In situ formed bifunctional primary amine-imine catalyst: Application to the construction of chiral tertiary alcohols through asymmetric aldol-type reaction

Article abstract of DOI:10.1002/adsc.201300108

An in situ formation method to obtain chiral bifunctional primary amine-imine catalysts from the C₂-symmetric chiral diimines has been developed. The efficiency of this method in the construction of chiral tertiary alcohols which are valuable p

Full text of DOI:10.1002/adsc.201300108

FULL PAPERS
DOI: 10.1002/adsc.201300108
In Situ Formed Bifunctional Primary Amine-Imine Catalyst:
Application to the Construction of Chiral Tertiary Alcohols
through Asymmetric Aldol-Type Reaction
Zhijie Mao,+a Xi Zhu,+a Aijun Lin,a Weipeng Li,a Yan Shi,a Haibin Mao,a
Chengjian Zhu,a,b,* and Yixiang Chenga,*
a
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, Peopleꢀs Republic of China
Fax : (+86)-25-8359-4886; e-mail: cjzhu@nju.edu.cn or yxcheng@nju.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, Peopleꢀs Republic of China
+
Zhijie Mao and Xi Zhu contributed equally to this work.
Received: February 3, 2013; Revised: April 27, 2013; Published online: July 12, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300108.
Abstract: An in situ formation method to obtain cellent diastereoselectivities and enantioselectivities
chiral bifunctional primary amine-imine catalysts (up to 96/4 dr, 96% ee for b,g-unsaturated a-keto
from the C2-symmetric chiral diimines has been de- esters and up to 91/9 dr, 94% ee for isatins) were ob-
veloped. The efficiency of this method in the con- tained. The active primary amine-imine catalylst and
struction of chiral tertiary alcohols which are valua- enamine intermediate in the reaction process could
ble pharmaceutical intermediates is proved by its ap- be demonstrated by ESI-MS analysis.
plication to the asymmetric aldol-type reaction of
cyclic ketones with other activated ketone com- Keywords: aldol reaction; chiral diimines; chiral pri-
pounds as the enamine acceptors, i.e., b,g-unsaturat- mary amine-imine; chiral tertiary alcohols; in situ
ed a-keto esters and isatins. In general, good to ex- formation
Introduction
ketone type[4] remain a challenge although significant
achievements have been made for the organocatalytic
As one class of compounds containing a quaternary direct aldol reactions of the ketone-aldehyde and al-
stereocenter, tertiary alcohols and especially chiral dehyde-aldehyde types.[5]
tertiary alcohols hold an important position in the
Chiral primary amines as an organocatalyst play an
pharmaceutical industry and biological sciences.[1] For increasingly important role in organocatalytic asym-
example, tertiary hydroxy esters are highly important metric reactions, and many reactions promoted by
intermediates in the asymmetric synthesis of natural chiral primary amine catalysts have been reported,
products and medicinal agents[2] containing a tertiary for example, aldol reactions,[6] Michael additions,[7] a-
hydroxyl moiety, such as oxybutynin (ditropan), aminations,[8] and cycloaddition reactions.[9] To im-
which is a widely prescribed medicine for the treat- prove the efficiency and universality of these catalysts,
ment of urinary incontinence. As another example, 3- several mutifunctional chiral primary amine catalysts
alkyl-3-hydroxyindolin-2-ones are particularly impor- such as chiral primary amine-thiourea,[10] primary-ter-
tant molecules in a number of biologically active nat- tiary diamine,[11] and sulfonamide-primary amine[12]
ural products and pharmaceuticals[3] among which 3- organocatalysts have also been successfully developed
cycloalkanone-3-hydroxy-2-oxindoles are quite prom- (Figure 1). Despite these significant advances,[13] the
ising in the field of medicinal chemistry because of multifunctional chiral primary amine catalysts can
their anticonvulsant activity. As an efficient method only be obtained by complex synthetic procedures,
to construct such compounds, organocatalytic asym- which limits their further applications. Given the im-
metric intermolecular aldol reactions of the ketone- portance of these mutifunctional primary amine cata-
Adv. Synth. Catal. 2013, 355, 2029 – 2036
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Zhijie Mao et al.
