A simple synthesis of polysubstituted pyrrolidines by an organocatalytic three-component approach featuring a one-pot condensation and [3+2]-cycloaddition reaction in aqueous medium

Article abstract of DOI:10.1055/s-0033-1338922

A simple one-pot procedure was developed for [3+2]-cycloaddition reactions of α,β-unsaturated aldehydes, diethyl aminomalonate, and aromatic aldehydes in the presence of diphenyl[(2S)-pyrrolidin-2-yl]methanol as catalyst. This reaction converts simple, co

Full text of DOI:10.1055/s-0033-1338922

SPECIAL TOPIC
▌2669
sApecSialitmopicple Synthesis of Polysubstituted Pyrrolidines by an Organocatalytic
Three-Component Approach Featuring a One-Pot Condensation and
[3+2]-Cycloaddition Reaction in Aqueous Medium
One-Pot Synthesis of Polysubstituted Pyrrolidines
Silvia Reboredo, Jose L. Vicario,* Luisa Carrillo, Efraím Reyes, Uxue Uria
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea
(UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain
Fax +34(94)6012748; E-mail: joseluis.vicario@ehu.es
Received: 14.02.2013; Accepted: 15.04.2013
provides a powerful method for the simple, rapid, and di-
Abstract: A simple one-pot procedure was developed for [3+2]-cy-
rect preparation of polysubstituted pyrrolidines.3 Scaf-
cloaddition reactions of α,β-unsaturated aldehydes, diethyl ami-
folds such as these are present in numerous natural
nomalonate, and aromatic aldehydes in the presence of
diphenyl[(2S)-pyrrolidin-2-yl]methanol as catalyst. This reaction
products, and they have a wide range of applications in the
converts simple, commercially available, starting materials into pharmaceutical industry.4 The first organocatalytic [3+2]
densely functionalized polysubstituted pyrrolidines under mild con-
ditions and in a fully stereoselective fashion. Moreover, the use of
cycloaddition reaction to use azomethine ylides as 1,3-di-
poles was developed by our group5 and is based on the im-
brine as the reaction medium has remarkable beneficial effects in
inium activation approach. Imines derived from diethyl
preventing the formation of self-condensation byproducts, cutting
aminomalonate were treated with α,β-unsaturated alde-
the reaction time, and reducing the production of wastes.
hydes in the presence of cheap and commercially avail-
Key words: asymmetric catalysis, asymmetric synthesis, organo-
catalysis, cycloadditions , multicomponent reactions, heterocycles
able
diphenyl[(2S)-pyrrolidin-2-yl]methanol
(α,α-
diphenylprolinol) as catalyst to give highly functionalized
polysubstituted pyrrolidines in good yields and as single
diastereoisomers of very high optical purity (Scheme 1).
The key to this reaction was the use of arylideneami-
nomalonates as sources of azomethine ylides. The aryli-
deneaminomalonates were prepared from commercially
available diethyl aminomalonate and aromatic aldehydes.
However, these imines had to be synthesized and purified
in advance, and they were found to be unstable and could
only be stored for a few days in a freezer.
During this century, enantioselective organocatalysis with
chiral secondary amine catalysts has seen rapid growth as
an environmentally benign and practical technique for
asymmetric synthesis, and as a result it has become the
subject of intensive research.1 In particular, organocata-
lytic 1,3-dipolar cycloaddition reactions constitute a high-
ly efficient approach to syntheses of many families of
five-membered heterocyclic structures from simple and
readily available starting materials.2 In particular, when
azomethine ylides are employed as 1,3-dipoles, an enantio-
selective organocatalytic version of this transformation
With these precedents in mind, and in connection with our
previous initial report, we decided to attempt the develop-
ment of a modified version of the transformation that
would allow us to prepare the same complex pyrrolidine
multistep cycloaddition: previous work
NH2
O
EtO2C
CO2Et
O
CO2Et
N CO2Et
R2
H
anhyd Na2SO4
CH2Cl2, r.t.
R1
H
R1
organocatalyst
OHC
R1
R2
CO2Et
CO2Et
N
multicomponent reaction: this work
NH2
CO2Et
H
O
O
organocatalyst
+
+
R1
H
R2
H
EtO2C
Scheme 1 Organocatalytic enantioselective synthesis of pyrrolidines through [3+2] cycloaddition: multistep and multicomponent versions of
the reaction
SYNTHESIS 2013, 45, 2669–2678
Advanced online publication: 11.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338922; Art ID: SS-2013-C0127-ST
© Georg Thieme Verlag Stuttgart · New York

2670
S. Reboredo et al.
SPECIAL TOPIC
adducts directly from commercially available reagents in ee. When we carried out the reaction in the absence of wa-
a single step by means of a multicomponent approach re- ter (entry 2), we obtained an even poorer yield of 4a to-
lying on a one-pot condensation/organocatalytic enantio- gether with larger quantities of the byproduct 5a. With
selective [3+2] process (Scheme 1).6 This proposed these results in mind, and taking into consideration that
alternative reaction design involved mixing an α,β-unsat- the presence of water appeared to assist the formation of
urated aldehyde, diethyl aminomalonate, and a second al- the desired cycloadduct 4a with respect to the undesired
dehyde in the presence of a chiral catalyst, in the hope that byproduct 5a,8 we decided to use a 1:1 mixture of tetrahy-
the iminium ion produced by activation of the enal with drofuran and water as the solvent (entry 3). As expected,
the catalyst would undergo [3+2] cycloaddition with the the formation of the 2-alkenyl-substituted pyrrolidine 5a
azomethine ylide generated in situ by condensation of the was completely inhibited, and adduct 4a was isolated in a
second aldehyde with the aminomalonate reagent.
higher, albeit still moderate, yield. We then examined the
effect of a Brønsted acid as an additive to assist the forma-
tion of the activated iminium intermediate under these
conditions (entry 4), but this resulted in a slight decrease
in the yield. Other aqueous solvents (entries 5 and 6) and
various protic solvents (entries 7–9) were also evaluated,
but in all cases the reaction gave lower yields of adduct
4a, although it should be stressed that the formation of by-
product 5a was not observed in any of these cases. We
then examined the effect of an increase in temperature,
and we found that the yield of 4a increased slightly at
room temperature (entry 10). We also found that 4a was
obtained in 50% yield when we used a 1:1 mixture of tet-
rahydrofuran and brine as the solvent (entry 11). The use
of the aqueous medium again resulted in complete inhibi-
tion of the side reaction that formed pyrrolidine 5a. Final-
ly, we were also able to reduce the amount of organic
cosolvent to a very interesting 1:19 ratio of tetrahydrofu-
ran to brine, and we obtained the required adduct 4a in
54% yield after only one day of reaction, while preserving
the excellent diastereo- and enantioselectivity (entry 12).
A reaction using brine as the sole reaction medium gave
4a in a slightly lower yield (entry 13). Several other con-
ditions or combinations of solvents were tested, but in all
cases these gave significantly lower yields than were ob-
tained under the conditions shown in entry 12.
Asymmetric multicomponent reactions are very powerful
tools for the construction of complex chiral molecular
scaffolds from readily available starting materials through
simple and efficient processes;7 moreover, such reactions
provide important benefits such as improved atom econo-
my, reduction of operating times, and minimization of
waste production. For these reasons, they are considered
to meet several of the requirements of green chemistry,
and can therefore help to solve several of the environmen-
tal problems that are emerging as important challenges for
process chemists.
Importantly, for the projected multicomponent process to
succeed, several issues relating to chemoselectivity have
to be controlled to give the target pyrrolidines stereoselec-
tively and in good yields. Because two aldehydes and two
amines are present in the reaction mixture, several dynam-
ic processes involving various combinations of these spe-
cies could take place simultaneously within the reaction
vessel. This implies that the role played by each reagent
has to be efficiently controlled, that the chiral secondary
amine catalyst must be involved exclusively in the activa-
tion of the α,β-unsaturated aldehyde through formation of
the iminium ion, and that the diethyl aminomalonate must
engage preferentially in a condensation reaction with the
other aldehyde. Other possible combinations would lead
to the formation of mixtures of products or to poor stereo-
control in the final pyrrolidine adducts.
Therefore, after screening the reaction conditions we con-
cluded that, despite not being able to improve on the mod-
erate overall yield, the procedure shown in entry 12 gave
the best results in preparing pyrrolidine 4a directly from
commercially available chemicals. Note that although this
protocol is not superior to the multistep approach that we
previously developed5a in terms of the overall yield, it is a
competitive methodology for enantioselective synthesis
of pyrrolidines because of its simplicity, lower reaction
time, and the absence of operations to purify intermedi-
ates. Moreover, it involves the use of a mainly aqueous
medium, requiring only small amounts of the organic co-
solvent.
