A Highly anti-selective asymmetric henry reaction catalyzed by a chiral copper complex: Applications to the syntheses of (+)-spisulosine and a pyrroloisoquinoline derivative

Article abstract of DOI:10.1002/chem.201201775

A highly anti-selective asymmetric Henry reaction has been developed, affording synthetically versatile β-nitroalcohols in a predominately anti-selective manner (mostly above 15:1) and excellent ee values (mostly above 95 %). Moreover, the anti-selective Henry reaction was carried out in the presence of water for the first time with up to 99 %-ee. The catalytic mechanism was proposed based on the detection of the intermediates by extractive electrospray ionization mass spectrometry (EESI-MS). Furthermore, the anti adducts have been successfully transformed into the biochemically important (+)-spisulosine and a pyrroloisoquinoline derivative. Copyright

Full text of DOI:10.1002/chem.201201775

FULL PAPER
DOI: 10.1002/chem.201201775
A Highly anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral
Copper Complex: Applications to the Syntheses of (+)-Spisulosine and a
Pyrroloisoquinoline Derivative
Kun Xu,[a] Guoyin Lai,[a] Zhenggen Zha,[a] Susu Pan,[b] Huanwen Chen,*[b] and
Zhiyong Wang*[a]
Abstract: A highly anti-selective asym-
metric Henry reaction has been devel-
oped, affording synthetically versatile
the presence of water for the first time
with up to 99% ee. The catalytic mech-
anism was proposed based on the de-
tection of the intermediates by extrac-
tive electrospray ionization mass spec-
trometry (EESI-MS). Furthermore, the
anti adducts have been successfully
transformed into the biochemically im-
portant (+)-spisulosine and a pyrroloi-
soquinoline derivative.
b-nitroalcohols in
a
predominately
anti-selective manner (mostly above
15:1) and excellent ee values (mostly
above 95%). Moreover, the anti-selec-
tive Henry reaction was carried out in
Keywords: amino alcohols · asym-
metric catalysis · copper · enantio-
selectivity · Henry reaction
Introduction
for syn-selectivity.[5a,d,6] Because optically active anti-amino
alcohols are versatile building blocks in many natural prod-
ucts,[8] the development of more efficient catalytic systems
for highly anti-selective Henry reactions with excellent
enantioselectivity is still of great significance.
The catalytic asymmetric nitroaldol reaction provides a
facile method to generate enantiomerically enriched b-
amino alcohols by reduction of the nitro group, which is an
important structural motif in natural and synthetically de-
signed compounds with interesting biological properties.[1]
Since the Shibasaki group reported the first catalytic asym-
metric nitroaldol reaction,[2] tremendous efforts have been
made to develop a catalytic asymmetric Henry reaction.[3]
Although there have been pioneering studies into anti-selec-
tive Henry reactions by the Ooi group,[4] which involved the
use of a chiral tetra-aminophosphonium salt, and by the Shi-
basaki group,[5] which utilized heterobimetallic catalysts, we
have found few examples of anti-selective asymmetric
Henry reactions[7] that overcome the simple chelation model
The design of ideal chiral catalysts that could catalyze the
desired reactions with high yield and excellent enantiomeric
excess is one of the primary goals for synthetic chemistry.
Enzymes are good examples of this principle because they
catalyze a wide range of chemical processes.[9] With an aim
to simulate nature by developing catalytic systems analogous
to enzymatic processes, the concept of a combined catalytic
system has been employed in catalyst design to enhance
their reactivity and selectivity.[10] However, asymmetric
transformations have typically been carried out in organic
solvents, despite the fact that many enzymatic processes
take place in an aqueous environment.[11] Herein we report
a highly anti-selective nitroaldol reaction that occurs with
excellent enantioselectivities, and, remarkably, the first ex-
ample of an anti-selective Henry reaction in the presence of
water. Furthermore, the synthetic utility of this methodology
was illustrated in the syntheses of (+)-spisulosine and a pyr-
roloisoquinoline derivative.
[a] K. Xu,+ G. Y. Lai,+ Z. G. Zha, Prof. Dr. Z. Y. Wang
Hefei National Laboratory for Physical Sciences at Microscale
CAS Key Laboratory of Soft Matter Chemistry and
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui, 230026 (P.R. China)
Fax : (+86)551-3603185
Results and Discussion
E-mail: zwang3@ustc.edu.cn
[b] S. S. Pan, Prof. Dr. H. W. Chen
Encouraged by the success of asymmetric Henry reactions
in our group,[12] we envisioned the possibility of employing
more challenging nitroalkanes than nitromethane as nucleo-
philes to realize high diastereo- and enantioselectivities.
