Synthesis of pharmacophores containing a prolinate core using a multicomponent 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tet.2017.10.030

A multicomponent 1,3-dipolar cycloaddition between heterocyclic aldehydes, amino esters and dipolarophiles is efficiently promoted by silver acetate as catalyst, and depending on the nature of the heterocycle and its reactivity the reaction requires 70 °C or rt to complete. Selected pharmacophores anchored to a formyl group are chromone, 5-methoxyindole, pyridoxal surrogates and a very attractive uracyl derivative. The preference of each tested amino esters towards different dipolarophiles is discussed. At the end, a selective reduction of the ester group allows to obtain a very interesting dideoxiazanucleoside derivative.

Full text of DOI:10.1016/j.tet.2017.10.030

Accepted Manuscript
Synthesis of pharmacophores containing a prolinate core using a multicomponent
1,3-dipolar cycloaddition of azomethine ylides
Elisabet Selva, Luis M. Castelló, Juan Mancebo-Aracil, Verónica Selva, Carmen
Nájera, Francisco Foubelo, José M. Sansano
PII:
S0040-4020(17)31044-X
10.1016/j.tet.2017.10.030
TET 29033
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 September 2017
Revised Date: 9 October 2017
Accepted Date: 10 October 2017
Please cite this article as: Selva E, Castelló LM, Mancebo-Aracil J, Selva Veró, Nájera C, Foubelo F,
Sansano JoséM, Synthesis of pharmacophores containing a prolinate core using a multicomponent 1,3-
dipolar cycloaddition of azomethine ylides, Tetrahedron (2017), doi: 10.1016/j.tet.2017.10.030.
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Synthesis of pharmacophores containing a prolinate core
using a multicomponent 1,3-dipolar cycloaddition of
azomethine ylides
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Elisabet Selva, Luis M. Castelló, Juan Mancebo-Aracil, Verónica Selva,
Carmen Nájera, Francisco Foubelo, José M. Sansano

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of pharmacophores containing a prolinate core using a multicomponent 1,3-
dipolar cycloaddition of azomethine ylides
Elisabet Selva,a,b,c Luis M. Castelló,c Juan Mancebo-Aracil,d Verónica Selva,a,b Carmen Nájera,a Francisco
Foubelo*a,b and José M. Sansano*a,b
a Departamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Ciencias, Universidad de Alicante
03080-Alicante, Spain.
b Instituto de Síntesis Orgánica, Facultad de Ciencias, Universidad de Alicante 03080-Alicante, Spain. Fax: +34-965903549 ; Tel : +34-965903728.
c Medalchemy, S. L. Avenida Ancha de Castelar, 46 – EA, San Vicente del Raspeig, 03690, Alicante
d Departamento de Química, Universidad Nacional del Sur (UNS), Av. Alem 1253, CP: 8000, Bahía Blanca, Buenos Aires, Argentina.
* indicates the main/corresponding author, foubelo@ua.es, jmsansano@ua.es
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A multicomponent 1,3-dipolar cycloaddition between heterocyclic aldehydes, amino esters and
dipolarophiles is efficiently promoted by silver acetate as catalyst, and depending on the nature
of the heterocycle and its reactivity the reaction requires 70 °C or rt to complete. Selected
pharmacophores anchored to a formyl group are chromone, 5-methoxyindole, pyridoxal
surrogates and a very attractive uracyl derivative. The preference of each tested amino esters
towards different dipolarophiles is discussed. At the end, a selective reduction of the ester group
allows to obtain a very interesting dideoxiazanucleoside derivative.
Available online
Keywords:
prolinates
cycloaddition
azomethine ylides
multicomponent
azanucleoside
2017 Elsevier Ltd. All rights reserved
.
1. Introduction
The alarm of a drug antimicrobial resistance reported case
reminds scientists the powerful evolution machinery in nature.
Infections with resistant organisms are very difficult to treat,
requiring costly and sometimes toxic alternatives. Bacteria,
viruses, fungi, and parasites can cause disease among humans,
other animals, and plants and have the ability to develop
resistance to the drugs created against them. To face this problem
when vaccines are not available, the development of new drugs
as well as new diagnostic tests to track the origin and mechanism
of resistance are prioritary.
Drug targets are usually proteins but are in some cases small
regions of DNA or RNA. Synthetic nucleotides and nucleosides
are currently being used to modify natural DNA/RNA sequences,
altering specifically gene expression.1 With this idea
commercially available antiviral agents such as, for example,
AZT, ribavirin, lamivudine, emtricitabine and stavudine
incorporate mimetic heterocycles at the 2 position.2,3 In addition,
another different (non-commercial) compounds have shown
interesting antiviral properties due to the presence of substituted
pyridine/quinoline/quinazoline
nucleus4
or
substituted
indole/benzimidazole rings.5 The synthesis of all these
compounds require several steps and occasionally chemical
yields are low.
Figure 1. Synthetic nucleosides possessing high antiviral
inhibition.

2
Tetrahedron
the imine with itself (Scheme 1). Compouds 8ab-8ae were
ACCEPTED MANUSCRIPT
isolated as unique endo-diastereoisomer (>95:5 dr).
In this work, the synthesis of prolinates and pseudo-
azanucleosides bearing a mimetic nucleo-base anchored in the
strategic position 5 and a nitrogen atom instead of the furan
oxygen is designed.6 The multicomponent7,8 1,3-dipolar
cycloaddition (1,3-DC)9 between heterocyclic aldehydes, amino
esters and the corresponding dipolarophile was choiced as
straightforward way10 to access this new family of compounds
8.11 Apart from conventional hydrogen bonds between
heterocycle and the genetic material of the microorganism, new
additional biological interactions through the proline nitrogen
atom can be envisaged.
