Highly active asymmetric Diels-Alder reactions catalyzed by C2-symmetric bipyrrolidines: catalyst recycling in water medium and insight into the catalytic mode

Article abstract of DOI:10.1016/j.tet.2010.03.042

A new class of C₂-symmetric 3,3′-dialkoxy-2,2′-bipyrrolidines have been designed and synthesized for asymmetric organocatalytic Diels-Alder reactions of α,β-unsaturated aldehydes. The remarkable rate-accelerating effect for the cycloaddition reaction has been observed in aqueous medium. The catalyst 1c·2HClO₄ can be recovered and reused several times by simple extraction without significant loss of catalytic activity and stereoselectivity. The catalytic mode has been demonstrated by DFT calculation, NMR, and X-ray crystallographic studies for diiminium intermediate.

Full text of DOI:10.1016/j.tet.2010.03.042

Tetrahedron 66 (2010) 3849–3854
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly active asymmetric Diels–Alder reactions catalyzed by C2-symmetric
bipyrrolidines: catalyst recycling in water medium and insight
into the catalytic mode
,
a,
*
Yuanhui Ma a, Shangbin Jin a, Yuhe Kan b, Yong Jian Zhang a , Wanbin Zhang
*
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
b School of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian, Jiangshu 223300, PR China
a r t i c l e i n f o
a b s t r a c t
A new class of C2-symmetric 3,30-dialkoxy-2,20-bipyrrolidines have been designed and synthesized for
asymmetric organocatalytic Diels–Alder reactions of -unsaturated aldehydes. The remarkable rate-
accelerating effect for the cycloaddition reaction has been observed in aqueous medium. The catalyst
1c$2HClO4 can be recovered and reused several times by simple extraction without significant loss of
catalytic activity and stereoselectivity. The catalytic mode has been demonstrated by DFT calculation,
NMR, and X-ray crystallographic studies for diiminium intermediate.
Article history:
Received 23 December 2009
Received in revised form 1 March 2010
Accepted 12 March 2010
a,b
Available online 27 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
An alternative promising strategy is the development of immo-
bilized and recyclable organocatalytic system.6 However, although
During the past decade, organocatalysis has witnessed an ex-
plosive growth in the field of asymmetric synthesis since it employs
small organic molecules that are relatively non-toxic, inexpensive
and stable to both air and moisture.1 Organocatalysis has become
the third main branch in catalytic asymmetric synthesis together
with enzymatic and organometallic catalysis and great numbers of
new asymmetric transformations have been developed by small
organic molecules as catalysts. The enantioselective Diels–Alder
reaction is one of the most powerful synthetic methods for con-
struction of cyclohexane frameworks, and is a versatile tool for the
synthesis of many important chiral building blocks for the total
synthesis of bioactive natural products.2 Since MacMillan and
co-workers reported the first metal-free organocatalytic asym-
metric Diels–Alder reaction,3 several efforts have been devoted to
the development of organocatalytic systems including active imi-
nium ion intermediates for this important transformation.4,5
However, in order to achieve reasonable reaction rates with these
organocatalysts, high catalyst loading is generally required. This
will raise a cost concern when a large amount of chiral catalysts,
which are usually prepared in multi-step, are used for a large scale
of synthesis in industrial applications. Therefore, the development
of highly active organocatalysts aiming to lower catalyst loading is
a significant challenging task.
facile recovery of iminium catalysts has been achieved, catalyst
modifications are generally required by connection of catalysts to
various supporting materials, and inferior efficiency and stereo-
selectivity were observed in comparison with their nonsupported
counterparts. Most recently, some efforts have also been devoted to
asymmetric organocatalytic reactions performed using water as
reaction medium.7 The high polarity of water has a possibility to
stabilize an ionic intermediate.8 In addition, the hydrophobicity of
organic compounds may give rise to cohesion of substrates, which
often enhances reaction kinetics.9 For Diels–Alder reaction, Breslow
demonstrated that the reaction is accelerated in the presence of
water.10 In fact, most of chiral amine-Brønsted acid catalyzed Diels–
Alder reactions were performed in wet-solvent system. It was
demonstrated that water played a significant role in the acceleration
of reaction rates. However, there are only few reports on asym-
metric organocatalysis in water for catalyst recycling,11 despite
water is an ideal solvent because it is nontoxic, cheap, hazardless in
handling, and environmentally benign.
Quite recently, we designed C2-symmetric bipyrrolidine orga-
nocatalysts 1,12 which can potentially accelerate the reaction rate of
iminium-catalyzed Diels–Alder reaction by providing two identical
reaction sites. In this article, we wish to present synthesis of
C2-symmetric bipyrrolidine organocatalysts 1, highly active orga-
nocatalytic Diels–Alder reactions using bipyrrolidine organ-
catalysts 1 in water, and convenient catalyst recycling without
further modification of the catalyst structure. Furthermore, we will
show that catalytic mode is demonstrated by DFT calculation, NMR,
and X-ray crystallographic studies for diiminium intermediate.
