The organocatalytic enantioselective [3+2] cycloaddition reaction of α,β-unsaturated aldehydes with azomethine ylides applied to the asymmetric synthesis of densely substituted pyrroloisoquinolines

Article abstract of DOI:10.1016/j.tet.2013.08.012

The synthesis of densely functionalized pyrrolo[2,1-a]isoquinolines was accomplished using the organocatalytic [3+2] cycloaddition between enals and azomethine ylides under iminium catalysis developed in our group some years ago as the key step. The cyclo

Full text of DOI:10.1016/j.tet.2013.08.012

Tetrahedron 69 (2013) 8878e8884
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Tetrahedron
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The organocatalytic enantioselective [3þ2] cycloaddition reaction of
a,b-unsaturated aldehydes with azomethine ylides applied to the
asymmetric synthesis of densely substituted pyrroloisoquinolines
*
*
Ainara Iza, Iratxe Ugarriza, Uxue Uria, Efraím Reyes, Luisa Carrillo , Jose L. Vicario
ꢀ
Departamento de Química Organica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU),
PO Box 644, E-48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2013
Received in revised form 30 July 2013
Accepted 6 August 2013
Available online 13 August 2013
The synthesis of densely functionalized pyrrolo[2,1-a]isoquinolines was accomplished using the orga-
nocatalytic [3þ2] cycloaddition between enals and azomethine ylides under iminium catalysis developed
in our group some years ago as the key step. The cycloaddition proceeds smoothly yielding the corre-
sponding pyrrolidine as a single endo diastereoisomer with enantiopurity in the range of 94e96% and
further manipulations of the obtained cycloadducts using high yielding reaction protocols and a final
mesylation/intramolecular N-alkylation sequence allowed the synthesis of target compounds in which
the integrity of all stereocenters installed during the first step is maintained.
Keywords:
Cycloaddition
Dipolar reaction
Organocatalysis
Heterocycles
Ó 2013 Elsevier Ltd. All rights reserved.
Pyrroloisoquinolines
1. Introduction
azabicyclo[4.3.0]nonane general structure. (þ)-Crispine A, an al-
kaloid isolated in 2002 by Zhao and co-workers from Carduus
Nitrogen-containing heterocycles are widely present among
naturally occurring bioactive compounds. Many of these alkaloids
contain benzo-fused substructures and in particular, those het-
erocycles containing the tetrahydroisoquinoline core can be
regarded as a privileged class among the pharmacologically active
isoquinoline alkaloid family1 and hence have attracted a great deal
of attention from many synthetic chemists. Molecules containing
tetrahydroisoquinoline unit are generally built up through
well-known synthetic protocols that typically consist of CeC bond
crispus, represents the prototypical example of this family of alka-
loids, which exhibit important activity against some human cancer
lines.4 Moreover, the pyrroloisoquinoline framework is also found
as the main structural motif of the Erythrina alkaloid, a group of
natural products, which have been used in indigenous medicine
and which are isolated from plants of the Erythrina genus, wide-
spreadly found in tropical and subtropical regions. Members of
the Erythrina family display hypnotic activity and a variety of
pharmacological effects are associated with the presence of the
erythrinane skeleton, which include sedative, hypotensive, neuro-
muscular blocking, and CNS activities (Fig. 1).5
formation involving the participation of the aromatic ring
p-elec-
trons in the cyclization step, such as PicteteSpengler, Bisch-
lereNapieralski, PomeranzeFritscheBobbitt, N-acyliminium ion
cyclization, Parham type cyclization, base induced aryl mediated
cyclization, and other more sophisticated methods.2,3 Most of these
methodologies either involve the use of harsh reaction conditions
or require multiple steps in order to reach the suitable precursor
required for the cyclization reaction.
With all these precedents in mind we envisaged a possible
direct and efficient approach for the preparation of pyrroloisoqui-
nolines with a complex substitution pattern at the pyrrolidine
In this context, the pyrroloisoquinoline skeleton constitutes
a particularly interesting framework, which is based on the
* Corresponding authors. Tel.: þ34 94 601 5434; fax: þ34 94 601 2748 (L.C.); tel.:
þ34 94 601 5454; fax: þ34 94 601 2748 (J.L.V.); e-mail addresses: marisa.carrillo@
ehu.es (L. Carrillo), joseluis.vicario@ehu.es (J.L. Vicario).
Fig. 1. Structure of pyrroloisoquinoline alkaloid Crispine
Erythrina alkaloids.
A and core structure of
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.012

A. Iza et al. / Tetrahedron 69 (2013) 8878e8884
8879
substructure by applying a organocatalytic enantioselective [3þ2]
cycloaddition reaction between -unsaturated aldehydes and
easily accessible by condensation between commercially available
diethyl aminomalonate and 2-substituted benzaldehyde.
a,b
azomethine ylides developed in our group as the key trans-
formation with respect to the stereocontrolled installation of all
We started our work with the preparation of a series of
2-substituted benzaldehyde derivatives 3aec by a simple and ef-
ficient protocol reaction starting from commercially available
2-bromoarylethanol derivatives 1aec. The sequence consisted of
the initial protection of the primary alcohol moiety by O-benzyla-
tion followed by a formylation reaction in which the bromoaryl
derivative was first metalated and subsequently treated with
dimethylformamide as acylating reagent. Under these conditions,
2-(benzyloxyethyl)benzaldehydes 3aec were obtained in good
stereocenters.6 In this transformation, we have shown that
a,b-
unsaturated aldehydes and a-iminomalonates react very efficiently
in the presence of a chiral secondary amine catalyst delivering the
corresponding pyrrolidine cycloadducts after a [3þ2] cycloaddition
reaction, which, under the optimized reaction conditions, pro-
ceeded with very high yields, delivering a single regioisomer and
also proceeded with outstanding endo-selectivity and excellent
enantioselectivity (Scheme 1). The key for the success of this
transformation relies both on the feasibility of a thermal 1,2-
prototropy process experienced by the a-iminomalonate reagent
under the reaction conditions employed, which generates in situ
the required azomethine ylide reagent and which is ready to react
overall yields. Next, we proceeded to prepare the corresponding a-
iminomalonates by reacting benzaldehydes 3aec with dieth-
ylamino malonate hydrochloride in CH2Cl2 and in the presence of
1 equiv of Et3N, which was necessary to release the free primary
amine reagent, and anhydrous Na2SO4 as water-scavenging re-
agent. Under these conditions, imines 4aec were directly isolated
as crude materials, which could not be further purified because of
the inherent instability of imines toward hydrolysis in the presence
of SiO2 and moisture. Nevertheless, NMR analysis indicated that
these compounds had been obtained pure enough to be used in the
subsequent step of the synthetic route without further purification
(Table 1, Scheme 2).
with the a,b-unsaturated aldehyde dipolarophile previously acti-
vated by the chiral secondary amine catalyst via iminium ion for-
mation. The chiral information present at the proline-derived
catalyst is the responsible of the extraordinarily high level of ster-
eocontrol achieved during the overall cycloaddition process, in
which up to three new stereocenters are generated.
Table 1
Synthesis of
a
-iminomalonates 4aec
R1
R2
Compd Yielda (%) Compd Yielda (%) Compd Yieldb (%)
H
H
2a
80
79
68
3a
3b
3c
70
86
76
4a
4b
4c
77
52
78
OMe OMe 2b
OCH2O
2c
a
Yield of pure product after flash column chromatography purification.
Yield of crude product after work-up. NMR analysis indicated that imines 4aec
b
were pure enough for further uses.
Scheme 1. The organocatalytic enantioselective [3þ2] cycloaddition reaction of azo-
methine ylides with a,b-unsaturated aldehydes developed in our group.