2. Results and Discussion
This operationally simple multicomponent 1,3-DC started
with the selection of four biologically attractive commercially
available heterocyclic aldehydes 9-12 (Figure 2) based on the
important role in nature of chromones,12 5-methoxyindole,13
pyridoxal14 and uracyl15 surrogates.
Figure 2. Commercially available formylheterocycles used in
this work.
Scheme 1. Synthesis of compound 8a series bearing 4-
chromenone nucleus.
The optimization of the reaction was very simple16 and only
solvents (DCM, EtOH, PhMe, THF) and temperature (rt-110 ºC
range) were studied for all the formylheterocycles involved,
silver acetate being necessary for the completion of the reaction.
In general, to the solution (or suspension) of the free amino ester
(or its hydrochloride), the aldehyde and triethylamine (1.1 equiv)
in the corresponding solvent, the dipolarophile and silver acetate
(5 mol%) were added in this order. Thus, 3-formyl-6-
methylchromone (9) was tested in the presence of phenylalanine
ethyl ester hydrochloride and N-methylmaleimide (NMM) as
dipolarophile. Whilst the reaction did not occur neither at room
temperature nor 70 °C in toluene, the expected endo-cycloadduct
8aa was obtained in 75% yield and 92:8 endo:exo ratio, after
flash chromatography when the reaction was performed in
refluxing ethanol (the best solvent for these series of compounds)
for 10 h (Scheme 1). N-Benzylmaleimide (NBM) and methyl
acrylate also gave good yields of cycloadducts 8ab (65%) and
8ac (76%), respectively (Scheme 1). Alanine methyl ester
hydrochloride was allowed to react under this reaction conditions
with maleimides giving rise to polycyclic compounds endo-8ad
and endo-8ae in 70 and 65% yields (Scheme 1). Unfortunately,
the in situ generated imine from glycine methyl ester
hydrochloride and aldehyde 9 afforded the expected cycloadduct
5-Methoxyindole-3-carbaldehyde (10) behaved similarly to
chromone 9. The cleanest reaction occurred in toluene at 70 °C in
the presence of α-substituted amino esters with maleimides,
triethylamine (1.1 equiv) and silver acetate (5 mol%) (Scheme 2).
Thus, the combination with NMM and NBM with phenylalanine
ethyl ester hydrochloride gave endo-cycloadducts 8ba and 8bb in
moderate yield (52 and 55%, respectively). Alanine methyl ester
hydrochloride also underwent 1,3-DC under standard conditions
with NMM furnishing product endo-8bc in 60% yield (Scheme
2). Glycine methyl ester hydrochloride gave the corresponding
mixture of stereoisomeric imidazolidines 13b (not drawn,
approx. 20% by 1H NMR) together with decomposed compounds
and a small amount of the desired cycloadduct (<10% by analysis
1
of H NMR spectra of the crude mixture). Acrylates are not
appropriate dipolarophiles in this particular transformation. As
well as occurred in the last series, compouds 8ba-8ac were
isolated as unique endo-diastereoisomer (>95:5 dr).
1
in very low yield (<10% by analysis of H NMR spectra of the
crude mixture) unpurified with decomposed compounds and a
noticeable amount (approx. 20% by 1H NMR) of several
stereoisomers of imidazolidine 13a as a result of the reaction of

3
nucleoside. The multicomponent reaction was implemented at
ACCEPTED MANUSCRIPT
room temperature in a different way to the reactions run before.
Toluene was the most appropriate solvent. Glycine methyl ester
hydrochloride reacted with maleimides and 12 to give endo-
cycloadducts 8da and endo-8db in 82 and 88% yield,
respectively (Scheme 4, eq. 1). When phenylalanine ethyl ester
was employed as free amine, base was not needed and the
reaction was completed in 10 h. NMM, NBM and ethyl acrylate
were appropriate dipolarophiles to access the interesting
azanucleosidic agents 8dc-8de (Scheme 4, eq. 2). The high yields
achieved in all these examples were obtained after
recrystallization/precipitation from warm ethanol taking
advantage of the poor solubility of molecules 8da-8de. The
preparation of compound endo-8da was also attempted in a 1.5 g
scale obtaining the same chemical yield. All of the cycloadducts
containing the uracyl moiety were isolated as unique endo-
diastereoisomers (>95:5 dr).
Scheme 2. Synthesis of compound 8b series bearing 5-
methoxyindole nucleus.
Pyridoxal hydrochloride (11·HCl) was the first example of a
formylheterocycle able to react with glycine methyl ester
hydrochloride under the standard reaction conditions in refluxing
ethanol (best solvent). When this two reagents were combined
with triethylamine (2.2 equiv), NMM and silver acetate (5 mol%)
in refluxing ethanol, cycloadduct endo-8ca was isolated in 96%
yield (Scheme 3) and no traces of imidazolidine 13c were
detected. Phenylalanine ethyl ester hydrochloride reacted with
maleimides producing endo-8cb and endo-8cc in excellent yields
and more than 95:5 endo:exo ratio (Scheme 3). Ethyl acrylate
was required in order to prevent transesterification from the
solvent. The reaction with 11·HCl, the already mentioned
acrylate and ethyl phenylalaninate furnished molecule 8cd in
very high yield (92%) and high diastereomeric ratio (90:10
endo:exo) (Scheme 3). It is noteworthy that the two hydroxyl
groups of the pyridoxal 11 were not protected previously to the
cycloaddition, which demonstrated a high functional group
tolerance.
Bn
N
N
O
O
O
O
O
O
HN
HN
CO2Me
CO2Me
N
N
H
H
O
O
N
N
H
H
endo-8da (82%)
endo-8db (88%)
Scheme 4. Synthesis of compound 8d series bearing a uracil
nucleus.
