Catalytic asymmetric 1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2-Acyl cycloheptatrienes: Efficient construction of bridged heterocycles bearing piperidine moiety

Article abstract of DOI:10.1021/ja503309u

Conjugated cyclic trienes without nonbenzenoid aromatic characteristic were successfully employed as fine-tunable dipolarophiles in the Cu(I)-catalyzed asymmetric azomethine ylide-involved 1,3-dipolar [3 + 6] cycloaddition for the first time, affording a variety of bridged heterocycles bearing piperidine moiety in good yield with exclusive regioselectivity and excellent stereoselectivity. 2-Acyl group is the key factor that determines the annulation preferentially through [3 + 6]-pathway, while 2-ester group modulates the annulation through [3 + 2]-pathway.

Full text of DOI:10.1021/ja503309u

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Article
Catalytic Asymmetric 1,3-Dipolar [3+6] Cycloaddition of
Azomethine Ylides with 2-Acyl Cycloheptatrienes: Efficient
Construction of Bridged Heterocycles Bearing Piperidine Moiety
Qing-Hua Li, Liang Wei, and Chun-Jiang Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja503309u • Publication Date (Web): 29 May 2014
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Catalytic Asymmetric 1,3-Dipolar [3+6] Cycloaddition of Azomethine
Ylides with 2-Acyl Cycloheptatrienes: Efficient Construction of
Bridged Heterocycles Bearing Piperidine Moiety
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QingꢀHua Li,† Liang Wei,† and ChunꢀJiang Wang,*†,‡
College of Chemistry and Molecular Sciences, Wuhan University, China 430072
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, China
300071
Email: cjwang@whu.edu.cn
Abstract: Conjugated cyclic trienes without nonbenzenoid aromatic characteristic
were successfully employed as fineꢀtunable dipolarophiles in the Cu(I)ꢀcatalyzed
asymmetric azomethine ylideꢀinvolved 1,3ꢀdipolar [3+6] cycloaddition for the first
time, affording a variety of bridged heterocycles bearing piperidine moiety in good
yield with exclusive regioselectivity and excellent stereoselectivity. 2ꢀAcyl group is
the key factor that determines the annulation preferentially through [3+6]ꢀpathway
while 2ꢀester group modulates the annulation through [3+2]ꢀpathway.
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Introduction
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Heterocyclic structures with multiple stereogenic centers are the core elements
prevalent in a variety of natural alkaloids and pharmaceutical ingredients exhibiting
significant biological activities.1ꢀ3 Metalꢀcatalyzed 1,3ꢀdipolar cycloaddition reaction
of azomethine ylides is one of the powerful tools for the convergent construction of
heterocyclic pyrrolidine frameworks from readilyꢀavailable organic compounds.4
However, the intrinsic limitation of 1,3ꢀdipolar cycloaddition reaction is that
fiveꢀmembered heterocycles are normally generated via [3+2] reaction model because
2ꢀπ olefins are usually served as the twoꢀatom dipolarophile units while azomethine
ylides are serving as the threeꢀatom 1,3ꢀdipole units.5 Recently, fulvenes6 and tropone7
were employed as efficient 6ꢀπ dipolarophiles in the catalytic asymmetric 1,3ꢀdipolar
[3+6]ꢀcycloaddition, which provided the direct and efficient approach to
enantioenriched nitrogenꢀcontaining nonꢀfive membered heterocycles. The intrinsic
nonbenzenoid aromatic characteristic exhibited by the resonance forms of fulvene and
tropone provides the driving force for those 1,3ꢀdipolar [3+6]ꢀcycloaddition
reactions.8
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As part of our research interest in the asymmetric construction of five9 and
nonꢀfiveꢀmembered6b,7b
nitrogenꢀcontaining
heterocycles
via
azomethine
ylideꢀinvolved 1,3ꢀdipolar cycloaddition, we planned to investigate the conjugated
polyenes without nonbenzenoid aromatic characteristic as the dipolarophiles to further
explore the feasibility of modulating the polyenes as potential different 2nꢀπ
components through varying the electronic property of polyenes, which may not only
diversify the existing 1,3ꢀdipolar cycloaddition reaction from the view point of
synthetic methodology but also be valuable in the facile and straightforward
construction of structurally and stereochemically complex heterocycles. To the best of
our knowledge, no studies on the substrateꢀcontrolled 1,3ꢀdipolar [3+2n]
cycloaddition have been carried out so far.
