Metal-catalyzed [6 + 3] cycloaddition of tropone with azomethine ylides: A practical access to piperidine-fused bicyclic heterocycles

Article abstract of DOI:10.1021/ja4122268

The first metal-catalyzed [6 + 3] cycloaddition of tropone with azomethine ylides has been developed. With the use of a chiral ferrocenylphosphine- copper(I) complex as the catalyst, the asymmetric variant of the [6 + 3] cycloaddition has also been successfully achieved. The reactions proceeded smoothly under mild conditions, affording piperidine-fused bicyclic heterocycles in moderate to high yields with good to excellent diastereo-and enantioselectivies. The procedures are operationally simple and the catalysts are cheap and readily accessible, thus providing a practical approach to piperidine-fused bicyclic heterocycles.

Full text of DOI:10.1021/ja4122268

Article
pubs.acs.org/JACS
Metal-Catalyzed [6 + 3] Cycloaddition of Tropone with Azomethine
Ylides: A Practical Access to Piperidine-Fused Bicyclic Heterocycles
Honglei Liu, Yang Wu, Yan Zhao, Zhen Li, Lei Zhang, Wenjun Yang, Hui Jiang, Chengfeng Jing, Hao Yu,
Bo Wang, Yumei Xiao, and Hongchao Guo*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
S
* Supporting Information
ABSTRACT: The first metal-catalyzed [6 + 3] cycloaddition
of tropone with azomethine ylides has been developed. With
the use of a chiral ferrocenylphosphine−copper(I) complex as
the catalyst, the asymmetric variant of the [6 + 3]
cycloaddition has also been successfully achieved. The
reactions proceeded smoothly under mild conditions, affording
piperidine-fused bicyclic heterocycles in moderate to high yields with good to excellent diastereo- and enantioselectivies. The
procedures are operationally simple and the catalysts are cheap and readily accessible, thus providing a practical approach to
piperidine-fused bicyclic heterocycles.
a single example of enantioselective catalysis being shown in the
last two cases, respectively. To the best of our knowledge,
metal-catalyzed [6 + 3] cycloaddition of tropone with
azomethine ylides have not yet been reported to date. In the
context of our ongoing endeavors in developing 1,3-dipole-
based cycloadditions,8 we explored metal-catalyzed [6 + 3]
cycloaddition of tropone with azomethine ylides, which are
versatile dipoles in catalytic [3 + 2],9 [3 + 3]8g,10 and [6 + 3]11
cycloaddition reactions. Herein, we report the first metal-
catalyzed [6 + 3] cycloaddition of tropone with azomethine
ylides and its asymmetric variant to provide 8-azabicyclo[4.3.1]-
deca-2,4-dienes (namely, piperidine-fused bicyclic hetero-
cycles), which are potential scaffolds for the synthesis of
natural products2,12 and biologically important molecules13
(Scheme 1).
INTRODUCTION
■
The higher-order cycloaddition has emerged as an efficient and
powerful tool for the convergent synthesis of a variety of
medium-sized carbo- and heterocycles from a wide range of
simpler precursors.1 Various cycloaddition reactions, such as [4
+ 3], [4 + 4], [5 + 2], [5 + 3], [6 + 2], [6 + 3], [6 + 4], [8 + 2],
[8 + 3], and so forth, have been developed over the last few
decades.1 Tropones are a class of highly valuable substrates for
the cycloaddition reactions,2 functioning as four-, six-, or eight-
member synthons to furnish [4 + 2],3 [6 + 3],4 [6 + 4],5 [8 +
2],6 or [8 + 3]7 annulation products that are valuable in the
synthesis of bioactive molecules2 and natural products.3h,4d,5g−i
Although numerous cycloaddition reactions using tropones as
reaction partners have been developed, only a few examples
involving 1,3-diploar cycloadditions of tropones with dipoles
have been reported so far. The early studies on this topic have
mostly been focused on the thermal cycloadditions of tropones
with dipoles.3a,5b−d Recently, Ph3P-mediated [8 + 2] cyclo-
addition of tropone with allenic ester/ketone-derived 1,3-
dipoles,6b Ph3P-catalyzed [6 + 3]4b and [8 + 3]7c cycloadditions
of tropone with modified allylic compounds-derived dipoles
have also been achieved, providing the corresponding carbo- or
heterobicyclic cycloadducts. Concurrently with the preparation
of the present manuscript, Ni7d and SnCl47e-catalyzed [8 + 3]
cycloadditions of tropones with dioples generated from 1,1-
cyclopropanediesters were reported, giving functionalized 4,5-
dihydrocyclohepta[b]pyran derivatives.