Based on previous studies, the Lewis acidity of the Cu atom
was considered to be crucial for the reactivity and selectivi-
ty,[3c,6] and therefore, a trifluoromethyl group was added to
Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation
East China Institute of Technology
Nanchang, 330013 (P.R. China)
E-mail: chw8866@gmail.com
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201775.
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Table 2. Diastereoselective Henry reaction catalyzed by a chiral copper
complex in THF.[a]
the phenoxy functionality of ligand 1 to increase the acidity
of the Lewis acid center.
The addition of benzaldehyde (2a) to nitroethane (3a)
was used as a model reaction, and initial experiments were
performed to optimize the ligand 1 (Table 1, entries 1–4).
Entry R1
R2 Product Time Yield[b] d.r.[c]
ee[d]
[%]
(anti/syn) [%]
Table 1. Selected optimization conditions.[a]
1
2[e]
3[e]
4[e]
5
6
7
8
C6H5
Me 4aa
Me 4ba
Me 4ca
Me 4da
Me 4ea
Me 4 fa
Me 4ga
Me 4ha
Me 4ia
Me 4ja
Me 4ka
Me 4la
Me 4ma
24
72
72
84
72
72
84
72
84
72
72
72
72
84
72
84
72
84
84
96
81
61
74
62
89
85
87
91
80
87
79
82
90
83
76
89
69
81
79
67
20:1
39:1
39:1
22:1
16:1
23:1
15:1
39:1
20:1
27:1
25:1
26:1
23:1
20:1
>50:1
15:1
19:1
15:1
10:1
18:1
95
99
97
99
95
95
97
96
96
97
96
96
98
91
88
99
93
92
96
95
2-MeC6H4
2-MeOC6H4
2-ClC6H4
2-BrC6H4
2-NO2C6H4
3-MeC6H4
3-Cl-C6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
(E)-cinnamyl Me 4na
2-furyl
9[e]
10[e]
11
12[e]
13
14
15
16
17
18
19
20
Entry
Ligand
Temp.
[8C]
Yield[b]
[%]
d.r.[c]
(anti/syn)
ee[d]
[%]
G
Me 4oa
Me 4pa
Me 4qa
Me 4ra
Me 4sa
Et 4ab
pentyl
1
2
3
4
1a
1b
1c
1d
1a
1a
1a
RT
RT
RT
RT
RT
71
73
71
65
67
49
81
6:1
7:1
2:1
4:1
11:1
90
75
87
85
92
95
95
phenylethyl
isobutyl
cyclohexyl
C6H5
5[e]
6[e]
7[e,f]
À15
22:1
20:1
[a] Reaction conditions: 2 (0.5 mmol), 3 (5 mmol), 1a (5 mol%), CuBr2
(5 mol%), Cs2CO3 (7.5 mol%). [b] Isolated yield. [c] Determined by
1H NMR analysis of the crude reaction mixture. [d] The ee value of anti-
4. [e] The reaction was performed at À108C.
À15
[a] Reaction conditions: 2a (0.5 mmol), 3a (5 mmol), 1 (5 mol%), CuBr2
(5 mol%), Cs2CO3 (5 mol%), THF (1 mL), RT, 12 h. [b] Isolated yield.
1
[c] Determined by H NMR analysis. [d] The ee value of anti-4aa. [e] Su-
pernatant was used after centrifugation (ca. 1ꢁ104 rpm). [f] 7.5 mol% of
Cs2CO3 was used, 24 h.
the yield to 81%, with only a slight decrease in the diaster-
eoselectivity (Table 1, entry 7).
With the optimized conditions in hand, the substrate
scope was examined. As presented in Table 2, a variety of
aldehydes, including challenging aliphatic aldehydes, were
successfully used in the Henry reaction to provide the b-ni-
troalcohols in moderate yields and excellent selectivities. In
most cases, the reactions were carried out at À158C. For
some of the less active substrates, the temperature was
raised to À108C to accelerate the reaction rate (Table 2, en-
tries 2–4, 9, 10, and 12). To examine the electronic and steric
effects of the substrate on the reaction, aromatic aldehydes
with different substituents at the ortho, meta, and para posi-
tions were employed. The reaction tolerated the use of aro-
matic aldehydes with substituents at any position of the aro-
matic ring and both electron-donating and electron-with-
drawing functionalities were compatible, affording the nitro-
aldol products in moderate yields and high selectivities
(anti/syn mainly above 20:1, 95–99% ee values; Table 1, en-
tries 2–13). It should be noted that reactions of the alde-
hydes with a strong electronic effect, including the strongly
electron-donating methoxy group (Table 2, entries 3 and 10)
and the electron-withdrawing nitro group (Table 2, entries 6
and 13), also proceeded smoothly with good yields and ex-
cellent selectivities.