We began by studying the reaction of commercially avail-
able diethyl aminomalonate (2), benzaldehyde (1a), and
crotonaldehyde (3a) as a model reaction (Table 1). We de-
cided to use diphenyl[(2S)-pyrrolidin-2-yl]methanol as
the chiral amine catalyst, as we had previously identified
this as this the most efficient promoter for a related [3+2]
cycloaddition process. However, when we applied our op-
timized reaction conditions (tetrahydrofuran as solvent at
4 °C with four equivalents of water as an additive), we iso-
lated pyrrolidine 4a in a very poor yield along with a com-
plex mixture of various byproducts, including pyrrolidine
5a, which was isolated in 15% yield (entry 1). However,
despite its low yield, cycloadduct 4a was isolated as a sin-
gle endo-diastereoisomer and in 98% ee. The formation of
5a is likely to have been the result of initial formation of
an azomethine ylide precursor through condensation of
enal 3a with diethyl aminomalonate, with subsequent cy-
cloaddition of a second molecule of 3a.5c The catalyst was
shown to participate in the process, because byproduct 5a
was isolated as a single diastereoisomer with a very high
Having identified the optimal conditions, we next exam-
ined the scope and limitations of the method with regard
to the use of aromatic aldehydes other than benzaldehyde,
together with other β-alkyl and β-aryl substituted α,β-un-
saturated aldehydes with various electronic properties
(Table 2). As can be seen from this table, the final cyclo-
adducts 4a–n were isolated in moderate yields in nearly
all the cases, but the overall processes occurred with very
high diastereoselectivities, giving the adducts in high de-
Synthesis 2013, 45, 2669–2678
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
One-Pot Synthesis of Polysubstituted Pyrrolidines
2671
grees of enantiomeric enrichment. With regard to the role selectivities. In a similar manner to that outlined above, no
played by the substitution pattern on aldehyde 1 (entries reaction took place when the solid enals 3e and 3f were
1–6), the yields and stereoselectivities did not appear to be used (entries 15 and 16).
directly related to the electronic nature of the β-substitu-
ent, and the yields obtained were similar to those achieved
in the model reaction with benzaldehyde (1a). The only
exception was that of 4-methoxybenzaldehyde (1c),
which gave the final cycloadduct 4c in yield that was
markedly lower than those of other members of this series.
In view of the performance of the reaction in an aqueous
medium, we also decided to examine the possibility of
carrying out the reaction with formaldehyde as the azo-
methine ylide precursor, which should have led to the for-
mation of 4-unsubstituted pyrrolidines after the [3+2]
cycloaddition, a substitution pattern that is not otherwise
It is significant that this aldehyde is a solid, whereas all the
easily accessible by this type of cycloaddition reaction.
others are liquids, and we therefore ascribed the lower
When we stirred a mixture of aminomalonate 2, crotonal-
dehyde, and aqueous formaldehyde under the optimized
reaction conditions, we did not detect the expected cyclo-
yield to the poorer miscibility/solubility of compound 1c
in the brine–tetrahydrofuran mixture; reagents that readily
formed emulsions in the reaction medium gave higher
addition product in the reaction mixture, but instead we
yields of the final cycloadducts.9 We also evaluated the ef-
obtained the bicyclic compound 7 (Scheme 2); this was
presumably formed by Michael reaction of diethyl ami-
fects on the overall process of β-substituents on the α,β-
unsaturated aldehyde 3 (entries 7–14). The reactions pro-
nomalonate (2) with crotonaldehyde (3a), followed by in-
ceeded in a similar manner to that observed with crotonal-
tramolecular formation of a hemiaminal that subsequently
dehyde, affording the target polysubstituted pyrrolidines
condensed with two equivalents of formaldehyde. The
in moderate yields but excellent diastereo- and enantio-
stable bicyclic compound 7 was isolated, fully character-
Table 1 Optimization of Experimental Conditions for the Multicomponent Reaction of Benzaldehyde (1a), Diethyl Aminomalonate (2), and
Crotonaldehyde (3a)
Ph
N
Ph
OH
(20 mol%)
OHC
OHC
Ph
H
O
NH2
EtO2C CO2Et
O
CO2Et
CO2Et
CO2Et
CO2Et
+
+
+
Ph
H
H
N
H
N
H
1a
2
3a
4a
5a
Entrya
Solvent
Additive (equiv)
Temp (°C)
Yieldb (%) of 4a eec (%)
Yieldb (%) of 5a
1
2
THF
THF
H2O (4)
4
11
21
31
29
24
10
20
27
36
47
50
54
45
98
15
25
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
–
4
n.d.d
98
3
THF–H2O (1:1)
THF–H2O (1:1)
CH2Cl2–H2O (1:1)
Et2O–H2O (1:1)
F3CCH2OH
–
4
4
BzOH (0.2)
4
n.d.
n.d.
n.d.
n.d.
97
5
–
–
–
–
–
–
–
–
–
4
6
4
7
4
8
EtOH
4
9
i-PrOH
4
97
10
11
12e
13e
THF–H2O (1:1)
THF–brine (1:1)
THF–brine (19:1)
brine
r.t.
r.t.
r.t.
r.t.
98
97
98
98
a All reactions were performed on a 0.57 mmol scale for 72 h, except where indicated otherwise. In all the conditions tested, the endo/exo ratio
for product 4a was >95:5, as measured by 1H NMR spectroscopy on the crude reaction mixture.
b Yield of pure product after flash column chromatography.
c Determined by chiral HPLC after reduction to the corresponding alcohol 6a (see experimental section).
d n.d. = not determined.
e Reaction time 24 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2669–2678

2672
S. Reboredo et al.
SPECIAL TOPIC
Table 2 Reaction Scope
Ph
Ph
OH
N
H
OHC
R1
R2
CO2Et
NH2
CO2Et
O
O
(20 mol%)
+
+
R2
H
R1
H
EtO2C
brine–THF (19:1)
r.t., 24 h
N
H
CO2Et
1a–f
2
3a–f
4a–n
Entrya
1
R1
Ph
3
R2
Product
Yieldb (%) endo/exoc
eed (%)
1
2
1a
1b
1c
1d
1e
1f
3a
3a
3a
3a
3a
3a
3b
3c
3d
3b
3c
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Bu
4a
4b
4c
4d
4e
4f
54
40
15
41
58
41
36
48
26
43
50
42
54
46
<5
<5
>95:5
>95:5
n.d.e
99
99
n.d.
>99
99
98
97
97
99
96
99
97
99
97
–
4-FC6H4
3
4-MeOC6H4
2-MeOC6H4
2-MeC6H4
2-furyl
4
84:16
>95:5
>95:5
>95:5
>95:5
>95:5
92:8
5
6
7
1e
1e
1e
1b
1b
1f
2-MeC6H4
2-MeC6H4
2-MeC6H4
4-FC6H4
4-FC6H4
2-furyl
4g
4h
4i
8
i-Pr
Ph
9
10
11
12
13
14
15
16
Bu
4j
i-Pr
Bu
4k
4l
>95:5
85:15
>95:5
92:8
1f
2-furyl
i-Pr
Ph
4m
4n
1f
2-furyl
1a
1a
Ph
4-MeOC6H4
4-O2NC6H4
–
–
–
Ph
–
–
a All the reactions were performed on a 0.57 mmol scale.
b Yield of pure product after flash column chromatography.
c Determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
d Determined by chiral HPLC after reduction to the corresponding alcohol 6 (see experimental part).
e n.d. = not determined.
ized, and shown to be a single diastereoisomer, although, results could then be extrapolated to all the new adducts
disappointingly, HPLC analysis on a chiral stationary that we prepared. Comparisons of data showed that ad-
phase under conditions previously optimized for the sep- ducts 4 were identical to those obtained in the multistep
aration of the corresponding racemic standard indicated version of this reaction that we previously reported.5a
that 7 was present in a racemic form. This suggests that
the amine catalyst may not have been involved in the for-
O
mation of this product. The use of other conditions and/or
catalysts always led to formation of 7 with no enantiocon-
trol.
Ph
H
H
N
Ph
OH
(20 mol%)
+
H
CO2Et
CO2Et
NH2
Because the formylpyrrolidines 4a–n were somewhat un-
stable compounds, to simplify their characterization we
reduced the products after they had been isolated (Scheme
3). The resulting alcohols 6a–n were stable and could be
stored without decomposition for several weeks. These
compounds could then be characterized and, in those cas-
es where we could compare their spectral properties with
those of previously prepared samples, we were able to
confirm their absolute and relative configurations. These
O
N
EtO2C
CO2Et
brine–THF (19:1)
r.t.
2
O
16%
+
7
O
H
3a
Scheme 2 Attempted condensation/cycloaddition sequence by using
formaldehyde to form the azomethine ylide precursor
Synthesis 2013, 45, 2669–2678
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
One-Pot Synthesis of Polysubstituted Pyrrolidines
2673
was stirred at r.t. for the appropriate time and then CH2Cl2 (10 mL)
was added. The phases were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The organic fractions were col-
lected, combined, dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography [silica gel, hexanes–EtOAc (19:1)] to give the cor-
responding cycloaddition product 4.
OHC
R1
R2
CO2Et
R2
CO2Et
HO
R1
NaBH4
N
H
N
H
6a–n
MeOH, 0 °C
CO2Et
CO2Et
4a–n
Scheme 3 Reduction of pyrrolidine adducts 4a–n
Diethyl 4-(Hydroxymethyl)pyrrolidine-2,2-dicarboxylates 6;
General Procedure
In conclusion, we have developed a simple and efficient
organocatalytic procedure for the preparation of highly
substituted pyrrolidines from commercially available aro-
matic aldehydes, diethyl malonate, and α,β-unsaturated
aldehydes as starting materials. The process involves the
condensation of the aromatic aldehyde with diethyl ami-
nomalonate in situ in the presence of an iminium catalyst.
This multicomponent transformation gives densely func-
tionalized pyrrolidines in moderate yields and excellent
diastereo- and enantioselectivities when the reaction is
carried out in a mainly aqueous medium. The use of the
aqueous environment was crucial for the reaction to pro-
ceed with high chemoselectivity without formation of un-
desirable cycloadducts through self-condensation side
reactions. Although our protocol gives the final cycload-
ducts 4 in lower yields than those obtained in our previous
multistep version of the reaction, the method has several
benefits from the practical point of view, especially in
terms of a lower reaction time, greater operational sim-
plicity, and reduced production of waste, because there is
no need to isolate and purify any synthetic intermediates.