Scheme 1. Metal-Catalyzed [6 + 3] Cycloaddition Reactions
of Tropone with Azomethine Ylides
RESULTS AND DISCUSSION
■
In initial studies, the reaction between tropone (1) and the
azomethine ylide precursor (2a) was surveyed in the presence
of 10 mol % of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
using Cu(I) salts as the precatalyst and commercial available
and cheap PPh3 as the ligand. To our delight, under the
catalysis of 10 mol % Cu(CH3CN)4ClO4 and 20 mol % of
Documented examples on the catalytic enantioselective
cycloaddtions of tropones are also quite rare, including Pd-
catalyzed asymmetric [6 + 3] cycloaddition of tropones with
trimethylenemethane,4c,d BINOL-Al-catalyzed asymmetric [4 +
2] cycloaddition of tropones with ketene diethyl acetal,3g Ni-
catalyzed asymmetric [8 + 3] cycloaddition of tropones with
1,1-cyclopropanediesters7d and BINOL-Ti-catalyzed intramo-
lecular [6 + 4] cycloaddition of tropone derivative,5h with only
Received: December 2, 2013
Published: January 23, 2014
© 2014 American Chemical Society
2625
dx.doi.org/10.1021/ja4122268 | J. Am. Chem. Soc. 2014, 136, 2625−2629

Journal of the American Chemical Society
Article
PPh3, the reaction proceeded smoothly in dichloromethane at
−5 °C to give the desired product 3a as the major product in
56% yield and 2:1 dr, along with a minor amount of the
coupling product 4 and an unidentified side product14 (Table 1,
Table 2. Substrate Scope of Ag-Catalyzed [6 + 3]
Cycloaddition of Tropone with Azomethine Ylides
a
a
Table 1. Screening of the Reaction Conditions
b
c
entry
2
R
3
yield [%]
dr
1
2a
2b
2c
2d
2e
2f
C6H5
3a
3b
3c
3d
3e
3f
91
70
63
58
85
75
70
67
73
64
65
61
77
76
68
83
76
81
75
70
63
5:1
2
2-MeC6H4
4-MeC6H4
3-MeOC6H4
2-FC6H4
6:1
3
6:1
b
b
c
entry
metal
solvent
3a/yield [%]
4/yield [%]
dr
4
5:1
1
CuClO4
CuClO4
CuClO4
CuOAc
CuBr
CH2Cl2
CHCl3
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CHCl3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
56
53
63
61
29
28
45
65
85
33
39
32
38
36
91
11
2:1
3:1
5:1
4:1
3:1
5:1
4:1
5:1
5:1
3:1
5:1
5:1
3:1
7:1
5:1
5
>20:1
11:1
4:1
2
trace
6
3-FC6H4
3
0
7
2g
2h
2i
4-FC6H4
3g
3h
3i
4
0
8
3,4,5−3FC6H2
2-ClC6H4
8:1
5
6
9
>20:1
5:1
6
CuOTf
AgOAc
AgOAc
AgOAc
AgBF4
AgClO4
AgPF6
0
10
11
12
13
14
15
16
17
18
19
20
21
2j
3-ClC6H4
3j
7
trace
2k
2l
4-ClC6H4
3k
3l
>20:1
>20:1
>20:1
5:1
8
0
2,4−2ClC6H3
2-BrC6H4
9
trace
2m
2n
2o
2p
2q
2r
2s
2t
3m
3n
3o
3p
3q
3r
3s
3t
10
11
12
13
14
0
3-BrC6H4
0
4-BrC6H4
5:1
trace
2,5−2BrC6H3
3,4−2BrC6H3
3,5−2BrC6H3
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
>20:1
3:1
AgF
8
0
0
AgOMs
AgOAc
17:1
>20:1
7:1
d
15
a
Unless otherwise specified, reactions of 1 (0.3 mmol) and 2a (0.33
2u
3u
8:1
mmol) were carried out at −5 °C in the presence of substoichiometric
a
amounts of the metal salt (0.03 mmol), PPh3 (0.06 mmol) and DBU
Reactions of 1 (0.3 mmol), 2 (0.33 mmol), AgOAc (0.03 mmol),
b
(0.03 mmol) in 3 mL of the solvent for 12 h. Isolated yield.