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In consideration of that a stepwise mechanism was revealed for the Cu(I) or
Ag(I)/TFꢀBiphamPhos catalytic system developed in this laboratory through both
theoretical calculations and experimental results,10 we envisaged that conjugated
cyclic trienes containing an electronꢀwithdrawing carbonyl group at the 2ꢀposition are
the potential 2, 4 or 6ꢀπ components in the metalꢀcatalyzed 1,3ꢀdipolar cycloaddition
(Scheme 2). The carboanion in the generated zwitterionic intermediate is stabilized by
the delocalization of the negative charge over the adjacent carbonyl and conjugated
diene. Having analyzed the electron factor and structural feature of the generated
zwitterionic intermediates from the electronꢀdeficient trienes, we are interested in the
application of 2ꢀcarbonyl substituted cycloheptatrienes as the potential 2nꢀπ reaction
partner in azomethine ylideꢀinvolved 1,3ꢀdipolar [3+2n] cycloaddition with the aid of
tuning the substituted group at the 2ꢀposition of cycloheptatrienes. We envisioned that
the subsequent intramolecular cyclization of the generated zwitterionic intermediate
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might undergo through three possible different pathways and therefore deliver three
types of adducts with different regioselectivities: a) bicyclic heterocycle 1 in which
2ꢀacyl cycloheptatriene was served as 2ꢀπ unit ([3+2]ꢀmodel, Scheme 2a); b) bridged
heterocyclic azabicyclo[3.3.2]decadiene 2 in which 2ꢀacyl cycloheptatriene was
served as 4ꢀπ unit ([3+4]ꢀmodel, Scheme 2b); and c) bridged heterocyclic
azabicyclo[4.3.1]decadiene 3 in which 2ꢀacyl cycloheptatriene was served as 6ꢀπ unit
([3+6]ꢀmodel, Scheme 1c). Therefore, it is a great challenge to control both the
exclusive regioselectivity and high stereoselectivity associated with this unknown
annulation process.
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Herein, we report an unprecedented catalytic asymmetric 1,3ꢀdipolar [3+6]
cycloaddition of azomethine ylides employing 2ꢀacyl cycloheptatrienes without
nonbenzenoid aromatic characteristic as the 6ꢀπ components, providing a facile access
to a variety of enantioenriched heterocycles containing a unique bridged piperidine
moiety,11 which is the core structures of many bioactive molecules. Another attractive
feature of the current methodology is the subtle change in the carbonyl group of
conjugated cylic trienes plays a significant role in controlling the reaction pathway in
[3+6] or [3+2]ꢀmodel.
Results and Discussion
At the outset of this study, we examined the reaction of 2ꢀethoxycarbonyl
cycloheptatriene 4 and 2ꢀbenzoyl cycloheptatriene 5a with Nꢀ(4ꢀchlorobenzylidene)ꢀ
glycine methyl ester 6a in the presence of different metalꢀcomplex as the catalysts.
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Initially, 5 mol % of Cu(CH3CN)4BF4/PPh3 complex was employed with Et3N as the
base in DCM at room temperature. Although full conversions of both trienes were
observed, only unidentified mixtures were generated from the messy reaction systems.
To our delight, using Cu(I)/racꢀ(±)TFꢀBiphamPhos complex9a as the catalyst, the
reactions became very clean and finish smoothly at room temperature. The common
[3+2]ꢀreaction pathway was occurred with 2ꢀethoxycarbonyl cycloheptatriene 4
(Scheme 3, left side) providing the bicyclic pyrrolidine 1 as single isomer, which was
confirmed by Xꢀray diffraction analysis of the corresponding enantiopure compound
later (vide infra).12 Neither [3+4] nor [3+6] cycloadduct was detected in this process.
