me)CH3], 172.3, 173.6, 176.4 (3 × CO2); MS (EI-GC) m/z: pale yellow oil; Rf 0.22 (n-hexane–ethyl acetate 7 : 3); IR (neat)
273 (M+ + 1, <2%), 215 (12), 214 (100), 200 (33), 140 (62), 108 νmax 3030, 2982, 2936, 1779, 1734, 1699 cm−1 1H NMR δH:
;
(20), 99 (24), 82 (23); HRMS calculated for C12H19NO6: 1.32, 1.34 (2t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.88, 3.30 (2d, J =
273.1212, found: 273.1215. 13.8 Hz, 2H, CH2Ph), 2.92 (s, 3H, NCH3), 3.38 [d, J = 8.0 Hz,
(2S*,3R*,5R*)-5-Ethyl 2,3-dimethyl 2-methylpyrrolidine-2,3,5- 1H, CHC(CO2Et)Bn], 3.55 [deform. dd, J = 8.4, 8.0 Hz, 1H,
tricarboxylate endo-cis-3f′. Yellowish oil; Rf 0.21 (n-hexane– CHCH(CO2Et)NH], 4.09 [d, J = 8.4 Hz, 1H, CH(CO2Et)NH], 4.24
ethyl acetate 7 : 3); IR (neat) νmax 2983, 2955, 1730, 1726, (q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.26 (q, J = 7.2 Hz, 2H,
1
1700 cm−1; H NMR δH: 1.26 (t, J = 7.1 Hz, 3H, CO2CH2CH3), CO2CH2CH3), NH nd; 13C NMR δC: 14.0 (2 × CO2CH2CH3),
1.51 [s, 3H, C(CO2CH3)CH3], 2.29–2.57 [m, 2H, CH2CH 25.4 (NCH3), 42.2 (CH2Ar), 50.4 [CHCH(CO2Et)NH], 56.6
(CO2Et)], 2.87 [dd, J = 9.5, 8.1 Hz, 1H, CHC(CO2Me)CH3], 3.65, [CHC(CO2Et)Bn], 62.0 [CH(CO2Et)NH], 62.1 (CO2CH2CH3),
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62.3 (CO2CH2CH3), 73.6 [C(CO2Et)Bn], 127.2, 128.3, 130.4,
(2R*,3S*,4S*,5S*)-Diethyl 2-benzyl-3,4-bis(phenylsulfonyl)-
135.7 (ArC), 169.6, 170.1 (2 × CO2), 175.0, 175.1 (2 × CON); MS pyrrolidine-2,5-dicarboxylate exo-cis-4e. Pale yellow prisms,
(EI-GC) m/z: 388 (M+ + 1, <1%), 315 (13), 298 (14), 297 (100), mp = 85–86 °C (from n-hexane–ethyl acetate); Rf 0.22 (7 : 3 n-
223 (11), 166 (45), 94 (11), 91 (17); HRMS calculated for hexane–ethyl acetate); IR (neat) νmax 2971, 1741, 1235,
1
C20H24N2O6: 388.1634, found: 388.1631.
1149 cm−1; H NMR δH: 1.04 (t, J = 7.2 Hz, 1H, CO2CH2CH3),
(1S*,3R*,3aS*,6aR*)-Diethyl 1,5-dibenzyl-4,6-dioxooctahydro- 1.21 (t, J = 7.2 Hz, 1H, CO2CH2CH3), 3.29, 3.40 (2 × d, J = 14.2
pyrrolo[3,4-c]pyrrole-1,3-dicarboxylate endo-cis-4b. Colorless Hz, 2H, CH2Ph), 3.88–4.29 (m, 4H, 2 × CO2CH2CH3), 4.20 [CH-
prisms, mp = 127–130 °C (from hexane/CDCl3); Rf 0.39 (n- (CO2Et)NH], 4.43 (br. s, 1H, NH), 4.51 [d, J = 5.2 Hz, 1H, CHC-
hexane–ethyl acetate 7 : 3); IR (neat) νmax 3030, 2989, 1741, (CO2Et)Bn], 4.89 [deform. dd, J = 5.2, 5.2 Hz, 1H, CHCH-
1719, 1699 cm−1 1H NMR δH: 1.23 (t, J = 7.2 Hz, 3H, (CO2Et)NH], 7.18–7.33 (m, 5H, ArH), 7.44–7.82 (m, 8H, ArH),
;
CO2CH2CH3), 1.28 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.89, 3.31 (2 7.88–7.98 (m, 2H, ArH); 13C NMR δC: 13.8, 14.0 (2
×
× d, J = 13.9 Hz, 2H, CH2Ph), 3.38 [d, J = 7.8 Hz, 1H, CHC- CO2CH2CH3), 41.0 (CH2Ph), 61.1, 62.2 (2 × CO2CH2CH3), 62.3
(CO2Et)Bn], 3.55 [deform. dd, J = 7.8, 7.8 Hz, 1H, CHCH- [CHCH(CO2Et)NH], 69.4 [CHCBn(CO2Et)NH], 72.0 [CH(CO2Et)-