PPh3 (0.06 mmol) and DBU (0.03 mmol) were carried out in 3 mL of
c
d
Determined by 1H NMR analysis of the crude product. The reaction
b
c
MeOH at −20 °C for 12 h. Isolated yields. Determined by 1H NMR
was conducted at −20 °C.
analysis of the crude product.
entry 1). The relative configuration of 3a was assigned by its
NMR data and X-ray crystallographic analysis of the
corresponding reduction product (+)-6o from (+)-3o,
independently prepared from the cycloaddition of tropone
with the α-iminoester 2o (vide infra).15 Shifting the solvent to
chloroform or methanol revealed that the latter is optimal,
resulting in an improved yield to 63% (entries 2−3). Other
Cu(I) salts such as CuOAc, CuBr and CuOTf were also found
to promote the reaction, albeit in lower yields (entries 4−6). A
number of Ag(I) salts (AgOAc, AgBF4, AgClO4, AgPF6, AgF,
AgOMs) have also been examined as the catalysts for the
reaction under otherwise identical conditions (entries 7−14),
among which AgOAc exhibited the best catalytic activity in
methanol. In this case, the product 3a was obtained in 85%
yield with 5:1 dr (entry 9). Lowering the reaction temperature
further to −20 °C led to an increased yield of 3a to 91%
without loss of the diastereoselectivity, probably as a result of
inhibition of byproduct formation (entry 15). Gratifyingly,
under the optimized conditions, the reaction could be scaled up
to the gram scale (2.12g, 20 mmol of 1), giving the desired
product 3a in 67% yield (see the Supporting Information for
details).
3a−3u, a class of 8-azabicyclo[4.3.1]deca-2,4-diene derivatives,
in moderate to excellent yields with moderate to excellent
diastereomeric ratios (entries 1−21). Unfortunately, aliphatic
α-iminoesters were not adaptable substrates for this protocol,
probably owing to the strong electron-donating effect of alkyl
group that might attenuate the reactivity of the resulting
azomethine ylides for cycloaddition reaction.
Next, we attempted to develop an asymmetric variant of [6 +
3] cycloaddition in the presence of chiral ligand. Some easily
accessible chiral ferrocenylphosphine ligands were evaluated for
the cycloaddition of 1 with 2a. The reactions were performed in
dichloromethane at −5 °C with a Ag(I) or Cu(I) salt as the
precatalyst, and the results were summarized in Table 3. With
the use of 10 mol % of L1/AgOAc as the catalyst, the reaction
of tropone with α-iminoester (2a) afforded the product (+)-3a
in 94% yield with 66% ee and 4:1 dr (entry 1). The absolute
and relative configurations as depicted were determined by X-
ray diffractional analysis of the reduction product (+)-6o
derived from chiral product (+)-3o.15 With the use of L1/
AgPF4 and L1/AgClO4 as the catalyst, the enantiomeric
excesses were improved to 86% and 78%, but the yields
dropped to 40% and 61%, respectively (entries 2, 3). The
combination of AgOAc with the commercially available and
cheap chiral ligand L2 was not satisfactory in terms of the
moderate enantioinduction (entry 4). Unfortunately, the
catalyst L1/CuClO4 could only afford trace of the product
(entry 5). To our delight, when L2/CuClO4 was used as the
catalyst, the product (+)-3a was obtained in 63% yield with
With the optimized conditions in hand, the catalytic [6 + 3]
cycloaddition reactions of tropone with a range of α-
iminoesters were evaluated using AgOAc/PPh3 as the catalyst.