2. Results and discussion
We therefore planned our synthesis according to retrosynthetic
analysis shown in Fig. 2, in which the formation of the isoquinoline
framework was devised by intramolecular N-alkylation from
a conveniently substituted 2-arylpyrrolidine incorporating a func-
tionalized side chain at the 2 position of the aromatic ring, which
should also contain the required leaving group. Access to this pyr-
rolidine was proposed to be carried out directly by the aforemen-
tioned enantioselective [3þ2] cycloaddition reaction under
organocatalytic conditions using the protocol previously developed
Scheme 2. Synthesis of a-iminomalonates 4aec. Reagents and conditions: (a) BnBr,
KOH, DMSO, rt, 4 h; (b) (1) n-BuLi, THF, ꢀ78 ꢁC, 1 h; (2) DMF, ꢀ78 ꢁC, 6 h; (c) diethyl
in our group and involving a suitably a-benzylideneiminomalonate
aminomalonate hydrochloride, Et3N, anhydrous Na2SO4, CH2Cl2, rt, 72 h.
derivative as azomethine ylide source, the latter being in principle
Next, imines 4aec were reacted with crotonaldehyde in the
presence of 20 mol % of
already optimized in our group for the [3þ2] cycloaddition reaction
between -iminomalonates and -unsaturated aldehydes
a,a-diphenylprolinol under the conditions
a
a,b
(Scheme 3).6 As it was expected, the reaction proceeded smoothly,
delivering cycloadducts 5aec in excellent yields, as single endo-
isomers of very high enantiomeric purity as 3R,4R,5S enantiomer
based on our previous results.6 At this point, and due to the ten-
dency found for this kind of cycloadducts toward decomposition,
we proceeded to carry out the reduction of the highly reactive
formyl group to the corresponding primary alcohol, and thus re-
duced cycloadducts 6aec could be isolated and conveniently
characterized. These compounds 6aec were also found to be rather
stable compounds, which could be stored for several weeks in
open-air vials at rt without significant decomposition (Table 2).
Fig. 2. Retrosynthetic analysis for the synthesis of pyrroloisoquinolines using an or-
ganocatalytic [3þ2] cycloaddition reaction as key step.

8880
A. Iza et al. / Tetrahedron 69 (2013) 8878e8884
Moreover, NMR analysis of the crude reaction mixtures obtained
in all cases indicated that all the reactions carried out from the
cycloadducts 6aec also proceeded without observable epimeriza-
tion in any of the stereocenters, which were initially generated
during the organocatalytic enantioselective cycloaddition process.
In conclusion, we have developed a very easy and straightway
method for the synthesis of densely functionalized pyrroloisoqui-
nolines, a core structure present in various families of alkaloids. The
key step of this synthesis relies on the organocatalytic enantiose-
Scheme 3. Synthesis of cycloadducts 6aec. Reagents and conditions: (a) crotonalde-
hyde, (S)-a,a
-diphenylprolinol (20 mol %), H2O (4 equiv), THF, 4 ꢁC, 72 h; (b) NaBH4,
MeOH, 0 ꢁC, 40 min.
lective [3þ2] cycloaddition reaction between
a,b-unsaturated al-
dehydes and azomethine ylides previously developed in our group,
which allows the synthesis of substituted pyrrolidines with good to
excellent yields, high endo-selectivity, and excellent values of en-
antiomeric excess. The accomplishment of the synthesis was car-
ried out after several high yielding functional group manipulations,
such as reduction, protection, and hydrogenation steps, and a final
intramolecular N-alkylation reaction. Importantly, all these sub-
sequent transformations occurred maintaining the integrity of all
stereocenters installed during the cycloaddition reaction.
Table 2
Synthesis of cycloadducts 6aec
R1
R2
Compd Yielda (%) endo/exob Compd Yielda (%) eec (%)
H
H
5a
80
70
80
>95:<5
>95:<5
>95:<5
6a
6b
6c
68
62
84
94
94
96
OMe OMe 5b
OCH2O
5c
a
Yield of pure product after flash column chromatography purification.
Determined by NMR analysis of crude reaction mixture.
Determined by HPLC on chiral stationary phase under conditions optimized for
b
c
a racemic standard (Chiralpack IA column, PDA detector, n-hexane/i-PrOH 90:10 or
95:5, flow rate: 1.00 mL/min).
3. Experimental section
3.1. General remarks
Continuing with the synthesis, we proceeded next to the for-
mation of the isoquinoline framework by the projected intra-
molecular N-alkylation reaction (Scheme 4). Therefore, we started
with the protection of the primary alcohol on cycloadducts 6aec in
order to avoid chemoselectivity problems when manipulating the
side chain located at the aryl ring. This protection was carried out in
a straightforward manner through the formation of the corre-
sponding silyl ether under standard conditions. Next, we carried
out the deprotection of the alcohol moiety present at the afore-
mentioned side chain, which proceeded smoothly by hydrogena-
tion under Pd/C catalysis and finally, the isoquinoline ring
formation was accomplished by mesylation of the resulting pri-
mary alcohol, which underwent in situ cyclization under basic
conditions. In this way, the target pyrrolo[2,1-a]isoquinolines 9aec
were obtained in good overall yields after flash column chroma-
tography purification (Table 3).
NMR spectra were recorded at 20e25 ꢁC, running at 300 MHz
for 1H and 75 MHz for 13C in CDCl3 solution and resonances are
reported in parts per million (ppm) relative to tetramethylsilane
unless otherwise stated. The following abbreviations were used to
designate chemical shift multiplicities: s¼singlet, d¼doublet,
t¼triplet, m¼multiplet, br s¼broad signal. All first-order splitting
patterns were assigned on the basis of the appearance of the
multiplet. Splitting patterns that could not be easily interpreted are
designated as multiplet (m) or broad signal (br s). Assignments of
individual signals were carried out using COSY, HMQC, and DEPT
experiments. IR spectra were measured in the interval between
4000 and 400 cmꢀ1, obtained by depositing a film on a KBr plate
and only characteristic bands are given. Mass spectra were recor-
ded under electron impact (EI) or chemical ionization (CI) at 70 eV.
The obtained data are presented in mass unit (m/z) and the values
found in brackets belong to relative intensities comparing to the
base peak (100%). Optical rotations were measured at 20 ꢁC and
recorded in solution on a 1 dm length cell using a Na lamp (589 nm)
in the solvent and concentration indicated in each case. TLC was
carried out with 0.2 mm thick silica gel plates and visualization was
accomplished by ultraviolet irradiation light or by spraying with
phosphomolybdic acid. Flash column chromatography on silica gel
was performed with silicagel (230e400 mesh). All solvents used in
reactions were dried and purified according to standard pro-
cedures. All other reagents were used as purchased. All air- or
moisture-sensitive reactions were performed under argon atmo-
sphere. The glassware was oven dried (140 ꢁC) overnight and
purged with argon prior to use. Enantiomeric excesses (ee) were
determined by HPLC under conditions specified in each case.
3.2. General procedure for the synthesis of a-iminomalonates
4aec
Scheme 4. Synthesis of pyrrolo[2,1-a]isoquinolines 9aec. Reagents and conditions: (a)
TBSCl, imidazole, DMAP (cat.), DMF, rt, 8 h; (b) H2, Pd/C (cat.), MeOH, rt, 24 h; (c) (1)
MsCl, Et3N, DMAP (cat.), CH2Cl2, rt, 90 min; (2) 4 M KOH (aq), 2 h.
Et3N (1.00 mmol) and the corresponding aldehyde
3
(1.00 mmol) were added to a stirred solution of diethyl amino-
malonate hydrochloride (1.00 mmol) in CH2Cl2 (20 mL) at rt.
Na2SO4 was added and the suspension was stirred for 72 h at this
temperature after which the crude reaction mixture was filtered
and the solvent was removed under reduced pressure. Et2O (20 mL)
was added over the resulting slurry and this ethereal phase
was washed with water (3ꢂ10 mL), dried over anhydrous Na2SO4,
filtered, and the solvent was removed under reduced pressure.
Table 3
Synthesis of pyrrolo[2,1-a]isoquinolines 9aec
R1
R2
Compd Yielda (%) Compd Yielda (%) Compd Yielda (%)
H
H
7a
91
72
84
8a
8b
8c
81
65
44
9a
9b
9c
75
82
86
OMe OMe 7b
OCH2O
7c
a
Yield of pure product after flash column chromatography purification.

A. Iza et al. / Tetrahedron 69 (2013) 8878e8884
8881
20
Iminomalonates 4aec were obtained as a yellowish oil and were
used in the following step without further purification.