(CO2Et)NH], 4.03–4.27 [m, 5H, 2 × CO2CH2CH3 and CH(CO2Et)- NH], 73.8 [CBn(CO2Et)NH], 127.4, 128.4, 128.8, 129.1, 129.2,
NH], 4.54, 4.60 (d, J = 14.3 Hz, 2H), 7.20–7.35 (m, 10H, 2 × 129.4, 130.7, 134.3, 134.4, 134.7, 138.5, 139.5 (ArC), 169.6,
CH2Ph), NH nd; 13C NMR δC: 14.0, 14.1 (2 × CO2CH2CH3), 42.2, 169.6 (2 × CO2); MS (EI-GC) m/z: 585 (M+ + 1, <1%), 512 (10),
43.0 (2 × CH2Ph), 50.4 [CHCH(CO2Et)NH], 56.6 [CHCH(CO2Et) 494 (34), 370 (14), 353 (13), 352 (69), 306 (33), 298 (10), 280
NH], 61.9, 62.1 (2 × CO2CH2CH3), 62.3 [CH(CO2Et)NH], 73.7 (26), 235 (10), 234 (82), 157 (13), 156 (23), 141 (10), 125 (15),
[CBn(CO2Et)NH], 127.2, 128.0, 128.3, 128.6, 128.7, 130.5, 112 (11), 94 (16), 91 (100), 80 (12), 77 (29); HRMS calculated for
135.2, 135.8 (ArC), 169.4, 169.9 (2 × CO2CH2CH3), 174.6, 174.7 C29H31NO8S2–C3H5O2: 512.1202, found: 512.1215.
(2 × CON); MS (EI-GC) m/z: 464 (M+ + 1, <1%), 391 (14), 374
(22), 373 (100), 166 (22), 91 (73); HRMS calculated for phenyloctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate endo-
C26H28N2O6–C7H7: 373.1400, found: 373.1401. cis-5a. Sticky pale yellow oil; Rf 0.21 (n-hexane–ethyl acetate
1-benzyl-4,6-dioxo-5-phenyl- 7 : 3); IR (neat) νmax 2982, 2954, 1779, 1736, 1698 cm−1 1H
endo-cis-4c. NMR δH: 1.25 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.91 (s, 3H,
(1R*,3R*,3aS*,6aR*)-3-Ethyl 1-methyl 5-methyl-4,6-dioxo-1-
(1S*,3R*,3aS*,6aR*)-Diethyl
;
octahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
Colorless prisms, mp = 169–172 °C (from hexane/CDCl3); Rf NCH3), 3.37 [deform. dd, J = 8.5, 7.5 Hz, 1H, CHCHCO2Et],
0.34 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2979, 2937, 3.69 (s, 3H, CO2CH3), 3.76 [d, J = 8.5, 1H, CH(CO2Et)NH], 3.96
1729, 1714 cm−1
;
1H NMR δH: 1.25–1.30 (m, 6H, 2 × [d, J = 7.5 Hz, 1H, CH(CO2Me)Ph], 4.20 (qd, J = 7.2, 1.1 Hz, 2H,
CO2CH2CH3), 2.96, 3.36 (2 × d, J = 13.9 Hz, 2H, CH2Ph), 3.51 (s, CO2CH2CH3), 7.22–7.36 (m, 3H, ArH), 7.58–7.63 (m, 2H, ArH),
1H, NH), 3.55 [d, J = 7.8 Hz, 1H, CHC(CO2Et)Bn], 3.73 [deform. NH nd; 13C NMR δC: 14.2 (CO2CH2CH3), 25.5 (NCH3), 50.3
dd, J = 7.8, 7.8 Hz, 1H, CHCH(CO2Et)NH], 4.15–4.30 [m, 5H, 2 [CHCH(CO2Et)NH], 53.4 [CHC(CO2Me)Ph], 56.5 (CHCO2Et),
× CO2CH2CH3 and CH(CO2Et)NH], 7.15–7.49 (m, 10H, ArH); 61.6 (CO2CH3), 62.1 (CO2CH2CH3), 74.8 [C(CO2Me)Ph], 127.4,
13C NMR δC: 13.9, 14.0 (CO2CH2CH3), 42.3 (CH2Ph), 50.4 128.5, 128.7, 138.1 (ArC), 169.6, 170.2 (2 × CO2), 175.1, 175.4 (2
[CHCH(CO2Et)NH], 56.6 [CHCH(CO2Et)NH], 62.1, 62.2 (2 × × CON); MS (EI-GC) m/z: 360 (M+ + 1, <1%), 302 (17), 301 (100),
CO2CH2CH3), 62.3 [CH(CO2Et)NH], 74.1 [CBn(CO2Et)NH], 228 (14), 227 (72), 170 (19), 143 (18), 142 (27); HRMS calculated
126.6, 127.2, 128.0, 128.2, 128.9, 129.2, 130.4, 135.6 (ArC), for C18H20N2O6: 360.1321, found: 360.1322.