The results are summarized in Table 2. The procedure worked
very well with various α-(benzylideneamino)acetates, irrespec-
tive of the stereoelectronic properties of the substituent on the
phenyl group, affording the corresponding bicyclic products
2626
dx.doi.org/10.1021/ja4122268 | J. Am. Chem. Soc. 2014, 136, 2625−2629

Journal of the American Chemical Society
Article
Table 3. Metal-Catalyzed Asymmetric [6 + 3] Cycloaddition
of Tropone with Azomethine Ylide
Table 4. Cu-Catalyzed Asymmetric [6 + 3] Cycloaddition of
Tropone with Azomethine Ylides
a
a
b
c
d
entry
2
R
(+)-3
yield [%]
dr
ee [%]
1
2a
2c
2d
2e
2f
C6H5
(+)-3a
(+)-3c
(+)-3d
(+)-3e
(+)-3f
(+)-3g
(+)-3i
(+)-3j
(+)-3k
(+)-3m
(+)-3n
(+)-3o
(+)-3t
(+)-3u
63
61
58
87
72
64
65
60
60
71
70
61
65
63
7:1
5:1
8:1
92
90
90
95
88
89
93
87
91
95
90
96
88
90
2
4-MeC6H4
3-MeOC6H4
2-FC6H4
3
4
>20:1
6:1
5
3-FC6H4
6
2g
2i
4-FC6H4
4:1
7
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-CF3C6H4
4-CF3C6H4
>20:1
5:1
8
2j
9
2k
2m
2n
2o
2t
>20:1
>20:1
5:1
10
11
12
13
14
b
c
d
entry
L*
metal
t/h
yield (%)
dr
ee (%)
1
L1
L1
L1
L2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L2
L2
AgOAc
AgPF4
12
12
12
6
94
4:1
6:1
4:1
2:1
-
66
86
78
54
-
5:1
2
40
5:1
3
AgClO4
AgOAc
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuBF4
61
2u
>20:1
4
60
a
Reactions of 1 (0.1 mmol), 2 (0.11 mmol), Cu(CH3CN)4ClO4 (0.01
5
48
6
trace
63
mmol), L2 (0.01 mmol) and DBU (0.01 mmol) were carried out in
b
c
CH2Cl2 (1 mL) at −5 °C for 6 h. Isolated yields. Determined by 1H
6
7:1
-
92
-
d
7
24
6
trace
40
NMR analysis of the crude product. Determined by chiral HPLC
8
4:1
4:1
5:1
4:1
6:1
-
87
79
76
77
61
-
analysis.
9
24
24
24
12
24
12
12
45
10
11
12
13
14
15
52
reactivity and selectivity, affording the bicyclic product (+)-3e
in 95% ee and >20:1 dr with 87% yield (entry 4). In contrast, 3-
MeO-substituted azomethine ylide gave slightly lower yield
(entry 3). Unfortunately, aliphatic azomethine ylides were
found unreactive in the reaction under these conditions.
The present asymmetric reaction could be performed on the
gram scale with excellent diastereoselectivity and enantiose-
lectivity without significant loss of yield (Scheme 2, see the
43
47
trace
45
3:1
4:1
90
76
CuOAc
45
a
Reactions of 1 (0.1 mmol), 2a (0.11 mmol), metal salt (0.01 mmol),
ligand (0.01 mmol) and DBU (0.01 mmol) were carried out in 1 mL
b
c
1
of CH2Cl2. Isolated yields. Determined by H NMR analysis of the
crude product. Determined by chiral HPLC analysis.
d
Scheme 2. Synthetic Transformations of the Cycloadducts
92% ee and 7:1 dr (entry 6). The ferrocenyl P,N ligands L4−
L8 bearing a structural skeleton similar to L2 gave good
enantioinduction and moderate yields (entries 8−12), but none
of them gave better results than L2 did. The chiral ligands L3
and L9 only resulted in negligible formation of the desired
product, respectively (entries 7, 13). When L2 was used as
chiral ligand, other cuprous salts such as CuBF4 and CuOAc
were also found to promote the reaction to give the product
(+)-3a in 90% ee and 76% ee, respectively, albeit in low yields
(45%) in both cases (entries 14−15). Finally, the combination
of L2 with Cu(CH3CN)4ClO4 was used as the optimal catalytic
system for subsequent asymmetric reactions.