When switching carbonyl group from CO2Et to benzoyl, we found that [3+2]ꢀpathway
was suppressed and [3+6]ꢀreaction occurred preferentially affording the bridged
adduct azabicyclo[4.3.1]decadiene 3aa with excellent diastereoselectivity (Scheme 3,
right side). Further Xꢀray diffraction analysis confirmed that an exclusive
regioselectivity was achieved in this case,12 and formation of any [3+2] and [3+4]
cycloadduct was not observed.
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The promising results encouraged us to conduct the asymmetric variant of this
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1,3ꢀdipolar [3+6] cycloaddition with chiral TFꢀBiphamPhos ligands,9a and the results
are tabulated in Table 1. Employing Ag(I)/(S)ꢀ(L1) complex as the catalyst, compound
3aa was separated in 81% yield albeit with moderate ee value (Table 1, entry 1).
Better catalytic activity and higher enantioselectivity were exhibited by Cu(I)/(S)ꢀL1
complex. Then, a series of chiral ligands were screened with copper(I) as the metal
precursor. Deleterious enantioselectivities were observed for ligand L2-L4 in which
the sterically hindered substituents with different electron properties were introduced
on the phosphorus atom (entries 3ꢀ5). Installing two bromine atom at the 3,3'ꢀposition
of the biphenyl backbone significantly improved the enantioselectivity, and L5 was
shown as the best chiral ligand in this [3+6] annulation affording 3aa in 85% yield
and 92% ee (entry 6) (see Supporting Information for the screening results of other
commonlyꢀused chiral ligands). Subsequent solvent screening revealed that reaction
medium had slight effect on this reaction, dichloromethane and toluene were the best
solvents in terms of stereoselectivity and reactivity (Table 1, entries 6ꢀ10). Reducing
the reaction temperature was beneficial for further enantioselectivity improvement,
and 95% and 98% ee were achieved when the cycloaddition was carried out at ꢀ20 oC
and ꢀ40 oC, respectively (entries 12 and 13).
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Table 1. Optimization of Cu(I)-catalyzed asymmetric [3+6] cycloaddition of 2-benzoyl cycloheptatriene 5a
with imino ester 6a.a
5
6
7
8
9
Ph
O
O
Ph
CO2Me
N
H
MeO2C
HN
[M]/L (3 mol%)
+
Et3N (15 mol%), solvent
C6H4-p-Cl
p-Cl-C6H4
H
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5a
6a
3aa (>20:1 dr)
CF3
R1
L1: R1 = H, R2 = Ph
L2: R1 = H, R2 = 3,5-bis(methyl)phenyl
L3: R1 = H, R2 = 3,5-bis(trifluoromethyl)phenyl
L4: R1 = H, R2 = cyclohexyl
F3C
F3C
NH2
NHPR2
2
R1
L5: R1 = Br, R2 = Ph
CF3
(S)-TF-BiphamPhos
ee (%)c
39
T (oC)
time (h)
12
yield (%)b
81
entry
1
Solvent
L1
[M]
AgOAc
CH2Cl2
rt
(S)-L1
2
3
4
5
6
Cu(CH3CN)4BF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
8
8
84
75
63
79
85
56
75
43
69
92
(S)-L1
(S)-L2
(S)-L3
(S)-L4
(S)-L5
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
15
12
8
Ether
THF
7
8
rt
rt
10
15
10
15
12
16
78
76
83
79
81
88
88
87
92
90
93
95
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(S)-L5
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
9
PhMe
EtOAc
CH2Cl2
CH2Cl2
rt
10
11
12
rt
0
-20
13
CH2Cl2
-40
20
86
98
(S)-L5
Cu(CH3CN)4BF4
a All reactions were carried out with 0.23 mmol of 5a and 0.35 mmol of 6a in 2 mL of solvent. b Yield of the
3aa
isolated compound
after purification by column chromatography on silica gel. c Ee was determined by
HPLC analysis using a chiral stationary phase, and dr was determined by the crude 1H NMR.