* Corresponding authors. Tel.: þ86 21 5474 3265; fax: þ86 21 5474 7486; e-mail
addresses: yjian@sjtu.edu.cn (Y.J. Zhang), wanbin@sjtu.edu.cn (W. Zhang).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.042

3850
Y. Ma et al. / Tetrahedron 66 (2010) 3849–3854
2. Results and discussions
performed in organic solvents, lower chemical yields and enan-
tioselectivities were observed (entries 2–7). Surprisingly, when we
used water as solvent, the reaction rate was remarkably accelerated
(entry 8). The reaction completed only within 2 h and afforded the
Diels–Alder adduct in 95% yield with good enantioselectivity and
moderate exo-selectivity (exo, 89% ee; endo, 83% ee). The Brønsted
acid cocatalyst had large effects on the reaction (entries 9–12).
While HCl was used as a cocatalyst, only trace amounts of product
was observed (entry 10). The results demonstrated that HClO4 was
a best Brønsted acid cocatalyst for the reaction in water. Notably,
the reaction with 1c and HClO4 run in water was much faster (2 h)
than the reaction run in MeOH (20 h) and in aqueous MeOH (12 h).
When further reducing catalyst loading to 5 and 1 mol %, the re-
actions still proceeded well without loss of stereoseletivities (en-
tries 13 and 14). The effect of the O-substituent of the bipyrrolidine
catalyst on the reaction was also investigated. While 3,30-dihy-
droxybipyrrolidine 1a was used in the combination with HClO4, the
reaction did almost not proceed (entry 15). When using other
catalysts 1b, 1d, and 1e, it has not significant effect on enantiose-
lectivity and diastereoselectivity even though there is some in-
fluence on reactivity (entries 16–18).
A series of 3,30-dialkoxy-2,20-bipyrrolidines 1 have been readily
synthesized from chiral diimine 2 as illustrated in Scheme 1 and
Scheme 2. Diastereoselective addition of propenylzinc reagent 3 to
diimine 2 led to optically pure diamino diol compound 4 after re-
crystallization in 40% yield.13 Protection of diol 4 with benzyl bro-
mide in the presence of NaH in DMF gave compound 5 in 98% yield.
Hydroboration of terminal alkenes with 9-BBN afforded diol 6 in
95% yield. Mesilation of terminal diol 6 in the presence of excess
triethylamine gave key intermediate bipyrrolidine 7 in 86% yield
(Scheme 1). Interestingly, hydrogenolysis of 7 with Pd(OH)2/C un-
der 20 bar hydrogen pressure only afforded N-debenzylated prod-
uct 1c in quantitative yield. However, under the hydrogenolysis
reaction conditions, addition of Boc anhydride furnished
O-debenzylated, N-Boc protected product 8 in 96% yield. Direct
deprotection of compound 8 gave (3R,2S,20S,30R)-3,30-dihydroxy-
2,20-bipyrrolidine (1a) in 95% yield. To test our hypothesis in cata-
lyst design, a number of substituents on oxygen were introduced.
O-alkylation of compound 8 with NaH and alkyl halide in DMF
followed by deprotection afforded bipyrrolidine catalysts 1b, 1d,
and 1e in 70–86% yields (Scheme 2).
THPO
ZnCl
3
THF,-78 o
C
HO
OH
BnBr
BnO
Ph
OBn
Ph
N
N
NaH, DMF
98%
HCl then NaOH
40%
NH HN
Ph
Ph
NH HN
5
Ph
Ph
2
4
OH HO
Ph
Ph
N
CH3SO2Cl,Et3N,
CH2Cl2
1)9-BBN,THF
N
BnO
OBn
86%
2)NaOH,H2O2
95%
NH HN
6
BnO OBn
7
Ph
Ph
Scheme 1.
Table 1
Asymmetric Diels–Alder reaction between cinnamaldehyde and cyclopentadiene
Ph
Ph
catalyzed by bipyrrolidine 1a
H
N
H
N
Pd(OH)2/C, H2
N
N
1 (10 mmol%)
CHO
Ph
CHO
HX (20 mmol%)
CHO
+
+
MeOH/CH2Cl2
95%
Ph
solvent, rt
Ph
BnO
OBn
BnO
OBn
1c
Time (h) Yieldb (%) exo:endoc ee (%)c exo, endo
7
Entry
1
Acid Solvent
1
2
3
4
5
6
7
8
1c HClO4 MeOH/H2O 12
93
91
50
42
47
78
17
95
81
Trace
62
27
91
97
Trace
63
84
86
2.5:1
2.5:1
0.9:1
1.8:1
2.2:1
2.7:1
0.3:1
2.7:1
3.0:1
nd
3.1:1
2.7:1
2.8:1
2.4:1
nd
91, 83
83, 69
48, 6
59, 26
59, 35
61, 28
31, 0
89, 83
84, 74
nd
82, 67
81, 71
87, 79
87, 82
nd
Pd(OH)2/C, H2
(Boc)2O, MeOH
96%
1c HClO4 MeOH
1c HClO4 Toluene
20
20
1c HClO4 Acetonitrile 20
1c HClO4 Dioxane
1c HClO4 THF
1c HClO4 CH2Cl2
1c HClO4 H2O
1c TfOH H2O
20
20
20
2
Boc Boc
H
N
H
N
N
N
1) RX, base, DMF
9
3
2) acid
10
11
12
1c HCl
1c TsOH H2O
1c TFA H2O
H2O
3
3
3
70-95%
RO
OR
HO
OH
8
1
1a
1b
1c
1d
1e
: R = H
13d 1c HClO4 H2O
8
: R = Me
: R = Bn
14e
15
16
17
18
1c HClO4 H2O
1a HClO4 H2O
1b HClO4 H2O
1d HClO4 H2O
1e HClO4 H2O
72
3
3
3
3
: R = 2'-phenylbenzyl
: R = 1-naphthylmethyl
2.2:1
3.1:1
2.2:1
87, 82
88, 82
88, 82
Scheme 2.