Under the optimized reaction conditions, the reactivities of
various azomethine ylides derived from the precursors (2) were
examined for the [6 + 3] cycloadditions with tropone (1)
(Table 4). When 10 mol % Cu-L2 was used as the chiral
catalyst, the cycloaddition reaction of a series of azomethine
ylides with tropone proceeded very well, providing the
corresponding chiral 8-azabicyclo[4.3.1]deca-2,4-diene deriva-
tives (+)-3 in 58−87% yield with 87−96% ee (entries 1−14).
The reactions were tolerant of the presence of electron-
withdrawing or donating functional groups on the phenyl group
of the iminoesters. In particular, 2-fluorophenyl substituted
azomethine ylide from the α-iminoester 2e displayed superior
Supporting Information for details).16 Furthermore, simple
derivatization of the cycloaddition products allows for
conversion to several types of valuable chiral bicyclic fused-
ring compounds (Scheme 2). For examples, the conjugated
diene motif in the product (+)-3a was reduced via Pd/C
catalyzed hydrogenation to give 8-azabicyclo[4.3.1]decan-10-
one derivative (+)-5a in 92% yield with 95% ee and >20/1 dr.
Alternatively, treatment of (+)-3a with NaBH4 in methanol
gave the azabicyclo[4.3.1]deca-2,4-dien-10-ol derivative (+)-6a
2627
dx.doi.org/10.1021/ja4122268 | J. Am. Chem. Soc. 2014, 136, 2625−2629

Journal of the American Chemical Society
Article
quenching with UV light at 254 nm. Flash column chromatography
was performed using Qingdao Haiyang flash silica gel (200−300
mesh). Infrared spectra were recorded using a Bruker Optics
in 88% yield and 93% ee with >20/1 dr. With this procedure,
the product (+)-3o could also be smoothly reduced to give the
corresponding alcohol (+)-6o in 85% yield with 96% ee and
>20/1 dr. The solid-state molecular structure of (+)-6o was
determined by single crystal X-ray diffractional analysis, which
thus allows for the unambiguous assignment of the absolute
configuration of the chiral cycloaddition product (+)-3
(Scheme 2).15
1
TENSOR 27 instrument. H and 13C NMR spectra were recorded
using a 300 MHz Bruker instrument (referenced internally to Me4Si).
Chemical shifts (δ, ppm) are relative to tetramethylsilane (TMS) with
the resonance of the nondeuterated solvent or TMS as the internal
standard. Optical rotation was obtained on an Autopol V Plus
polarimeter. HRMS measurements were performed using an Agilent
instrument with the ESI-MS technique.
General Procedure for the [6 + 3] Cycloadditions of Tropone
1 and α-Iminoesters 2 Catalyzed by AgOAc/PPh3 Complex.
Under nitrogen atmosphere, PPh3 (17.60 mg, 0.06 mmol) and AgOAc
(5.0 mg, 0.03 mmol) were dissolved in 1 mL of MeOH. The resulting
mixture was stirred at −20 °C for about 1 h, followed by sequential
addition of tropone 1 (0.3 mmol), α-iminoesters 2 (0.33 mmol), DBU
(5.0 μL, 0.03 mmol), and MeOH (2 mL). Upon the completion of the
reaction as monitored by TLC, the mixture was concentrated in vacuo.
The residue was purified through flash column chromatography
(EtOAc/petroleum ether) to afford the corresponding cycloaddition
product.
On the basis of previous studies,3−7 a plausible stepwise
mechanism was proposed in Scheme 3 for the Cu(I)-catalyzed
Scheme 3. Proposed Mechanism for the Catalytic
Asymmetric [6 + 3] Cycloaddition
General Procedure for the [6 + 3] Cycloadditions of Tropone
1 and α-Iminoesters 2 Catalyzed by Cu(I)/L2 Complex. Under
nitrogen atmosphere, L2 (4.4 mg, 0.01 mmol) and Cu(CH3CN)4ClO4
(3.3 mg, 0.01 mmol) were dissolved in 0.3 mL of CH2Cl2. The
resulting mixture was stirred at −5 °C for about 1 h, followed by
sequential addition of tropone 1 (0.1 mmol), α-iminoesters 2 (0.11
mmol), DBU (1.7 μL, 0.01 mmol) and 0.7 mL of CH2Cl2. Upon the
completion of the reaction as monitored by TLC, the mixture was
concentrated in vacuo. The residue was purified through flash column
chromatography (EtOAc/petroleum ether) to afford the correspond-
ing cycloaddition product.