Having established the optimal reaction conditions, we explored various imino
esters to examine the substrate scope. The representative results are summarized in
Table 2. A wide range of imino esters are compatible with this [3+6]ꢀcycloaddition
reaction. Aryl imino esters containing different substitution patterns (e.g., paraꢀ,
metaꢀ or orthoꢀ) at the phenyl ring were well tolerated, regardless of the electron
properties (e.g., electronꢀneutral, electronꢀrich or electronꢀdeficient), and the desired
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adducts 5 were obtained in good yield (77ꢀ87%) with high diastereoselectivity (>20:1
dr) and excellent enantioselectivity (93ꢀ98%) (Table 2, entries 1ꢀ10). It is worth
mentioning that excellent diastereoselectivity and enantioselectivity could be
maintained with sterically hindered orthoꢀchloro (6b), orthoꢀmethyl (6g) and fused
aromatic 1ꢀnaphthyl (6j) imino esters (entries 2, 7 and 10). This cycloaddition was
also compatible with heteroaromatic frameworks as shown in entries 11 and 12, and
98% and 94% ee were observed for 2ꢀfuryl (6k) and 2ꢀthienyl (6l) substituted imino
esters, respectively. Notably, the substrate scope of this cycloaddition was
successfully extended to less reactive aliphatic and alkenyl substituted imino esters
6m and 6n, and the desired adducts 3am and 3an were separated in good yield with
excellent diastereoselectivity and enantioselectivity in the presence of stronger
inorganic base Cs2CO3 (entries 13 and 14).
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Table 2.
S
L5
Substrate scope of Cu(I)/( )- -catalyzed asymmetric [3+6]
5a
6 a
.
cycloaddition of 2-benzoyl cycloheptatrienes
with imino esters
5
6
7
8
Ph
H
O
O
Ph
CO2Me
N
MeO2C
HN
L5
Cu(I)/(S)- (3 mol%)
Et3N, CH2Cl2
+
-40 oC, 18-24 h
(>20:1 dr)
9
R
H
R
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5a
6
3
entry
yield (%)b
ee (%)c
Prod.
R
1
2
p-Cl-C6H4 (6a)
3aa
3ab
3ac
3ad
3ae
3af
86
82
85
87
83
82
84
77
83
81
81
83
75
81
98
95
98
98
98
97
93
95
98
96
98
94
91
97
6b
o
-Cl-C6H4
-Br-C6H4
(
)
3
p
6c
( )
4
p
6d
( )
-NO2-C6H4
5
Ph (
-Me-C6H4
o-Me-C6H4 (6g)
6e
)
6
p
6f
( )
7
3ag
3ah
3ai
8
m-MeO-C6H4 (6h)
p-MeO-C6H4 (6i)
9
10
11
12
13d
14d
6j
3aj
1-Naphthyl (
)
6k
)
3ak
3al
Furyl (
6l
)
Thienyl (
3am
3an
Pr (6m)
6n
PhCH=CH (
)
a
5a
6
All reactions were carried out with 0.23 mmol of
and 0.35 mmol of
b
3
in 2 mL of CH2Cl2. Yield of the isolated compound after purification
by column chromatography on silica gel. c Ee was determined by HPLC
analysis using a chiral stationary phase. Minor diastereomer was not
detected on the crude 1H NMR. Inorganic Cs2CO3 was employed as
d
the base.
The relative and absolute configuration of the adduct 3aa was unequivocally
determined as (1S,6R,7R,9S) based on the Xꢀray diffraction analysis12 (Figure 1).
Those of other [3+6]ꢀcycloadducts were deduced based on these results.