a
All the reactions were carried out with 0.25 mmol of (E)-cinnamaldehyde,
0.75 mmol of cyclopentadiene, 0.025 mmol of 1, and 0.05 mmol of acid in 1 mL of
the proper solvent at room temperature.
Initially, we chose the model reaction between (E)-cinna-
maldehyde and cyclopentadiene, which we have found to be pro-
moted by combination of bipyrrolidine 1c and HClO4 as a cocatalyst
in aqueous MeOH (MeOH/H2O¼19:1) at room temperature for 12 h
(Table 1, entry 1). As shown in Table 1, when the reactions were
b
Isolated yield of a mixture of exo and endo isomers.
exo/endo ratios and ee values were determined by HPLC analysis.
Using 5 mol % catalyst loading.
c
d
e
Using 1 mol % catalyst loading.

Y. Ma et al. / Tetrahedron 66 (2010) 3849–3854
3851
With the optimized catalyst 1c$2HClO4, we next examined its
recyclability for the standard reaction in water. As shown in Table 2,
after the catalyst was employed to promote the Diels–Alder re-
action, we found that the catalyst was effectively immobilized in
aqueous medium by simple diethyl ether extraction. The catalyst
could be used directly in the next run after removing residual
diethyl ether under the vacuum at low temperature. Until fourth
cycle, the recovered catalyst retained its high activity, high levels of
enantioselectivity, and good diastereoselectivity, even though it
was observed that the catalytic activity reduced in fifth cycle. To the
best of our knowledge, this is the first example of an effective re-
cyclable asymmetric iminium-catalyzed Diels–Alder reaction in
water without further catalyst modification.14
We propose that the mechanism of bipyrrolidine-catalyzed
Diels–Alder reaction involves the formation of the diiminium in-
termediate 9. Three possible diiminium intermediate are illustrated
in Figure 1. For each diiminiium ion, two conjugated iminiums faced
each other and the cyclization can occur from above or below. (E,E)-
Diiminium intermediate 9a give two identical Re faces for cyclo-
addition. (Z,Z)-Diiminium intermediate 9c afford two identical Si
faces for cycloaddition giving opposite absolute configuration in the
products. However, for (E,Z)-diiminium intermediate 9b, two dif-
ferent stereofaces are exposed for cycloaddition, which will kill
enantioselection in the Diels–Alder reaction. In order to elucidate
the origin of stereoselectivity in the bipyrrolidine-catalyzed Diels–
Alder reaction, the energy of three possible diiminium in-
termediates have been calculated by Density Field Theory. As shown
in Figure 1, (E,E)-diiminium intermediate 9a was calculated to have
lowest energy. Intermediate 9a is 30 kcal molꢀ1 lower in energy
compared to 9b and 9c. This energy difference predicts the forma-
tion of the experimentally formed enantiomer.
Table 2
Recycling of bipyrrolidine 1c$2HClO4 catalyst for asymmetric Diels–Alder reaction
between cinnamaldehyde and cyclopentadienea
1c
(10 mol%)
CHO
Ph
CHO
HClO4 (20 mol%)
CHO
+
+
Ph
H2O, rt
Ph
exo:endoc
ClO4
ClO4
ClO4
Yieldb (%)
ee (%)c exo, endo
N
N
N
Run
Time (h)
BnO
BnO
BnO
BnO
BnO
BnO
1
2
3
4
5
4
4
4
12
24
95
94
94
88
50
2.7:1
2.7:1
2.7:1
2.5:1
2.5:1
89, 83
87, 80
88, 82
86, 80
89, 83
N
N
N
ClO4
ClO4
ClO4
9c
9a
9b
= -1809.4189516
hartree
= -1809.3703298
hartree
= -1809.3697836
hartree
G
G
G
a
The reactions were carried out with 0.25 mmol of (E)-cinnamaldehyde,
0.75 mmol of cyclopentadiene, 0.025 mmol of 1c, and 0.050 mmol of HClO4 at room
temperature in water (1 mL).