Among the ligands examined, ligand 1a was found to be
ideal with regard to selectivities and chemical yield (Table 1,
entry 1). Screening the other typical reaction parameters in-
dicated that THF was the best solvent in combination with
CuBr2 as the CuII source (see the Supporting Information
for details). A detailed inspection of the reaction progress
showed that a heterogeneous reaction mixture was formed.
When the precipitate was removed by centrifugation, the su-
pernatant solution of the catalyst gave a better reaction
result (Table 1, entry 5). Inductively coupled plasma mass
spectrometry (ICP-MS) and X-ray photoelectron spectro-
scopy (XPS) analyses indicated that the precipitate was an
inorganic salt instead of the chiral copper complex (the con-
centration ratio of Cs/Cu in the precipitate was 28:1; see the
Supporting Information for details). The supernatant was
then subjected to extractive electrospray ionization mass
spectrometry (EESI-MS) analysis, and the results showed
that the supernatant included the copper complex coordinat-
ed with the chiral ligand (see the mechanistic study for de-
tails). Additional studies suggested that better selectivities
could be obtained by decreasing the reaction temperature
(Table 1, entry 6). Because basic additives are known to ac-
celerate the Henry reaction,[3i,6] a larger amount of Cs2CO3
was added to increase the reactivity of the reaction. It was
found that the addition of 7.5 mol% of Cs2CO3 improved
The a,b-unsaturated (E)-cinnamylaldehyde gave the ni-
troaldol product 4na in 83% yield with a diastereomeric
ratio (d.r.) of 20:1 and 91% ee (Table 2, entry 14). Although
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anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral Cu Complex
FULL PAPER
a slight decrease in the ee value resulted when the heteroar-
omatic 2-furylaldehyde was employed as a reaction sub-
strate, the highest d.r. value (anti/syn above 50:1) was ob-
tained in this case (Table 2, entry 15). Aliphatic aldehydes
have proven to be challenging substrates in previously re-
ported examples; however, the simple aliphatic aldehydes
were suitable electrophiles under these optimized condi-
tions. In case of the linear aliphatic aldehydes, good diaster-
eoselectivities and excellent enantioselectivities were ach-
ieved (Table 2, entries 16–18). When sterically hindered cy-
clohexanecarboxaldehyde was employed as the reaction sub-
strate, the corresponding nitroaldol product 4sa was ob-
tained in 96% ee and a 10:1 d.r. (Table 2, entry 19). The use
of the less reactive nitropropane as a nucleophile afforded
the desired product 4ab in 67% yield with 18:1 anti/syn se-
lectivity and 95% ee, although a longer reaction time was
Scheme 2. Proposed catalytic cyclic for the anti-selective Henry reaction
in THF.
required (Table 2, entry 20).
Upon scaling up to gram quantities (10 mmol), the desired
product 4aa was obtained in good yield (79%) with excel-
lent selectivities (95% ee, 14:1 d.r.) by using 5 mol% of the
1a–Cu complex (Scheme 1). When the catalyst loading for
this reaction was increased to 10 mol%, the corresponding
product 4aa was obtained in 80% yield and excellent selec-
tivities (98% ee and 37:1 d.r., see the Supporting Informa-
tion for details).
4 was formed and the reactive metal–nitronate II was regen-
erated to undergo the next reaction cycle. Possible transi-
tion-state structures that account for the observed stereose-
lectivity are shown in the Supporting Information (see Fig-
ure S10 for details).
To enhance the applicability of the catalyst, the diastereo-
selective Henry reaction was studied in the presence of
water. By using the addition of benzaldehyde (2a) to nitro-
ethane (3a) as a model reaction, a library of phase-transfer
catalysts (PTCs) and additives was examined (Table 3; see
Tables S3–S5 in the Supporting Information for details). Ini-
tially, a series of PTCs were screened in the absence of any
additives (Table 3, entries 1–9). Hexadecyltrimethylammo-
niumbromide (CTAB) was found to be the PTC of choice
with regard to the chemical yield and selectivities (Table 3,
entry 7). A series of weak acid additives were then added to
the reaction mixture to improve the chemical yield (Table 3,
entries 10–14). The best result was obtained with the use of
ortho-chlorophenol as an additive (Table 3, entry 10).[14]
Lowering the reaction temperature to 08C improved the di-
astereo- and enantioselectivities but slowed the reaction,
thus prolonged reaction times were needed to obtain an ac-
ceptable yield (Table 3, entry 15). Increasing the amount of
the nitroethane starting material improved the diastereo-
and enantioselectivities slightly (Table 3, entry 16). The con-
trol experiments showed that the diastereoselective Henry
reaction was not promoted by CTAB or ortho-chlorophenol
in the absence of a copper complex. CTAB may play a key
role in the migration of organic reactants into water and the
achiral ortho-chlorophenol additive, a weak acid, may facili-
tate the proton transfer in the reaction process;[14] however,
these mechanisms are speculative and other possible mecha-
nisms may exist. Further studies are required to firmly eluci-
date the roles of the PTC and the acid additive.