169.7, 170.1 (2 × CO2), 174.0, 174.2 (2 × CON); MS (EI-GC) m/z:
(1S*,3R*,3aS*,6aR*)-3-Ethyl 1-methyl 5-methyl-4,6-dioxo-1-
450 (M+ + 1, <1%), 377 (14), 360 (22), 359 (100), 207 (44), 166 phenyloctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate endo-
(40), 156 (10), 119 (10), 94 (13), 91 (45); HRMS calculated for trans-5a. Sticky pale yellow oil; Rf 0.12 (n-hexane–ethyl acetate
C25H26N2O6: 450.1791, found: 450.1801.
7 : 3); IR (neat) νmax 2983, 2954, 2926, 1781, 1729, 1702 cm−1
;
(2S*,3S*,4S*,5R*)-5-Ethyl 2,3,4-trimethyl 2-benzylpyrroli- 1H NMR δH: 1.39 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.79 (s, 3H,
dine-2,3,4,5-tetracarboxylate endo-cis-4d. Colorless oil; Rf 0.35 NCH3), 3.08 (d, J = 3.5 Hz, 1H, NH), 3.55 [deform. dd, J = 7.6,
(n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2983, 2954, 2906, 7.6 Hz, 1H, CHCHCO2Et], 3.79 (s, 3H, CO2CH3), 3.86 [dd, J =
1732, 1727 cm−1 1H NMR δH: 1.22, 1.26 (2t, J = 7.1 Hz, 3H, 7.6, 3.5 Hz, 1H, CH(CO2Et)NH], 4.25 [d, J = 7.6 Hz, 1H, CHC
;
CO2CH2CH3), 3.13, 3.37 (2d, J = 13.8 Hz, 2H, CH2Ph), 3.34 [d, J (CO2Me)Ph], 4.30–4.41 (m, 2H, CO2CH2CH3), 7.33–7.41 (m, 3H,
= 10.1 Hz, 1H, CHC(CO2Et)Bn], 3.65 [dd, J = 10.1, 8.5 Hz, 1H, ArH), 7.47–7.54 (m, 2H, ArH); 13C NMR δC: 14.2 (CO2CH2CH3),
CHCH(CO2Et)NH], 3.70, 3.78 (2s, 3H, CO2CH3), 3.86 [d, J = 8.5 25.2 (NCH3), 45.3 [CHCH(CO2Et)NH], 50.4 [CHC(CO2Me)Ph],
Hz, 1H, CH(CO2Et)NH], 4.05–4.25 (m, 4H, 2 × CO2CH2CH3), 53.7 (CHCO2Et), 59.8 (CO2CH3), 61.7 (CO2CH2CH3), 74.1
7.24–7.36 (m, 5H, ArH), NH nd; 13C NMR δC: 14.0, 14.2 (2 × [C(CO2Me)Ph], 126.0, 128.5, 128.9, 135.4 (ArC), 169.3, 173.5 (2 ×
CO2CH2CH3), 42.6 (CH2Ar), 49.3 [CHC(CO2Et)Bn], 52.4, 52.6 (2 CO2), 174.1, 175.6 (2 × CON); MS (EI-GC) m/z: 360 (M+ + 1,
× CO2CH3), 54.8 [CHCH(CO2Et)NH], 61.6 [CH(CO2Et)NH], 62.0, <1%), 302 (18), 301 (100), 228 (13), 227 (63), 170 (20), 143 (22),
61.7 (2 × CO2CH2CH3), 72.3 [C(CO2Et)Bn], 127.1, 128.3, 130.9, 142 (30), 115 (15); HRMS calculated for C18H20N2O6: 360.1321,
135.9 (ArC), 170.5, 171.9, 172.3, 172.9 (4 × CO2); MS (EI-GC) m/ found: 360.1336.