The relative configuration of products 8 were determined by
selective nOe experiments identifying clearly in the most
representative examples of each series the all cis-arrangement
typical of the major endo-approach of the dipolarophile to the
intermediate W-shape conformer of the azomethine ylide.
Moreover, all compounds described in this article are being
tested as potential antibacterial, antitumor and antiviral agents.
Scheme 3. Synthesis of compound 8c series bearing a pyridoxal
surrogate nucleus.
To demonstrate the utility of this methodology the
preparation of more similar structures to natural scaffolds such as
endo-14dc was achieved by selective reduction of the ester group
of the uracyl derivative endo-8dc in good yield (80%) using
NaBH4 in methanol under reflux of THF for 10 h (Scheme 5).17,18
The 1,3-DC involving 5-formyluracil (12) are perhaps the
most attractive series because it resembles the natural uridine

4
Tetrahedron
To a stirred solution of amino ester hydrochloride (1.1 equiv, 0.6
ACCEPTED MANUSCRIPT
mmol) in EtOH (3 mL, for 8a) or toluene (3 mL, for 8b), aldehyde (1
equiv, 0.5 mmol) was added. After that, Et3N (1.1 equiv, 70 µL), the
dipolarophile (1 equiv, 0.5 mmol) and AgOAc (5 mol%) were added
in this order. The reaction mixture was stirred overnight at 70 °C.
The solvent was evaporated under reduced pressure. The crude
mixture was extracted with ethyl acetate and washed with brine. The
organic phase was dried (MgSO4), filtrated and evaporated. The
corresponding pyrrolidines were obtained in good yields after
purification by flash chromatography (Hex/AcOEt).
Scheme 5. Synthesis of mimetic dideoxiazanucleoside endo-
14dc.
4.2.1. (1S*,3R*,3aS*,6aR*)-Ethyl 1-benzyl-5-methyl-3-(6-methyl-4-
oxo-4H-chromen-3-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-
3. Conclusions
According to all these results we can conclude that a large
family of azanucleosides can be efficiently and easily prepared in
a multicomponent process from readily accessible starting
compounds. The versatility of the 1,3-DC has been demonstrated
once more allowing the presence of many functional groups
ensuring a 2,4,5-cis-arrangement or all. Among this, the
operational simplicity of this procedure permits its
implementation in a larger scale. A reduction of the ester group
can be the key to new family of potential drugs whose study of
activity is in their infancy. The asymmetric 1,3-DC version of
these transformations is a difficult task and are currently
underway.
carboxylate (8aa): White solid, (178 mg, 75% yield). IR (neat) ʋmax
:
730, 1098, 1288, 1436, 1484, 1642, 1703, 1736, 2959 cm-1. 1H NMR
(300 MHz, CDCl3) δ: 1.41 (t, J = 7.2 Hz, 3H), 2.45 (s, 3H), 2.84 (s,
3H), 3.19 (d, J = 13.7 Hz, 1H), 3.48 (d, J = 7.2 Hz 1H), 3.57 (d, J =
13.7 Hz, 1H), 3.75 (br s, 1H), 4.35 (q, J = 8.5 Hz, 2H), 4.90 (d, J =
9.0 Hz, 1H), 7.20-7.26 (m, 5H), 7.33 (d, J = 8.6 Hz, 1H), 7.48 (dd, J
= 8.6, 2.3 Hz, 1H) 7.96 (s, 1H), 8.01 (d, J = 0.9 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ: 14.1, 21.0, 25.1, 40.1, 47.5, 54.1, 62.0, 71.3,
77.3, 118.0, 123.0, 125.1, 127.6, 128.9, 129.6, 129.8, 134.9, 135.2,
135.4, 152.9, 154.7, 170.3, 174.6, 175.2, 177.6. LRMS (EI): m/z =
474 (M+, >1%), 401 (14), 384 (23), 383 (100), 337 (34), 252 (14), 91
(22). HRMS (EI): calcd. for [C27H26N2O6] 474.1791; found
474.1781.
4. Experimental Section
4.2.2. (1S*,3R*,3aS*,6aR*)-Ethyl 1,5-dibenzyl-3-(6-methyl-4-oxo-4H-
chromen-3-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-
4.1. General
All commercially available reagents and solvents were used
without further purification, only aldehydes were also distilled prior
to use. Analytical TLC was performed on Schleicher & Schuell
F1400/LS 254 silica gel plates, and the spots were visualised under
UV light (λ = 254 nm). Flash chromatography was carried out on
handpacked columns of Merck silica gel 60 (0.040-0.063 mm).
Melting points were determined with a Reichert Thermovar hot plate
apparatus and are uncorrected. The structurally most important peaks
of the IR spectra (recorded using a Nicolet 510 P-FT) are listed and
wave numbers are given in cm-1. NMR spectra were obtained using a
Bruker AC-300 or AC-400 and were recorded at 300 or 400 MHz for
1H NMR and 75 or 100 MHz for 13C NMR, using CDCl3 or DMSO-
d6 as solvent and TMS as internal standard (0.00 ppm). The
following abbreviations are used to describe peak patterns where
appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet or unresolved and br s = broad signal. All coupling
constants (J) are given in Hz and chemical shifts in ppm. 13C NMR
spectra were referenced to CDCl3 at 77.16 ppm. DEPT-135
experiments were performed to assign CH, CH2 and CH3. Low-
resolution electron impact (EI) mass spectra were obtained at 70 eV
using a Shimadzu QP-5000 by injection or DIP; fragment ions in m/z
are given with relative intensities (%) in parentheses. High-resolution
mass spectra (HRMS) were measured on an instrument using a
quadrupole time-of-flight mass spectrometer (QTOF) and also
through the electron impact mode (EI) at 70 eV using a Finnigan VG
Platform or a Finnigan MAT 95S. Microanalyses were performed in
a Thermo Finnigan Flash 1112 Series.