(0.04 mL, 2.41 mmol). Yield: 80%. [
a
]
ꢀ69.0 (c 1.0, CH2Cl2). IR
D
(neat): 1728 (C]O) cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 1.12 (d, 3H,
J¼7.0 Hz, CH3CH), 1.31 (t, 6H, J¼7.1 Hz, 2ꢂCH3CH2O), 2.81e3.03 (m,
4H, CH2CH2OþCHCHOþNH), 3.24e3.38 (m, 1H, CHCH3), 3.63e3.74
(m, 2H, CH2OBn), 4.19e4.39 (m, 4H, 2ꢂCH3CH2O), 4.50 (s, 2H,
PhCH2), 5.45 (dd, 1H, J¼9.7, 4.5 Hz, CHN), 7.14e7.85 (m, 9H,
3.2.1. (E)-Diethyl N-[2-(2-benzyloxyethyl)benzylideneamino]malo-
nate (4a). Iminomalonate 4a (1.85 g, 4.67 mmol) was prepared
according to the general procedure using Et3N (0.84 mL,
5.98 mmol), aldehyde 3a (1.43 g, 5.98 mmol), and diethyl amino-
malonate hydrochloride (1.27 g, 5.98 mmol). Yield: 77%. 1H NMR
C
aromeH), 8.92 (d, 1H, J¼3.5 Hz, CHO). 13C NMR (75 MHz, CDCl3):
14.0,14.2 (CH3CH2O),15.2 (CH3CH), 32.9 (CH2CH2O), 38.8 (CHCH3),
d
(300 MHz, CDCl3):
d
1.28 (t, 6H, J¼6.9 Hz, 2ꢂCH3CH2O), 3.19 (t, 2H,
56.9 (CHCHO), 59.9 (CHN), 61.6, 61.7 (CH3CH2O), 70.8 (CH2OBn),
73.1 (PhCH2), 74.9 (CCO2Et), 126.8, 127.3, 127.5, 127.6, 127.7, 128.4,
129.8 (CaromeH), 136.1, 138.0, 138.2 (CaromeC), 169.5, 171.7 (CO2Et),
201.4 (CHO). MS (CI) [m/z (rel abundance)]: 468 [(MþH)þ, 100], 450
(8), 394 (34), 376 (10), 360 (7), 256 (3), 228 (3), 133 (7), 105 (2).
HRMS: m/z calculated for [C27H34NO6]þ: 468.2386 [(MþH)þ];
found: 468.2388.
J¼7.0 Hz, CH2CH2O), 3.69 (t, 2H, J¼7.1 Hz, CH2OBn), 4.18e4.23 (m,
4H, 2ꢂCH3CH2O), 4.49 (s, 2H, PhCH2), 4.84 (s, 1H, CHCO2Et),
7.03e7.99 (m, 9H, CaromeH), 8.69 (s, 1H, HC]N). 13C NMR (75 MHz,
CDCl3):
d 14.0, 14.1 (CH3CH2O), 33.3 (CH2CH2O), 61.9, 62.0
(CH3CH2O), 71.0 (CH2OBn), 72.9 (PhCH2), 75.4 (CHCO2Et), 126.8,
127.4, 128.3, 128.8, 130.8, 131.2, 132.0 (CaromeH), 133.6, 138.4, 139.5
(CaromeC), 166.0 (HC]N), 166.9, 167.0 (CO2Et).
3.3.2. (3R,4R,5S)-Diethyl 5-[2-(2-benzyloxyethyl)-4,5-
dimethoxyphenyl]-4-formyl-3-methylpyrrolidine-2,2-dicarboxylate
(5b). Cycloadduct 5b (1.26 g, 2.39 mmol) was prepared according
to the general procedure using trans-crotonaldehyde (0.57 mL,
6.84 mmol), (S)-a,a-diphenylprolinol (0.17 g, 0.68 mmol), imine 4b
(1.53 g, 3.42 mmol), and H2O (0.25 mL, 13.68 mmol). Yield: 70%.
3 . 2 . 2 . ( E ) - D i e t h y l N - [ 2 - ( 2 - b e n z y l o x y e t h y l ) - 4 , 5 -
dimethoxybenzylideneamino]malonate (4b). Iminomalonate 4b
(2.19 g, 4.80 mmol) was prepared according to the general pro-
cedure using Et3N (1.30 mL, 9.24 mmol), aldehyde 3b (2.77 g,
9.24 mmol), and diethyl aminomalonate hydrochloride (1.96 g,
9.24 mmol). Yield: 52%. 1H NMR (300 MHz, CDCl3):
d
1.20e1.34 (m,
[
a
]
ꢀ45.4 (c 1.0, CH2Cl2). IR (neat): 1734 (C]O) cmꢀ1
.
1H NMR
20
D
6H, 2ꢂCH3CH2O), 3.09 (t, 2H, J¼7.0 Hz, CH2CH2O), 3.65 (t, 2H,
J¼7.0 Hz, CH2OBn), 3.86 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.10e4.33
(m, 4H, 2ꢂCH3CH2O), 4.48 (s, 2H, PhCH2), 4.80 (s, 1H, CHCO2Et),
6.69 (s, 1H, CaromeH), 7.17e7.38 (m, 5H, CaromeH), 7.57 (s, 1H,
(300 MHz, CDCl3):
d
1.09 (d, 3H, J¼7.0 Hz, CH3CH), 1.21e1.36 (m, 6H,
2ꢂCH3CH2O), 2.73e2.96 (m, 4H, CH2CH2OþCHCHOþNH),
3.22e3.35 (m, 1H, CHCH3), 3.59e3.64 (m, 2H, CH2OBn), 3.81 (s, 3H,
CH3O), 3.81 (s, 3H, CH3O), 3.91 (s, 1H, PhCHaHb), 3.94 (s, 1H,
PhCHaHb), 4.15e4.37 (m, 4H, 2ꢂCH3CH2O), 5.36 (d, 1H, J¼8.0 Hz,
CHN), 6.64 (s, 1H, CaromeH), 7.10 (s, 1H, CaromeH), 7.24e7.35 (m, 5H,
C
aromeH), 8.60 (s, 1H, CH]N). 13C NMR (75 MHz, CDCl3):
d 14.0, 14.1
(CH3CH2O), 32.7 (CH2CH2O), 55.8, 56.1 (CH3O), 62.0 (CH3CH2O),
71.3 (CH2OBn), 73.0 (PhCH2), 75.1 (CHCO2Et), 109.8, 112.9
(CaromeH), 126.1 (CaromeC), 127.5, 127.5, 128.4 (CaromeH), 133.7,
138.3 (CaromeC), 147.8, 151.7 (CaromeO), 164.9 (CH]N), 167.2, 169.6
(CO2Et).
C
d
aromeH), 8.92 (d, 1H, J¼3.3 Hz, CHO). 13C NMR (75 MHz, CDCl3):
14.0,14.2 (CH3CH2O),15.1 (CH3CH), 32.5 (CH2CH2O), 38.7 (CHCH3),
55.9, 56.0 (CH3O), 56.7 (CHCHO), 60.0 (CHN), 61.6, 61.7 (CH3CH2O),
70.9 (CH2OBn), 73.1 (PhCH2), 74.8 (CCO2Et), 110.4, 111.3, 127.3, 127.6,
128.3 (CaromeH), 128.9, 130.1, 138.2 (CaromeC), 147.7, 148.0
(CaromeO), 169.6, 171.7 (CO2Et), 201.4 (CHO). MS (CI) [m/z (rel
abundance)]: 528 [(MþH)þ, 100], 454 (31), 420 (12), 346 (10), 256
(16), 228 (28), 193 (20). HRMS: m/z calculated for [C29H38NO8]þ:
528.2597 [(MþH)þ]; found: 528.2614.
3 . 2 . 3 . ( E ) - D i e t h y l N - [ 2 - ( 2 - b e n z y l o x y e t h y l ) - 4 , 5 -
methylenedioxybenzylideneamino]malonate
(4c). Iminomalonate
4c (1.71 g, 3.89 mmol) was prepared according to the general
procedure using Et3N (0.70 mL, 4.98 mmol), aldehyde 3c (1.41 g,
4.98 mmol), and diethyl aminomalonate hydrochloride (1.05 g,
4.98 mmol). Yield: 78%. 1H NMR (300 MHz, CDCl3):
d
1.28 (t, 6H,
3.3.3. (3R,4R,5S)-Diethyl
5-[6-(2-benzyloxyethyl)benzo[d][1,3]di-
J¼7.1 Hz, 2ꢂCH3CH2O), 3.09e3.15 (m, 2H, CH2CH2O), 3.52e3.78 (m,
2H, CH2OBn), 4.07e4.36 (m, 4H, 2ꢂCH3CH2O), 4.48 (s, 2H, PhCH2),
4.78 (s, 1H, CHCO2Et), 5.95 (s, 2H, OCH2O), 6.68 (s, 1H, CaromeH),
7.19e7.37 (m, 5H, CaromeH), 7.56 (s, 1H, CaromeH), 8.57 (s, 1H, HC]
oxol-5-yl]-4-formyl-3-methylpyrrolidine-2,2-dicarboxylate
(5c). Cycloadduct 5c (0.51 g, 0.80 mmol) was prepared according to
the general procedure using trans-crotonaldehyde (0.08 mL,
1.00 mmol), (S)-a,a-diphenylprolinol (0.05 g, 0.20 mmol), imine 4c
20
N). 13C NMR (75 MHz, CDCl3):
d
14.0 (CH3CH2O), 32.5 (CH2CH2O),
(0.52 g, 1.30 mmol), and H2O (0.07 mL, 3.82 mmol). Yield: 80%. [a]
D
62.0 (CH3CH2O), 70.9 (CH2OBn), 71.1 (PhCH2), 73.0 (CHCO2Et), 101.4
(OCH2O), 108.1, 110.1, 111.0, 127.5, 128.4 (CaromeH), 135.3, 138.0,
139.0 (CaromeC), 146.8, 152.1 (CaromeO), 164.5 (HC]N), 167.0, 169.6
(CO2Et).