Because products 4 were somewhat unstable and to permit better
characterization, they were reduced to the corresponding primary
alcohols 6. NaBH4 (0.68 mmol) was added to a cooled (0 °C) soln
of pyrrolidine 4 in MeOH (2.00 mL), and the mixture was stirring
for 30 min at 0 °C. Sat. aq NH4Cl (3.00 mL) and CH2Cl2 (5.00 mL)
were added and the mixture was stirred for a further 30 min at r.t.
The mixture was then extracted with CH2Cl2 (3 × 10 mL) and the
organic fractions were combined, collected, dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography [silica gel, hexanes–
EtOAc (1:1)].
Diethyl (3R,4R,5S)-4-Formyl-3-methyl-5-phenylpyrrolidine-
2,2-dicarboxylate (4a)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-crotonaldehyde (48 μL, 0.57 mmol),
PhCHO (0.12 mL, 1.14 mmol), and diethyl aminomalonate (100
mg, 0.57 mmol) with reaction for 1 d gave a colorless oil; yield: 103
mg (0.31 mmol, 54%); exo/endo (1H NMR): >95:5.
Diethyl (3R,4R,5S)-4-(Hydroxymethyl)-3-methyl-5-phenylpyr-
rolidine-2,2-dicarboxylate (6a)
Reduction of 4a (103 mg, 0.31 mmol) by the general procedure us-
ing NaBH4 (14 mg, 0.37 mmol) gave a colorless oil; yield: 97 mg
(0.29 mmol, 94%); 99% ee.
HPLC: Chiralcel OD, hexane–i-PrOH (95:05), flow rate: 1.00
mL/min; tR = 12.97 min (major, 3R,4R,5S-isomer), 15.17 min (mi-
nor, 3S,4S,5R-isomer).
NMR spectra were recorded in CDCl3 at 20 °C on a Bruker AC-300
or Bruker AC-500 spectrometer operated at 300 or 500 MHz for 1H
and 75 MHz or 125.7 MHz for 13C. TMS was used as an internal
standard unless otherwise stated. IR spectra were recorded for
CHCl3 solns on a PerkinElmer FT-IR 600 spectrophotometer; only
the characteristic signals are reported. Mass spectra were recorded
by EI (70 eV) or CI on a Waters Micromass GCT or Hewlett-
Packard 5989B mass spectrometer. Optical rotations were deter-
mined on a PerkinElmer 241 polarimeter (λ = 589 nm, 1 dm cell).
TLC was carried out on 0.2 mm thick plates of silica gel (Merck
Kieselgel GF254), and visualization was performed by UV irradia-
tion or by spraying with phosphomolybdic acid or 4-anisaldehyde
soln. Flash column chromatography was performed on silica gel
(Merck Kiesegel 60, 230–400 mesh). Enantiomeric excesses were
determined by HPLC in a Waters 2695 chromatograph equipped
with a Waters 2998 photodiode array UV detector and a Chiracel
OJ, Chiralcel OD, or Chiralpak IA column. Chemicals were ob-
tained from Acros, Sigma-Aldrich, or Alfa-Aesar. Solvents were
purchased from Carlo-Erba SDS and used directly without further
purification. Diphenyl[(2S)-pyrrolidin-2-yl]methanol, diethyl ami-
nomalonate (2), aromatic aldehydes 1a–f, and α,β-unsaturated alde-
hydes 3a–f, employed as starting materials, were used as purchased.
The racemic standards needed for optimization of the conditions for
the separation of enantiomers were prepared by using DL-proline as
a catalyst in each case.
All physical and spectroscopic data for compounds 4a and 6a
agreed with the values reported in the literature.5a
Diethyl (3R,4R,5S)-5-(4-Fluorophenyl)-4-formyl-3-methylpyr-
rolidine-2,2-dicarboxylate (4b)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-crotonaldehyde (48 μL, 0.57 mmol),
4-fluorobenzaldehyde (0.12 mL, 1.14 mmol), and diethyl ami-
nomalonate (100 mg, 0.57 mmol) with reaction for 1 d gave a col-
orless oil; yield: 80 mg (0.23 mmol, 40%); exo/endo (1H NMR):
>95:5.
Diethyl (3R,4R,5S)-5-(4-Fluorophenyl)-4-(hydroxymethyl)-3-
methylpyrrolidine-2,2-dicarboxylate (6b)
Reduction of 4b (80 mg, 0.23 mmol) by the general procedure using
NaBH4 (11 mg, 0.27 mmol) gave a colorless oil; yield: 72 mg (0.20
mmol, 87%).
HPLC: Chiralcel OJ, hexane–i-PrOH (98:02), flow rate: 1.00
mL/min; tR = 17.53 min (major, 3R,4R,5S-isomer), 22.95 min (mi-
nor, 3S,4S,5R-isomer); 99% ee.
All physical and spectroscopic data for compounds 4b and 6b
agreed with the values reported in the literature.5a
Diethyl (3R,4R,5S)-4-Formyl-5-(4-methoxyphenyl)-3-methyl-
pyrrolidine-2,2-dicarboxylate (4c)
Diethyl 4-Formylpyrrolidine-2,2-dicarboxylates 4; General
Procedure
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-crotonaldehyde (48 μL, 0.57 mmol),
4-methoxybenzaldehyde (0.12 mL, 1.14 mmol), and diethyl ami-
nomalonate (100 mg, 0.57 mmol) with reaction for 3 d gave 4c (27
mg, 0.08 mmol, 15%) as a colorless oil; exo/endo (1H NMR): 86:14.
Aldehyde 1 (1.14 mmol) was added to a suspension of diethyl ami-
nomalonate (2; 0.57 mmol) in a mixture of sat. brine (3.80 mL) and
THF (0.20 mL) at r.t. The mixture was stirred for 30 min and then
α,β-unsaturated aldehyde 3 (0.57 mmol) and diphenyl[(2S)-pyrro-
lidin-2-yl]methanol (0.11 mmol) were added at once. The mixture
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2669–2678

2674
S. Reboredo et al.
SPECIAL TOPIC
Diethyl (3R,4R,5S)-4-(Hydroxymethyl)-5-(4-methoxyphenyl)-3-
methylpyrrolidine-2,2-dicarboxylate (6c)
Reduction of 4c (27 mg, 0.08 mmol) by the general procedure using
NaBH4 (4 mg, 0.10 mmol) gave a colorless oil; yield: 22 mg (0.06
mmol, 75%).
Diethyl (3R,4R,5S)-3-Butyl-4-formyl-5-(2-tolyl)pyrrolidine-2,2-
dicarboxylate (4g)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), (2E)-hept-2-enal (78 μL, 0.57 mmol), 2-
methylbenzaldehyde (0.14 mL, 1.14 mmol), and diethyl aminomal-
onate (100 mg, 0.57 mmol) with reaction for 3 d gave a colorless oil;
yield: 58 mg (0.15 mmol, 36%); exo/endo (1H NMR): >95:5.
All physical and spectroscopic data for compounds 4c and 6c
agreed with the values reported in the literature.5a
IR (CHCl3): 3375 (NH), 1734 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.86 [t, J = 6.7 Hz, 3 H,
Diethyl (3R,4R,5S)-4-Formyl-5-(2-methoxyphenyl)-3-methyl-
pyrrolidine-2,2-dicarboxylate (4d)
(CH2)3CH3], 1.23–1.40 [m, 11 H,
2 × CO2CH2CH3 +
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-crotonaldehyde (48 μL, 0.57 mmol),
2-methoxybenzaldehyde (0.12 mL, 1.14 mmol), and diethyl ami-
nomalonate (100 mg, 0.57 mmol) with reaction for 3 d gave a col-
orless oil; yield: 76 mg (0.23 mmol, 41%); exo/endo (1H NMR):
84:16.
(CH2)2CHaHbCH3], 1.71–1.82 [m, 1 H, (CH2)2CHaHbCH3], 2.26 (s,
3 H, ArCH3), 2.81 (d, J = 3.9 Hz, 1 H, NH), 2.89–3.00 (m, 1 H,
CHCHO), 3.20–3.26 [m, 1 H, CH(CH2)3CH3], 4.19–4.41 (m, 4 H, 2
× CO2CH2CH3), 5.32 (d, J = 3.9 Hz, 1 H, CHAr), 7.06–7.22 (m, 3
H, C{Ar}H), 7.70 (d, J = 6.8 Hz, 1 H, C{Ar}H), 8.95 (d, J = 4.9
Hz, 1 H, CHO).
Diethyl (3R,4R,5S)-4-(Hydroxymethyl)-5-(2-methoxyphenyl)-3-
methylpyrrolidine-2,2-dicarboxylate (6d)
Reduction of 4d (76 mg, 0.23 mmol) by the general procedure using
NaBH4 (11 mg, 0.28 mmol) gave a colorless oil; yield: 76 mg (0.21
mmol, 91%).
13C NMR (75.4 MHz, CDCl3): δ = 13.8 (CO2CH2CH3), 14.0
(CO2CH2CH3), 14.2 [CH(CH2)3CH3], 19.4 (ArCH3), 22.7
[CH(CH2)3CH3], 30.1 [CH(CH2)3CH3], 30.7 [CH(CH2)3CH3], 44.3
[CH(CH2)3CH3], 57.8 (CHCHO), 58.4 (CHAr), 61.7
(CO2CH2CH3), 61.7 (CO2CH2CH3), 75.0 [C(CO2Et)2], 126.0
(C{Ar}H), 126.3 (C{Ar}H), 127.4 (C{Ar}H), 130.5 (C{Ar}H),
134.9 (C{Ar}C), 136.7 (C{Ar}C), 169.6 (CO2Et), 171.9 (CO2Et),
201.6 (CHO).