Scheme 1. The anti-selective Henry reaction on a gram scale. Reaction
conditions: a) 2a (10 mmol), 3a (100 mmol), 1a (5 mol%), CuBr2
(5 mol%), Cs2CO3 (7.5 mol%), THF (20 mL), À158C, 48 h; b) 2a
(10 mmol), 3a (100 mmol), 1a (10 mol%), CuBr2 (10 mol%), Cs2CO3
(15 mol%), THF (20 mL), À158C, 48 h.
A possible catalytic cycle that accounts for the complexa-
tion system of the reaction in THF is shown in Scheme 2.
EESI-MS analysis[13] provided reliable structural information
about the intermediates shown in Scheme 2. When the
ligand 1a was reacted with CuBr2 and Cs2CO3 in THF, the
complex I was indicated by the ion peak at m/z 548
([I+CH3CN+H2O+H]+; see Figures S2–S5 in the Support-
ing Information for details). After the addition of nitro-
ethane, the copper–alkoxide moiety in intermediate I func-
tioned as a Lewis base to deprotonate EtNO2, generating
the five-coordinate copper complex II, which was indicated
by the ion peak at m/z 680 ([II+CH3CN+H]+; see Fig-
ures S6–S9 in the Supporting Information for details). It is
worth noting that copper(II) was bonded to one molecule of
nitronate and coordinated with one molecule of EtNO2 in
the intermediate II. With the subsequent addition of the al-
dehyde, two contiguous stereocenters were formed simulta-
neously (intermediate III). With the participation of another
prenucleophlic reagent (nitroethane), the nitroaldol adduct
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H. Chen, Z. Wang et al.
Table 3. Selected optimization conditions.[a]
in Table 4, a series of aryl-substituted aldehydes efficiently
underwent the Henry reaction to give the adducts 4aa–ma
in moderate to high yields with good enantioselectivities
(90–99% ee) and moderate diastereoselectivities (anti/syn
ratio up to 10:1; Table 4, entries 1–10). It was found that the
nature of the substituents on the aryl groups had a slight in-
fluence on the diastereo- and enantioselectivities, whereas
the chemical yield was largely influenced by the electronic
effect. Generally, electron-deficient aldehydes gave better
results than the electron-rich aldehydes. For instance, elec-
tron-deficient para-nitrobenzaldehyde gave the Henry
adduct 4ma in 84% yield with 99% ee and 10:1 d.r.
(Table 4, entry 10), whereas the electron-rich para-methoxy-
benzaldehyde gave the corresponding adduct 4ja in only
67% yield with 91% ee and 7.4:1 d.r. (Table 4, entry 7).
When a,b-unsaturated (E)-cinnamaldehyde was employed
as the electrophile, the adduct 4na was obtained in moder-
ate yield and selectivities (94% ee, 3:1 d.r.; Table 4,
entry 11). However, aliphatic aldehydes were found to be
poor substrates under the standard reaction conditions, pro-
viding the corresponding products in low yields and selectiv-
ities (Table 4, entries 12 and 13).