ꢀ47.6 (c 1.07, CH2Cl2). IR (neat): 1731 (C]O) cmꢀ1
.
1H NMR
(300 MHz, CDCl3):
d
1.08 (d, 3H, J¼7.0 Hz, CH3CH), 1.30 (t, 6H,
J¼7.1 Hz, 2ꢂCH3CH2O), 2.64e3.01 (m, 4H, CH2CH2OþCHCHOþNH),
3.09e3.37 (m,1H, CHCH3), 3.63 (t, 2H, J¼6.2 Hz, CH2OBn), 4.17e4.40
(m, 4H, 2ꢂCH3CH2O), 4.49 (s, 2H, PhCH2), 5.45 (d, 1H, J¼9.8 Hz,
CHN), 5.89 (s, 2H, OCH2O), 6.62 (s, 1H, CaromeH), 7.13 (s, 1H,
3.3. General procedure for the organocatalytic [3D2] cyclo-
addition of
a
,b
-unsaturated aldehydes and azomethine ylides
C
aromeH), 7.18e7.56 (m, 5H, CaromeH), 8.96 (d, 1H, J¼3.5 Hz, CHO).
13C NMR (75 MHz, CDCl3):
d
14.0, 14.2 (CH3CH2O), 15.2 (CH3CH),
a
,
b
-Unsaturated aldehyde (1.00 mmol) was added over a cooled
32.8 (CH2CH2O), 38.7 (CHCH3), 56.7 (CHCHO), 59.8 (CHN), 61.6, 61.7
(CH3CH2O), 70.8 (CH2OBn), 73.1 (PhCH2), 74.8 (CCO2Et), 100.9
(OCH2O), 107.6, 109.7, 127.6, 127.8, 128.4 (CaromeH), 129.5, 131.5,
138.2 (CaromeC), 146.5, 146.7 (CaromeO), 169.3, 171.7 (CO2Et), 201.4
(CHO). MS (CI) [m/z (rel abundance)]: 512 [(MþH)þ, 100], 511 (7),
438 (24), 404 (12), 403 (10), 402 (6), 333 (6). HRMS: m/z calculated
for [C28H34NO8]þ: 512.2284 [(MþH)þ]; found: 512.2263.
(4 ꢁC) solution of
a,a-diphenylprolinol (0.20 mmol) in THF (4 mL).
After stirring for 30 min at this temperature, imine 4 (1.30 mmol)
and water (4.00 mmol) were added at once. The reaction mixture
was stirred at 4 ꢁC for 72 h, after which the crude reaction mixture
was purified by flash column chromatography (hexanes/EtOAc 8:2),
affording the corresponding cycloaddition products 5aec.
3.3.1. (3R,4R,5S)-Diethyl 5-[2-(2-benzyloxyethyl)phenyl]-4-formyl-3-
methylpyrrolidine-2,2-dicarboxylate (5a). Cycloadduct 5a (0.23 g,
0.48 mmol) was prepared according to the general procedure using
3.4. General procedure for the reduction of the cycloadducts
5aec. Synthesis of primary alcohols 6aec
trans-crotonaldehyde (0.05 mL, 0.60 mmol), (S)-
a
,a
-diphenylpro-
NaBH4 (4.00 mmol) was added over a cooled (0 ꢁC) solution of
linol (0.03 g, 0.12 mmol), imine 4a (0.31 g, 0.78 mmol), and H2O
the corresponding cycloadducts 5aec (3.32 mmol) in MeOH (3 mL).

8882
A. Iza et al. / Tetrahedron 69 (2013) 8878e8884
After stirring for 15 min at this temperature, saturated NH4Cl (3 mL)
and CH2Cl2 (5 mL) were added and the mixture was stirred for
further 30 min at rt. The mixture was extracted with CH2Cl2
(3ꢂꢂ10 mL) and the combined organic fractions were collected,
dried over Na2SO4, filtered, and the solvent removed under reduced
pressure. Pure alcohols 6aec were isolated after flash column
chromatography purification (hexanes/EtOAc 7:3).
(3S,4S,5R) isomer¼49.61 min (96% ee). [
a
]
20 ꢀ39.6 (c 1.0, CH2Cl2). IR
D
(neat): 1729 (C]O), 3458 (OHþNH) cmꢀ1
.
1H NMR (300 MHz,
CDCl3):
d
1.15 (d, 3H, J¼7.2 Hz, CH3CH), 1.21e1.49 (m, 6H,
2ꢂCH3CH2O), 2.10e2.38 (m, 1H, CHCH2OH), 2.74e3.02 (m, 4H,
CHCH3þCH2CH2OþOH), 3.15e3.35 (m, 2H, CH2OH), 3.65 (t, 2H,
J¼7.0 Hz, CH2OBn), 4.08e4.39 (m, 4H, 2ꢂCH3CH2O), 4.49 (d,
J¼12.3 Hz, 1H, PhCHaHb), 4.53 (d, J¼12.3 Hz, 1H, PhCHaHb), 5.09 (d,
1H, J¼7.9 Hz, CHN), 5.90 (s, 2H, OCH2O), 6.67 (s, 1H, CaromeH), 7.20
(s, 1H, CaromeH), 7.23e7.54 (m, 5H, CaromeH). 13C NMR (75 MHz,
3.4.1. (3R,4R,5S)-Diethyl 5-[2-(2-benzyloxyethyl)phenyl]-4-
hydroxymethyl-3-methylpyrrolidine-2,2-dicarboxylate (6a). The re-
duction of cycloadduct 5a (1.13 g, 2.42 mmol) according to the
general procedure using NaBH4 (0.11 g, 2.91 mmol) afforded alcohol
6a (0.77 g, 1.65 mmol). Yield: 68%. The ee was determined by HPLC
using Chiralpak IA column, [n-hexane/i-PrOH (90:10)]; flow rate
CDCl3):
d 14.0, 14.2 (CH3CH2O), 16.4 (CH3CH), 32.4 (CH2CH2O), 40.2
(CHCH3), 50.8 (CHCH2OH), 57.4 (CHN), 61.5, 61.6 (CH3CH2O), 62.2
(CH2OH), 70.6 (CH2OBn), 73.1 (PhCH2), 74.4 (CCO2Et), 100.9
(OCH2O), 107.9, 109.5, 127.6, 127.7, 128.4 (CaromeH), 129.5, 132.4,
138.2 (CaromeC),146.2,146.5 (CaromeO),170.5,172.0 (CO2Et). MS (CI)
[m/z (rel abundance)]: 514 [(MþH)þ, 100], 441 (12), 440 (42), 422
(9), 327 (9). HRMS: m/z calculated for [C26H36NO8]þ: 514.2441
[(MþH)þ]; found: 514.2445.
1.00 mL/min;
s
major (3R,4R,5S) isomer¼28.58 min;
sminor (3S,4S,5R)
20
isomer¼31.33 min (94% ee). [
a]
ꢀ58.4 (c 1.0, CH2Cl2). IR (neat):
D
1728 (C]O), 3568 (OHþNH) cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 1.18
(d, 3H, J¼7.2 Hz, CH3CH), 1.30 (t, 6H, J¼7.1 Hz, 2ꢂCH3CH2O),
2.19e2.31 (m, 1H, CHCH2OH), 2.83 (br s, 1H, OH), 2.85e3.10 (m, 3H,
CHCH3þCH2CH2O), 3.15e3.35 (m, 2H, CH2OH), 3.71 (t, 2H, J¼7.0 Hz,
CH2OBn), 4.15e4.37 (m, 4H, 2ꢂCH3CH2O), 4.51 (d, J¼12.6 Hz, 1H,
PhCHaHb), 4.55 (d, J¼12.6 Hz, 1H, PhCHaHb), 5.17 (d, 1H, J¼7.5 Hz,
3.5. General procedure for the protection of cycloadducts
6aec. Synthesis of pyrrolidines 7aec
Imidazole (3.00 mmol) and TBSCl (3.00 mmol) were sequen-
tially added over a solution of 6aec (1.00 mmol) and DMAP
(0.1 mmol) in dry DMF (15 mL) at rt. After stirring at this temper-
ature for 8 h, water (10 mL) was added and the mixture was
extracted with Et2O (3ꢂ15 mL). The combined organic layers were
collected, washed sequentially with a saturated NaHCO3 solution
(1ꢂ15 mL), brine (1ꢂ15 mL) and water (1ꢂ15 mL), dried over an-
hydrous Na2SO4, filtered, and the solvent removed under reduced
pressure. Compounds 7aec were obtained after flash column
chromatography purification (hexanes/EtOAc 9:1).