z: 407 (M+ + 1, <1%), 348 (18), 330 (48), 316 (44), 298 (100), 166
(32), 138 (11), 91 (60); HRMS calculated for C20H25NO8: 2,3,5-tricarboxylate endo-cis-5f. Yellowish oil; Rf 0.41
(2R*,3R*,5R*)-5-Ethyl 2,3-dimethyl 2-phenylpyrrolidine-
407.1580, found: 407.1586.
(n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2985, 2953, 1734,
672 | Org. Biomol. Chem., 2013, 11, 662–675
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1700 cm−1; H NMR δH: 1.29 (t, J = 7.1 Hz, 3H, CO2CH2CH3), 126.4, 128.1, 128.2, 139.7 (ArC), 171.1, 171.6, 172.0, 172.1 (4 ×
2.29–2.36 [m, 2H, CH2CH(CO2Et)], 3.51 [dd, J = 7.6, 4.5 Hz, 1H, CO2); MS (EI-GC) m/z: 393 (M+ + 1, <1%), 335 (19), 334 (100),
CHC(CO2Me)Ph], 3.68, 3.70 (2s, 3H, CO2CH3), 3.85 [dd, J = 9.0, 303 (11), 302 (60), 274 (14), 260 (25), 242 (11), 228 (27), 202
5.7 Hz, 1H, CH(CO2Et)NH], 4.23 (q,
J = 7.1 Hz, 2H, (21), 170 (56), 143 (24), 115 (14); HRMS calculated for
CO2CH2CH3), 7.25–7.35 (m, 3H, ArH), 7.73–7.77 (m, 2H, ArH), C19H23NO8: 393.1424, found: 393.1426.
NH nd; 13C NMR δC: 14.3 (CO2CH2CH3), 33.8 [CH2CH(CO2Et)-
(2R*,3R*,4R*,5S*)-5-Ethyl 2-methyl 2-phenyl-3,4-bis(phenyl-
NH], 52.2, 52.9 (2 × CO2CH3), 54.0 [CHC(CO2Me)Ph], 58.6 sulfonyl)pyrrolidine-2,5-dicarboxylate exo-trans-5e. Orange oil;
[CH(CO2Et)NH], 61.5 (CO2CH2CH3), 75.5 [C(CO2Me)Ph], 126.9, Rf 0.10 (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2981, 2954,
1
128.1, 128.4, 140.2 (ArC), 172.2, 173.1, 173.6 (3 × CO2); MS 2926, 1738, 1692, 1309, 1147 cm−1; H NMR δH: 1.04 (t, J = 7.2
(EI-GC) m/z: 335 (M+ + 1, <2%), 277 (18), 276 (100), 262 (19), Hz, 3H, CO2CH2CH3), 3.74 (s, 3H, CO2CH3), 4.01 (q, J = 7.2 Hz,
202 (41), 170 (19), 144 (20), 143 (14), 115 (10), 99 (15); HRMS 2H, CO2CH2CH3), 4.35 [d, J = 5.0 Hz, 1H, CH(CO2Et)NH], 4.86
calculated for C17H21NO6: 335.1369, found: 335.1313.