Figure 1. ORTEP representation of (1S,6R,7R,9S)ꢀ3aa at 10% probability for the drawing of
thermal ellipsoids.
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Remarkably, αꢀsubstituted imino esters 6o and 6p derived from alanine worked
well in this cyclization process, furnishing the corresponding chiral bridged
azabicyclo[4.3.1]decadienes 3ao and 3ap containing one unique quaternary13 and
three tertiary stereogenic centers, which highlighted the generality of this [3+6]
cycloaddition protocol (Scheme 4).
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The substrate scope of this cycloaddition with respect to the cycloheptatrienes
was also explored to further investigate the generality of the method. As shown in
Table 3, the efficient catalytic system is amenable to a variety of 2ꢀacyl
cycloheptatrienes including aromatic (entries 1ꢀ8), heteroaromatic (entries 9ꢀ10) and
aliphatic groups (entry 11), affording the desired cycloadducts in good yields (75ꢀ88%)
with high diastereoselectivities (>20:1 dr) and excellent enantioselectivities (96ꢀ98%
ee). Electronꢀdeficient (entries 6 and 7) and electronꢀrich (entries 2ꢀ5) phenyl ring in
the acyl moiety of cycloheptatrienes had negligible influence on the results of
asymmetric induction. Substitution at the paraꢀ, metaꢀ or orthoꢀpositions of the
phenyl ring in 2ꢀacyl cycloheptatrienes could also be well tolerated without effect on
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the enantioselectivity. Notably, aliphatic 2ꢀacyl cycloheptatriene 5k worked well in
this process as viable 6ꢀπꢀcomponent, producing the desired cycloadduct 3ka in 78%
yield with 96% ee (entry 11). 2ꢀFormyl cycloheptatriene 5l could also be compatible
in this [3+6] cycloaddition affording the desired adduct 3la in good yield with high
diastereoselectivity albeit moderate enantioselectivity. Fortunately, the enantiopure
3la can be easily achieved by simple crystallization (entry 12).
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Table 3.
S
L5
Substrate scope of Cu(I)/( )- -catalyzed asymmetric [3+6]
5
6a a
cycloaddition of 2-acyl cycloheptatrienes with imino ester
.
R
O
R
O
CO2Me
N
L5
Cu(I)/(S)- (3 mol%)
H
MeO2C
HN
Et3N, CH2Cl2
+
-40 oC, 18-24 h
(>20:1 dr)
p-Cl-C6H4
p-Cl-C6H4
H
5
6a
3
Prod.
entry
yield (%)b
ee (%)c
R
3aa
3ba
3ca
3da
3ea
3fa
1
2
3
4
5
6
7
86
81
84
86
78
81
83
98
96
97
98
98
97
96
5a
Ph (
)
p-Me-C6H4 (5b)
o-Me-C6H4 (5c)
m-Me-C6H4 (5d)
p-MeO-C6H4 (5e)
5f
( )
p-Cl-C6H4
p-CF3-C6H4 (5g)
5h
3ga
3ha
8
88
75
81
78
85
98
97
97
96
1-Naphthyl (
)
3ia
3ja
3ka
3la
9
5i
Furyl (
)
10
11
12
5j
Thienyl (
)
5k
Me (
)
71(99)d
5l
H (
)
a
5
6a
All reactions were carried out with 0.23 mmol of and 0.35 mmol of
b
3
in 2 mL of CH2Cl2. Yield of the isolated compound after purification
by column chromatography on silica gel. c Ee was determined by HPLC
analysis using a chiral stationary phase. Minor diastereomer was not
detected on the crude 1H NMR. d Data in parentheses was achieved
after simple recrystallization in ethyl acetate.
The synthetic utility of this reaction was further investigated. The reaction
between 5a and 6a was performed on a gram scale to test the scalability of this
cycloaddition, and compound 3aa was obtained in 85% yield and 98% ee (Scheme 5).