CHN), 7.17e7.69 (m, 9H, CaromeH). 13C NMR (75 MHz, CDCl3):
d 14.1,
14.2 (CH3CH2O), 16.5 (CH3CH), 32.5 (CH2OBn), 40.2 (CHCH3), 50.8
(CHCH2OH), 57.6 (CHN), 61.4, 61.5 (CH3CH2O), 62.2 (CH2OH), 70.6
(CH2CH2O), 73.0 (PhCH2), 74.5 (CCO2Et), 126.5, 127.1, 127.2, 127.6,
127.7, 128.4, 129.5 (CaromeH), 136.2, 138.2, 138.9 (CaromeC), 170.6,
172.1 (CO2Et). MS (CI) [m/z (rel abundance)]: 470 [(MþH)þ, 100],
452 (11), 424 (21), 396 (42), 378 (10), 316 (6), 283 (4),192 (2), 91 (3).
HRMS: m/z calculated for [C27H35NO6]þ: 470.2543 [(MþH)þ];
found: 470.2549.
3.4.2. (3R,4R,5S)-Diethyl 5-[2-(2-benzyloxyethyl)-4,5-
dimethoxyphenyl]-4-hydroxymethyl-3-methylpyrrolidine-2,2-
dicarboxylate (6b). The reduction of cycloadduct 5b (1.30 g,
2.47 mmol) according to the general procedure using NaBH4 (0.11 g,
2.96 mmol) afforded alcohol 6b (0.81 g, 1.53 mmol). Yield: 62%. The
ee was determined by HPLC using Chiralpak IA column, [n-hexane/
i-PrOH (95:5)]; flow rate 1.00 mL/min; smajor (3R,4R,5S)
3.5.1. (3R,4R,5S)-Diethyl 5-[2-(2-benzyloxyethyl)phenyl]-4-(tert-bu-
tyldimethylsilyloxymethyl)-3-methylpyrrolidine-2,2-dicarboxylate
(7a). Compound 7a (1.04 g, 1.78 mmol) was prepared according to
the general procedure using imidazole (0.40 g, 5.90 mmol), TBSCl
(0.89 g, 5.90 mmol), 6a (0.92 g, 1.97 mmol), and DMAP (13 mg,
20
0.1 mmol). Yield: 91%. [
a]
ꢀ50.5 (c 1.0, CH2Cl2). IR (neat): 1732
D
(C]O) cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
ꢀ0.19 (s, 3H, CH3Si),
isomer¼66.69 min; sminor (3S,4S,5R) isomer¼75.40 min (94% ee).
ꢀ0.17 (s, 3H, CH3Si), 0.76 (s, 9H, (CH3)3C), 1.19 (d, 3H, J¼7.1 Hz,
CH3CH), 1.29 (m, 6H, 2ꢂCH3CH2O), 2.16e2.30 (m, 1H, CHCH2OSi),
2.70 (br s, 1H, OH), 2.75e3.20 (m, 5H, CHCH3þCH2CH2OþCH2OSi),
3.62e3.74 (m, 2H, CH2OBn), 4.14e4.36 (m, 4H, 2ꢂCH3CH2O), 4.52
(d, J¼12.6 Hz, 1H, PhCHaHb), 4.56 (d, J¼12.6 Hz, 1H, PhCHaHb), 5.15
(d, 1H, J¼8.4 Hz, CHN), 6.96e7.71 (m, 9H, CaromeH). 13C NMR
20
[
a]
ꢀ49.3 (c 1.0, CH2Cl2). IR (neat): 1731 (C]O), 3541
D
(OHþNH) cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
1.16 (d, 3H, J¼7.1 Hz,
CH3CH), 1.21e1.42 (m, 6H, 2ꢂCH3CH2O), 2.07e2.35 (m, 1H,
CHCH2OH), 2.70e3.05 (m, 4H, CHCH3þCH2CH2OþOH), 3.10e3.40
(m, 2H, CH2OH), 3.67 (t, 2H, J¼6.7 Hz, CH2OBn), 3.81 (s, 3H, CH3O),
3.83 (s, 3H, CH3O), 4.12e4.37 (m, 4H, 2ꢂCH3CH2O), 4.49 (d,
J¼11.5 Hz, 1H, PhCHaHb), 4.53 (d, J¼11.5 Hz, 1H, PhCHaHb), 5.10 (d,
1H, J¼8.0 Hz, CHN), 6.68 (s, 1H, CaromeH), 7.20 (s, 1H, CaromeH),
(75 MHz, CDCl3):
d
ꢀ5.7, ꢀ5.6 ((CH3)2Si), 14.0, 14.2 (CH3CH2O), 16.8
(CH3CH), 18.2 ((CH3)3C), 25.8 ((CH3)3C), 32.9 (CH2CH2O), 41.8
(CHCH3), 50.3 (CHCH2OH), 57.5 (CHN), 61.2, 61.3 (CH3CH2O), 63.7
(CH2OSi), 70.9 (CH2OBn), 73.0 (PhCH2), 74.7 (CCO2Et), 126.0, 126.6,
127.5, 127.6, 127.7, 128.4, 129.2 (CaromeH), 136.0, 138.4, 139.4
(CaromeC), 170.4, 172.4 (CO2Et). MS (CI) [m/z (rel abundance)]: 584
[(MþH)þ, 100], 568 (19), 526 (16), 510 (44), 492 (8), 452 (6), 397 (7),
360 (3), 289 (7), 91 (2). HRMS: m/z calculated for [C33H49NO6Si]þ:
584.3407 [(MþH)þ]; found: 584.3400.
7.24e7.37 (m, 5H, CaromeH). 13C NMR (75 MHz, CDCl3):
d 14.0, 14.2
(CH3CH2O), 16.2 (CH3CH), 32.1 (CH2CH2O), 40.1 (CHCH3), 51.0
(CHCH2OH), 55.8, 55.8 (CH3O), 57.3 (CHN), 61.4, 61.6 (CH3CH2O),
62.1 (CH2OH), 70.7 (CH2OBn), 73.1 (PhCH2), 74.6 (CCO2Et), 110.5,
112.8, 127.6, 127.7 (CaromeH), 127.8 (CaromeC), 128.4 (CaromeH),
131.2, 138.2 (CaromeC), 147.4, 147.7 (CaromeO), 170.7, 172.0 (CO2Et).
MS (CI) [m/z (rel abundance)]: 530 [(MþH)þ, 100], 512 (13), 485
(22), 484 (100), 456 (31), 376 (35), 348 (13), 310 (29), 212 (13).
HRMS: m/z calculated for [C29H40NO8]þ: 530.2754 [(MþH)þ];
found: 530.2778.
3.5.2. (3R,4R,5S)-Diethyl 5-[2-(2-benzyloxyethyl)-4,5-
dimethoxyphenyl]-4-(tert-butyldimethylsilyloxymethyl)-3-
methylpyrrolidine-2,2-dicarboxylate (7b). Compound 7b (0.52 g,
0.81 mmol) was prepared according to the general procedure using
imidazole (0.23 g, 3.41 mmol), TBSCl (0.51 g, 3.41 mmol), 6b (0.60 g,
3.4.3. (3R,4R,5S)-Diethyl
5-[6-(2-benzyloxyethyl)benzo[d][1,3]di-
oxol-5-yl]-4-hydroxymethyl-3-methylpyrrolidine-2,2-dicarboxylate
(6c). The reduction of cycloadduct 5c (0.39 g, 0.76 mmol) according
to the general procedure using NaBH4 (0.03 g, 0.91 mmol) afforded
alcohol 6c (0.33 g, 0.63 mmol). Yield: 84%. The ee was determined
by HPLC using Chiralpak IA column, [n-hexane/i-PrOH (95:5)];
flow rate 1.00 mL/min; smajor (3R,4R,5S) isomer¼43.63 min; sminor
1.13 mmol), and DMAP (7 mg, 0.06 mmol). Yield: 72%. [
a
]
20 ꢀ39.7 (c
1.02, CH2Cl2). IR (neat): 3370 (NH), 1733 (C]O) cmꢀ1D
.