(2S*,3R*,5R*)-5-Ethyl 2,3-dimethyl 2-phenylpyrrolidine-2,3,5- 5.0 Hz, 1H, CHCHCO2Et], 7.35–8.05 (m, 15H, ArH), NH nd; 13
tricarboxylate endo-trans-5f. Yellowish oil; Rf 0.29 (n-hexane– NMR δC: 14.0 (CO2CH2CH3), 53.2 [CH(CO2Et)NH], 60.9
ethyl acetate 7 : 3); IR (neat) νmax 2984, 2953, 1727, 1658 cm−1
(CO2CH3), 62.3 (CO2CH2CH3), 69.4 [CHCH(CO2Et)NH], 74.6
[d, J = 5.3 Hz, 1H, CHC(CO2Me)Ph], 4.91 [deform. dd, J = 5.3,
C
;
1H NMR δH: 1.30 (t, J = 7.1 Hz, 3H, CO2CH2CH3), 2.36–2.46 [m, [CHC(CO2Me)Ph], 75.1 [C(CO2Me)Ph], 128.2, 128.3, 128.6,
2H, CH2CH(CO2Et)], 3.19, 3.72 (2s, 3H, CO2CH3), 3.92 [deform. 128.8, 128.9, 129.2, 129.3, 134.0, 134.3, 136.8, 138.6, 140.1
dd, J = 8.0, 7.6 Hz, Ph1H, CHC(CO2Me)Ph], 4.04 [deform. dd, J (ArC), 170.0, 170.1 (2 × CO2); MS (EI-GC) m/z: 557 (M+ + 1,
= 6.5, 5.9 Hz, 1H, CH(CO2Et)NH], 4.26 (q, J = 7.1 Hz, 2H, <1%), 357 (11), 356 (51), 342 (10), 310 (15), 299 (11), 298 (54),
CO2CH2CH3), 7.24–7.37 (m, 3H, ArH), 7.49–7.53 (m, 2H, ArH), 284 (17), 283 (21), 215 (37), 158 (11), 157 (11), 144 (11), 143
NH nd; 13C NMR δC: 14.3 (CO2CH2CH3), 32.7 [CH2CH(CO2Et)- (100), 142 (11), 115 (24), 77 (11); HRMS calculated for
NH], 50.6, 51.5 (2 × CO2CH3), 53.4 [CHC(CO2Me)Ph], 58.5 [CH- C27H27NO8S2: 557.1168, found: 557.1173.
(CO2Et)NH], 61.3 (CO2CH2CH3), 76.0 [C(CO2Me)Ph], 126.3,
(2S*,5R*)-3,4,5-Triethyl 2-methyl 2-methyl-2,5-dihydro-1H-
128.3, 128.5, 137.5 (ArC), 172.6, 173.0, 173.9 (3 × CO2); MS pyrrole-2,3,4,5-tetracarboxylate cis-3g. Yellowish oil; Rf 0.20 (n-
(EI-GC) m/z: 335 (M+ + 1, <2%), 277 (21), 276 (100), 262 (15), hexane–ethyl acetate 7 : 3); IR (neat) νmax 3021, 2988, 1732,
202 (38), 201 (10), 170 (25), 144 (13), 143 (11), 115 (11), 99 (17); 1720, 1676, 1619 cm−1 1H NMR δH: 1.20–1.38 (m, 9H,
;
HRMS calculated for C17H21NO6: 335.1369, found: 335.1308.
CO2CH2CH3), 1.85 [s, 3H, C(CO2CH3)CH3], 3.67 (s, 3H,
(2R*,3S*,4S*,5R*)-5-Ethyl 2,3,4-trimethyl 2-phenylpyrrol- CO2CH3), 4.05–4.35 (m, 7H, CH(CO2Et)NH and
3
×
idine-2,3,4,5-tetracarboxylate endo-cis-5d. Colorless oil; Rf 0.25 CO2CH2CH3), NH nd; 13C NMR δC: 14.1, 14.2, 15.4 (3 ×
(n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2984, 2954, 1735, CO2CH2CH3), 24.9 [CC(CO2Me)CH3], 53.0 (CO2CH3), 61.9 [CH-
1716, 1713, 1700 cm−1 1H NMR δH: 1.14 (t, J = 7.1 Hz, 3H, (CO2Et)NH], 62.1, 62.2, 62.8 (3 × CO2CH2CH3), 70.0 [C(CO2Me)-
;
CO2CH2CH3), 3.64, 3.67, 3.75 (3s, 3H, CO2CH3), 3.82 [dd, J = Me], 142.0 [CC(CO2Me)Me], 143.9 [CCH(CO2Et)NH], 168.6,
10.1, 8.5 Hz, 1H, CHCH(CO2Et)NH], 3.98 [d, J = 8.5 Hz, 1H, CH 168.8, 169.3, 169.6 (4 × CO2); MS (EI-GC) m/z: 357 (M+ + 1,
(CO2Et)NH], 4.04 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 4.38 [d, J = <5%), 285 (10), 284 (100), 256 (24), 239 (14), 226 (11), 212 (26),
10.1 Hz, 1H, CHC(CO2Me)Ph], 7.26–7.38 (m, 2H, ArH), 7.51 211 (15), 180 (60), 166 (40), 140 (10), 134 (15), 108 (10), 73 (10);
(dd, J = 8.5, 2.8 Hz, 1H, ArH), 7.70 (dd, J = 8.5, 2.8 Hz, 2H, HRMS calculated for C16H23NO8: 357.1424, found: 357.1419.