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The adduct 3aa contains functional groups that are feasible toward synthetic
transformations as exemplified in Scheme 6. Treatment of 3aa with NaBH4 led to the
reduction of both carbonyl and ester groups providing the diol (R)ꢀ(1R,6S,7S,9R)ꢀ7 in
good yield with high diastereoselectivity. In addition, irradiation of 3aa with Nꢀphenyl
maleimide using a 500 W lamp underwent excellent regioselective and
diastereoselective [2+2] annulation14 to afford enantioenriched compound 8
containing eight stereogenic centers in 75% yield as a single isomer.
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The asymmetric variant of 1,3ꢀdipolar [3+2] cycloaddition with 2ꢀethoxycarbonyl
cycloheptatriene 4 as the 2ꢀπ dipolarophiles was also carried out under the established
optimal reaction condition for the above [3+6]ꢀcycloaddition, and the results are listed
in Scheme 7. Employing Cu(I)/(S)ꢀ(L5) complex as the catalyst and
Nꢀ(4ꢀchlorobenzylidene)ꢀglycine methyl ester 6a as the dipole precursor, the
[3+2]ꢀcycloadduct 1 was separated in 82% yield with high diastereoselectivity and
excellent enantioselectivity. The absolute configuration of 1 achieved by Cu(I)/(S)ꢀL5
was unequivocally determined to be (1R,3R,3aR,8aR) by Xꢀray analysis of the
corresponding Nꢀtosylated amide 1'.
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Based on the Xꢀray structure and the absolute configuration of the cycloadducts
3aa and 1', a plausible stepwise mechanism is proposed to rationalize the
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regioselectivity and stereoselectivity of [3+6]ꢀand [3+2]ꢀcycloaddition (Scheme 8).
5
6
7
8
9
Scheme 8.
with 2-benzoyl cycloheptatriene
Postulated catalytic cycle for Cu(I)/TF-BiphamPhos-catalyzed 1,3-dipolar [3+6] cycloaddition of azomethine ylide
5a
4
.
and 1,3-dipolar [3+2] cycloaddition with 2-ethoxycarbonyl cycloheptatriene
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O
R
OMe
O
N
OMe
Cu
B
*L
O
N
*LCu
D
O
+
'
-
R = OEt
O
+
R = Ph
'
'
R
-
4
( )
Ph
(5a
'
)
'
'
R
EtO
'
'
F3C
OMe
O
N
Cu
C
H
*L
P
OMe
O
1,3-Dipolar [3+6]
Cycloaddition
F3C
N
1,3-Dipolar [3+2]
Cycloaddition
Cu
H
O
'
F3C
N
N
'
R
H
Ph
'
'
R
Imino ester
OMe
A
Imino ester
CF3
O
O
*LCu
Ph
OMe
'
N
O
'
O
'
'
*L Cu
R
EtO
'
'
'
N
'
C'
E
Ph
H
MeO2C
HN
O
H
R
MeO2C
HN
R
OEt
O
R
H
3
1
The catalytically active species is the distorted tetrahedral Cu(I)ꢀspecies A
formed by the coordination of the chiral ligand and the in situꢀformed azomethine
ylide in such manner to avoid otherwise unfavourable steric repulsion.10a The back
side of the azomethine ylide is shielded by the bulky PPh2 group. The initial Michael
addition of ylide A to the positively charged βꢀposition of 5a and 4 via Re face attack
generate the zwitterionic intermediates C and E, respectively. The more
electronꢀdeficient benzoyl group of the species C renders the carboanion more stable
than ester group of E does, which favors greater weight to its resonance form C'. The
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negative charge at αꢀposition in C is more easily delocalized to ω
'
ꢀposition than that
which could
in E because of the lower pKa value of the corresponding ωꢀproton in C
'
'
7
8
9
be deduced from the different pKa values of the αꢀproton in acetophenone (24.7)17 and
in ethyl acetate (30.5).18 Subsequent intramolecular Mannich addition of the
carboanion to the Si face of the imino moiety prefers to adopt a sixꢀmembered
chairꢀlike transition state, undergoing [3+6]ꢀreaction pathway with exclusive
regioselectivity and excellent stereoselectivity (Scheme 8, left side). On the contrary,
the less stable anion of the intermediate E is believed to undergo the subsequent
intramolecular cyclization directly through [3+2]ꢀpathway15 (Scheme 8, right side).