carboxylate (8ab): Yellow solid, (179 mg, 65% yield). IR (neat) ʋmax
:
709, 1173, 1345, 1398, 1484, 1640, 1707, 1736, 2933 cm-1. 1H NMR
(300 MHz, CDCl3) δ: 1.42 (t, J = 7.2 Hz, 3H), 2.48 (s, 3H), 3.15 (d, J
= 13.7 Hz, 1H), 3.47 (d, J = 7.7 Hz, 1H), 3.59 (d, J = 13.7 Hz, 1H),
3.87 (d, J = 7.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.54 (q, J = 14.1
Hz, 2H), 4.98 (d, J = 8.8 Hz, 1H), 7.16-7.32 (m, 11H), 7.49 (dd, J =
8.6, 2.1 Hz, 1H) 7.62 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H). 13C NMR (75
MHz, CDCl3) δ: 14.2, 21.0, 40.1, 42.5, 46.9, 53.9, 61.8, 71.1, 77.3,
117.9, 123.0, 125.2, 127.5, 127.9, 128.5, 128.6, 128.7, 128.9, 129.6,
135.0, 135.1, 135.2, 135.7, 152.7, 154.6, 170.5, 174.2, 174.9, 177,4.
LRMS (EI): m/z = 550 (M+, >1%), 447 (16), 460 (31), 459 (100),
413 (46), 252 (26), 91 (92). HRMS (EI): calcd. for [C33H30N2O6]
550.2104; found 550.2078.
4.2.3. (2R*,4S*,5R*)-2-Ethyl 4-methyl 2-benzyl-5-(6-methyl-4-oxo-
4H-chromen-3-yl)pyrrolidine-2,4-dicarboxylate (8ac): Yellow oil,
(170 mg, 76% yield). IR (neat) ʋmax: 1198, 1437, 1485, 1619, 1645,
1
1733, 2251, 2950, 2981, 3339 cm-1. H NMR (300 MHz, CDCl3) δ:
1.25 (t, J = 7.1 Hz, 3H), 2.26 (dd, J = 13.6, 7.7 Hz, 1H), 2.42 (s, 3H),
2.75 (dd, J = 13.6, 4.7 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 3.18 (d, J
= 13.4 Hz, 1H), 3.31 (s, 3H), 3.54 (td, J = 7.5, 4.8 Hz, 1H), 4.18 (tq,
J = 7.2, 3.4 Hz, 3H), 4.79 (d, J = 7.5 Hz, 1H), 7.14-7.33 (m, 5H),
7.32 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.6, 2.0 Hz, 1H), 7.97 (d, J =
1.3 Hz, 1H), 8.08 (s, 1H). 13C NMR (75 MHz, CDCl3) δ: 14.2. 21.0,
38.9, 45.0, 47.1, 51.5, 56.5, 61.3, 69.3, 117.9, 123.1, 125.1, 127.0,
128.2, 128.3, 130.0, 135.0, 135.1, 136.5, 153.5, 154.6, 173.1, 174.8,
177.2. LRMS (EI): m/z = 449 (M+, >1%), 376 (27), 359 (21), 358
(100), 280 (15), 259 (52), 252 (26), 226 (15), 91 (33). HRMS (EI):
calcd. for [C26H27NO6] 449.1838; found 449.1840.
4.2. General procedure for the synthesis of products 8a and 8b.

5
4.2.4. (1S*,3R*,3aS*,6aR*)-Methyl 1,5-dimethyl-3-(6-methyl-4-oxo-
4H-chromen-3-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-
4.2.8.
(1S*,3R*,3aS*,6aR*)-Methyl-3-(5-methoxy-1H-indol-3-yl)-
ACCEPTED MANUSCRIPT
1,5-dimethyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-
carboxylate (8bc): Brown solid, (110 mg, 60% yield). IR (neat) ʋmax
carboxylate (8ad): Pale brown solid, (134 mg, 70% yield). IR (neat)
ʋmax: 709, 1173, 1345, 1398, 1484, 1640, 1707, 1736, 2933. 1H NMR
(300 MHz, CDCl3) δ: 1.70 (s, 3H), 2.44 (s, 3H), 2.86 (s, 3H), 3.35 (d,
J = 7.7 Hz, 1H), 3.78 (t, J = 8.2 Hz, 1H), 3.88 (s, 3H), 4.88 (d, J =
8.9 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 8.6, 2.2 Hz, 1H),
7.95 (dd, J = 2.0, 1.0 Hz, 1H), 8.08 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ: 21.1, 23.0, 25.4, 48.2, 53.4, 55.8, 57.6, 68.5, 118.1, 123.1,
125.1, 135.7, 135.9, 154.2, 154.8, 171.2, 174.5, 175.0, 178.5. LRMS
(EI): m/z = 384 (M+, >1%), 369 (18), 326 (20), 325 (100), 273 (19),
266 (26), 213 (23), 119 (21). HRMS (EI): calcd. for [C20H20N2O6]
384.1321; found 384.1305.
:
1289, 1439, 1702, 1751, 2957, 3265. 1H NMR (300 MHz, CDCl3) δ:
1.62 (s, 3H), 2.72 (s, 3H), 3.33 (d, J = 7.6 Hz, 1H), 3.57 (dd, J = 9.1,
7.5 Hz, 1H), 3.82 (s, 3H), 3.89 (s, 3H), 5.04 (d, J = 9.1 Hz, 1H), 6.80
(dd, J = 8.8, 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 2.1
Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 8.45 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ: 23.9, 25.1, 50.4, 52.8, 55.8, 56.5, 56.9, 67.4, 100.8, 111.6,
112.4, 112.5, 123.4, 126.5, 131.8, 154.0, 173.2, 175.3, 176.3. LRMS
(EI): m/z = 371 (M+, >1%), 269 (20), 261 (16), 260 (100), 200 (62),
185 (63), 169 (29), 159 (40). HRMS (EI): calcd. for [C19H21N3O5]
371.1481; found 371.1473.