ArH), NH nd; 13C NMR δC: 14.0 (CO2CH2CH3), 51.1, 52.3, 52.6
(2S*,5R*)-3,4,5-Triethyl 2-methyl 2-benzyl-2,5-dihydro-1H-
(3 × CO2CH3), 53.3 [CHC(CO2Me)Ph], 53.5 [CHCH(CO2Et)NH], pyrrole-2,3,4,5-tetracarboxylate cis-4g. Pale yellow oil; Rf 0.10
60.7 [CH(CO2Et)NH], 61.4 (CO2CH2CH3), 75.0 [C(CO2Me)Ph], (n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 3030, 2982, 1734,
127.0, 128.1, 128.3, 140.9 (ArC), 170.8, 171.3, 171.7, 172.8 (4 × 1728, 1656, 1609 cm−1 1H NMR δH: 1.20–1.38 (m, 12H,
;
CO2); MS (EI-GC) m/z: 393 (M+ + 1, <2%), 335 (19), 334 (100), CO2CH2CH3), 2.91, 3.09 (2d, J = 13.8 Hz, 2H, CH2Ph), 3.78 [s,
302 (24), 288 (11), 274 (35), 260 (25), 242 (13), 228 (51), 202 1H, CH(CO2Et)NH], 4.05–4.30 (m, 8H, CO2CH2CH3), 7.24–7.30
(25), 201 (11), 170 (11), 143 (26), 115 (16); HRMS calculated for (m, 5H, ArH), NH nd; 13C NMR δC: 14.2, 14.3, 14.3, 15.4 (4 ×
C19H23NO8: 393.1424, found: 393.1421.
CO2CH2CH3), 40.8 (CH2Ar), 59.5, 61.1, 61.4, 62.0 (4 ×
(2R*,3R*,4R*,5R*)-5-Ethyl 2,3,4-trimethyl 2-phenylpyrroli- CO2CH2CH3), 60.7 [CH(CO2Et)NH], 77.1 [C(CO2Me)Ph], 127.0,
dine-2,3,4,5-tetracarboxylate exo-cis-5d. Colorless oil; Rf 0.30 128.7, 129.6, 137.1 (ArC), 144.9 [CCH(CO2Et)NH], 145.5[CC-
(n-hexane–ethyl acetate 7 : 3); IR (neat) νmax 2990, 2950, 1748, (CO2Me)Ph], 168.2, 168.8, 169.0, 170.6 (4 × CO2); MS (EI-GC)
1733, 1730, 1715 cm−1 1H NMR δH: 1.30 (t, J = 7.1 Hz, 3H, m/z: 447 (M+ + 1, <1%), 363 (17), 281 (15), 207 (28), 177 (15),
;
CO2CH2CH3), 3.56, 3.69, 3.72 (3s, 3H, CO2CH3), 3.64 [deform. 176 (100), 148 (18), 131 (24), 119 (24), 91 (28), 77 (10); HRMS
dd, J = 6.9, 6.7 Hz, 1H, CHCH(CO2Et)NH], 3.89 [d, J = 6.7 Hz, calculated for C23H29NO8: 447.1893, found: 447.1889.
1H, CHC(CO2Me)Ph], 4.17 [d, J = 6.9 Hz, 1H, CH(CO2Et)NH],
(2S*,5R*)-3,4,5-Triethyl 2-methyl 2-phenyl-2,5-dihydro-1H-
4.26 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 7.28–7.38 (m, 2H, ArH), pyrrole-2,3,4,5-tetracarboxylate cis-5g. Colorless oil; Rf 0.11 (n-
7.51 (dd, J = 7.0, 2.3 Hz, 1H, ArH), 7.70 (dd, J = 7.0, 2.3 Hz, 2H, hexane–ethyl acetate 7 : 3); IR (neat) νmax 3068, 2925, 1743,
ArH), NH nd; 13C NMR δC: 14.3 (CO2CH2CH3), 51.8, 52.6, 52.8 1727, 1656, 1606 cm−1 1H NMR δH: 1.20, 1.21, 1.28 (3t, J =
;
(3 × CO2CH3), 53.6 [CHC(CO2Me)Ph], 54.7 [CHCH(CO2Et)NH], 7.2 Hz, 9H, 3 × CO2CH2CH3), 3.71 (s, 3H, CO2CH3), 3.48, 4.13,
61.6 [CH(CO2Et)NH], 61.9 (CO2CH2CH3), 75.2 [C(CO2Me)Ph], 4.19 (3 × q, J = 7.2 Hz, 6H, CO2CH2CH3), 5.70 [s, 1H,