The proposed transitionꢀstate model is fully consistent with the observed regioꢀ and
stereochemical outcome. Nevertheless, a precise understanding of the real mechanism
for the current 1,3ꢀdipolar [3+6] cycloaddition system awaits further study.
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Conclusion
In summary, we have developed an unprecedented substrateꢀcontrolled catalytic
asymmetric 1,3ꢀdipolar cycloaddition of azomethine ylides employing 2ꢀsubstituted
cycloheptatrienes without nonbenzenoid aromatic characteristic as the fineꢀtunable
dipolarophiles for the first time. A variety of enantiopure heterocycles bearing a
bridged piperidine moiety were achieved in generally good yield with exclusive
regioselectivity and excellent stereoselectivity. 2ꢀAcyl group of the cycloheptatriene is
the key factor that determines the annulation preferentially through [3+6]ꢀpathway
while 2ꢀester group modulates the annulation through [3+2]ꢀpathway. Subsequent
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synthetic transformation of the cycloadduct provided facile access to synthetically
useful compounds with diverse functionality. Further investigation of mechanism and
synthetic application are currently underway.
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EXPERIMENTAL SECTION
1
General Information. H NMR spectra were recorded on a VARIAN Mercury 300
MHz spectrometer in CDCl3. Chemical shifts are reported in ppm with the internal
TMS signal at 0.0 ppm as a standard. The data are reported as (s = single, d = double,
13
t = triple, q = quartet, m = multiple or unresolved, and brs = broad single). C NMR
spectra were recorded on a Bruker 75 MHz spectrometer in CDCl3. Chemical shifts
are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard.
Commercially available reagents were used without further purification. All reactions
were monitored by TLC with silica gelꢀcoated plates. Diastereomeric ratios were
1
determined from crude H NMR or HPLC analysis. Enantiomeric ratios were
determined by HPLC, using a chiralpak IBꢀH column, a chiralpak ADꢀH column or a
chiralcel ODꢀH column with hexane and iꢀPrOH as solvents and 2ꢀsubstituted
cycloheptatrienes were prepared according to the literature procedure.16 Imino esters 2
and Chiral ligands L1-L5 were prepared according our previous procedure.9a The
racemic adducts were obtained by using Cu(CH3CN)4BF4/(±)ꢀ TFꢀBiphamPhos as the
catalyst.
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General Procedure for Cu(I)/(S)-L5-Catalyzed Asymmetric 1,3-Dipolar [3+6]
5
6
7
Cycloaddition of
Azomethine Ylides with 2-Acyl Cycloheptatrienes 5 Under
8
9
argon atmosphere, (S)ꢀTFꢀBiphamPhos (L5) (6.1 mg, 0.0076 mmol) and
Cu(CH3CN)4BF4 (2.2 mg, 0.0069 mmol) were dissolved in 2 mL of DCM, and stirred
at room temperature for about 0.5 h. After imine substrate (0.35 mmol) was added, the
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o
mixture was dropped to ꢀ40 C. Then, 2ꢀacylcycloheptatrienes (0.23 mmol) and Et3N
(0.03 mmol) was added sequentially. Once starting material was consumed
(monitored by TLC), the organic solvent was removed and the residue was purified by
column chromatography to give the cycloaddition product 3, which was then directly
analyzed by HPLC analysis to determine the enantiomeric excess.