HPLC: Chiralcel OJ, hexane–i-PrOH (95:05), flow rate: 1.00
mL/min; tR = 15.91 min (major, 3R,4R,5S-isomer), 19.34 min (mi-
nor, 3S,4S,5R-isomer); >99% ee.
MS (EI): m/z (%) = 389 (4) [M+], 360 (2), 316 (100), 298 (4), 277
(8), 242 (8), 203 (15), 131 (19).
All physical and spectroscopic data for compounds 4d and 6d
agreed with the values reported in the literature.5a
Diethyl (3R,4R,5S)-4-Formyl-3-methyl-5-(2-tolyl)pyrrolidine-
2,2-dicarboxylate (4e)
Diethyl (3R,4R,5S)-3-Butyl-4-(hydroxymethyl)-5-(2-tolyl)pyr-
rolidine-2,2-dicarboxylate (6g)
Reduction of 4g (58 mg, 0.15 mmol) by the general procedure using
NaBH4 (10 mg, 0.25 mmol) gave alcohol 6g as a colorless oil; yield:
52 mg (0.13 mmol, 87%); [α]D20 –98.9 (c 1.0, CH2Cl2).
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-crotonaldehyde (48 μL, 0.57 mmol),
2-methylbenzaldehyde (0.14 mL, 1.14 mmol), and diethyl ami-
nomalonate (100 mg, 0.57 mmol) with reaction for 3 d gave a col-
orless oil: yield: 115 mg (0.33 mmol, 58%); exo/endo (1H NMR):
>95:5.
HPLC: Chiralpak IA, hexane–i-PrOH (98:02), flow rate: 1.00
mL/min; tR = 18.55 min (minor, 3S,4S,5R-isomer), 21.22 min (ma-
jor, 3R,4R,5S-isomer); 97% ee.
IR (CHCl3): 3352 (NH + OH), 1730 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.91 [t, J = 6.9 Hz, 3 H,
(CH2)3CH3], 1.30 (t, J = 7.1, 1.0 Hz, 3 H, CO2CH2CH3), 1.31 (t, J =
Diethyl (3R,4R,5S)-4-(Hydroxymethyl)-3-methyl-5-(2-tol-
yl)pyrrolidine-2,2-dicarboxylate (6e)
Reduction of 4e (115 mg, 0.33 mmol) by the general procedure us-
ing NaBH4 (15 mg, 0.40 mmol) gave a colorless oil; yield: 105 mg
(0.30 mmol, 91%).
7.1, 1.0 Hz,
3 H, CO2CH2CH3), 1.35–1.52 [m, 5 H,
CH(CH2)2CHaHbCH3], 1.62 [m, 1 H, (CH2)2CHaHbCH3], 2.32 [s, 3
H, ArCH3), 2.37 (m, 1 H, CH(CH2)3CH3], 2.80 (br s, 1 H, OH or
NH), 2.93 (m, 1 H, CHCH2OH), 3.15–3.31 (m, 2 H, CH2OH), 4.16–
4.36 (m, 4 H, 2 × CO2CH2CH3), 5.02 (d, J = 5.6 Hz, 1 H, CHAr),
7.09–7.24 (m, 3 H, C{Ar}H), 7.71 (d, J = 8.4 Hz, 1 H, C{Ar}H).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 [CH(CH2)3CH3], 14.0
(CO2CH2CH3), 14.2 (CO2CH2CH3), 19.3 (ArCH3), 22.8
[CH(CH2)3CH3], 30.6 [CH(CH2)3CH3], 30.8 [CH(CH2)3CH3], 45.4
[CH(CH2)3CH3], 47.1 (CHCH2OH), 58.9 (CHAr), 61.6
(CHCH2OH), 62.9 (CO2CH2CH3), 62.9 (CO2CH2CH3), 74.2
[C(CO2Et)2], 126.0 (C{Ar}H), 126.1 (C{Ar}H), 127.0 (C{Ar}H),
130.3 (C{Ar}H), 135.3 (C{Ar}C), 138.1 (C{Ar}C), 170.9 (CO2Et),
172.2 (CO2Et).
HPLC: Chiralcel OD, hexane–i-PrOH (98:02), flow rate: 1.00
mL/min; tR = 16.64 min (major, 3R,4R,5S-isomer), 19.14 min (mi-
nor, 3S,4S,5R-isomer); 99% ee.
All physical and spectroscopic data for compounds 4e and 6e
agreed with the values reported in the literature.5a
Diethyl (3R,4R,5S)-4-Formyl-5-(2-furyl)-3-methylpyrrolidine-
2,2-dicarboxylate (4f)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-crotonaldehyde (48 μL, 0.57 mmol),
2-furaldehyde (96 μL, 1.14 mmol), and diethyl aminomalonate (100
mg, 0.57 mmol) with reaction for 1 d gave a colorless oil; yield: 76
mg (0.23 mmol, 41%); exo/endo (1H NMR): >95:5.
MS (EI): m/z (%) = 345 (4) [M – EtOH]+, 318 (100), 300 (8), 286
(9), 272 (19), 244 (55), 228 (56), 203 (29), 170 (36).
Diethyl (3R,4R,5S)-5-(2-Furyl)-4-(hydroxymethyl)-3-methyl-
pyrrolidine-2,2-dicarboxylate (6f)
Reduction of 4f (76 mg, 0.23 mmol) by the general procedure using
NaBH4 (11 mg, 0.27 mmol) gave a colorless oil; yield: 69 mg (0.21
mmol, 91%).
Anal. Calcd for C22H33NO5: C, 67.49; H, 8.50; N, 3.58. Found: C,
67.73; H, 8.21; N, 3.54.
Diethyl (3R,4R,5S)-4-Formyl-3-isopropyl-5-(2-tolyl)pyrro-
lidine-2,2-dicarboxylate (4h)
HPLC: Chiralcel OD, hexane–i-PrOH (85:15), flow rate: 1.00
mL/min; tR = 7.50 min (major, 3R,4R,5S-isomer), 11.93 min (minor,
3S,4S,5R-isomer); 98% ee.
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), (2E)-4-methylpent-2-enal (70 μL, 0.57
mmol), 2-methylbenzaldehyde (0.14 mL, 1.14 mmol), and diethyl
aminomalonate (100 mg, 0.57 mmol) with reaction for 3 d gave a
colorless oil; yield: 103 mg (0.27 mmol, 48%); exo/endo (1H
NMR): >95:5.
All physical and spectroscopic data for compounds 4f and 6f agreed
with the values reported in the literature.5a
IR (CHCl3): 3344 (NH), 1731 (CO) cm–1.
Synthesis 2013, 45, 2669–2678
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
One-Pot Synthesis of Polysubstituted Pyrrolidines
2675
1H NMR (300 MHz, CDCl3): δ = 0.82 [d, J = 6.7 Hz, 3 H,
CH(CH3)2], 1.00 [d, J = 6.7 Hz, 3 H, CH(CH3)2], 1.20–1.40 (m, 6
H, 2 × COCH2CH3), 2.05–2.17 [m, 1 H, CH(CH3)2], 2.27 (s, 3 H,
ArCH3), 2.85 (d, J = 3.3 Hz, 1 H, NH), 3.03 (ddd, J = 8.8, 7.5, 5.0
Hz, 1 H, CHCHO), 3.31 [dd, J = 7.5, 5.0 Hz, 1 H, CHCH(CH3)2],
4.16–4.42 (m, 4 H, 2 × CO2CH2CH3), 5.19 (dd, J = 8.8, 3.3 Hz, 1
H, ArCH), 7.08–7.21 (m, 3 H, C{Ar}H), 7.60–7.73 (m, 1 H,
C{Ar}H), 8.99 (d, 1 H, J = 5.0 Hz, CHO).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 (CO2CH2CH3), 14.0
(CO2CH2CH3), 19.3 (CH(CH3)2), 19.4 (CH(CH3)2), 23.4 (ArCH3),
27.8 [CH(CH3)2], 50.3 [CHCH(CH3)2], 53.8 (CHCHO), 59.2
(CHAr), 61.8 (CO2CH2CH3), 61.9 (CO2CH2CH3), 74.5
[C(CO2Et)2], 126.0 (C{Ar}H), 126.2 (C{Ar}H), 127.4 (C{Ar}H),
130.5 (C{Ar}H), 135.0 (C{Ar}C), 136.6 (C{Ar}C), 170.0 (CO2Et),
172.2 (CO2Et), 202.0 (CHO).
126.3 (C{Ar}H), 126.3 (C{Ar}H), 127.6 (C{Ar}H), 128.4
(C{Ar}H), 128.9 (C{Ar}H), 130.6 (C{Ar}H), 130.6 (C{Ar}H),
134.9 (C{Ar}C), 136.7 (C{Ar}C), 137.8 (C{Ar}C), 169.4 (CO2Et),
171.6 (CO2Et), 200.4 (CHO).
MS (EI): m/z (%) = 409 (1) [M+], 336 (100), 318 (9), 272 (8), 234
(10), 203 (12), 131 (35), 77 (10).