cycloaddition of tropone with azomethine ylides. Treatment of
2 with a base in the presence of the in situ generated cuprous
complex CuL* would lead to the formation of the metal-
loazomethine ylide 7 as an active species. The carboxyl enolate
cuprous salt 7 might undergo a nucleophilic addition to the
electron-deficient tropone to give the zwitterionic intermediate
9 through the transition state 8. In this case, the steric crowding
at the front side of the metalloazomethine ylide 7 would guide
the approach of tropone from the backside. Subsequent
intramolecular nucleophilic addition to the si face of the
imine moiety would give the intermediate 10, which was
protonated to accomplish the final [6 + 3] cycloadduct 3 with
simultaneous release of the Cu(I) catalyst and the base for next
cycle of the reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral data and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
hchguo@cau.edu.cn
■
Notes
The authors declare no competing financial interest.
CONCLUSION
■
ACKNOWLEDGMENTS
This work is supported by the NSFC (21172253, 21372256).
■
In summary, we have developed the first metal-catalyzed [6 +
3] cycloaddition of tropone with azomethine ylides and its
asymmetric variant. The reactions are operationally simple and
proceed smoothly under mild conditions, affording piperidine-
fused bicyclic heterocycles in moderate to high yields with good
to excellent diastereo- and enantioselectivies. Both achiral and
chiral catalysts for the reactions are cheap and highly accessible,
and moreover, the reactions could be carried out on the gram
scale, thus allowing the reaction to be a practical method for the
synthesis of piperidine-fused bicyclic heterocycles. Further
application of the reaction to asymmetric synthesis of
biologically important molecules is underway.
REFERENCES
■
(1) For selected reviews, see: (a) Rigby, J. H. Acc. Chem. Res. 1993,
26, 579. (b) Rigby, J. H. Tetrahedron 1999, 55, 4521. (c) Harmata, M.
Acc. Chem. Res. 2001, 34, 595. (d) Harmata, M. Adv. Synth. Catal.
2006, 348, 2297. (e) Nair, V.; Abhilash, K. G. Synlett 2008, 301.
(f) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791. (g) Yu,
Z.-X.; Wang, Y.; Wang, Y. Y. Chem.Asian J. 2010, 5, 1072.
(h) Lohse, A. G.; Hsung, R. P. Chem.Eur. J. 2011, 17, 3812.
(i) Pellissier, H. Adv. Synth. Catal. 2011, 353, 189. (j) Ylijoki, K. E. O.;
Stryker, J. M. Chem. Rev. 2013, 113, 2244.
(2) For reviews on synthetic versatility of tropones, see: (a) Pauson,
P. L. Chem. Rev. 1955, 55, 9. (b) Pietra, F. Chem. Rev. 1973, 73, 293.
(c) Pietra, F. Acc. Chem. Res. 1979, 12, 132. (d) Rigby, J. H. Stud. Nat.
Prod. Chem. 1988, 1, 545. (e) Fischer, G. Adv. Heterocycl. Chem. 1996,
66, 285. (f) Zhao, J. Curr. Med. Chem. 2007, 14, 2597. (g) Bentley, R.
Nat. Prod. Rep. 2008, 25, 118.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under N2 atm
in oven-dried glassware with magnetic stirring. Unless otherwise
stated, all reagents were purchased from commercial suppliers and
used without further purification. Dichloromethane employed in the
reactions was freshly distilled from CaH2. Reactions were monitored
through thin layer chromatography (TLC) on silica gel−precoated
glass plates. Chromatograms were visualized by fluorescence
(3) (a) De Micheli, C.; Gandolfi, R.; Grunanger, P. Tetrahedron
̈
1974, 30, 3765. (b) Rigby, J. H.; Sage, J.-M.; Raggon, J. J. Org. Chem.