Entry
PTC
Additive
Yield[b]
[%]
d.r.[c]
(anti/syn)
ee[d]
[%]
G
1
2
3
4
5
nBu4NBr
nBu4NF
nEt4NBr
nBu4NPF6
nBu4NBF4
PVP
–
–
–
–
–
–
51
44
13
31
26
27
64
25
27
77
73
69
68
58
74
73
5.4:1
6.7:1
2.6:1
4:1
4:1
3.3:1
5:1
3.6:1
2.6:1
5:1
4:1
3.8:1
6:1
86
92
79
88
86
81
87
83
76
86
84
86
86
85
92
94
6
7
8
CTAB
SDS
–
–
9
SLS
–
10
11
12
13
14
15[e]
16[f]
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
2-ClC6H4OH
2-MeOC6H4OH
2-tBuC6H4OH
4-tBuC6H4OH
HFIP
4.6:1
7.3:1
8.5:1
2-ClC6H4OH
2-ClC6H4OH
[a] Reaction conditions: 2a (0.25 mmol), 3a (2.5 mmol, 10 equiv), 1a
(10 mol%), CuBr2 (10 mol%), Cs2CO3 (10 mol%), PTC (10 mol%), ad-
ditive (10 mol%), H2O (0.5 mL), 58C, 24 h. [b] Isolated yield. [c] Deter-
The utility of the reaction was further demonstrated in
the syntheses of the biochemically important (+)-spisulosine
1
mined by H NMR analysis. [d] The ee value of anti-4aa. [e] The reaction
was performed at 08C for 72 h. [f] Reaction conditions: 2a (0.25 mmol),
3a (4 mmol), 1a (10 mol%), CuBr2 (10 mol%), Cs2CO3 (10 mol%),
CTAB (10 mol%), ortho-chlorophenol (10 mol%), H2O (0.5 mL), 08C,
72 h. PVP=polyvinyl pyrrolidone, SDS=sodium dodecylsulfate, SLS=
sodium laurylsulfonate, HFIP=hexafluoroisopropanol.
7
(Scheme 3) and a pyrroloisoquinoline derivative 12
Table 4. Diastereoselective Henry reaction in the presence of water.[a]
Scheme 3. Enantioselective synthesis of (+)-spisulosine. Reaction condi-
tions: a) EtNO2 (10 equiv), ent-1a (10 mol%), CuBr2 (10 mol%), Cs2CO3
(15 mol%), THF, 08C, 72 h, 82% yield; b) 10% Pd/C (10 mol%), H2,
MeOH, RT, 12 h, 73% yield.
Entry
R1
Product
Yield[b]
[%]
d.r.[c]
(anti/syn)
ee[d]
[%]
N
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
4aa
4ba
4ca
4 fa
4ha
4ia
4ja
4ka
4la
4ma
4na
4pa
4qa
73
66
61
76
74
69
67
75
76
84
68
62
64
8.5:1
5.6:1
5.7:1
9:1
8.3:1
7.8:1
7.4:1
7.9:1
8:1
10:1
3:1
1.1:1
1.4:1
94
93
90
97
93
92
91
92
93
99
94
83
85
2-MeC6H4
2-MeOC6H4
2-NO2C6H4
3-ClC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
PhCH=CH
pentyl
(Scheme 4). (+)-Spisulosine ES285 was isolated from Spisu-
la polynyma, and has been shown to possess long-lasting an-
titumor cytotoxic activity on the nanomolar scale, both in
vitro and in vivo.[15] The pyrroloisoquinoline ring system
forms the central skeleton of the erythrina alkaloid group.[16]
The treatment of n-hexadecanal 5 and nitroethane with
10 mol% of the ent-1a–CuII complex in THF at 08C for 72 h
resulted in the formation of the anti-nitroalcohol 6 (anti/
syn=10.6:1) in 82% yield with 95% ee. Reduction of the
nitro group by the Pd/C catalyst gave spisulosine 7, which
contains a long, saturated alkyl chain (C18) and a 1,2-ami-
noalcohol motif arranged in an anti manner. It should be
mentioned that this is the shortest enantioselective synthesis
of ES285 reported so far.[8,17]
PhCH2CH2
[a] Reaction conditions: 2 (0.25 mmol), 3a (4 mmol), 1a (10 mol%),
CuBr2 (10 mol%), Cs2CO3 (10 mol%), ortho-chlorophenol (10 mol%),
CTAB (10 mol%), H2O (0.5 mL), 08C, 72 h. [b] Isolated yield. [c] Deter-
mined by 1H NMR analysis of the crude reaction mixture. [d] The ee
value of anti-4.
The scope of the diastereoselective Henry reaction in the
presence of water was then examined with a variety of alde-
hydes under the optimized conditions (Table 4). As shown
With the anti-nitroalcohol 4aa in hand, aminoalcohol 8
could be obtained in 87% yield (Scheme 4). Then, the cyclo-
condensation process between aminoalcohol 8 and levulinic
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anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral Cu Complex
FULL PAPER
(0.5 mL, 1m), and then extracted with ethyl acetate (3ꢁ15 mL). The com-
bined organic phases were dried with Na2SO4 and evaporated under
vacuum. Purification of the residue by flash column chromatography
gave the desired b-nitroalcohol 4. The anti/syn ratio was determined by
1H NMR analysis of the crude mixture. The enantiomeric excess was de-
termined by HPLC analysis.