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CH(CO2Et)NH], 7.31–7.37 (m, 5H, ArH), NH nd; 13C NMR δC: 7.17–7.35 (m, 10H, ArH); 13C NMR δC: 44.3 (CH2Ph), 45.8
14.0, 14.5, 15.4 (3 × CO2CH2CH3), 52.9 (CO2CH3), 59.8, 62.1, (CHCHCH2OH), 50.5 (CHCH2OH), 54.3, 55.5 (2 × CH2NBn),
66.0 (3 × CO2CH2CH3), 60.7 [CH(CO2Et)NH], 77.2 [C(CO2Me) 59.7 (CHCCH2OH), 60.2 (NCH2Ph), 62.4, 64.8 (2 × CH2OH),
Ph], 127.5, 128.6, 129.1, 137.7 (ArC), 146.0 [CCH(CO2Et)NH], 67.1 [CBn(CH2OH)NH], 127.5, 128.3, 128.5, 128.8, 128.9, 130.5,
146.5[CC(CO2Me)Ph], 168.3, 168.8, 169.2, 171.7 (4 × CO2); MS 137.5, 137.6 (ArC); MS (EI-GC) m/z 352 (M+ + 1, <1%), 243 (41),
(EI-GC) m/z: 419 (M+ + 1, <1%), 342 (10), 277 (18), 276 (100), 207 (11), 158 (14), 134 (10), 133 (13), 132 (13), 92 (11), 91 (100),
249 (21), 202 (10), 171 (10), 170 (38), 77 (11), 73 (10); HRMS cal- 65 (12); microanalysis calculated for C22H28N2O2: C, 75.0; H,
culated for C21H25NO8: 419.1580, found: 495.1596.
8.0; N, 8.0%; found: C, 74.8; H, 8.0; N, 8.3%.
Synthesis of aminoalcohols 6 and 7
Synthesis of molecule 8
To a solution of endo-cis-4b (928 mg, 2 mmol) in DMF (2 ml)
was added benzoyl chloride (707 μl, 6 mmol) and Et3N (278 μl,
2 mmol). After stirring (0.5 h at 25 °C) the resulting suspen-
sion was heated at 100 °C for an additional 12 h. Then the
DMF was evaporated and dry THF was added.17 The resulting
solution was added into a LiAlH4 suspension (390.6 mg,
10 mmol, 97%) in dry THF. The resulting suspension was
stirred for 0.5 h at 25 °C and then refluxed for 12 h. The
mixture was cooled at 0 °C and NaOH 10% was added, stirring
the emulsion for 30 min. The resulting mixture was filtered off
and extracted with ethyl acetate (2 × 8 mL). The organic layer
was dried over MgSO4, and the solvent evaporated giving a
residue, which was purified by flash chromatography obtain-
ing 215 mg of 6 and 162 mg of 7 (65% overall yield).
A solution of 6 (120 mg, 0.27 mmol) in dichloromethane was
cooled at 0 °C. Then MsCl (21.5 μl, 0.27 mmol, 98%) and Et3N
(38 μl, 0.27 mmol) were added. After stirring for 1 h at 25 °C,
the solvent was evaporated and MeCN was added. Then
BnNH2 (30 μl, 0.27 mmol, 98%) was added and the resulting
solution was refluxed for an additional 15 h. Then the solvent
was evaporated and the resulting crude was extracted with
ethyl acetate (2 × 8 mL). The organic phase was washed with
brine, dried over MgSO4, evaporated in vacuo, and the residue
purified by flash chromatography obtaining 74 mg of 8 (53%
yield).