Figure 1. DFT calculation of possible diiminium intermediates 9.
b
Isolated yield of a mixture of exo and endo isomers.
exo/endo ratios and ee values were determined by HPLC analysis.
c
With these calculated results in hand, we tried to make iminium
intermediate 9 by mixing catalyst 2c with 2 equiv HClO4 and
2 equiv cinnamaldehyde in MeOH. After stirring for 10 min, we
observed that a substantial amount of cinnamaldehyde was con-
sumed and diiminium intermediate 9 was formed on the basis of 1H
NMR spectroscopic studies. The results demonstrated that diimi-
nium intermediate rapidly formed in the reaction system. In order
to gain further evidence for the catalytic mode of the Diels–Alder
Having established the recoverable and reusable capacity of
bipyrrolidine 1c$2HClO4 as the catalyst, we next probed the gen-
erality of its use as a promoter for Diels–Alder reactions. As
revealed in Table 3, substituted cinnamaldehyde dienophiles (en-
tries 1–6) and alkyl-substituted acrolein (entry 7) were subjected to
the cycloaddtion reaction with cyclopentadiene in water. All of the
reactions afforded Diels–Alder adducts in excellent yields within
2–3.5 h. However, the enantioselectivities decreased comparing
with corresponding reactions in aqueous MeOH solution.12
Table 3
Bipyrrolidine 1c$2HClO4 catalyzed asymmetric Diels–Alder reaction between vari-
ous dienophiles and cyclopentadiene in watera
1c (10 mmol%)
R
CHO
HClO4 (20 mmol%)
CHO
+
+
R
H2O, r.t.
CHO
R
Entry
R
T (h)
Yieldb (%)
exo:endoc
ee (%)d
exo, endo
1e
2
3
4
5
Ph
3
95
62
94
82
95
98
94
2.7:1
0.8:1
1.4:1
2.2:1
1.8:1
1.6:1
1.3:1
89, 83
87, 85
65, 67
76, 67
76, 69
70, 59
76, 79
2-NO2–Ph
4-NO2–Ph
4-OMe–Ph
4-Cl–Ph
4-Br–Ph
n-Pr
3.5
3.5
3.5
3.5
3.5
2
6
7e
a
All the reactions were carried out with 0.25 mmol of dienophile, 1.5 mmol of
diene, 0.025 mmol of catalyst 1c, and 0.05 mmol of HClO4 at room temperature in
water (1 mL).
b
Isolated yield of a mixture of exo and endo isomers.
c
Determined by 1H NMR.
d
The ee was determined by chiral HPLC analysis.
0.75 mmol of diene was used.
e
Figure 2. X-ray structure of diiminium intermediate 9.

3852
Y. Ma et al. / Tetrahedron 66 (2010) 3849–3854
reaction, a single crystal of diiminium intermediate 9 was grown
from methanol and ethyl acetate (20:1, v/v) and submitted for X-ray
analysis. As we proposed, two conjugated iminiums faced each
other in nearly a parallel fashion, and two Si faces of the diiminium
are facing each other giving each other the same enantiofacial
discriminations (Fig. 2).
d 146.57, 139.11, 137.85, 128.31, 128.30, 127.77, 127.37, 126.91, 117.60,
82.85, 70.43, 58.60, 56.15, 24.64. HRMS (ESI-TOF) calcd for
C38H45N2O2 ([MþH]þ): 561.3481, found: 561.3483.
4.1.2. Synthesis of (3R,4S,5S,6R)-4,5-bis((S)-1-phenyl ethylamino)-
3,6-bis(benzyloxy)octane-1,8-diol (6). Under
a nitrogen atmo-
sphere, to a solution of compound 5 (4.0 g, 7.1 mmol) in anhydrous
THF (20 mL), 9-BBN (0.5 M in THF, 49 mL, 25 mmol) was added at
0 ꢁC. The resulting solution was stirred at room temperature over-
night, and then cooled to 0 ꢁC. Aqueous NaOH (3 M, 37 mL) was
added, followed by H2O2 (30% in water, 25 mL). The mixture was
stirred at room temperature for 8 h, diluted with water, and
extracted with Et2O (60 mLꢂ3). The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The residue was
recrystallized from ethyl acetate to afford (3R,4S,5S,6R)-4,5-bis((S)-
3. Conclusion
In summary, we have designed and synthesized a new class of
C2-symmetric 3,30-dialkoxy-2,20-bipyrrolidine catalysts for asym-
metric organocatalytic Diels–Alder reactions of
a,b-unsaturated
aldehydes. The remarkable rate-accelerating effect for the cyclo-
addition reaction has been observed in aqueous medium. The cat-
alyst 1c$2HClO4 was readily recovered and reused several times
without significant loss of catalytic activity and stereoselectivity.
The catalytic mode has been demonstrated by DFT calculation,
NMR, and X-ray crystallographic studies for diiminium in-
termediate 9. Further studies on modification of catalyst structure
based on the crystal structure of diiminium intermediate 9 and
other asymmetric transformations using C2-symmetric bipyrroli-
dine catalysts will be described shortly.
1-phenylethyl amino)-3,6-bis(benzyloxy)octane-1,8-diol (6) (4.0 g,
21
95% yield): [
a
]
D
ꢀ45.0 (c 1.00, CHCl3); 1H NMR (CDCl3)
d 7.15–7.31
(m, 20H), 4.36 (d, J¼11.6 Hz, 2H), 4.04 (d, J¼11.6 Hz, 2H), 3.72 (m,
2H), 3.62 (m, 2H), 3.51 (m, 2H), 3.33 (m, 2H), 2.57 (d, J¼7.6 Hz, 2H),
1.94 (m, 2H), 1.76 (m, 2H), 1.17 (d, J¼6 Hz, H); 13C NMR (100 MHz,
CDCl3),
d 145.09, 137.52, 128.82, 128.74, 128.55, 128.12, 127.45,
127.07, 81.24, 70.74, 60.29, 56.75, 36.60, 23.16. HRMS (ESI-TOF)
calcd for C38H49N2O4 ([MþH]þ): 597.3692, found: 597.3683.