General procedure for the anti-selective Henry reaction in water: Nitro-
ethane (3a; 4 mmol) was added to a mixture of ligand 1a (0.025 mmol),
CuBr2 (0.025 mmol), Cs2CO3 (0.025 mmol), ortho-chlorophenol
(0.025 mmol), and CTAB (0.025 mmol) in H2O (0.5 mL). The mixture
was allowed to stir at room temperature for 1 h. After cooling to 08C,
compound 2 (0.25 mmol) was added to the reactor. The mixture was re-
acted for 72 h, quenched with dilute HCl (0.5 mL, 1m), and then extract-
ed with ethyl acetate (3ꢁ10 mL). The combined organic phases were
dried with Na2SO4 and evaporated under vacuum. Purification of the res-
idue by column chromatography gave the desired b-nitroalcohol 4. The
anti/syn ratio was determined by 1H NMR analysis of the crude mixture.
The enantiomeric excess was determined by HPLC analysis.
Scheme 4. Enantioselective synthesis of a pyrroloisoquinoline derivative.
Reaction conditions: a) 10% Pd/C (10 mol%), H2, EtOH, RT, 10 h, 87%
yield; b) levulinic acid (1 equiv), toluene, reflux, 24 h, 79% yield; c) TiCl4
(3 equiv), dichloromethane, À788C to 408C, 30 h, 69% yield; d) 10% Pd/
C (10 mol%), H2, EtOH, RT, 10 h, 87% yield.
acid led to the formation of compound 9 in 79% yield. With
the participation of TiCl4, lactam 9 could be transformed
into enamide 10 in 69% yield. During the reaction process,
compound 11 was observed, which suggests that this inter-
mediate (11) may be formed by a Pictet–Spengler-type reac-
tion from lactam 9 and was then dehydrated to yield enam-
ide 10. The desired pyrroloisoquinoline derivative 12 was
obtained in 87% yield by the catalytic hydrogenation of en-
amide 10 at room temperature (see the Supporting Informa-
tion for details). The stereochemistry of the resulting com-
pounds (compounds 9, 11, and 12) was determined by
NOESY experiments (see the Supporting Information for
details).
Acknowledgements
The authors are grateful to the National Nature Science Foundation of
China (20932002, 20972144, 90813008, 21172205, 20772118, J1030412),
the 973 program (2010CB912103), and the fund from the Ministry of Na-
tional Education.
[1] a) M. T. Reetz, Chem. Rev. 1999, 99, 1121–1162; b) S. C. Bergmeier,
Tetrahedron 2000, 56, 2561–2576; c) F. A. Luzzio, Tetrahedron 2001,
57, 915–945; d) J. Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetra-
hedron: Asymmetry 2006, 17, 3315–3326; e) C. Palomo, M. Oiar-
bide, A. Laso, Eur. J. Org. Chem. 2007, 2561–2574.
[2] H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J. Am. Chem.
Soc. 1992, 114, 4418–4420.
[3] For examples of metal-catalyzed reactions, see: a) H. Sasai, T.
Suzuki, N. Itoh, K. Tanaka, T. Date, K. Okamura, M. Shibasaki, J.
Am. Chem. Soc. 1993, 115, 10372–10373; b) B. M. Trost, V. S. C.
Yeh, Angew. Chem. 2002, 114, 889–891; Angew. Chem. Int. Ed.
2002, 41, 861–863; c) D. A. Evans, D. Seidel, M. Rueping, H. W.
Lam, J. T. Shaw, C. W. Downey, J. Am. Chem. Soc. 2003, 125,
12692–12693; d) B. M. Choudary, K. V. S. Ranganath, U. Pal, M. L.
Kantam, B. Sreedhar, J. Am. Chem. Soc. 2005, 127, 13167–13171;
e) C. Palomo, M. Oiarbide, A. Laso, Angew. Chem. 2005, 117, 3949–
3952; Angew. Chem. Int. Ed. 2005, 44, 3881–3884; f) T. Arai, M.
Watanabe, A. Fujiwara, N. Yokoyama, A. Yanagisawa, Angew.
Chem. 2006, 118, 6124–6127; Angew. Chem. Int. Ed. 2006, 45, 5978–
5981; g) Y. Xiong, F. Wang, X. Huang, Y. Wen, X. Feng, Chem. Eur.