Diethyl (3R,4R,5S)-4-(Hydroxymethyl)-3-phenyl-5-(2-tol-
yl)pyrrolidine-2,2-dicarboxylate (6i)
Reduction of 4i (61 mg, 0.15 mmol) by the general procedure using
NaBH4 (7 mg, 0.18 mmol) gave a colorless oil; yield: 45 mg (0.11
mmol, 73%); [α]D20 –3.4 (c 0.5, CH2Cl2).
HPLC: Chiralcel OD, hexane–i-PrOH (98:02), flow rate: 1.00
mL/min; tR = 15.91 min (major, 3R,4R,5S-isomer), 19.34 min (mi-
nor, 3S,4S,5R-isomer); 99% ee.
MS (EI): m/z (%) = 375 (1) [M+], 346 (1), 302 (100), 277 (8), 256
IR (CHCl3): 3395 (NH + OH), 1730 (CO) cm–1.
(5), 228 (7), 203 (11), 131 (16).
1H NMR (300 MHz, CDCl3): δ = 0.75 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.25–1.32 (m, 4 H, CO2CH2CH3 + OH), 2.40 (s, 3 H,
ArCH3), 2.80–2.99 (m, 1 H, CHCH2OH), 3.03 (d, J = 4.2 Hz, 1 H,
Diethyl (3R,4R,5S)-4-(Hydroxymethyl)-3-isopropyl-5-(2-tol-
yl)pyrrolidine-2,2-dicarboxylate (6h)
Reduction of 4h (103 mg, 0.27 mmol) by the general procedure us-
ing NaBH4 (13 mg, 0.33 mmol) gave a colorless oil; yield: 96 mg
(0.26 mmol, 96%); [α]D20 –93.8 (c 1.0, CH2Cl2).
NH), 3.26–3.37 (m,
2 H, CH2OH), 3.30–3.49 (m, 1 H,
CO2CHaHbCH3), 3.71–3.87 (m, 1 H, CO2CHaHbCH3), 4.18–4.40
(m, 3 H, COCH2CH3 + CHPh), 5.42 (dd, J = 7.2, 4.2 Hz, 1 H,
CHN), 7.14–7.38 (m, 6 H, C{Ar}H), 7.38 (d, J = 7.2 Hz, 2 H,
C{Ar}H), 7.74 (d, J = 7.2 Hz, 1 H, C{Ar}H).
13C NMR (75.4 MHz, CDCl3): δ =13.3 (CO2CH2CH3), 14.0
(CO2CH2CH3), 19.5 (ArCH3), 49.5 (PhCH), 51.7 (CHCH2OH),
60.3 (NCH), 61.4 (CO2CH2CH3), 61.7 (CO2CH2CH3), 63.0
(CH2OH), 76.2 [C(CO2Et)2], 126.0 (C{Ar}H), 126.2 (C{Ar}H),
127.1 (C{Ar}H), 127.2 (C{Ar}H), 128.4 (C{Ar}H), 128.8
(C{Ar}H), 130.4 (C{Ar}H), 135.3 (C{Ar}C), 138.3 (C{Ar}C),
140.5 (C{Ar}C), 170.0 (CO2Et), 171.9 (CO2Et).
HPLC: Chiralpak IA, hexane–i-PrOH (98:02), flow rate: 1.00
mL/min; tR = 19.69 min (minor, 3S,4S,5R-isomer), 21.98 min (ma-
jor, 3R,4R,5S-isomer); 97% ee.
IR (CHCl3): 3570 (NH + OH), 1731 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.92 [d, J = 6.7 Hz, 3 H,
CH(CH3)2], 1.06 [d, J = 6.7 Hz, 3 H, CH(CH3)2], 1.22–1.37 (m, 6
H, CO2CH2CH3), 2.19–2.37 [m, 4 H, ArCH3 + CH(CH3)2], 2.46 (m,
1 H, CHCH2OH), 2.86 (br s, 1 H, OH or NH), 3.00 [m, 1 H,
CHCH(CH3)2], 3.14–3.42 (m, 2 H, CH2OH), 4.15–4.37 (m, 4 H, 2
× CO2CH2CH3), 4.85 (d, J = 6.5 Hz, 1 H, ArCH), 7.09–7.25 (m, 3
H, C{Ar}H), 7.71 (d, J = 7.8 Hz, 1 H, C{Ar}H).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 (CO2CH2CH3), 14.0
(CO2CH2CH3), 17.7 [CHCH(CH3)2], 19.4 [CHCH(CH3)2], 23.6
(ArCH3), 27.4 [CHCH(CH3)2], 42.4 [CHCH(CH3)2], 51.2
(CHCH2OH), 60.4 (ArCH), 61.7 (CO2CH2CH3), 61.9
(CO2CH2CH3), 63.9 (CH2OH), 73.5 [C(CO2Et)2], 125.6 (C{Ar}H),
126.1 (C{Ar}H), 127.1 (C{Ar}H), 130.3 (C{Ar}H), 135.3
(C{Ar}C), 138.1 (C{Ar}C), 170.6 (CO2Et); 172.5 (CO2Et).
MS (EI): m/z (%) = 365 (7) [M – EtOH]+, 338 (60), 292 (14), 277
(10), 248 (25), 232 (56), 191 (60), 131 (100).
Anal. Calcd for C24H29NO5: C, 70.05; H, 7.10; N, 3.40. Found: C,
70.38; H, 7.37; N, 3.20.
Diethyl (3R,4R,5S)-3-Butyl-4-formyl-5-(4-fluorophenyl)pyrro-
lidine-2,2-dicarboxylate (4j)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), (2E)-hept-2-enal (78 μL, 0.57 mmol), 4-
fluorobenzaldehyde (0.12 mL, 1.14 mmol), and diethyl aminomal-
onate (100 mg, 0.57 mmol) with reaction for 1 d gave a colorless oil;
yield: 97 mg (0.25 mmol, 43%); exo/endo (1H NMR): 92:8.
MS (EI): m/z (%) = 331 (1) [M – EtOH]+, 304 (100), 272 (7), 244
(45), 203 (15), 170 (23), 131 (24), 105 (14).
IR (CHCl3): 3352 (NH), 1731 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.86 [t, J = 6.8 Hz, 3 H,
Anal. Calcd for C21H31NO5: C, 66.82; H, 8.28; N, 3.71. Found: C,
66.42; H, 8.40; N, 3.39.
CH(CH2)3CH3], 1.18–1.38 [m, 11 H, 2 × CO2CH2CH3
+
Diethyl (3R,4R,5S)-4-Formyl-3-phenyl-5-(2-tolyl)pyrrolidine-
2,2-dicarboxylate (4i)
CH(CH2)2CHaHbCH3], 1.70–1.78 [m, 1 H, CH(CH2)2CHaHbCH3],
2.77–2.82 (m, 1 H, CHCHO), 2.98 (d, J = 4.5 Hz, 1 H, NH), 3.20–
3.30 [m, 1 H, CH(CH2)3CH3], 4.17–4.41 (m, 4 H, 2 × COCH2CH3),
5.13 (dd, J = 8.7, 4.5 Hz, 1 H, ArCH), 6.93–7.05 (m, 2 H, C{Ar}H),
7.27–7.37 (m, 2 H, C{Ar}H), 9.04 (d, J = 4.3 Hz, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): δ = 13.8 (CO2CH2CH3), 14.0
(CO2CH2CH3), 14.2 [CH(CH2)3CH3], 22.7 [CH(CH2)3CH3], 30.2
[CH(CH2)3CH3], 30.4 [CH(CH2)3CH3], 43.9 [CH(CH2)3CH3], 59.5
(CHCHO), 61.3 (ArCH), 61.8 (CO2CH2CH3), 61.8 (CO2CH2CH3),
75.1 [C(CO2Et)2], 115.5 (d, JC–F = 21.4 Hz, C{Ar}H), 128.7 (d,
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-cinnamaldehyde (73 μL, 0.57
mmol), 2-methylbenzaldehyde (0.14 mL, 1.14 mmol), and diethyl
aminomalonate (100 mg, 0.57 mmol) with reaction for 3 d gave a
colorless oil; yield: 61 mg (0.15 mmol, 26%); exo/endo (1H NMR):
>95:5.
IR (CHCl3): 3374 (NH), 1729 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.78 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.29 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 2.39 (s, 3 H,
ArCH3), 3.09 (d, J = 4.8 Hz, 1 H, NH), 3.42–3.58 (m, 2 H,
CO2CHaHbCH3 + CHCHO), 3.80–3.94 (m, 1 H, CO2CHaHbCH3),
4.20–4.43 (m, 2 H, COCH2CH3), 4.82 (d, J = 6.7 Hz, 1 H, CHPh),
5.59 (dd, J = 8.4, 4.8 Hz, 1 H, CHN), 7.09–7.40 (m, 8 H, C{Ar}H),
7.70 (d, J = 7.1 Hz, 1 H, C{Ar}H), 9.04 (d, J = 3.6 Hz, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): δ = 13.3 (CO2CH2CH3), 14.0
(CO2CH2CH3), 19.5 (ArCH3), 48.6 (PhCH), 58.3 (CHCHO), 59.8
(CHN), 61.6 (CO2CH2CH3), 61.9 (CO2CH2CH3), 76.7 [C(CO2Et)2],
J
C–F = 8.0 Hz, C{Ar}H), 134.7 (C{Ar}C), 162.0 (d, JC–F = 190.5
Hz, C{Ar}F), 170.0 (CO2Et), 171.8 (CO2Et), 202.0 (CHO).