(1S,6R,7R,9S)-methyl 5-benzoyl-9-(4-chlorophenyl)-8-azabicyclo[4.3.1]deca-2,4-
diene-7-carboxylate (3aa, Table 2, entry 1) Yield (86%); [α]25 = ꢀ461.2 (c 0.74,
D
CHCl3); 1H NMR (CDCl3, TMS, 300 MHz) δ 7.67 (d, J = 7.2 Hz, 2H), 7.52ꢀ7.41 (m,
3H), 7.32 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 6.11
(dd, J1 = 7.8 Hz, J2 = 11.7 Hz, 1H), 5.70 (dd, J1 = 7.8 Hz, J2 = 11.7 Hz, 1H), 4.24 (m,
1H), 4.16 (m, 1H), 4.04 (m, 1H), 3.45 (s, 3H), 3.11 (m, 1H), 2.50ꢀ2.45 (m, 1H),
1.80ꢀ1.66 (m, 2H); 13C NMR (CDCl3, TMS, 75 MHz) δ 198.3, 172.3, 140.7, 139.8,
139.7, 139.3, 138.4, 132.5, 131.3, 129.4, 128.2, 127.9, 127.2, 125.8, 65.0, 64.1, 51.7,
40.7, 34.0, 27.7; HRMS: calcd. for C24H22NO3Cl + H+: 408.1361, found: 408.1374.
The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee
(Chiralpak IBꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm); tr =
13.54 and 17.38 min.
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Procedure for Cu(I)/(S)-L5-Catalyzed Asymmetric 1,3-Dipolar [3+2]
Cycloaddition of Azomethine Ylide 6a with 2-Ethoxycarbonyl Cycloheptatriene 4
Under argon atmosphere, (S)ꢀTFꢀBiphamPhos (L5) (6.1 mg, 0.0076 mmol) and
Cu(CH3CN)4BF4 (2.2 mg, 0.0069 mmol) were dissolved in 2 mL of DCM, and stirred
at room temperature for about 0.5 h. After imino ester 6a (0.35 mmol, 74 mg) was
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added, the mixture was dropped to ꢀ40 C. Then, 2ꢀethoxycarbonyl cycloheptatriene
(0.23 mmol, 38 mg) and Et3N (0.03 mmol) was added sequentially. Once starting
material was consumed (monitored by TLC), the organic solvent was removed and the
residue was purified by column chromatography to give the cycloaddition product 1
in 82% yield, which was then directly analyzed by HPLC analysis to determine the
enantiomeric excess.
(1R,3R,3aR,8aR)-3a-ethyl 1-methyl 3-(4-chlorophenyl)-1,2,3,3a,8,8a-hexahydro-
cyclohepta[c]pyrrole-1,3a-dicarboxylate (1) Yield (82%); [α]25 = ꢀ14.3 (c 0.86,
D
1
CHCl3); H NMR (CDCl3, TMS, 300 MHz) δ 7.27 (m, 4H), 6.34ꢀ6.30 (m, 1H),
6.15ꢀ6.01 (m, 3H), 4.37 (s, 1H), 3.95 (d, J = 11.8 Hz, 1H), 3.83 (s, 3H), 3.76ꢀ3.68 (m,
2H), 3.42ꢀ3.38 (m, 1H), 2.52ꢀ2.37 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
TMS, 75 MHz) δ 173.5, 172.5, 137.0, 133.7, 133.0, 128.4, 128.2, 128.1, 127.0, 72.8,
64.3, 63.4, 61.0, 57.4, 52.2, 28.9, 13.6; HRMS: calcd. for C20H22NO4Cl + H+:
376.1310, found: 376.1311. The product was analyzed by HPLC to determine the
enantiomeric excess: 98% ee (Chiralpak ASꢀH, iꢀpropanol/hexane = 2/98, flow rate
1.0 mL/min, λ = 240 nm); tr = 15.94 and 25.86 min.
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ASSOCIATED CONTENT
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Supporting Information. Experimental procedures and compound characterization
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data. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
cjwang@whu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is supported by 973 Program (2011CB808600), NSFC (21172176,
21372180), NCETꢀ10ꢀ0649, and Hubei Province NSF (ZRZ0273). The authors thank
all referees for their helpful comments and suggestions.
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