4. Experimental
4.1. General
4.1.3. Synthesis of (2S,20S,3R,30R)-3,30-bis(benzyloxy)-1,10-bis((S)-1-
phenylethyl)-2,20-bipyrrolidine (7). Et3N (5.6 mL, 40 mmol) was
added to a stirred solution of compound 6 (4.0 g, 6.7 mmol) in
anhydrous CH2Cl2 (50 mL) under nitrogen at 0 ꢁC, and then meth-
anesulfonyl chloride (1.6 mL, 20 mmol) was added dropwise. The
mixture was stirred for 10 min, and quenched by addition of water,
extracted with CH2Cl2 (50 mLꢂ3). The combined organic layers
were dried over Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate¼10:1) to afford (2S,20S,3R,30R)-3,30-bis(benzy-
1H NMR spectra were measured on a MERCURY plus 400
(400 MHz) spectrometer. Chemical shifts were reported in parts per
million from tetramethylsilane as an internal standard. 13C NMR
spectra were recorded on a MERCURY plus 400 (100 MHz) spec-
trometer with complete proton decoupling. Chemical shifts were
reported in parts per million from the residual solvent as an in-
ternal standard. Optical rotations were taken on a SGWÒ-1 auto-
matic polarimeter. High performance liquid chromatography
(HPLC) was performed on Class-Vp6x using Daicel Chiralcel OJ-H as
a column. Mass spectra were recorded by ESI, and HRMS were
measured on a HP-5989 instrument. For thin layer chromatography
(TLC) analysis throughout this work, TLC plates were used. TLC
spots were visualized under ultraviolet light or developed by
heating after treatment with potassium permanganate. The prod-
ucts were purified by flash column chromatography on silica gel
(100–200 mesh). In experiments requiring dry solvents, tetrahy-
drofuran (THF), dichloromethane (CH2Cl2), 1,4-dioxane, acetoni-
trile, toluene, and N,N-dimethylformamide (DMF) were purified
according to the standard method. (E)-Cinnamaldehyde and
cyclopentadiene were distilled and stored under argon atmosphere
at ꢀ20 ꢁC.
loxy)-1,10-bis((S)-1-phenylethyl)-2,20-bipyrrolidine (7) (3.2 g, 86%
20
yield): [
a]
þ22.7 (c 0.42, CHCl3); 1H NMR (CDCl3)
d 7.22–7.44 (m,
D
20H), 4.61 (d, J¼12.4 Hz, 2H), 4.56 (d, J¼12.4 Hz, 2H), 3.82 (d,
J¼5.2 Hz, 2H), 3.67 (q, J¼6.4 Hz, 2H), 2.76–2.86 (m, 6H), 1.89 (d,
J¼5.2 Hz, 1H), 1.86 (d, J¼5.2 Hz, 1H), 1.48–1.58 (m, 2H), 1.22 (d,
J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3),
d 145.22, 139.44, 128.44,
128.31, 128.25, 127.65, 127.39, 126.95, 80.63, 70.40, 69.92, 60.63,
47.31, 32.04,16.33. HRMS (ESI-TOF) calcd for C38H45N2O2 ([MþH]þ):
561.3481, found: 561.3471.
4.1.4. Synthesis of (2S,20S,3R,30R)-1,10-bis-tert-butoxy carbonyl-3,30-
dihydroxy-2,20-bipyrrolidine (8). A suspension of compound
7
(2.7 g, 4.9 mmol), Pd(OH)2/C (1.5 g, 20%) and (Boc)2O (4.3 g,
20 mmol) in MeOH (15 mL) was stirred under 20 atm of H2 atmo-
sphere for 24 h. After filtration over a Celite pad, which was washed
with MeOH, the solvent was concentrated, The residue was purified
by flash column chromatography on silica gel (petroleum ether/
ethyl acetate¼2:1) to afford (2S,20S, 3R,30R) -1,10-bis-tert-butoxy-
4.1.1. Synthesis of (3R,4S,5S,6R)-3,6-bis(benzyloxy)-N4,N5-bis((S)-1-
phenylethyl)octa-1,7-diene-4,5-diamine (5). To a suspension of NaH
(1.8 g, 60%, 44 mmol) in anhydrous DMF (8.0 mL) was added a so-
lution of compound 4 (5.6 g, 14.7 mmol) in anhydrous DMF (15 mL)
at 0 ꢁC under a nitrogen atmosphere and stirred at the same tem-
perature for 0.5 h. And then, benzyl bromide (4.8 mL, 44 mmol)
was added dropwise, the resulting solution was stirred at room
temperature overnight. Water (50 mL) was added at 0 ꢁC and
extracted by Et2O (50 mLꢂ3). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. The res-
idue was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate¼8:1) to afford (3R,4S,5S,6R)-3,6-
carbonyl-3,30-dihydroxy-2,20-bipyrrolidine (8) (1.7 g, 96% yield):
[a
]
þ67.0 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3)
d 4.19 (br, 2H),
20
D
3.42 (br, 6H), 2.30 (br, 2H), 2.18 (br, 2H), 1.87 (br, 2H), 1.42 (s, 18H);
13C NMR (100 MHz, CDCl3)
d 155.87, 79.94, 79.79, 79.57, 74.85,
74.39, 73.85, 67.39, 66.95, 60.64, 50.57, 45.30, 45.12, 31.89, 31.64,
31.19, 28.68, 28.59. HRMS (ESI-TOF) calcd for C18H33N2O6
([MþH]þ): 373.2338, found: 373.2339.