MS (EI): m/z (%) = 393 (4) [M+], 364 (4), 320 (100), 302 (6), 274
(12), 246 (13), 207 (12), 135 (16).
Diethyl (3R,4R,5S)-3-Butyl-5-(4-fluorophenyl)-4-(hydroxy-
methyl)pyrrolidine-2,2-dicarboxylate (6j)
Reduction of 4j (97 mg, 0.25 mmol) by the general procedure using
NaBH4 (11 mg, 0.29 mmol) gave a colorless oil; yield: 52 mg (0.13
mmol, 52%); [α]D20 –81.2 (c 1.0, CH2Cl2).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2669–2678

2676
S. Reboredo et al.
SPECIAL TOPIC
HPLC: Chiralpak IA, hexane–i-PrOH (95:05), flow rate: 1.00
mL/min; tR = 15.42 min (minor, 3S,4S,5R-isomer), 17.88 min (ma-
jor, 3R,4R,5S-isomer); 96% ee.
IR (CHCl3): 3354 (NH + OH), 1729 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.92 [t, J = 6.9 Hz, 3 H,
CH(CH2)3CH3], 1.29 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.30 (t, J =
7.1 Hz, 3 H, CO2CH2CH3), 1.23–1.45 [m, 6 H, CH(CH2)3CH3],
2.23–2.32 (m, 1 H, CHCH2OH), 2.87–3.01 [m, 2 H, CH(CH2)3CH3
+ OH or NH], 3.20–3.42 (m, 2 H, CH2OH), 4.15–4.36 (m, 4 H, 2 ×
COCH2CH3), 4.78–4.85 (m, 1 H, ArCH), 7.02 (t, J = 8.6 Hz, 2 H,
C{Ar}H), 7.37 (dd, J = 8.6, 5.3 Hz, 2 H, C{Ar}H).
4.38 (m, 4 H, 2 × CO2CH2CH3), 4.76 (d, J = 7.1 Hz, 1 H, ArCH),
6.95–7.07 (m, 2 H, C{Ar}H), 7.32–7.42 (m, 2 H, C{Ar}H).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 (CO2CH2CH3), 14.0
(CO2CH2CH3), 17.6 [CH(CH3)2], 23.6 [CH(CH3)2], 27.0
[CH(CH3)2], 45.2 [CHCH(CH3)2], 50.8 (CHCH2OH), 61.7
(CO2CH2CH3), 62.0 (CO2CH2CH3), 62.8 (ArCH), 63.3 (CH2OH),
74.0 [C(CO2Et)2], 115.2 (d, JC–F = 21.2 Hz, C{Ar}H), 128.4 (d,
J
C–F = 7.8 Hz, C{Ar}H), 136.0 (d, JC–F = 3.1 Hz, C{Ar}C), 162.0
(d, JC–F = 255.5 Hz, C{Ar}F), 170.5 (CO2Et), 172.5 (CO2Et).
MS (EI): m/z (%) = 335 (2) [M – EtOH]+, 308 (65), 291 (10), 248
(100), 234 (12), 174 (33), 135 (43), 109 (25).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 [CH(CH2)3CH3], 14.0
(CO2CH2CH3), 14.1 (CO2CH2CH3), 22.8 [CH(CH2)3CH3], 30.3
[CH(CH2)3CH3], 30.5 [CH(CH2)3CH3], 45.0 [CH(CH2)3CH3], 49.7
(CHCH2OH), 61.6 (ArCH), 61.7 (CO2CH2CH3), 61.7
Diethyl (3R,4R,5S)-3-Butyl-4-formyl-5-(2-furyl)pyrrolidine-
2,2-dicarboxylate (4l)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), (2E)-hept-2-enal (78 μL, 0.57 mmol), 2-
furaldehyde (96 μL, 1.14 mmol), and diethyl aminomalonate (100
mg, 0.57 mmol) with reaction for 1 d gave a colorless oil; yield: 88
mg (0.24 mmol, 42%); exo/endo (1H NMR): 85:15.
(CO2CH2CH3), 62.2 (CH2OH), 74.8 [C(CO2Et)2], 115.2 (d, JC–F
21.3 Hz, C{Ar}H), 128.4 (d, JC–F = 7.8 Hz, C{Ar}H), 136.1 (d,
C–F = 2.9 Hz, C{Ar}C), 162.0 (d, JC–F = 245.6 Hz, C{Ar}F), 170.9
=
J
(CO2Et), 172.1 (CO2Et).
MS (EI): m/z (%) = 349 (4) [M – EtOH]+, 322 (100), 305 (13), 276
(24), 248 (75), 232 (86), 174 (42), 135 (88).
IR (CHCl3): 3355 (NH), 1728 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.83 [t, J = 6.8 Hz, 3 H,
CH(CH2)3CH3], 1.15–1.35 [m, 11 H, 2 × CO2CH2CH3
+
Anal. Calcd for C21H30NO5F: C, 63.78; H, 7.65; N, 3.54. Found: C,
63.64; H, 7.93; N, 3.56.
CH(CH2)2CHaHbCH3], 1.61–1.77 [m, 1 H, CH(CH2)2CHaHbCH3],
2.90–2.96 (m, 1 H, CHCHO), 3.08 (br s, 1 H, NH), 3.25–3.32 [m, 1
H, CH(CH2)3CH3], 4.13–4.33 (m, 4 H, 2 × CO2CH2CH3), 4.99 (d,
J = 8.7 Hz, 1 H, CHfuryl), 6.18–6.30 (m, 2 H, C{HetAr}H), 7.25–
7.32 (m, 1 H, C{HetAr}H), 9.21 (d, J = 4.1 Hz, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): δ = 13.8 (CO2CH2CH3), 13.9
(CO2CH2CH3), 14.1 [CH(CH2)3CH3], 22.7 [CH(CH2)3CH3], 30.2
[CH(CH2)3CH3], 30.3 [CH(CH2)3CH3], 44.4 [CH(CH2)3CH3], 56.2
(CHCHO), 59.6 (CHfuryl), 61.8 (CO2CH2CH3), 61.9
(CO2CH2CH3), 75.0 [C(CO2Et)2], 108.0 (C{HetAr}H), 110.3
(C{HetAr}H), 142.4 (C{HetAr}H), 152.8 (C{HetAr}C), 169.7
(CO2Et), 171.4 (CO2Et), 201.1 (CHO).
Diethyl (3R,4R,5S)-5-(4-Fluorophenyl)-4-formyl-3-isopropyl-
pyrrolidine-2,2-dicarboxylate (4k)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), (2E)-4-methylpent-2-enal (70 μL, 0.57
mmol), 4-fluorobenzaldehyde (0.12 mL, 1.14 mmol), and diethyl
aminomalonate (100 mg, 0.57 mmol) with reaction for 1 d gave a
colorless oil; yield: 108 mg (0.28 mmol, 50%); exo/endo (1H
NMR): >95:5.
IR (CHCl3): 3347 (NH), 1731 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.78 [d, J = 6.7 Hz, 3 H,
CH(CH3)2], 0.98 [d, J = 6.7 Hz, 3 H, CH(CH3)2], 1.29 (t, J = 7.1 Hz,
3 H, COCH2CH3), 1.29 (t, J = 7.1 Hz, 3 H, COCH2CH3), 2.01–2.15
[m, 1 H, CHCH(CH3)2], 2.94–3.07 (m, 2 H, CHCHO + NH), 3.32
[dd, J = 7.8, 5.2 Hz, 1 H, CHCH(CH3)2], 4.13–4.46 (m, 4 H, 2 ×
CO2CH2CH3), 5.04 (d, J = 9.2 Hz, 1 H, ArCH), 6.92–7.04 (m, 2 H,
C{Ar}H), 7.26–7.41 (m, 2 H, C{Ar}H), 9.03 (d, J = 4.6 Hz, 1 H,
CHO).
MS (EI): m/z (%) = 365 (7) [M+], 336 (4), 308 (1); 292 (100), 274
(7), 246 (17), 218 (24), 179 (21), 137 (25).
Diethyl (3R,4R,5S)-3-Butyl-5-(2-furyl)-4-(hydroxymethyl)pyr-
rolidine-2,2-dicarboxylate (6l)
Reduction of 4l (88 mg, 0.24 mmol) by the general procedure using
NaBH4 (12 mg, 0.29 mmol) gave a colorless oil; yield: 62 mg (0.17
mmol, 71%); [α]D20 –33.7 (c 1.0, CH2Cl2).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 (CO2CH2CH3), 14.0
(CO2CH2CH3), 19.2 [CH(CH3)2], 23.6 [CH(CH3)2], 27.6
[CH(CH3)2], 49.9 [CHCH(CH3)2], 55.7 (CHCHO), 61.8
(CO2CH2CH3), 61.9 (ArCH), 62.0 (CO2CH2CH3), 74.6
HPLC: Chiralpak IA, hexane–i-PrOH (95:05), flow rate: 1.00
mL/min; tR = 17.80 min (minor, 3S,4S,5R-isomer), 22.89 min (ma-
jor, 3R,4R,5S-isomer); 97% ee.
IR (CHCl3): 3375 (NH + OH), 1730 (CO) cm–1.
[C(CO2Et)2], 115.4 (d, JC–F = 21.4 Hz, C{Ar}H), 128.8 (d, JC–F
=
8.1 Hz, C{Ar}H), 134.6 (C{Ar}C), 162.2 (d, JC–F = 190.5 Hz,
1H NMR (300 MHz, CDCl3): δ = 0.87 [t, J = 7.0 Hz, 3 H,
C{Ar}F), 169.6 (CO2Et), 172.1 (CO2Et), 202.5 (CHO).