1982, 47, 4815. (c) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1986,
2628
dx.doi.org/10.1021/ja4122268 | J. Am. Chem. Soc. 2014, 136, 2625−2629

Journal of the American Chemical Society
Article
108, 4655. (d) Kato, H.; Kobayashi, T.; Tokue, K.; Shirasawa, S. J.
Chem. Soc., Perkin Trans. 1 1993, 1617. (e) Ishar, M. P. S.; Gandhl, P.
R. Tetrahedron 1993, 49, 6729. (f) Asao, T.; Ito, S.; Murata, I. Eur. J.
Org. Chem. 2004, 899. (g) Li, P.; Yamamoto, H. J. Am. Chem. Soc.
2009, 131, 16628. (h) Li, P.; Yamamoto, H. Chem. Commun. 2010,
6294.
(4) (a) Trost, B. M.; Seoane, P. R. J. Am. Chem. Soc. 1987, 109, 615.
(b) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (c) Trost, B. M.;
McDougall, P. J.; Hartmann, O.; Wathen, P. T. J. Am. Chem. Soc. 2008,
130, 14960. (d) Trost, B. M.; McDougall, P. J. Org. Lett. 2009, 11,
3782.
(5) (a) Houk, K. N.; Luskus, L. J.; Bhacca, N. S. J. Am. Chem. Soc.
1970, 92, 6392. (b) Houk, K. N.; Watts, C. R. Tetrahedron Lett. 1970,
11, 4025. (c) Bonadeo, M.; De Micheli, C.; Gandolfi, R. J. Chem. Soc.,
Perkin Trans. 1 1977, 939. (d) Mukherjee, D.; Watts, C. R.; Houk, K.
N. J. Org. Chem. 1978, 43, 817. (e) Rigby, J. H.; Ateeq, H. S.; Charles,
N. R.; Cuisiat, S. V.; Ferguson, M. D.; Henshilwood, J. A.; Krueger, A.
C.; Ogbu, C. O.; Short, K. M.; Heeg, M. J. J. Am. Chem. Soc. 1993, 115,
1382. (f) Rigby, J. H.; Cuisiat, S. V. J. Org. Chem. 1993, 58, 6286.
(g) Isakovic, L.; Ashenhurst, J. A.; Gleason, J. L. Org. Lett. 2001, 3,
4189. (h) Rigby, J. H.; Fleming, M. Tetrahedron Lett. 2002, 43, 8643.
(i) Rigby, J. H.; Chouraqui, G. Synlett 2005, 2501. (j) Ashenhurst, J.
A.; Isakovic, L.; Gleason, J. L. Tetrahedron 2010, 66, 368.
Eur. J. 2009, 15, 2050. (f) Shaikh, T. M.; Sudalai, A. Tetrahedron:
Asymmetry 2009, 20, 2287. (g) Suga, H.; Hashimoto, Y.; Yasumura, S.;
Takezawa, R.; Itoh, K.; Kakehi, A. J. Org. Chem. 2013, 78, 10840.
(14) The pure compound could not be obtained for NMR data
collection, although various methods had been tried for the
purification of the side product. Therefore, the structure of this side
product could not be determined.
(15) Crystallographic data for (+)-6o has been deposited with the
Cambridge Crystallographic Data Centre as deposition number
CCDC 963393. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.
ac.uk, or by contacting The Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(16) Both the ee and dr values were better than those obtained in the
reaction on a 0.1 mmol scale. The reason might be that the reaction on
the gram scale was performed with a concentration of 0.05 mol/L of
the substrate 1; in contrast, the reaction on a 0.1 mmol scale was
carried out at a substrate concentration of 0.1 mol/L. Interestingly,
even if the reaction on a 0.1 mmol scale was carried out at a
concentration of 0.05 or 0.025 mol/L, both the ee and dr values could
not be increased.
(6) For a review, see: (a) Nair, V.; Abhilash, K. G. Top. Heterocycl.
Chem. 2008, 13, 173. For selected examples, see: (b) Kumar, K.;
Kapur, A.; Ishar, M. P. S. Org. Lett. 2000, 2, 787. (c) Okamoto, J.;
Yamabe, S.; Minato, T.; Hasegawa, T.; Machiguchi, T. Helv. Chim. Acta
2005, 88, 1519. (d) Lage, M. L.; Fernan
M. R. Org. Lett. 2011, 13, 2892. (e) Rivero, A. R.; Fernan
M. A. J. Org. Chem. 2012, 77, 6648. (f) Xie, M.; Liu, X.; Wu, X.; Cai,
Y.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2013, 52, 5604.