(3aS*,4S*,8R*,8aR*)-2,4,6,9-Tetrabenzyldecahydro-4,8-epimi-
nopyrrolo[3,4-d]azepine (8). Sticky brown oil; Rf 0.30 (n-
hexane–ethyl acetate 7 : 3); IR (neat) νmax 3060, 2925, 1669,
1
1602 cm−1; H NMR δH: 2.52, 2.72 (2d, J = 12.8, 2H, CCH2APh),
(1R*,3S*,3aR*,6aS*)-1,2,5-Tribenzyloctahydropyrrolo[3,4-c]
pyrrole-1,3-diol 6a. Sticky oil; Rf 0.45 (ethyl acetate–methanol
2.90–3.05 (m with d at 3.01, J = 13.9, 3H, CH2K, CHE and CHF),
3.25–3.41 (m with d at 3.30, J = 13.9, 3H, CH2K, CH2J and CHG),
3.42–3.70 (4d at 3.47, 3.48, 3.64, 3.65, J = 12.9 and 13.0 Hz, 4H,
CH2BPh and CH2DPh), 3.70–4.15 (m, 5H, CH2H, CH2I and CH2J),
4.30 (s, 2H, CH2CPh), 7.15–7.50 (m, 20H, 4 × ArH); 13C NMR δC:
40.0 (CFH), 44.2 (CKH2), 44.5 (CEH), 47.2 (CCH2Ph), 49.9
(CAH2Ph), 56.5 (CGH), 60.3, 60.8 (CBH2Ph and CDH2Ph), 61.6
(CJH2), 65.1, 65.4 (CHH2 and CIH2), 69.5 (CL), 127.3, 128.1,
128.2, 128.4, 128.6, 128.7, 128.9, 128.9, 129.5, 130.5, 131.1,
132.2, 134.7, 135.0, 136.4, 137.2 (ArC); MS (EI-GC) m/z 513 (M+
+ 1, <1%), 195 (17), 194 (17), 106 (100), 105 (23), 104 (49), 132
(13), 92 (20), 91 (94), 79 (28), 78 (15), 77 (29), 65 (18), 51 (17),
43 (10); HRMS calculated for C36H39N3: 513.3144, found:
513.3130.
1
9 : 1); IR (neat) νmax 3300, 2923, 1650, 1615 cm−1; H NMR δH:
2.18–2.26 (m, 2H, CHCHCH2OH and CHCCH2OH), 2.73–2.87
(2d, J = 13.2 Hz, 4H, CCH2Ph,), 3.05–3.27 (m, 4H, 2 × CH2NBn),
3.30–3.61 [m with 2d at 3.53 and 3.57, J = 14.2 Hz, 7H,
NCH2Ph, 2 × CH2OH, CH(CH2OH)NBn], 7.15–7.35 (m, 13H,
ArH), 7.46–7.52 (m, 2H, ArH), OH nd; 13C NMR δC: 44.3
(CH2Ph), 46.0 (CHCHCH2OH), 48.3 (CHCCH2OH), 52.9
(CHCH2OH), 55.1, 57.8 (2 × CH2NBn), 60.3, 61.5 (2 × NCH2Ph),
63.1 (CCH2Ph), 64.1, 65.0 (2 × CH2OH), 126.5, 127.5, 127.6,
128.2, 128.8, 128.9, 129.2, 130.0, 130.6, 135.5, 137.6, 137.9
(ArC); MS (EI-GC) m/z 442 (M+ + 1, <1%), 281 (10), 247 (10), 207
(16), 171 (38), 158 (24), 156 (15), 134 (15), 133 (35), 132 (15), 92
(18), 91 (100); microanalysis calculated for C29H34N2O2: C,
79.0; H, 8.0; N, 6.0%; found: C, 78.6; H, 7.9; N, 6.2%.
Also product 6 was obtained from 7. To a solution of 7
(162 mg, 0.46 mmol) in MeCN was added K2CO3 (190 mg,
1.40 mmol) and BnBr (54.83 μl, 0.46 mmol). After stirring for
0.5 h at 25 °C the resulting suspension was refluxed for an
additional 12 h. Then the solvent was evaporated and the
resulting crude was extracted with ethyl acetate (2 × 10 mL)
and was washed with brine. After drying over MgSO4, the
solvent was evaporated and the residue purified by flash
chromatography obtaining 146 mg of 6 (72% yield).
(1S*,3R*,3aR*,6aS*)-1,5-Dibenzyl-1,3-bis(hydroxymethyl)
octahydropyrrolo[3,4-c]pyrrole 7a. Sticky oil; Rf 0.33 (ethyl
Acknowledgements
acetate–methanol 9 : 1); IR (neat) νmax 3300, 2923 cm−1 1H
;
NMR δH: 2.27–2.33 and 2.95–3.05 (m, 4H, 2 × CH2NBn), This work has been supported by the Spanish Ministerio de
2.62–2.90 (m with 2d at 2.65 and 2.83, J = 13.4, 4H, CH2Ph, Ciencia e Innovación (MICINN) (Consolider INGENIO 2010
CHCHCH2OH, and CHCH2OH), 3.44–3.75 (m with 2d at 3.48 CSD2007-00006, CTQ2010-20387), FEDER, Generalitat Valenci-
and 3.63, J = 11.4, 7H, NCH2Ph, 2 × CH2OH, CHCCH2OH), ana (PROMETEO/2009/039), and by the University of Alicante.
674 | Org. Biomol. Chem., 2013, 11, 662–675
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