4.2.5. (1S*,3R*,3aS*,6aR*)-Methyl 5-benzyl-1-methyl-3-(6-methyl-4-
oxo-4H-chromen-3-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-
4.3. General procedure for the synthesis of product 8c.
carboxylate (8ae): Yellow solid, (150 mg, 65% yield). IR (neat) ʋmax
:
To a stirred solution of ester hydrochloride as amine (1.1 equiv,
0.5 mmol) in EtOH (3 mL) was added pyridoxal hydroclorhide (1
equiv, 0.5 mmol). After, Et3N (2 equiv, 140 µL), dipolarophile (1
equiv, 0.5 mmol) and AgOAc (5 mol%). The reaction mixture was
stirred overnight at 70 °C. The solvent was removed under reduced
pressure. The crude mixture was extracted with ethyl acetate and was
washed with brine. The organic phase was dried (MgSO4) and after
filtration and evaporation, the corresponding pyrrolidines were
obtained without purification.
700, 1170, 1344, 1399, 1485, 1640, 1705, 1740, 2952. 1H NMR (300
MHz, CDCl3) δ: 1.72 (s, 3H), 2.46 (s, 3H), 3.35 (d, J = 7.9 Hz, 1H),
3.79 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 4.50 (d, J = 4.8 Hz, 1H), 5.01
(d, J = 6.3 Hz, 1H), 7.26-7.30 (m, 6H), 7.34 (d, J = 8.6 Hz, 1H), 7.50
(dd, J = 8.6, 2.0 Hz, 1H), 7.95 (s, 1H). 13C NMR (75 MHz, CDCl3)
δ: 21.0, 22.8, 42.9, 47.6, 53.3, 55.2, 56.7, 68.2, 118.0, 122.9, 125.1,
128.0, 128.5, 128.7, 128.9, 135.4, 135.6, 135.7, 154.2, 154.7, 171.0,
174.0, 174.6, 178.2. LRMS (EI): m/z = 460 (M+, >1%), 445 (24),
402 (27), 401 (100), 273 (33), 266 (70), 240 (28), 213 (26), 91 (74).
HRMS (EI): calcd. for [C26H24N2O6] 460.1634; found 460.1629.
4.3.1.
(hydroxymethyl)-2-methylpyridin-4-yl)-4,6-
(1R*,3S*,3aR*,6aS*)-Methyl
5-benzyl-3-(3-hydroxy-5-
4.2.6. (1S*,3R*,3aS*,6aR*)-Ethyl 1-benzyl-3-(5-methoxy-1H-indol-3-
yl)-5-methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(8ba): Grey solid, (119 mg, 52% yield). IR (neat) ʋmax: 703, 1214,
1381, 1283, 1437, 1485, 1704, 2938, 3375. 1H NMR (300 MHz,
CDCl3) δ: 1.26 (t, J = 7.2 Hz, 3H), 2.98 (s, 3H), 3.30 (d, J = 13.4 Hz,
1H), 3.37-3.44 (m, 1H), 3.48-3.54 (m, 1H), 3.51 (d, J = 13.7 Hz,
1H), 3.82 (s, 3H), 4.16 (q, J = 7.2 Hz, 2H), 4.86 (d, J = 6.4 Hz, 1H),
6.85 (dd, J = 8.9, 2.4 Hz, 1H), 7.16 (s, 1H), 7.22-7.36 (m, 7H), 8.18
(s, 1H). 13C NMR (75 MHz, CDCl3) δ: 14.1, 25.2, 40.0, 48.9, 54.0,
55.7, 56.5, 62.5, 71.5, 100.3, 112.3, 112.7, 126.0, 127.8, 128.3,
128.9, 130.1, 131.1, 131.5, 134.7, 153.9, 174.2, 174.5, 175.1. LRMS
(EI): m/z = 461 (M+, >1%), 388 (67), 371 (23), 370 (100), 350 (28),
212 (20), 185 (30), 147 (22), 91 (27). HRMS (EI): calcd. for
[C26H27N3O5] 461.1951; found 461.1941.
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (8ca): Yellow
solid, (110 mg, 96% yield). IR (neat) ʋmax: 1211, 1393, 1714, 1745,
1
2802, 3264. H NMR (300 MHz, CDCl3) δ: 2.26 (s, 3H), 3.50-3.73
(m, 2H), 3.77 (s, 3H), 4.09 (d, J = 7.5 Hz, 1H), 4.40 (d, J = 14.3 Hz,
1H), 4.51 (d, J = 14.3 Hz, 1H), 4.90 (d, J = 8.9 Hz, 1H), 7.22-7.28
(m, 5H), 7.71 (s, 1H). 13C NMR (75 MHz, CDCl3) δ: 18.3, 43.1,
47.1, 48.4, 52.6, 59.3, 61.0, 61.3, 126.1, 128.0, 128.5, 129.0, 132.0,
134.9, 138.6, 148.6, 152.7, 169.6, 174.8, 175.0. LRMS (EI): m/z =
425 (M+, >1%), 348 (30), 337 (30), 220 (44), 215 (22), 187 (40), 165
(18), 161 (100), 150 (31), 139 (17), 91 (95). HRMS (EI): calcd. for
C22H23N3O6 [M - CH3O, - CO2CH3] 336.1336; found 336.1348.
4.3.2.