J. 2007, 13, 829–833; h) J. Park, K. Lang, K. A. Abbaud, S. Hong, J.
Am. Chem. Soc. 2008, 130, 16484–16485; i) G. Blay, L. R. Domingo,
V. Hernandez-Olmos, J. R. Pedro, Chem. Eur. J. 2008, 14, 4725–
4730; j) K. Lang, J. Park, S. Hong, J. Org. Chem. 2010, 75, 6424–
6435; k) L. Cheng, J. Dong, J. You, G. Gao, J. Lan, Chem. Eur. J.
2010, 16, 6761–6765; l) B. V. Subba Reddy, S. M. Reddy, S. Manisha,
C. Madan, Tetrahedron: Asymmetry 2011, 22, 530–535; for examples
of organocatalyzed reactions, see: m) T. Ooi, K. Doda, K. Maruoka,
J. Am. Chem. Soc. 2003, 125, 2054–2055; n) H. M. Li, B. M. Wang,
L. Deng, J. Am. Chem. Soc. 2006, 128, 732–733.
[4] a) D. Uraguchi, S. Sakaki, T. Ooi, J. Am. Chem. Soc. 2007, 129,
12392–12393; b) D. Uraguchi, S. Nakamura, T. Ooi, Angew. Chem.
2010, 122, 7724–7727; Angew. Chem. Int. Ed. 2010, 49, 7562–7565.
[5] a) T. Nitabaru, N. Kumagai, M. Shibasaki, Tetrahedron Lett. 2008,
49, 272–276; b) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga,
M. Shibasaki, Angew. Chem. 2008, 120, 3274–3277; Angew. Chem.
Int. Ed. 2008, 47, 3230–3233; c) Y. Sohtome, Y. Kato, S. Handa, N.
Aoyama, K. Nagawa, S. Matsunaga, M. Shibasaki, Org. Lett. 2008,
10, 2231–2234; d) T. Nitabaru, A. Nojiri, M. Kobayashi, N. Kuma-
gai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 13860–13869; e) T.
Conclusion
An efficient catalytic system for highly anti-selective Henry
reactions in organic media has been developed with excel-
lent enantioselectivities. Moreover, the anti-selective Henry
reaction in the presence of water was carried out for the
first time with good diastereoselectivities and excellent
enantioselectivities. The key intermediates in the catalytic
cycle were structurally illustrated by EESI-MS analyses. Fur-
thermore, the synthetically useful anti-nitroalcohol motif has
been successfully transformed into the biochemically impor-
tant (+)-spisulosine and a pyrroloisoquinoline derivative.
Further studies to clearly understand the mechanism of the
PTC and the role of the acidic additive are ongoing in our
group.
Experimental Section
General procedure for the anti-selective Henry reaction in THF: Nitroal-
kane 3 (5 mmol) was added to a mixture of ligand 1a (0.025 mmol),
CuBr2 (0.025 mmol), and Cs2CO3 (0.0375 mmol) in dry THF (1 mL). The
mixture was allowed to stir at room temperature for 4 h and a white pre-
cipitate appeared. The tube was centrifuged for 5 min (ca. 1ꢁ104 rpm)
and the supernatant was transferred into a reactor (10 mL). After cooling
to À158C, compound 2 (0.5 mmol) was added to the reactor. The mixture
was reacted for the time indicated in Table 2, quenched with dilute HCl
Chem. Eur. J. 2012, 00, 0 – 0
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H. Chen, Z. Wang et al.
Nitabaru, N. Kumagai, M. Shibasaki, Angew. Chem. 2012, 124,
1676–1679; Angew. Chem. Int. Ed. 2012, 51, 1644–1647.
[6] T. Arai, R. Takashita, Y. Endo, M. Watanabe, A. Yanagisawa, J.
Org. Chem. 2008, 73, 4903–4906.
[11] For reviews of organic reactions in water, see: a) U. M. Lindstrçm,
Chem. Rev. 2002, 102, 2751–2772; b) S. Kobayashi, K. Manabe, Acc.
Chem. Res. 2002, 35, 209–217; c) K. Manabe, S. Kobayashi, Chem.
Eur. J. 2002, 8, 4094–4101; d) C. J. Li, L. Chen, Chem. Soc. Rev.
2006, 35, 68–82.
[12] G. Y. Lai, F. F. Guo, Y. Q. Zheng, Y. Fang, H. G. Song, K. Xu, S. J.
Wang, Z. G. Zha, Z. Y. Wang, Chem. Eur. J. 2011, 17, 1114–1117.
[13] For examples of some applications of EESI-MS analysis, see: a) X.
Li, B. Hu, J. H. Ding, H. W. Chen, Nat. Protoc. 2011, 6, 1010–1025;
b) H. W. Chen, S. P. Yang, M. Li, B. Hu, J. Q. Li, J. Wang, Angew.