4.1.5. Synthesis of (2S,20S,3R,30R)-2,20-bipyrrolidine-3,30-diol di-
chlorate (1a$2HClO4). To a solution of compound 8 (51.2 mg,
0.14 mmol) in CH2Cl2 and MeOH (2 mL/1 mL) was added HClO4
bis(benzyloxy)-N4,N5-bis((S)-1-phenylethyl)octa-1,7-diene -4,5-di-
25
amine (5) (8.1 g, 98% yield): [
(CDCl3)
a]
ꢀ55.1 (c 2.16, EtOH); 1H NMR
D
d
7.08–7.25 (m, 20H), 5.59–5.68 (m, 2H), 5.17 (s, 2H), 5.14
(100 mL, 1.40 mmol). The resulting solution was stirred at room
(m, 2H), 4.29 (d, J¼12 Hz, 2H), 3.66–3.79 (m, 6H), 2.66 (d, J¼5.6 Hz,
temperature. Upon consumption of the starting material, the sol-
vent was removed via vacuum and the residue was recrystallized
2H), 1.90 (br, 2H), 1.20 (d, J¼6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3),

Y. Ma et al. / Tetrahedron 66 (2010) 3849–3854
3853
from ethyl acetate to afford (2S,20S,3R,30R)-2,20-bipyrrolidine-3,30-
45.29, 32.30. HRMS (ESI-TOF) calcd for C34H37N2O2 ([MþH]þ):
19
diol dichlorate (1a$2HClO4) (49.6 mg, 95%): [
EtOH); 1H NMR (400 MHz, D2O)
3.42 (m, 4H), 2.13–2.22 (m, 2H), 1.85–1.93 (m, 2H); 13C NMR
a
]
þ54.9 (c 0.23,
505.2855, found: 505.2852.
D
d
4.47 (m, 2H), 3.5 (m, 2H), 3.29–
4.1.9. Synthesis of (2S,20S,3R,30R)-3,30-bis(naphthalen-1-ylmethoxy)-
2,20-bipyrrolidine dichlorate (1e$2HClO4). Under a nitrogen atmo-
sphere, to a suspension of NaH (32 mg, 60%, 0.81 mmol) in
anhydrous DMF (3.0 mL) was added the solution of compound 8
(0.10 g, 0.27 mmol) in anhydrous DMF (1.0 mL) at 0 ꢁC and stirred for
0.5 h at the same temperature. And then the solution of 1-(chlor-
omethyl)naphthalene (0.14 g, 0.81 mmol) in dry DMF (0.50 mL) was
added dropwise and stirred at room temperature. Upon consump-
tion of the starting material, water (10 mL) was added at 0 ꢁC and
then extracted by Et2O (15 mLꢂ3). The combined organic layers
were washed with brine, dried over K2CO3, and concentrated. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate¼4:1) to afford (2S,20S, 3R,30R)- 1,10-
bis-tert-butoxycarbonyl-3,30-bis(naphthalen-1-ylmethoxy)-2,20-bi-
pyrrolidine (144 mg, 82% yield), which was dissolved in MeOH
(2 mL), and 72% HClO4 (0.15 mL,1.8 mmol) was added at 0 ꢁC, stirred
at rt overnight. The solvent was removed viavacuum and the residue
was purified by flash column chromatography on silica gel (CH2Cl2/
MeOH¼10:1) to afford (2S,20S,3R,30R)-3,30- bis(naphthalen-1-
(100 MHz, D2O) d 71.4, 64.00, 44.39, 31.65. HRMS (ESI-TOF) calcd for
C8H18Cl2N2O10 ([MþHꢀ2HClO4]þ): 173.1290, found: 173.1289.