FULL PAPERS
Figure 1. Bifunctional primary amine catalysts.
lysts, it is necessary to develop more easily available
chiral primary aminocatalysts to enrich the types of
organocatalyst. Just recently, we successfully devel-
oped a bifunctional primary-imine catalyst[14] from the
stable C2-symmetric chiral diimines[15] for the first
time through a new concept in organocatalysis – the
use of an in situ formation method, which promotes
the direct aldol reaction between different ketones
and a-keto esters in high yields and excellent enantio-
selectivities. To broaden its potential applications,
herein, we would like to report the details for the
construction of several valuable chiral tertiary alco-
hols using aldol-type reaction of cyclic ketones with
b,g-unsaturated a-keto esters and isatins based on the
enamine process through this protocol.
Figure 2. Chiral diimines derived from (1R,2R)-cyclohexane-
1,2-diamine.
Results and Discussion
Our preliminary study demonstrated that a chiral di-
ACHTUNGTRENNUNGimine could be hydrolyzed efficiently in acid condi-
tions to obtain a chiral primary-imine catalyst, which
could further activate unactivated ketones through
enamine intermediates.[14] Based on these observa-
tions, a series of synthetic easily accessible chiral di-
Figure 3. Chiral diimines derived from (1R,2R)-1,2-diphenyl-
ethane-1,2-diamine.
ACHTUNGTRENNUNG
the substrate, 10 mol% Id as the precatalyst, at 258C
At first, the synthesis of b,g-unsaturated tertiary hy- in 0.2 mL cyclohexanone under solvent-free condi-
droxy esters was studied using the reaction of cyclo- tions with 5 equiv. acetic acid as the additive (Table 1,
hexanone and b,g-unsaturated a-keto ester 1a as entry 12). Of all the Brønsted acids screened (formic
a model reaction, and the results are summarized in acid, acetic acid, TFA, TfOH, benzoic acid, n-butyric
Table 1. As expected, the aldol-type reaction of the acid, n-hexanoic acid, trimethylacetic acid, propane-
b,g-unsaturated a-keto ester occurred preferentially dioic acid), acetic acid was found to be the most effec-
under these conditions to give the desired product tive. As shown in Table 1, the yield and ee value of
successfully. The best result was obtained when preca- the product increased with increased amount of acetic
talyst Id was employed with up to 96/4 dr and 92% ee acid (Table 1, entry 4 and entries 9–11), which under-
(Table 1, entry 4). Encouraged by this result, further lines that the generation of the primary amine-imine
optimization of the reaction conditions was carried catalyst could be affected by the concentration of
out. Subsequent investigation of the reaction parame- acetic acid. Both the dr and ee value of the product
ters gave as the optimal conditions: 0.2 mmol 1a as remained almost unchanged when lowering the preca-
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In Situ Formed Bifunctional Primary Amine-Imine Catalyst
Table 1. Screening of the reaction conditions for the synthe-
sis of b,g-unsaturated tertiary hydroxy esters using in situ
formed primary-imine catalysts.[a]
clohexanone (Table 2, entries 18–22). A mixture of
diastereoisomers with only 23% ee for major product
was obtained for cyclobutanone (Table 2, entry 18).
Cycloheptanone was found to react slowly and only
7% yield was achieved even after 96 h (Table 2,
entry 20). The 6-membered heterocyclic ketones gave
high diastereoselectivities and good ee values
(Table 2, entries 21 and 22). Unfortunately, no ee
value was observed under the same conditions for the
acyclic ketone such as acetone although the reaction
proceeded well to afford the desired product.
An additional scaled-up experiment was performed
to show the potential of this method in the practical
synthesis of chiral b,g-unsaturated tertiary hydroxy
esters (Scheme 1). By treatment of 4 mmol (0.88 g) of
1c under the optimal reaction conditions, the desired
product 2c was obtained in 85% yield without obvious
loss of diastereoselectivity and enantioselectivity (dr:
93/7, ee: 95%).
In a further extension of this methodology, we
expand the scope of activated ketone compounds, and
isatin was introduced to synthesize 3-alkyl-3-hydrox-
yindolin-2-ones, which are present in many important
biologically active natural products and medicinal
compounds. The reaction of isatin and cyclohexanone
using precatalysts derived from (1R,2R)-1,2-diphenyl-
ethane-1,2-diamine was selected as a model reaction
to explore the feasibility of this strategy. The results
are summarized in Table 3.