(1R*,3S*,3aR*,6aS*)-Ethyl
1-benzyl-3-(3-hydroxy-5-
(hydroxymethyl)-2-methylpyridin-4-yl)-5-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (8cb): Pale
green solid, (204 mg, 90% yield). IR (neat) ʋmax: 731, 1096, 1198,
1288, 1385, 1437, 1702, 1739, 2664, 2942, 3302. 1H NMR (300
MHz, CDCl3) δ: 1.38 (t, J = 7.1 Hz, 3H), 2.78 (s, 3H), 2.32 (s, 3H),
3.10 (d, J = 13.8 Hz, 1H), 3.50 (d, J = 7.9 Hz, 1H), 3.69 (d, J = 13.9
Hz, 1H), 3.98 (t, J = 8.6 Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 4.63 (q, J
= 13.2 Hz, 2H), 5.34 (d, J = 9.8 Hz, 1H), 7.17-7.28 (m, 5H), 7.74 (s,
1H). 13C NMR (75 MHz, CDCl3) δ: 14.1, 17.9, 25.1, 40.5, 48.5, 53.7,
57.0, 61.0, 62.4, 71.1, 127.9, 128.1, 129.4, 129.6, 133.0, 134.2,
137.3, 147.9, 153.2, 170.1, 174.3, 174.4. LRMS (EI): m/z = 453 (M+,
>1%), 362 (22), 345 (19), 344 (100), 187 (24), 91 (17). HRMS (EI):
calcd. for [C24H27N3O6] 453.1900; found 453.1922.
4.2.7. (1S*,3R*,3aS*,6aR*)-Ethyl 1,5-dibenzyl-3-(5-methoxy-1H-
indol-3-yl)-4,6- dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(8bb): Brown solid, (148 mg, 55% yield). IR (neat) ʋmax: 701, 1174,
1
1211, 1396, 1704, 2932, 3348. H NMR (300 MHz, CDCl3) δ: 1.43
(t, J = 7.2 Hz, 3H), 3.18 (d, J = 13.5 Hz, 1H), 3.48-3.60 (m, 3H),
3.87 (s, 3H), 4.32 (d, J = 14.1 Hz, 1H), 4.39 (qd, J = 7.2, 1.0 Hz,
2H), 4.47 (d, J = 14.1 Hz, 1H), 5.17 (d, J = 8.9 Hz, 1H), 6.76 (d, J =
2.5 Hz, 1H), 6.84 (dd, J = 8.9, 2.5 Hz, 1H), 7.22-7.30 (m, 12H), 8.36
(s, 1H). 13C NMR (75 MHz, CDCl3) δ: 14.2, 40.1, 42.6, 49.0, 54.9,
52.2, 55.9, 61.7, 71.1, 100.9, 111.8, 112.2, 112.4, 127.4, 127.8,
128.5, 128.8, 128.9, 129.8, 135.4, 135.7, 153.9, 171.2, 174.7, 175.6.
LRMS (EI): m/z = 537 (M+, >1%), 464 (13), 447 (16), 446 (57), 444
(20), 351 (23), 350 (100), 276 (29), 212 (22), 185 (37), 158 (21), 91
(65). HRMS (EI): calcd. for [C32H31N3O5] 537.2264; found
537.2244.
4.3.3.
(1S*,3R*,3aR*,6aS*)-Ethyl
1,5-dibenzyl-3-(3-hydroxy-5-
(hydroxymethyl)-2-methylpyridin-4-yl)-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (8cc): Pale
green solid, (225 mg, 85% yield). IR (neat) ʋmax: 702, 1200, 1349,
1397, 1708, 1736, 2658, 2935, 3298. 1H NMR (300 MHz, CDCl3) δ:

6
Tetrahedron
ACCEPTED MANUSCRIPT
1.35 (t, J = 7.1 Hz, 3H), 2.31 (s, 3H), 2.99 (d, J = 14.0 Hz, 1H),
4.4.2. (1S*,3R*,3aS*,6aR*)-Methyl 5-benzyl-3-(2,4-dioxo-1,2,3,4-
3.48 (d, J = 7.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 3.95 (t, J = 8.3
Hz, 1H), 4.34-4.36 (m, 1H), 4.53 (d, J = 14.0 Hz, 1H), 5.27 (d, J =
9.7 Hz, 1H), 7.14-7.34 (m, 10H), 7.81 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ: 14.0, 40.9, 43.1, 48.1, 53.8, 57.1, 59.4, 62.7, 71.5, 128.1,
128.6, 128.7, 129.1, 129.2, 129.4, 130.0, 134.3, 134.6, 135.7, 137.8,
142.2, 155.9, 170.1, 173.5, 173.9. LRMS (EI): m/z = 529 (M+, >1%),
438 (14), 421 (26), 420 (100), 187 (26), 91 (65). HRMS (EI): calcd.
for C30H31N3O6 [M - CH3O] 498.2029; found 498.2026.
tetrahydropyrimidin-5-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-
1-carboxylate (8db): Pale yellow solid, (175 mg, 88% yield). IR
(neat) ʋmax: 1157, 1211, 1400, 1445, 1659, 1693, 1740, 3029. 1H
NMR (300 MHz, DMSO-d6) δ: 3.42 (d, J = 3.4 Hz, 1H), 3.46 (d, J =
8.3 Hz, 1H), 3.64 (d, J = 3.4 Hz, 1H), 3.67 (s, 3H), 3.97 (dd, J = 7.1,
4.2 Hz, 1H), 4.35 (dd, J = 7.1, 4.2 Hz, 1H), 4.41 (d, J = 4.0 Hz, 2H),
7.16-7.36 (m, 8H). 13C NMR (75 MHz, DMSO-d6) δ: 41.3, 47.6,
48.6, 51.4, 60.9, 62.7, 127.1, 127.3, 127.6, 128.2, 135.7, 138.2,
170.4, 174.9, 176.4. LRMS (EI): m/z = 398 (M+, >1%), 383 (3), 365
(38), 339 (33), 211 (100), 206 (23), 204 (32), 187 (15), 151 (70), 106
(17), 91 (75). HRMS (EI): calcd. for C19H18N4O6 [M - H+] 397.1158;
found 397.1148.