4.1.6. Synthesis of (2S,20S,3R,30R)-3,30-dimethoxy-2,20-bipyrrolidine
1b. Under a nitrogen atmosphere, to a suspension of NaH (32 mg,
60%, 0.81 mmol) in anhydrous DMF (3.0 mL) was added a solution
of compound 8 (0.10 g, 0.27 mmol) in anhydrous DMF (1.0 mL) at
0 ꢁC and stirred for 0.5 h at the same temperature. And then
iodomethane (50 mL, 0.81 mmol) was added dropwise and stirred
at room temperature. Upon consumption of the starting material,
water (10 mL) was added at 0 ꢁC and then extracted by Et2O
(15 mLꢂ3). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate¼4:1) to afford (2S,20S,3R,30R)-1,10-bis-tert-butoxycarbonyl-
21
3,30-dimethoxy-2,20-bipyrrolidine (93.2 mg, 86% yield): [
a
]
þ60.3
D
(c 0.93, EtOH); 1H NMR (400 MHz, CDCl3)
d 3.46–3.65 (m, 4H), 3.27–
3.42 (m, 4H), 3.23–3.24 (m, 6H), 1.84–2.31 (m, 4H), 1.35–1.40 (m,
18H). To the solution of this compound (93.2 mg, 0.23 mmol) in
MeOH (2 mL) was added acetyl chloride (0.15 mL) at 0 ꢁC and the
mixture was stirred at room temperature overnight. The solvent
was removed via vacuum and the crude product was dissolved in
water, then aqueous solution of sodium hydroxide (3 M) was added
till pH¼8, the solution was extracted with CH2Cl2 (10 mLꢂ3). The
combined organic layers were dried over Na2SO4 and concentrated
ylmethoxy)-2,20-bipyrrolidine dichlorate (1e$2HClO4) (0.14 g, 99%).
19
[a
]
þ52.6 (c 0.06, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.81 (m, 2H),
D
7.73 (m, 2H), 7.66 (m, 2H), 7.43–7.50 (m, 4H), 7.22–7.31 (m, 4H), 5.73
(br, 2H), 4.59 (d, J¼12 Hz, 2H), 4.41 (d, J¼12 Hz, 2H), 3.86 (s, 2H), 3.67
(s, 2H), 3.44 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 133.80,132.25, 131.57, 129.27, 128.82, 127.17, 126.76, 126.25,
125.51, 124.03, 78.87, 69.62, 64.06, 45.64, 32.16. HRMS (ESI-TOF)
calcd for C30H34Cl2N2O10 ([MþHꢀ2HClO4]þ): 453.2542, found:
453.2541.
to afford (2S,20S,3R,30R)-3,30-dimethoxy-2,20- bipyrrolidine (1b)
19
(46 mg, 100% yield). [
a
]
þ11.9 (c 0.54, EtOH); 1H NMR (400 MHz,
D
CDCl3)
d
3.65 (m, 2H), 3.27 (s, 6H), 2.90–2.96 (m, 6H), 2.27 (br, 2H),
1.73–1.88 (m, 4H); 13C NMR (100 MHz, CDCl3)
45.13, 32.00. Compound 2b and 2 mol equiv HClO4 was mixed to
afford 1b$2HClO4; 1H NMR (400 MHz, CDCl3)
4.21 (m, 2H), 3.76
(m, 6H), 3.53–3.59 (m, 6H), 2.33–2.39 (m, 2H), 2.14–2.17 (m, 2H);
d
84.59, 66.84, 56.97,
4.1.10. (2S,20S,3R,30R)-3,30-Bis(benzyloxy)-1,10-bis((E)-3-phenyl-
allylidene)-2,20-bipyrrolidine-1,10-diium dichlorate 9a. A solution of
bipyrrolidine 1c (0.05 mmol), HClO4 (0.10 mmol), and (E)-cinna-
d
maldehyde (13
The solvent was removed giving white solid. 1H NMR (400 MHz,
CDCl3)
mL, 0.10 mmol) in MeOH was stirred at rt for 10 min.
13C NMR (100 MHz, CDCl3)
d 80.27, 62.53, 56.42, 44.81, 28.44. HRMS
(ESI-TOF) calcd for C10H22Cl2N2O10 ([MþHꢀ2HClO4]þ): 201.1603,
d
8.74 (d, J¼10 Hz, 2H), 8.08 (d, J¼14.8 Hz, 2H), 7.11–7.59 (m,
found: 201.1606.
20H), 4.96 (t, J¼12 Hz, 2H), 4.46 (s, 4H), 4.24 (s, 2H), 4.05 (m, 2H),
3.84 (s, 2H), 3.47 (s, 2H), 2.50 (m, 2H), 2.35 (m, 2H); 13C NMR
4.1.7. Synthesis of (2S,20S,3R,30R)-3,30-bis(benzyloxy)-2,20-bipyrroli-
dine (1c). The suspension of compound 7 (4.5 g, 8.1 mmol) and Pd
(OH)2/C (1.5 g, 20%) in MeOH and CH2Cl2 (30:15, v/v, 45 mL) was
stirred under 20 atm of H2 atmosphere at room temperature for
24 h. The solution was filtrated and the filtrate was concentrated,
the residue was dissolved in water, and an aqueous solution of
sodium hydroxide (3 M) was added till pH¼8, and extracted with
CH2Cl2 (100 mLꢂ3). The combined organic layers were dried over
(100 MHz, CDCl3) d 170.75, 167.56, 136.08, 135.38, 133.31, 131.77,
129.70, 129.22, 128.98, 128.62, 117.26, 78.39, 72.23, 71.84, 51.07,
29.49.