́
dez, I.; Sierra, M. A.; Torres,
dez, I.; Sierra,
́
(7) (a) Ishizu, T.; Mori, M.; Kanematsu, K. J. Org. Chem. 1981, 46,
526. (b) Nair, V.; Poonoth, M.; Vellalath, S.; Suresh, E.; Thirumalai, R.
J. Org. Chem. 2006, 71, 8964. (c) Chen, C.; Shao, X.; Yao, K.;
Shangguan, W.; Kawaguchi, T.; Shimazu, K. Langmuir 2011, 27,
11958. (d) Tejero, R.; Ponce, A.; Adrio, J.; Carretero, J. C. Chem.
́
Commun. 2013, 49, 10406. (e) Rivero, A. R.; Fernandez, I.; Sierra, M.
́
A. Org. Lett. 2013, 15, 4928.
(8) (a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.;
Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A., III; Guo, H.;
Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337. (b) Jing, C.; Na, R.;
Wang, B.; Liu, H.; Zhang, L.; Liu, J.; Wang, M.; Zhong, J.; Kwon, O.;
Guo, H. Adv. Synth. Catal. 2012, 354, 1023. (c) Liu, J.; Liu, H.; Na, R.;
Wang, G.; Li, Z.; Yu, H.; Wang, M.; Zhong, J.; Guo, H. Chem. Lett.
2012, 41, 218. (d) Na, R.; Liu, H.; Li, Z.; Wang, B.; Liu, J.; Wang, M.-
A.; Wang, M.; Zhong, J.; Guo, H. Tetrahedron 2012, 68, 2349. (e) Wu,
X.; Na, R.; Liu, H.; Liu, J.; Wang, M.; Zhong, J.; Guo, H. Tetrahedron
Lett. 2012, 53, 342. (f) Zhang, L.; Jing, C.; Liu, H.; Wang, B.; Li, Z.;
Jiang, H.; Yu, H.; Guo, H. Synthesis 2013, 45, 53. (g) Guo, H.; Liu, H.;
Zhu, F.-L.; Na, R.; Jiang, H.; Wu, Y.; Zhang, L.; Li, Z.; Yu, H.; Wang,
B.; Xiao, Y.; Hu, X.-P.; Wang, M. Angew. Chem., Int. Ed. 2013, 52,
12641.
(9) For a review, see: Adrio, J.; Carretero, J. C. Chem. Commun. 2011,
47, 6784.
(10) Tong, M.-C.; Chen, X.; Tao, H.-Y.; Wang, C.-J. Angew. Chem.,
Int. Ed. 2013, 52, 12377.
(11) (a) Potowski, M.; Bauer, J. O.; Strohmann, C.; Antonchick, A.
P.; Waldmann, H. Angew. Chem., Int. Ed. 2012, 51, 9512. (b) Potowski,
M.; Antonchick, A. P.; Waldmann, H. Chem. Commun. 2013, 49, 7800.
(c) He, Z.-L.; Teng, H.-L.; Wang, C.-J. Angew. Chem., Int. Ed. 2013, 52,
2934.
(12) Zhang, J.; Wang, Y.-Q.; Wang, X.-W.; Li, W.-D. Z. J. Org. Chem.
2013, 78, 6154.
(13) (a) Cook, C. E.; Wani, M. C.; Jump, J. M.; Lee, Y.-W.; Fail, P. A.
J. Med. Chem. 1995, 38, 753. (b) Nakamura, M.; Kido, K.; Kinjo, J.;
Nohara, T. Phytochemistry 2000, 53, 253. (c) Tsai, A. S.; Bergman, R.
G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316. (d) Bilke, J. L.;
Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11, 1935.
(e) Gnamm, C.; Krauter, C. M.; Brodner, K.; Helmchen, G. Chem.
2629
dx.doi.org/10.1021/ja4122268 | J. Am. Chem. Soc. 2014, 136, 2625−2629