CH(CH2)3CH3], 1.22–1.43 [m, 11 H, 2 × CO2CH2CH3 +
CH(CH2)2CHaHbCH3], 1.47–1.63 [m, 1 H, CH(CH2)2CHaHbCH3],
1.82 (br s, 1 H, OH or NH), 2.30–2.42 (m, 1 H, CHCH2OH), 2.62–
2.80 [m, 1 H, CH(CH2)3CH3], 3.06 (br s, 1 H, OH or NH), 3.23–3.33
(m, 1 H, CHaHbOH), 3.45–3.56 (m, 1 H, CHaHbOH), 4.13–4.34 (m,
4 H, 2 × CO2CH2CH3), 4.80 (d, J = 7.4 Hz, 1 H, furylCH), 6.23–
6.27 (m, 1 H, C{HetAr}H), 6.28–6.33 (m, 1 H, C{HetAr}H), 7.32–
7.36 (m, 1 H, C{HetAr}H).
13C NMR (75.4 MHz, CDCl3): δ = 13.9 (CO2CH2CH3), 14.0
(CO2CH2CH3), 14.1 [CH(CH2)3CH3], 22.9 [CH(CH2)3CH3], 30.1
[CH(CH2)3CH3], 30.5 [CH(CH2)3CH3], 44.8 [CH(CH2)3CH3], 49.9
(CHCH2OH), 57.0 (furylCH), 61.6 (CO2CH2CH3), 61.7
(CO2CH2CH3), 62.6 (CH2OH), 74.8 [C(CO2Et)2], 107.2
(C{HetAr}H), 110.4 (C{HetAr}H), 141.9 (C{HetAr}H), 155.3
(C{HetAr}C), 170.8 (CO2Et), 171.9 (CO2Et).
MS (EI): m/z (%) = 379 (2) [M+], 350 (4), 306 (100), 281 (6), 260
(8), 232 (10), 207 (10), 190 (7), 162 (15), 135 (17).
Diethyl (3R,4R,5S)-5-(4-Fluorophenyl)-4-(hydroxymethyl)-3-
isopropylpyrrolidine-2,2-dicarboxylate (6k)
Reduction of 4k (108 mg, 0.28 mmol) by the general procedure us-
ing NaBH4 (13 mg, 0.34 mmol) gave a colorless oil; yield: 78 mg
(0.20 mmol, 72%); [α]D20 –74.2 (c 1.0, CH2Cl2).
HPLC: Chiralcel OJ, hexane–i-PrOH (99:01), flow rate: 1.00
mL/min; tR = 21.42 min (major, 3R,4R,5S-isomer), 32.33 min (mi-
nor, 3S,4S,5R-isomer); >99% ee.
IR (CHCl3): 3325 (NH + OH), 1730 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.88 [d, J = 6.8 Hz, 3 H,
CH(CH3)2], 1.03 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.22–1.35 (m, 6
H, 2 × COCH2CH3), 1.75 (br s, 1 H, OH or NH), 2.20–2.26 [m, 1 H,
CHCH(CH3)2], 2.26–2.42 [m, 1 H, CHCH(CH3)2], 2.96–3.04 (m, 2
H, CHCH2OH + OH or NH), 3.17–3.37 (m, 2 H, CH2OH), 4.13–
MS (EI): m/z (%) = 367 (2) [M+], 321 (11), 294 (100), 277 (18), 248
(23), 220 (84), 204 (75), 139 (45), 107 (98).
Synthesis 2013, 45, 2669–2678
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
One-Pot Synthesis of Polysubstituted Pyrrolidines
2677
Anal. Calcd for C19H29NO6: C, 62.11; H, 7.96; N, 3.81. Found: C,
62.54; H, 7.10; N, 3.88.
1H NMR (300 MHz, CDCl3): δ = 0.75 (t, J = 7.1 Hz, 3 H,
COCH2CH3), 1.26 (t, J = 7.1 Hz, 3 H, COCH2CH3), 3.35–3.61 (m,
2 H, CO2CHaHbCH3 + NH), 3.62–3.73 (m, 1 H, CHCHO), 3.78–
3.88 (m, 1 H, CO2CHaHbCH3), 4.15–4.38 (m, 2 H, CO2CH2CH3),
4.85 (d, J = 10.1 Hz, 1 H, PhCH), 5.22 (d, J = 8.5 Hz, 1 H, fu-
rylCH), 6.25–6.35 (m, 2 H, C{HetAr}H), 7.18–7.40 (m, 6 H,
C{Ar}H + C{HetAr}H), 9.29 (d, J = 3.1 Hz, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): δ = 13.3 (CO2CH2CH3), 13.9
(CO2CH2CH3), 48.8 (PhCH), 56.5 (CHCHO), 59.5 (furylCH), 61.8
(CO2CH2CH3), 61.9 (CO2CH2CH3), 76.6 [C(CO2Et)2], 108.4
(C{HetAr}H), 110.4 (C{HetAr}H), 127.6 (C{Ar}H), 128.3
(C{Ar}H), 128.7 (C{Ar}H), 136.4 (C{Ar}C), 142.4 (C{HetAr}H),
153.1 (C{HetAr}C), 169.8 (CO2Et), 170.9 (CO2Et), 199.3 (CHO).
Diethyl (3R,4R,5S)-4-Formyl-5-(2-furyl)-3-isopropylpyrro-
lidine-2,2-dicarboxylate (6m)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), (2E)-4-methylpent-2-enal (70 μL, 0.57
mmol), 2-furaldehyde (96 μL, 1.14 mmol), and diethyl aminomalo-
nate (100 mg, 0.57 mmol) with reaction for 1 d gave a colorless oil;
yield: 108 mg (0.31 mmol, 54%); exo/endo (1H NMR): >95:5.
IR (CHCl3): 3351 (NH), 1725 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.75 [d, J = 6.8 Hz, 3 H,
CH(CH3)2], 0.97 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.19–1.36 (m, 6
H, 2 × CO2CH2CH3), 2.00–2.10 [m, 1 H, CH(CH3)2], 2.97–3.16 (m,
2 H, CHCHO + NH), 3.33 [dd, J = 8.7, 4.9 Hz, 1 H, CHCH(CH3)2],
4.10–4.36 (m, 4 H, 2 × COCH2CH3), 4.90–5.01 (m, 1 H, furylCH),
6.14–6.32 (m, 2 H, C{HetAr}H), 7.25–7.32 (m, 1 H, C{HetAr}H),
9.21 (d, J = 4.3 Hz, 1 H, CHO).
MS (EI): m/z (%) = 385 (2) [M+], 312 (100), 294 (3), 266 (13), 238
(27), 210 (15), 180 (17), 131 (17).
Diethyl (3R,4R,5S)-5-(2-Furyl)-4-(hydroxymethyl)-3-phenyl-
pyrrolidine-2,2-dicarboxylate (6n)
Reduction of 4n (101 mg, 0.26 mmol) by the general procedure us-
ing NaBH4 (15 mg, 0.32 mmol) gave a colorless oil; yield: 37 mg
(0.09 mmol, 35%); [α]D20 +30.8 (c 1.0, CH2Cl2).
IR (CHCl3): 3372 (NH + OH), 1728 (CO) cm–1.
13C NMR (75.4 MHz, CDCl3): δ = 13.9 (CO2CH2CH3), 19.1
[CH(CH3)2], 23.4 [CH(CH3)2], 27.4 [CH(CH3)2], 50.2
[CHCH(CH3)2], 55.7 (CHCHO), 56.7 (furylCH), 61.8
(CO2CH2CH3), 62.1 (CO2CH2CH3), 74.6 [C(CO2Et)2], 108.0
(C{HetAr}H), 110.3 (C{HetAr}H), 142.4 (C{HetAr}H), 152.7
(C{HetAr}C), 170.0 (CO2Et), 171.7 (CO2Et), 201.5 (CHO).
HPLC: Chiralpak IA, hexane–i-PrOH (80:20), flow rate: 1.00
mL/min; tR = 12.70 min (minor, 3S,4S,5R-isomer), 22.29 min (ma-
jor, 3R,4R,5S-isomer); 97% ee.
MS (EI): m/z (%) = 351 (2) [M+], 322 (2), 308 (2), 278 (100), 253
(6), 232 (11), 204 (13), 179 (16), 137 (20).
1H NMR (300 MHz, CDCl3): δ = 0.74 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.25 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 3.06–3.23 (m,
2 H, CH2OH), 3.34–3.55 (m, 2 H, CHCH2OH + CO2CHaHbCH3),
3.75–3.89 (m, 1 H, CO2CHaHbCH3), 4.12 (d, J = 11.1 Hz, 1 H,
PhCH), 4.17–4.37 (m, 2 H, COCH2CH3), 4.99 (d, J = 6.9 Hz, 1 H,
furylCH), 6.26 (d, J = 3.2 Hz, 1 H, C{HetAr}H), 6.32–6.36 (m, 1
H, C{HetAr}H), 7.20–7.44 (m, 6 H, C{Ar}H + C{HetAr}H).
13C NMR (75.4 MHz, CDCl3): δ = 13.3 (CO2CH2CH3), 14.0
(CO2CH2CH3), 50.2 (PhCH), 50.3 (CHCH2OH), 57.1 (furylCH),
61.7 (CO2CH2CH3), 61.7 (CO2CH2CH3), 62.0 (CH2OH), 76.8
[C(CO2Et)2], 107.5 (C{HetAr}H), 110.5 (C{HetAr}H), 127.4
(C{Ar}H), 128.3 (C{Ar}H), 128.8 (C{Ar}H), 137.1 (C{Ar}C),
141.9 (C{HetAr}H), 155.7 (C{HetAr}C), 170.7 (CO2Et), 171.4
(CO2Et).