1H NMR
(300 MHz, CDCl3):
d
ꢀ0.16 (s, 3H, CH3Si), ꢀ0.13 (s, 3H, CH3Si), 0.77
(s, 9H, (CH3)3C), 1.17 (d, 3H, J¼7.0 Hz, CH3CH), 1.22e1.36 (m, 6H,
2ꢂCH3CH2O), 2.13e2.26 (m, 1H, CHCH2OSi), 2.71e2.85 (m, 2H,
CH2CH2O), 2.86e3.31 (m, 4H, CHCH3þCH2OSiþNH), 3.61e3.71

A. Iza et al. / Tetrahedron 69 (2013) 8878e8884
8883
(m, 2H, CH2OBn), 3.81 (s, 3H, CH3O), 3.81 (s, 3H, CH3O), 4.15e4.32
(m, 4H, 2ꢂCH3CH2O), 4.50 (d, J¼12.3 Hz, 1H, PhCHaHb), 4.54 (d,
J¼12.3 Hz, 1H, PhCHaHb), 5.08 (d, 1H, J¼8.6 Hz, CHN), 6.65 (s, 1H,
436 (19), 420 (39), 402 (4), 372 (3), 361 (5), 307 (3). HRMS: m/z
calculated for [C26H43NO6Si]þ: 494.2938 [(MþH)þ]; found:
494.2942.
C
aromeH), 7.09 (s, 1H, CaromeH), 7.29e7.37 (m, 5H, CaromeH). 13C
NMR (75 MHz, CDCl3):
d
ꢀ5.6, ꢀ5.5 ((CH3)2Si), 14.0, 14.2 (CH3CH2O),
3.6.2. (3R,4R,5S)-Diethyl 4-(tert-butyldimethylsilyloxymethyl)-5-[2-
(2-hydroxyethyl)-4,5-dimethoxyphenyl]-3-methylpyrrolidine-2,2-
dicarboxylate (8b). Compound 8b (0.12 g, 0.22 mmol) was prepared
16.6 (CH3CH), 18.2 ((CH3)3C), 25.9 ((CH3)3C), 32.6 (CH2CH2O), 41.8
(CHCH3), 50.5 (CHCH2OSi), 55.8, 55.9 (CH3O), 57.3 (CHN), 61.2, 61.4
(CH3CH2O), 63.7 (CH2OSi), 71.1 (CH2OBn), 73.0 (PhCH2), 74.8
(CCO2Et), 110.9, 112.7, 127.5, 127.6, 128.3 (CaromeH), 128.4, 131.8,
138.4 (CaromeC), 147.0, 147.3 (CaromeO), 170.5, 172.4 (CO2Et). MS (CI)
[m/z (rel abundance)]: 644 [(MþH)þ, 100], 571 (22), 570 (57), 536
(36), 535 (17), 462 (21), 372 (20), 349 (42). HRMS: m/z calculated for
[C35H54NO8Si]þ: 644.3619 [(MþH)þ]; found: 644.3614.
according to the general procedure using 7b (0.22 g, 0.34 mmol)
20
and Pd/C (10 mg). Yield: 65%. [
a]
ꢀ47.9 (c 1.0, CH2Cl2). IR (neat):
D
1732 (C]O), 3360 (OHþNH) cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
ꢀ0.25 (s, 3H, CH3Si), ꢀ0.18 (s, 3H, CH3Si), 0.69 (s, 9H, (CH3)3C), 1.13
(d, 3H, J¼7.1 Hz, CH3CH), 1.17e1.30 (m, 6H, 2ꢂCH3CH2O), 2.16e2.28
(m, 1H, CHCH2OSi), 2.40e2.88 (br s, 1H, OH), 2.71e2.89 (m, 3H,
CH2CH2OHþCHCH3), 3.10e3.27 (m, 2H, CH2OSi), 3.68e3.75 (m, 1H,
CH2OH), 3.76 (s, 3H, CH3O), 3.80 (s, 3H, CH3O), 4.10e4.30 (m, 4H,
2ꢂCH3CH2O), 5.08 (d,1H, J¼8.5 Hz, CHN), 6.59 (s,1H, CaromeH), 7.06
3.5.3. (3R,4R,5S)-Diethyl
5-[6-(2-benzyloxyethyl)benzo[d][1,3]di-
oxol-5-yl]-4-(tert-butyldimethylsilyloxymethyl)-3-methylpyrrolidine-
2,2-dicarboxylate (7c). Compound 7c (0.26 g, 0.41 mmol) was
prepared according to the general procedure using imidazole
(0.10 g, 1.47 mmol), TBSCl (0.22 g, 1.47 mmol), 6c (0.25 g,
(s, 1H, CaromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.9, ꢀ5.7 ((CH3)2Si),
14.0, 14.1 (CH3CH2O), 16.5 (CH3CH), 18.2 ((CH3)3C), 25.6 ((CH3)3C),
35.5 (CH2CH2OH), 41.7 (CHCH3), 50.6 (CHCH2OSi), 55.7, 55.8 (CH3O),
57.2 (CHN), 61.3, 61.4 (CH3CH2O), 63.5 (CH2OSi), 63.7 (CH2OH), 74.6
(CCO2Et), 111.2, 112.8 (CaromeH), 128.6, 132.0 (CaromeC), 147.2, 147.6
(CaromeO), 170.3, 172.2 (CO2Et). MS (CI) [m/z (rel abundance)]: 554
[(MþH)þ, 100], 536 (62), 480 (56), 462 (36), 372 (19), 349 (52), 193
(20). HRMS: m/z calculated for [C28H48NO8Si]þ: 554.3149
[(MþH)þ]; found: 554.3141.
0.49 mmol), and DMAP (3 mg, 0.02 mmol). Yield: 84%. [
(c 1.0, CH2Cl2). IR (neat): 1733 (C]O), 3368 (NH) cmꢀ1
(300 MHz, CDCl3):
a
.
]
20 ꢀ32.5
D
1H NMR
d
ꢀ0.16 (s, 3H, CH3Si), ꢀ0.13 (s, 3H, CH3Si), 0.78
(s, 9H, (CH3)3C), 1.16 (d, 3H, J¼7.1 Hz, CH3CH), 1.24e1.33 (m, 6H,
2ꢂCH3CH2O), 2.10e2.23 (m, 1H, CHCH2OSi), 2.63e3.23 (m, 6H,
CHCH3þCH2OSiþCH2CH2OþNH), 3.63 (t, 2H, J¼7.1 Hz, CH2OBn),
4.10e4.37 (m, 4H, 2ꢂCH3CH2O), 4.51 (d, J¼12.3 Hz, 1H, PhCHaHb),
4.55 (d, J¼12.3 Hz, 1H, PhCHaHb), 5.07 (d, 1H, J¼8.8 Hz, CHN), 5.88
(s, 2H, OCH2O), 6.63 (s, 1H, CaromeH), 7.12 (s, 1H, CaromeH),
3.6.3. (3R,4R,5S)-Diethyl 4-(tert-butyldimethylsilyloxymethyl)-5-[6-
(2-hydroxyethyl)benzo[d][1,3]dioxol-5-yl]-3-methylpyrrolidine-2,2-
dicarboxylate (8c). Compound 8c (0.09 g, 0.17 mmol) was prepared
according to the general procedure using 7c (0.24 g, 0.38 mmol)
7.28e7.40 (m, 5H, CaromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.7, ꢀ5.6
((CH3)2Si), 14.0, 14.2 (CH3CH2O), 16.7 (CH3CH), 18.1 ((CH3)3C), 25.9
((CH3)3C), 32.8 (CH2CH2O), 41.6 (CHCH3), 50.2 (CHCH2OSi), 57.3
(CHN), 61.2, 61.3 (CH3CH2O), 63.4 (CH2OSi), 70.9 (CH2OBn), 73.0
(PhCH2), 74.6 (CCO2Et), 100.6 (OCH2O), 108.2, 109.2, 127.5, 127.6,
128.4 (CaromeH), 129.4, 133.2, 138.4 (CaromeC), 145.8, 146.0
(CaromeO), 170.2, 172.5 (CO2Et). MS (CI) [m/z (rel abundance)]: 628
[(MþH)þ, 100], 612 (21), 555 (24), 554 (70), 520 (41), 446 (36), 441
(29), 372 (20), 333 (76). HRMS: m/z calculated for [C34H50NO8Si]þ:
628.3306 [(MþH)þ]; found: 628.3312.