4.3.4.
(2R*,4S*,5R*)-Diethyl
2-benzyl-5-(3-hydroxy-5-
(hydroxymethyl)-2-methylpyridin-4-yl)pyrrolidine-2,4-dicarboxylate
(8cd): Yellow oil, (203 mg, 92% yield). IR (neat) ʋmax: 702, 1029,
1189, 1378, 1735, 2664, 2981, 3322. 1H NMR (300 MHz, CDCl3) δ:
0.81 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 2.27-2.42 (m, 4H),
2.90-2.99 (m, 2H), 3.39 (d, J = 13.7 Hz, 1H), 3.52 (td, J = 8.3, 4.6
Hz, 1H), 3.70 (qd, J = 7.2, 2.5 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H),
4.50 (d, J = 13.0 Hz, 1H), 4.62 (d, J = 13.0 Hz, 1H), 5.19 (d, J = 8.6
Hz, 1H), 6.87-7.39 (m, 5H), 7.68 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ: 13.6, 14.1, 16.2, 38.5, 44.4, 47.6, 59.7, 59.9, 61.4, 61.9,
69.6, 127.8, 129.1, 129.1, 129.7, 132.1, 132.4, 135.0, 135.3, 154.9,
171.3, 173.9. LRMS (EI): m/z = 442 (M+, >1%), 351 (23), 333 (53),
323 (31), 305 (100), 287 (62), 259 (17), 91 (41). HRMS (EI): calcd.
for C24H30N2O6 [M - CH3O, - OH] 394.1534; found 394.1529.
4.4.3.
(1S*,3R*,3aS*,6aR*)-Ethyl
1-benzyl-3-(2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)-5-methyl-4,6-dioxooctahydropyrrolo[3,4-
c]pyrrole-1-carboxylate (8dc): Grey solid, (198 mg, 93% yield). IR
(neat) ʋmax: 1098, 1436, 1678, 1697, 3031. 1H NMR (300 MHz,
DMSO-d6) δ: 1.24 (t, J = 7.1 Hz, 3H), 2.65 (s, 3H), 2.89 (d, J = 6.7
Hz, 1H), 3.00 (d, J = 13.9 Hz, 1H), 3.16 (d, J = 14.0 Hz, 1H), 3.45-
3.54 (m, 2H), 4.01-4.14 (m, 2H), 4.51 (d, J = 8.5 Hz, 1H), 7.11-7.23
(m, 8H), 7.39 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ: 15.2, 25.9,
50.5, 57.1, 57.6, 62.0, 62.2, 72.9, 126.6, 127.9, 128.1, 129.3, 129.6,
129.8, 130.2, 130.5, 131.4, 137.6, 165.8, 171.8, 177.1, 177.3. LRMS
(EI): m/z = 426 (M+, <1%), 353 (11), 336 (16), 335 (100), 289 (14),
206 (8), 91 (16). Elemental Analysis required for C21H22N4O6: C
59.20, H 5.20, N 13.10%; found: C 59.40, H 5.00, N 12.85%.
4.4. General procedure for the synthesis of products 8d.
8da-8db: to a stirred solution of ester hydrochloride as amine (1.1
equiv, 0.6 mmol) in toluene (2 mL) was added 5-formyluracile (1
equiv, 0.5 mmol) and Et3N (1.1 equiv). After that, dipolarophile (1.0
equiv) and AgOAc (5 mol%). The reaction mixture was stirred
overnight at room temperature. The solvent was removed under
reduced pressure. The crude mixture was filtrated through celite with
warm EtOH to furnish the corresponding product. To remove the
ammonium salt, it was washed with DCM.
4.4.4. (1S*,3R*,3aS*,6aR*)-Ethyl 1,5-dibenzyl-3-(2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-
1-carboxylate (8dd): Yellow solid, (240 mg, 96% yield). IR (neat)
1
ʋmax: 1199, 1400, 1674, 1703, 3031. H NMR (300 MHz, DMSO-d6)
δ: 1.24 (t, J = 7.1 Hz, 3H), 3.09 (d, J = 13.9 Hz, 1H), 3.24 (d, J =
14.0 Hz, 1H), 3.57-3.68 (m, 2H), 4.04-4.12 (m, 2H), 4.37 (d, J = 14.0
Hz, 1H), 4.47 (d, J = 14.0 Hz, 1H), 4.61 (d, J = 8.5 Hz, 1H), 7.16-
7.31 (m, 14H). 13C NMR (75 MHz, DMSO-d6) δ: 14.3, 42.1, 48.9,
55.6, 55.8, 61.2, 71.7, 127.1, 127.6, 127.7, 128.6, 128.8, 129.7,
130.5, 136.6, 136.2, 139.1, 151.5, 164.7, 170.8, 175.7, 176.1. LRMS
(EI): m/z = 502 (M+, <1%), 429 (9), 412 (23), 411 (100), 365 (9), 91
(63). Elemental Analysis required for C27H26N4O6: C 64.50, H 5.20,
N 11.15%; found C 64.65, H 5.10, N 11.50%.
8dc-8de: to a stirred solution of free amine ester (1 equiv was
previously isolated: 1 equiv of the corresponding hydrochloride with
1.3 equiv K2CO3, in a mixture of AcOEt/H2O during 1h. It was
washed with water and the organic fase evaporated), in toluene (2
mL) was added 5-formyluracile (1 equiv, 0.5 mmol). After that,
dipolarophile (1.0 equiv, 0.5 mmol) and AgOAc (5 mol%). The
solvent was removed under reduced pressure. The crude mixture was
filtrated through celite with warm EtOH to furnish the corresponding
product.