Diethyl (3R,4R,5S)-5-(2-Furyl)-4-(hydroxymethyl)-3-isopropyl-
pyrrolidine-2,2-dicarboxylate (6m)
Reduction of 4m (108 mg, 0.31 mmol) by the general procedure us-
ing NaBH4 (14 mg, 0.37 mmol) gave a colorless oil; yield: 89 mg
(0.25 mmol, 81%); [α]D20 –55.6 (c 1.0, CH2Cl2).
HPLC: Chiralcel OD, hexane–i-PrOH (95:05), flow rate: 1.00
mL/min; tR = 8.38 min (major, 3R,4R,5S-isomer), 10.02 min (minor,
3S,4S,5R-isomer); 99% ee.
IR (CHCl3): 3412 (NH + OH), 1729 (CO) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.83 [t, J = 6.9 Hz, 3 H,
CH(CH3)2], 0.99 [t, J = 6.9 Hz, 3 H, CH(CH3)2], 1.18–1.31 (m, 6 H,
2 × CO2CH2CH3), 1.94 (br s, 1 H, OH or NH), 2.15–2.25 [m, 1 H,
CH(CH3)2], 2.40–2.53 (m, 1 H, CHCH2OH), 2.86 [dd, J = 6.9, 2.9
Hz, 1 H, CHCH(CH3)2], 3.23–3.28 (m, 1 H, CHaHbOH), 3.40–3.52
(m, 1 H, CHaHbOH), 4.09–4.34 (m, 5 H, 2 × COCH2CH3 + OH or
NH), 4.74 (d, J = 7.4 Hz, 1 H, furylCH), 6.24 (d, J = 3.2 Hz, 1 H,
C{HetAr}H), 6.30–6.32 (m, 1 H, C{HetAr}H), 7.33–7.36 (m, 1 H,
C{HetAr}H).
13C NMR (75.4 MHz, CDCl3): δ = 14.0 (CO2CH2CH3), 14.0
(CO2CH2CH3), 17.4 [CH(CH3)2], 23.7 [CH(CH3)2], 26.4
[CH(CH3)2], 45.3 [CHCH(CH3)2], 50.3 (CHCH2OH), 57.6 (fu-
rylCH), 61.6 (CO2CH2CH3), 62.0 (CO2CH2CH3), 63.5 (CH2OH),
74.1 [C(CO2Et)2], 107.1 (C{Ar}H), 110.4 (C{Ar}H), 141.8
(C{Ar}H), 155.1 (C{Ar}C), 170.5 (CO2Et), 172.3 (CO2Et).
MS (EI): m/z (%) = 387 (1) [M+], 341 (6), 314 (34), 297 (24), 268
(6), 224 (18), 139 (24), 107 (100).
Anal. Calcd for C21H25NO6: C, 65.10, H, 6.50; N, 3.62. Found: C,
65.39; H, 6.39; N, 3.69.
Diethyl (7R,8aS)-7-Methyldihydro-4H-pyrrolo[2,1-d][1,3,5]di-
oxazine-6,6(7H)-dicarboxylate (7)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (59 mg, 0.23 mmol), trans-crotonaldehyde (96 μL, 1.14 mmol),
HCHO (0.10 mL, 1.37 mmol), and diethyl aminomalonate (200 mg,
1.14 mmol) with reaction for 1 d gave a colorless oil; yield: 52 mg
(0.18 mmol, 16%).
MS (EI): m/z (%) = 353 (2) [M+], 307 (3), 280 (96), 263 (12), 234
IR (CHCl3): 1725 (CO) cm–1.
(12), 220 (100), 174 (15), 107 (44).
1H NMR (300 MHz, CDCl3): δ = 1.12 (d, J = 6.2 Hz, 3 H, CHCH3),
1.23 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.26 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.41–1.52 (m, 1 H, CHCHaHbCH), 1.62–1.69 (m, 1
H, CHCHaHbCH), 3.40–3.60 (m, 1 H, CHCH3), 4.10 (d, J = 8.3 Hz,
1 H, NCHaHbO), 4.15–4.30 (m, 4 H, 2 × CO2CH2CH3), 4.54 (d, J =
11.3 Hz, 1 H, OCHaHbO), 4.77 (d, J = 8.8 Hz, 1 H, NCHaHbO), 4.91
(dd, J = 9.9, 4.3 Hz, 1 H, OCHN), 5.07 (d, J = 11.3 Hz, 1 H,
OCHaHbO).
13C NMR (75.4 MHz, CDCl3): δ = 13.8 (CO2CH2CH3), 14.0
(CO2CH2CH3), 21.5 (CHCH3), 37.1 (CHCH2CH), 61.9
(CO2CH2CH3), 62.5 (CO2CH2CH3), 69.4 [C(CO2CH2CH3)2], 70.8
(CHCH3), 72.0 (NCH2O), 76.0 (OCH2O), 90.0 (CHOCH2), 169.2
(CO2CH2CH3), 169.6 (CO2CH2CH3).
Anal. Calcd for C18H27NO6: C, 61.17; H, 7.70; N, 3.96. Found: C,
61.47; H, 7.56; N, 3.57.
Diethyl (3R,4R,5S)-4-Formyl-5-(2-furyl)-3-phenylpyrrolidine-
2,2-dicarboxylate (4n)
The general procedure using diphenyl[(2S)-pyrrolidin-2-yl]metha-
nol (30 mg, 0.11 mmol), trans-cinnamaldehyde (73 μL, 0.57
mmol), 2-furaldehyde (96 μL, 1.14 mmol), and diethyl aminomalo-
nate (100 mg, 0.57 mmol) with reaction for 1 d gave a colorless oil;
yield: 101 mg (0.26 mmol, 46%); exo/endo (1H NMR): 92:8.
IR (CHCl3): 3351 (NH), 1728 (CO) cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2669–2678

2678
S. Reboredo et al.
SPECIAL TOPIC
MS (EI): m/z (%) = 286 (4) [M – H]+, 272 (4), 230 (6), 214 (100),
184 (7), 170 (9), 142 (85), 127 (6), 96 (10), 70 (35).
L.; Chen, Y.-C. Chem. Eur. J. 2008, 14, 9873. (e) Xue, M.-
X.; Zhang, X.-M.; Gong, L.-Z. Synlett 2008, 691.
(4) (a) Inaf, S. S.; Witiak, D. T. Synthesis 1999, 435. For
conventional synthetic routes, see: (b) Salvatore, R. N.;
Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785.
(5) (a) Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L.
Angew. Chem. Int. Ed. 2007, 46, 5168. For a later report, see:
(b) Ibrahem, I.; Rios, R.; Vesely, J.; Córdova, A.
Acknowledgment
This work was supported by the Spanish MICINN (CTQ2011-
22790), the Basque Government (IT328-10 and a fellowship to
U.U.), and UPV/EHU (UFI QOSYC 11/22 and a fellowship to
S.R.). Membership in the COST Action CM0905 is also acknow-
ledged.
Tetrahedron Lett. 2007, 48, 6252. See also: (c) Reboredo,
S.; Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L.; de Cozár,
A.; Cossío, F. P. Chem. Eur. J. 2012, 18, 7179. (d) Iza, A.;
Carrillo, L.; Vicario, J. L.; Badía, D.; Reyes, E. Org. Biomol.
Chem. 2010, 8, 2238. (e) Fernández, N.; Carrillo, L.;
Vicario, J. L.; Badía, D.; Reyes, E. Chem. Commun. 2011,
47, 12313. (f) Reboredo, S.; Vicario, J. L.; Badia, D.;
Carrillo, L.; Reyes, E. Adv. Synth. Catal. 2011, 353, 3307.
(6) For related transformations using hydrogen-bonding
catalysts, see refs. 3c, 3d and: (a) Li, N.; Song, J.; Tu, X.-F.;
Liu, B.; Chen, X.-H.; Gong, L.-Z. Org. Biomol. Chem. 2010,
8, 2016. (b) Lin, S.; Deiana, L.; Zhao, G.-L.; Sun, J.;
Córdova, A. Angew. Chem. Int. Ed. 2011, 33, 7624.
(7) For reviews, see: (a) Moyano, A.; Rios, R. Chem. Rev. 2011,
111, 4703. (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(c) Tejedor, D.; García-Tellado, F. Chem. Soc. Rev. 2007,
36, 484. (d) Dömling, A. Chem. Rev. 2006, 106, 17.
(e) Ramón, D. J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44,
1602. (f) Trost, B. M. Science 1991, 254, 1471.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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(8) Previous reports on multicomponent versions of this
cycloaddition reaction using related O-TMS-protected
α,α-diarylprolinol derivatives as catalysts (refs. 5b and 6b)
do not mention the occurrence of this side reaction. In our
case, byproduct 5a was always observed when the reaction
medium did not contain significant amounts of water.
(9) This behavior was also observed in other cases in which one
of the reactants (either the aromatic aldehyde 1 or the enal 3)
was a solid. In particular, when we examined the use of 3,4-
dimethoxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 3,4-
methylenedioxybenzaldehyde, or 3-(2-furyl)acrylaldehyde
in combination with other liquid aromatic aldehydes or
enals, we obtained the cycloaddition products in trace
amounts only.
Synthesis 2013, 45, 2669–2678
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