and Pd/C (10 mg). Yield: 44%. [
a
]
20 ꢀ40.3 (c 1.0, CH2Cl2). IR (neat):
D
1732 (C]O), 3359 (OHþNH) cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
ꢀ0.19 (s, 3H, CH3Si), ꢀ0.13 (s, 3H, CH3Si), 0.75 (s, 9H, (CH3)3C), 1.16
(d, 3H, J¼7.1 Hz, CH3CH), 1.22e1.34 (m, 6H, 2ꢂCH3CH2O), 1.69 (br s,
1H, OH), 2.13e2.32 (m, 1H, CHCH2OSi), 2.68e2.92 (m, 3H,
CH2CH2OHþCHCH3), 3.27 (d, 2H, J¼6.7 Hz, CH2OSi), 3.65e3.90 (m,
2H, CH2OH), 4.08e4.39 (m, 4H, 2ꢂCH3CH2O), 5.12 (d, 1H, J¼8.5 Hz,
CHN), 5.89 (s, 2H, OCH2O), 6.61 (s, 1H, CaromeH), 7.13 (s, 1H,
C
aromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.9, ꢀ5.7 ((CH3)2Si), 14.0,
3.6. General procedure for the debenzylation reaction. Syn-
thesis of pyrrolidines 8aec
14.2 (CH3CH2O), 16.6 (CH3CH), 18.2 ((CH3)3C), 25.8 ((CH3)3C), 35.9
(CH2CH2OH), 41.6 (CHCH3), 50.4 (CHCH2OSi), 57.2 (CHN), 61.3, 61.4
(CH3CH2O), 63.5 (CH2OSi), 63.6 (CH2OH), 74.5 (CCO2Et), 100.7
(OCH2O),108.4,109.3 (CaromeH), 129.8, 133.3 (CaromeC), 146.0, 146.2
(CaromeO), 170.1, 172.3 (CO2Et). MS (CI) [m/z (rel abundance)]: 538
[(MþH)þ, 100], 520 (65), 464 (91), 446 (57), 372 (44), 333 (98), 177
(59), 141 (62). HRMS: m/z calculated for [C27H44NO8Si]þ: 538.2862
[(MþH)þ]; found: 538.2836.
A solution of 7aec (0.18 mmol) in MeOH (10 mL) was stirred in
the presence of a catalytic amount of Pd/C (10% w/w) under a H2
atmosphere (balloon) at rt for 24 h. Next, the mixture was filtered
and the solvent was removed under reduced pressure. Compounds
8aec were obtained as a colorless oil after flash column chroma-
tography purification (hexanes/EtOAc 8:2).
3.7. General procedure for the cyclization reaction. Synthesis
3.6.1. (3R,4R,5S)-Diethyl 4-(tert-butyldimethylsilyloxymethyl)-5-[2-
(2-hydroxyethyl)phenyl]-3-methylpyrrolidine-2,2-dicarboxylate
(8a). Compound 8a (0.08 g, 0.17 mmol) was prepared according to
the general procedure using 7a (0.11 g, 0.18 mmol) and Pd/C
of pyrrolo[2,1-a]isoquinolines 9aec
Et3N (2.00 mmol) and MsCl (2.00 mmol) were sequentially
added over a solution of 8aec (1.00 mmol) and DMAP (0.05 mmol)
in CH2Cl2 (20 mL) at 0 ꢁC. After stirring at this temperature for
90 min, a 2 M solution of KOH (10 mL) was added and the mixture
stirred another 2 h. The mixture was then extracted with CH2Cl2
(3ꢂ15 mL) and the combined organic layers were collected, dried
over anhydrous Na2SO4, filtered, and the solvent removed under
reduced pressure. Compounds 9aec were obtained as a colorless oil
after flash column chromatography purification (hexanes/EtOAc
9:1).
(10 mg). Yield: 81%. [
a
]
20 ꢀ51.5 (c 1.0, CH2Cl2). IR (neat): 1729 (C]
O), 3433 (OHþNH) cmꢀD1. 1H NMR (300 MHz, CDCl3):
ꢀ0.25 (s, 3H,
d
CH3Si), ꢀ0.18 (s, 3H, CH3Si), 0.73 (s, 9H, (CH3)3C), 1.18 (d, 3H,
J¼7.1 Hz, CH3CH), 1.28 (t, 6H, J¼7.0 Hz, 2ꢂCH3CH2O), 2.22e2.36 (m,
1H, CHCH2OSi), 2.72e3.00 (m, 3H, CHCH3þCH2OSi), 3.12e3.32 (m,
2H, CH2CH2OH), 3.73e3.93 (m, 2H, CH2OH), 4.12e4.36 (m, 4H,
2ꢂCH3CH2O), 5.19 (d, 1H, J¼8.5 Hz, CHN), 7.09e7.58 (m, 4H,
C
aromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.9, ꢀ5.7 ((CH3)2Si), 14.0,
14.2 (CH3CH2O), 16.6 (CH3CH), 18.2 ((CH3)3C), 25.9 ((CH3)3C), 36.0
(CH2CH2OH), 41.8 (CHCH3), 50.5 (CHCH2OSi), 57.3 (CHN), 61.3, 61.4
(CH3CH2O), 63.5 (CH2OSi), 63.7 (CH2OH), 74.6 (CCO2Et), 126.2,
126.8, 128.1, 129.6 (CaromeH), 136.5, 139.6 (CaromeC), 170.2, 172.3
(CO2Et). MS (CI) [m/z (rel abundance)]: 494 [(MþH)þ,100], 478 (21),
3.7.1. (1R,2R,10bS)-Diethyl 1-(tert-butyldimethylsilyloxymethyl)-2-
methyl-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-3,3(10bH)-di-
carboxylate (9a). Pyrrolo[2,1-a]isoquinoline 9a (0.12 g, 0.25 mmol)
was prepared according to the general procedure using Et3N

8884
A. Iza et al. / Tetrahedron 69 (2013) 8878e8884
(0.09 mL, 0.65 mmol), MsCl (0.05 mL, 0.65 mmol), 8a (0.16 g,
3.44e3.53 (m, 1H, CHaHbCH2N), 3.57 (dd, 1H, J¼10.0, 4.6 Hz,
CHaHbOSi), 4.14e4.30 (m, 4H, 2ꢂCH3CH2O), 4.47 (d, 1H, J¼6.0 Hz,
CHN), 5.87 (s, 1H, OCHaHbO), 5.90 (s, 1H, OCHaHbO), 6.54 (s, 2H,
0.32 mmol), and DMAP (2 mg, 0.02 mmol). Yield: 75%. [
(c 1.0, CH2Cl2). IR (neat): 1731 (C]O) cmꢀ1
CDCl3):
a
]
20 ꢀ93.5
D
.
1H NMR (300 MHz,
d
ꢀ0.08 (s, 3H, CH3Si), ꢀ0.07 (s, 3H, CH3Si), 0.85 (s, 9H,
C
aromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.5, ꢀ5.4 ((CH3)2Si), 14.1,
(CH3)3C), 1.20e1.34 (m, 9H, CH3CHþ2ꢂCH3CH2O), 2.22e2.33 (m,
1H, CHCH2OSi), 2.65 (dt, 1H, J¼15.6, 1.2 Hz, CHaHbCH2N), 2.72e3.26
(m, 4H, CH2NþCHCH3þCHaHbCH2N), 3.47e3.63 (m, 2H, CH2OSi),
4.14e4.32 (m, 4H, 2ꢂCH3CH2O), 4.59 (d, 1H, J¼6.4 Hz, CHN),
14.4 (CH3CH2O), 17.7 (CH3CH), 18.1 ((CH3)3C), 25.9 ((CH3)3C), 30.9
(CH2CH2N), 42.6 (CHCH3), 44.1 (CH2N), 49.8 (CHCH2Si), 60.6, 61.0
(CH3CH2O), 61.6 (CHN), 63.4 (CH2OSi), 77.2 (CCO2Et), 100.6
(OCH2O),106.2,108.7 (CaromeH),128.8,129.0 (CaromeC),145.5,145.6
(CaromeO), 168.6, 170.4 (CO2Et). MS (CI) [m/z (rel abundance)]: 520
[(MþH)þ, 100], 518 (28), 504 (30), 446 (74), 387 (32), 334 (25),
314 (25). HRMS: m/z calculated for [C27H42NO7Si]þ: 520.2731
[(MþH)þ]; found: 520.2756.
6.98e7.23 (m, 4H, CaromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.5, ꢀ5.4
((CH3)2Si), 14.1, 14.4 (CH3CH2O), 17.7 (CH3CH), 18.1 ((CH3)3C), 25.9
((CH3)3C), 30.9 (CH2CH2N), 42.7 (CHCH3), 44.1 (CH2N), 49.5
(CHCH2OSi), 60.5, 61.0 (CH3CH2O), 61.6 (CHN), 63.4 (CH2OSi), 76.6
(CCO2Et), 125.3, 125.6, 126.3, 128.9 (CaromeH), 135.8, 135.9
(CaromeC), 168.6, 170.5 (CO2Et). MS (CI) [m/z (rel abundance)]: 476
[(MþH)þ, 100], 460 (29), 418 (24), 402 (61), 343 (22), 289 (37), 270
(8), 233 (10). HRMS: m/z calculated for [C26H42NO5Si]þ: 476.2832
[(MþH)þ]; found: 476.2833.