4.2. General procedure for bipyrrolidine catalyzed
asymmetric Diels–Alder reaction
To a solution of bipyrrolidine (0.025 mmol) in 1 mL of a proper
solvent was added the corresponding acid (0.05 mmol). To this so-
K2CO3 and concentrated to afford (2S,20S,3R,30R)-3,30-bis(benzy-
19
loxy)-2,20-bipyrrolidine (1c) (2.8 g, 95%). [
a
]
þ96.1 (c 1.10,
lution, freshly distilled (E)-cinnamaldehyde (32
added at 0 ꢁC and the mixture was stirred at the same temperature
for 2 min. And then, freshly distilled cyclopentadiene (62 L,
mL, 0.25 mmol) was
D
EtOH); 1H NMR (400 MHz, CDCl3)
d 7.24–7.37 (m, 10H), 4.47 (d,
J¼11.6 Hz, 2H), 4.35 (d, J¼11.6 Hz, 2H), 3.86 (s, 2H), 2.94–3.07 (m,
m
6H), 2.29 (br, 2H), 1.86–1.91 (m, 4H); 13C NMR (100 MHz, CDCl3)
0.75 mmol) was added dropwise. The resulting mixture was stirred
at room temperature. Upon consumption of (E)-cinnamaldehyde,
the reaction mixture was diluted with Et2O and washed with H2O
and brine. The organic layer was dried over Na2SO4, filtrated, and
concentrated. When the solvent is moist MeOH or MeOH, hydrolysis
of formed dimethyl acetal was performed by stirring the crude
product mixture in TFA/H2O/CHCl3 (1:1:2) for 2 h at room temper-
ature, followed by neutralization with saturated aqueous NaHCO3
and extracted with Et2O. Purification of the Diels–Alder adduct was
accomplished by silica gel chromatography. The enantiomeric ex-
cess was determined by reduction of the formyl group to the cor-
responding alcohol with NaBH4 and HPLC analysis. Enantiomers
were separated by HPLC using a Daicel Chiralcel OJ-H column (80/20
d
138.56, 128.62, 127.93, 127.84, 82.43, 71.38, 66.69, 45.16, 32.38.
HRMS (ESI-TOF) calcd for C22H29N2O2 ([MþH]þ): 353.2229, found:
353.2222.
4.1.8. Synthesis of (2S,20S,3R,30R)-3,30-bis(biphenyl-2-ylmethoxy)-
2,20-bipyrrolidine (1d). Compound 1d was prepared in a similar
manner as described above (preparation of 1b) using biphenyl-2-
19
ylmethyl methanesulfonate (85% yield).
[a
]
ꢀ72.9 (c 0.41,
D
EtOH); 1H NMR (400 MHz, CDCl3)
d
7.46–7.48 (m, 2H), 7.31–7.39 (m,
14H), 7.25–7.27 (m, 2H), 4.34 (d, J¼10.8 Hz, 2H), 4.24 (d, J¼10.8 Hz,
2H), 3.69 (m, 2H), 2.87–2.99 (m, 6H), 1.93 (br, 2H), 1.69–1.74 (m,
4H); 13C NMR (100 MHz, CDCl3)
d
142.08, 141.06, 135.66, 130.19,
129.65, 129.39, 128.24, 127.92, 127.72, 127.35, 82.92, 69.34, 66.60,
hexane/i-PrOH, flow rate 1.0 mL/min,
l¼210 nm) endo isomer

3854
Y. Ma et al. / Tetrahedron 66 (2010) 3849–3854
Science 2006, 313, 1584; (d) MacMillan, D. W. C. Nature 2008, 455, 304; (e)
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(TR1¼13.7 min (major), TR2¼32.9 min (minor)). exo Isomer
(TR1¼45.9 min (major), TR2¼63.2 min (minor)). 1H NMR, 13C NMR
data are in agreement with the published data.4,5
2. For recent reviews of enantioselective Diels–Alder reactions, see: (a) Evans, D.
A.; Johnson, J. S. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
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4.3. Recycling procedure of asymmetric Diels–Alder reaction
catalyzed by bipyrolidine 1c in combination with HClO4
in water
To an emulsion of bipyrrodine 1c (8.8 mg, 0.025 mmol), HClO4
(4.2
hyde (32
pentadiene (62
m
L, 0.050 mmol, 72% aqueous solution), and (E)-cinnamalde-
L, 0.25 mmol) in water (1 mL), freshly distilled cyclo-
L, 0.75 mmol) was added at 0 ꢁC. The reaction
`
Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504; (d) Bonini, B. F.; Capito, E.;
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Comes-Franchini, M.; Fochi, M.; Ricci, A.; Zwanenburg, B. Tetrahedron: Asym-
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mixture was stirred at room temperature for 4 h. Diethyl ether
(2.0 mL) was added and stirred for a few minutes, and then keep
the mixture stand for minutes to separate into two layers, and the
organic layer was removed via syringe. Repeat this operation for
another two times. Combined the organic layers and dried with
anhydrous Na2SO4, filtrated, concentrated. The residue was purified
by silica gel chromatography. Keeping the aqueous layer above at
ꢀ78 ꢁC, the residual diethyl ether was removed via vacuum. The
dienophile and diene were added, respectively at 0 ꢁC, and the
reaction mixture was stirred at room temperature to run next cycle.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China and Shanghai Jiao Tong University (Chenxing
Program).
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.042.
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