4.4.5. (2R*,4S*,5R*)- Ethyl 4-methyl 2-benzyl-5-(2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)pyrrolidine-2,4-dicarboxylate (8de): Pale
yellow solid, (180 mg, 90% yield). IR (neat) ʋmax: 1202, 1438, 1676,
1719, 2977, 3061. 1H NMR (300 MHz, DMSO-d6) δ: 1.18 (t, J = 7.1
Hz, 3H), 2.09 (dd, J = 13.9 Hz, 1H), 2.46 (dd, J = 14.0 Hz, 1H),
2.86-3.02 (m, 2H), 3.14-3.21 (m, 1H), 3.38 (s, 3H), 4.04-4.11 (m,
2H), 4.39 (d, J = 8.5 Hz, 1H), 7.20-7.28 (m, 8H), 7.39 (s, 1H). 13C
NMR (75 MHz, DMSO-d6) δ: 8.9, 14.5, 45.9, 47.3, 51.6, 56.8, 60.9,
69.1, 111.9, 127.0, 128.4, 130.3, 137.4, 138.2, 151.3, 164.1, 173.1,
174.7. LRMS (EI): m/z = 401 (M+, <1%), 328 (19), 311 (15), 310
(100), 232 (23), 211 (7), 204 (8), 91 (27). HRMS (EI): calcd. for
C20H23N3O6 [M - CO2CH3], 342.1460; found 342.1454.
4.4.1.
(1S*,3R*,3aS*,6aR*)-Methyl
3-(2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)-5-methyl-4,6-dioxooctahydropyrrolo[3,4-
c]pyrrole-1-carboxylate (8da): Pale yellow solid, (132 mg, 82%
1
yield). IR (neat) ʋmax: 1098, 1223, 1439, 1694, 1741, 2978. H NMR
(300 MHz, DMSO-d6) δ: 2.66 (s, 3H), 3.39-3.44 (m, 1H), 3.53-3.56
(m, 1H), 3.67 (s, 3H), 3.92 (d, J = 7.1 Hz, 1H), 4.32 (d, J = 8.7 Hz,
1H), 7.19-7.27 (m, 4H). 13C NMR (75 MHz, DMSO-d6) δ: 24.6,
48.0, 49.1, 51.7, 61.0, 63.0, 127.4, 127.5, 128.0, 138.7, 171.8, 175.5,
176.9. LRMS (EI): m/z = 322 (M+, >1%), 307 (30), 289 (46), 263
(69), 259 (17), 211 (93), 206 (51), 204 (41), 178 (24), 151 (93), 121
(46), 107 (28), 44 (100). LRMS (EI): calcd. for [C13H14N4O6]
322.0913; found 322.0924.
4.5. General procedure for the synthesis of product 14dc.
Finely powdered sodium borohydride (6 equiv, 1.3 mmol) was
suspended in THF (4 mL) in presence of the respective ester (100
mg, 0.2 mmol) during a period of 15 minutes under reflux (70 °C)

7
and stirring. Then methanol (0.45 mL) was added dropwise during a
(25). HRMS (EI): calcd. for C H N O [M – 2xCH O – H O]:
282.1249; found 282.1260.
ACCEPTED MANUSCRIPT
18 23 3 5 2 2
period of 5 minutes and effervescence was observed. Stirring and
reflux were maintained during a period of 10 h. After the end of the
reaction, the alcohol was cooled to room temperature and quenched
with a saturated solution of NH4Cl. For purification the organic layer
was separated and the aqueous phase extracted with DCM. The
organic phase was dried (MgSO4) and concentrated under low
pressure to give the corresponding triol 14dc.
Acknowledgements
We gratefully acknowledge financial support from the Spanish
Ministerio de Ciencia e Innovación (MICINN) (projects
CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-
00006), the Spanish Ministerio de Economía y Competitividad
(MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-
REDC), the Spanish Ministerio de Economía, Industria y
Competitividad, Agencia Estatal de Investigación (AEI) and
Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects
4.5.1.
5-[(2R*,3R*,4R*,5S*)-5-Benzyl-3,4,5-tris(hydroxymethyl)-
pyrrolidin-2-yl]pyrimidine-2,4(1H,3H)-dione (14dc): Pale yellow
solid, (65 mg, 80% yield). IR (neat) ʋmax: 702, 1098, 1454, 1698,
1
1775, 2926, 3390. H NMR (300 MHz, DMSO-d6) δ: 2.42 (dd, J =
CTQ2016-76782-P
Generalitat Valenciana
PROMETEOII/ 2014/017), the University of Alicante and
Medalchemy S. L. E. Selva thanks Univerisdad de Alicante and
Medalchemy S. L. for a predoctoral fellowship.
and
CTQ2016-81797-REDC),
(PROMETEO2009/039
the
and
13.2, 7.5 Hz, 1H), 2.55-2.59 (m, 1H), 2.64-2.67 (m, 3H), 2.81-2.84
(m, 1H), 3.03 (d, J = 10.5 Hz, 1H), 3.15-3.18 (m, 1H), 3.25 (td, J =
11.3, 10.5, 5.1 Hz, 4H), 3.45 (dd, J = 11.3, 3.3 Hz, 1H), 4.62 (d, J =
6.1 Hz, 1H), 4.88-5.07 (m, 3H), 7.20-7.32 (m, 8H). 13C NMR (75
MHz, DMSO-d6) δ: 34.8, 40.4, 54.6, 59.6, 60.5, 63.0, 66.0, 126.3,
126.7, 128.6, 128.9, 129.5, 129.6, 138.7, 140.1. LRMS (EI): m/z =
361 (M+, <1%), 164 (29), 120 (21), 117 (37), 105 (13), 91 (100), 70
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