Acknowledgements
The authors thank the Spanish MICINN (CTQ2011-22790), the
Basque Government (Grupos IT328-10 and fellowship to U.U.), and
UPV/EHU (UFI QOSYC 11/22 and fellowship to A.I. and I.U.) for fi-
nancial support. Membership in the COST Action CM0905 is also
acknowledged.
3.7.2. (1R,2R,10bS)-Diethyl 1-(tert-butyldimethylsilyloxymethyl)-8,9-
dimethoxy-2-methyl-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-
3,3(10bH)-dicarboxylate
(9b). Pyrrolo[2,1-a]isoquinoline
9b
(0.049 g, 0.092 mmol) was prepared according to the general pro-
cedure using Et3N (0.03 mL, 0.22 mmol), MsCl (0.02 mL,
0.22 mmol), 8b (0.072 g, 0.11 mmol), and DMAP (3 mg, 0.02 mmol).
Supplementary data
1H and 13C NMR spectra of all prepared compounds. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2013.08.012.
Yield: 82%. [
a
]
20 ꢀ90.0 (c 0.52, CH2Cl2). IR (neat): 1731 (C]O) cmꢀ1
.
D
1H NMR (300 MHz, CDCl3):
d
ꢀ0.06 (s, 3H, CH3Si), ꢀ0.05
(s, 3H, CH3Si), 0.84 (s, 9H, (CH3)3C), 1.20e1.34 (m, 9H,
CH3CHþ2ꢂCH3CH2O), 2.21 (dd, 1H, J¼6.2, 4.2 Hz, CHCH2OSi), 2.54
(d,1H, J¼15.2 Hz, CHaHbN), 2.79 (dt, 1H, J¼11.4, 3.0 Hz, CHaHbCH2N),
2.91e3.04 (m, 1H, CHaHbN), 3.10e3.22 (m, 2H, CHaHbOSiþCHCH3),
3.51 (dd, 1H, J¼10.9, 4.8 Hz, CHaHbCH2N), 3.60 (dd, 1H, J¼10.0,
4.3 Hz, CHaHbOSi), 3.81 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 4.13e4.30
(m, 4H, 2ꢂCH3CH2O), 4.49 (d, 1H, J¼6.0 Hz, CHN), 6.56 (s, 1H,
References and notes
1. For pharmacological activity examples, see: (a) Moreno, L.; Parraga, J.; Galan, A.;
Cabedo, N.; Primo, J.; Cortes, D. Bioorg. Med. Chem. 2012, 20, 6589; (b) Bentley, K.
W. Nat. Prod. Rep. 2005, 22, 249; (c) Kubota, H.; Kakefuda, A.; Watanabe, T.; Ishii,
N.; Wada, K.; Masuda, N.; Sakamoto, S.; Tsukamoto, S.-I. J. Med. Chem. 2003, 46,
4728; (d) Paluchowska, M. H.; Bojarski, A. J.; Charakchieva-, M. S.; Wesolowska,
A. Eur. J. Med. Chem. 2002, 37, 273; (e) Kuo, R.-Y.; Wu, C.-C.; Chang, F.-R.; Yeh, J.-L.;
Chen, I.-J.; Wu, Y.-C. Bioorg. Med. Chem. Lett. 2003, 13, 821.
C
aromeH), 6.56 (s, 1H, CaromeH). 13C NMR (75 MHz, CDCl3):
d
ꢀ5.4,
ꢀ5.3 ((CH3)2Si), 14.1, 14.4 (CH3CH2O), 17.8 (CH3CH), 18.2 ((CH3)3C),
25.9 ((CH3)3C), 30.4 (CH2CH2N), 42.7 (CHCH3), 44.2 (CH2N), 49.7
(CHCH2OSi), 55.8, 56.0 (CH3O), 60.5, 61.0 (CH3CH2O), 61.2 (CHN),
63.5 (CH2OSi), 76.6 (CCO2Et), 109.0, 111.6 (CaromeH), 127.8, 128.0
(CaromeC), 147.0, 147.1 (CaromeO), 168.6, 170.4 (CO2Et). MS (CI) [m/z
(rel abundance)]: 536 [(MþH)þ, 100], 534 (19), 520 (25), 463 (20),
462 (60), 403 (18), 349 (61). HRMS: m/z calculated for
[C28H46NO7Si]þ: 536.3044 [(MþH)þ]; found: 536.3040.
2. For BischlereNapieralski examples, see: (a) Xu, X.; Guo, S.; Dang, Q.; Chen, J.; Bai,
X. J. Comb. Chem. 2007, 9, 773; (b) Ishikawa, T.; Shimooka, K.; Narioka, T.; No-
guchi, S.; Saito, T.; Ishikawa, A.; Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi,
K. J. Org. Chem. 2000, 65, 9143; (c) Bischler, A.; Napieralski, B. Ber. Dtsch. Chem.
Ges. 1893, 26, 1903; For PomeranzeFritsch examples, see: (d) Brown, E. V. J. Org.
Chem. 1977, 42, 3208; (e) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77, 6355; (f)
Fritsch, P. Ber. Dtsch. Chem. Ges. 1893, 26, 419; (g) Pomeranz, C. Monatsh. Chem.
1893, 14, 116; For PicteteSpengler examples, see: (h) Youn, S. W. J. Org. Chem.
2006, 71, 2521; (i) Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030.
3. For selected recent metal-catalyzed isoquinoline syntheses, see: (a) Guimond,
N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050; (b) Hwang, S.; Lee, Y.; Lee, P. H.;
Shin, S. Tetrahedron Lett. 2009, 50, 2305; (c) Gao, H.; Zhang, J. Adv. Synth. Catal.
2009, 351, 85; (d) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 46, 4764; (e) Konno, T.; Chae, J.; Miyabe, T.; Ishihara,
T. J. Org. Chem. 2005, 70, 10172; (f) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7,
5179; (g) Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920; (h) Huang, Q.; Larock,
R. C. J. Org. Chem. 2003, 68, 980; (i) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002,
67, 86; (j) Dai, G.; Larock, R. C. Org. Lett. 2002, 4, 193; (k) Huang, Q.; Hunter, J. A.;
Larock, R. C. J. Org. Chem. 2002, 67, 3437; (l) Huang, Q.; Larock, R. C. Tetrahedron
Lett. 2002, 43, 3557.
3.7.3. (1R,2R,10bS)-Diethyl 1-(tert-butyldimethylsilyloxymethyl)-2-
methyl-1,2,5,6-tetrahydro[1,3]-dioxol[4,5-g]-pyrrolo[2,1-a]isoquino-
line-3,3(10bH)-dicarboxylate (9c). Pyrrolo[2,1-a]isoquinoline 9c
(0.06 g, 0.16 mmol) was prepared according to the general pro-
cedure using Et3N (0.04 mL, 0.27 mmol), MsCl (0.02 mL,
0.27 mmol), 8c (0.07 g, 0.13 mmol), and DMAP (2 mg, 0.01 mmol).
Yield: 86%. [
a
]
20 ꢀ104.3 (c 1.0, CH2Cl2). IR (neat): 1731 (C]O) cmꢀ1
.
D
4. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795.
5. Reimann, E. Prog. Chem. Org. Nat. Prod. 2007, 88, 1.
1H NMR (300 MHz, CDCl3):
d
ꢀ0.06 (s, 3H, CH3Si), ꢀ0.06
6. (a) Reboredo, S.; Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L.; de Cozar, A.; Cossío,
F. P. Chem.dEur. J. 2012, 18, 7179; (b) Reboredo, S.; Vicario, J. L.; Badía, D.; Carrillo,
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Badía, D.; Reyes, E.; Martinez, J. I. Org. Biomol. Chem. 2010, 8, 2238; (d) Vicario, J.
L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168.
(s, 3H, CH3Si), 0.85 (s, 9H, (CH3)3C), 1.18e1.33 (m, 9H,
CH3CHþ2ꢂCH3CH2O), 2.11e2.23 (m, 1H, CHCH2OSi), 2.50 (d, 1H,
J¼15.1 Hz, CHaHbN), 2.77 (dt, 1H, J¼11.3, 2.8 Hz, CHaHbCH2N),
2.87e3.03 (m, 1H, CHaHbN), 3.06e3.22 (m, 2H, CHCH3þCHaHbOSi),