Chem. 2010, 122, 3117–3120; Angew. Chem. Int. Ed. 2010, 49, 3053–
3056.
[7] For examples of anti-selective Henry reactions involving silyl nitro-
nates, see: a) T. Risgaard, K. V. Gothelf, K. A. Jørgensen, Org.
Biomol. Chem. 2003, 1, 153–156; b) Ref. [3m]; for examples of
other anti-selective Henry reactions using nitroalkanes, see:
c) Ref. [3i]; d) K. Lang, J. Park, S. Hong, Angew. Chem. 2012, 124,
1652–1656; Angew. Chem. Int. Ed. 2012, 51, 1620–1624; for exam-
ples of enzymatic approaches, see: e) T. Purkarthofer, K. Gruber,
M. Gruber-Khadjawi, K. Waich, W. Skranc, D. Mink, H. Griengl,
Angew. Chem. 2006, 118, 3532–3535; Angew. Chem. Int. Ed. 2006,
45, 3454–3456; f) M. Gruber-Khadjawi, T. Purkarthofer, W. Skranc,
H. Griengl, Adv. Synth. Catal. 2007, 349, 1445–1450.
[14] The use of phenols as achiral additives to improve the enantioselec-
tivity of Henry reactions has been reported by Shibasaki and co-
workers, see Ref. [5b] for details.
[8] C. Sꢂguin, F. Ferreira, C. Botuha, F. Chemla, A. Pꢂrez-Luna, J. Org.
Chem. 2009, 74, 6986–6992.
[15] K. L. Rinehart, R. A. Warwick, J. Avila, N. L. Fregeau Gallagher, D.
Garcia Gravalos, G. T. Faircloth, US-A 6800661B1, 2004.
[16] J. W. Daly, T. W. Spande, N. Whittaker, R. J. Highet, D. Feigl, N.
Noshimori, T. Tokuyama, C. W. Meyers, J. Nat. Prod. 1986, 49, 265–
280.
[17] a) P. Ghosal, A. K. Shaw, Tetrahedron Lett. 2010, 51, 4140–4142;
b) G. Malik, A. Estoule, P. Retailleau, P. Dauban, J. Org. Chem.
2011, 76, 7438–7448; c) B. S. Chen, L. H. Yang, J. L. Ye, T. Huang,
Y. P. Ruan, J. Fu, P. Q. Huang, Eur. J. Med. Chem. 2011, 46, 5480–
5486.
[9] For reviews, see: T. D. Machajewski, C. H. Wong, Angew. Chem.
2000, 112, 1406–1430; Angew. Chem. Int. Ed. 2000, 39, 1352–1375.
[10] For reviews, see: a) J. A. Ma, D. Cahard, Angew. Chem. 2004, 116,
4666–4683; Angew. Chem. Int. Ed. 2004, 43, 4566–4583; b) H. Ya-
mamoto, K. Futatsugi, Angew. Chem. 2005, 117, 1958–1977; Angew.
Chem. Int. Ed. 2005, 44, 1924–1942; c) M. S. Taylor, E. N. Jacobsen,
Angew. Chem. 2006, 118, 1550–1573; Angew. Chem. Int. Ed. 2006,
45, 1520–1543; d) D. H. Paull, C. J. Abraham, M. T. Scerba, E.
Alden-Danforth, T. Lectka, Acc. Chem. Res. 2008, 41, 655–663;
e) M. Shibasaki, M. Kanai, S. Matsunaga, N. Kumagai, Acc. Chem.
Res. 2009, 42, 1117–1127.
Received: May 20, 2012
Published online: && &&, 0000
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These are not the final page numbers!

anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral Cu Complex
FULL PAPER
Asymmetric Synthesis
K. Xu, G. Y. Lai, Z. G. Zha, S. S. Pan,
H. W. Chen,* Z. Y. Wang* . . &&&& — &&&&
A Highly anti-Selective Asymmetric
Henry Reaction Catalyzed by a Chiral
Copper Complex: Applications to the
Syntheses of (+)-Spisulosine and a
Pyrroloisoquinoline Derivative
Friendly water: An asymmetric Henry
reaction that affords synthetically ver-
satile b-nitroalcohols in an anti-selec-
tive manner and with excellent ee
values has been developed (see
in water for the first time with up to
99% ee, and the anti-adducts were suc-
cessfully transformed into the bio-
chemically important (+)-spisulosine
and a pyrroloisoquinoline derivative.
scheme). The reaction was carried out
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!