Initially, diimine IIa was investigated as the preca-
talyst. As we anticipated, the desired product was af-
forded in 92% yield with good enantioselectivity and
diastereoselectivity in the presence of 5 equiv. of
AcOH and 5 mol% of IIa (Table 3, entry 1). (1R,2R)-
1,2-Diphenylethane-1,2-diamine as the catalyst gave
the desired adduct in high yield (96%) but with low
enantioselectivity and diastereoselectivity (Table 3,
entry 2). Subsequent investigation showed that preca-
Entry Precat (mol%) t [h] Yield [%][b] dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
Ia (20)
Ib (20)
Ic (20)
Id (20)
Ie (20)
If (20)
Ig (20)
Ih (20)
Id (20)
Id (20)
Id (20)
Id (10)
Id (5)
24
24
24
24
24
24
24
24
24
24
24
30
30
74
80
57
95
72
73
61
35
31
63
94
93
75
92/8 86
92/8 83
95/5 89
96/4 92
91/9 77
94/6 93
96/4 90
89/11 80
95/5 75
96/4 85
96/4 92
96/4 92
94/6 92
9[e]
10[f]
11[g]
12
13
[a]
The reaction was carried out with 1a (0.2 mmol), precata-
lyst, AcOH (5 equiv.) in cyclohexanone (0.2 mL) at 258C
for the indicated time.
Yield of isolated products containing a mixture of diaste-
reoisomers.
Determined by chiral HPLC.
Determined by chiral HPLC for the major product.
0.2 equiv. AcOH were added.
[b]
[c]
[d]
[e]
[f]
1 equiv. AcOH was added.
10 equiv. AcOH were added.
[g]
talyst loading from 20% to 1% despite the decrease talyst IIb exhibited the best enantioselectivity and
in yields (Table 1, entries 4, 12 and 13). diastereoselectivity (Table 3, entries 3–6). Further-
With the optimized conditions in hands, we next more, a primary amine-imine hydrochloride similar to
studied the scope of the reaction. At first, the reac- the in situ formed primary amine-imine catalyst from
tions of cyclohexanone with different b,g-unsaturated IIb was also tested but unfortunately an unsatisfactory
a-keto esters were tested. The alkoxy group of the result was obtained, presumably caused by the strong
ester had little effect on the stereoselectivity of the acidity of hydrochloric acid (90/10 dr, 30% ee, for
reaction, and the best result was obtained in the pres- more details see the Supporting Information). Further
ence of an isopropoxy group (Table 2, entries 1–4). optimization of reaction condition revealed that the
Except for some discrepancies in yields, high diaste- reaction carried out with 10 mol% loading of IIb and
reoselectivities and enantioselectivities were obtained 10 equiv. AcOH in 0.2 mL cyclohexanone at 258C af-
for a series of b,g-unsaturated keto esters having dif- forded the best result (95% yield, 93/7 dr, 93% ee) in
ferently substituted phenyl groups regardless of the 24 h (Table 3, entry 15). AcOH was proven to be the
electron-withdrawing or electron-donating properties most effective Brønsted acid once again, achieving
of the substituents (Table 2, entries 5–14). Moreover, the highest enantioselectivity (Table 3, entry 3, en-
fused ring and heteroaromatic substrates were also in- tries 9–12). Increasing the precatalyst loading of IIb
vestigated, giving the desired products with similar re- to 10 mol% led to an improvement of the enantiose-
sults (Table 2, entries 15–17). As for other cyclic ke- lectivity (Table 3, entry 13). Further increasing the
tones, both yields and selectivities were inferior to cy- amount of IIb did no help the reaction (Table 3,
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Table 2. Asymmetric aldol reaction of cyclic ketones with b,g-unsaturated a-keto esters using in situ formed primary-imine
catalyst.[a]
Entry
1
t [h]
Product
Yield [%][b]
dr [%][c]
ee [%][d]
R1, R2
R3
R4
1
2
3
4
5
6
7
8
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-H, CH2-
-CH2CH2-
-(CH2)4-
-CH2OCH2-
-CH2SCH2-
Ph
Ph
Ph
Ph
Me
Et
i-Pr
Bn
30
30
30
30
36
36
36
36
36
36
36
36
36
36
36
36
36
36
36
96
36
36
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
93
90
93
92
81
86
84
83
91
93
83
94
61
74
66
88
87
57
69
7
96/4
96/4
96/4
96/4
93/7
92/8
94/6
93/7
93/7
94/6
92/8
91/9
89/11
91/9
94/6
89/11
94/6
70/30
87/13
n.d.
92
93
96
95
92
93
92
91
91
92
90
95
90
94
94
84
92
22/0
52
n.d.
76
81
2-ClC6H4
2-BrC6H4
3-ClC6H4
3-BrC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4- CH3C6H4
4- CF3C6H4
4-OCH3C6H4
2-naphthyl
3-pyridinyl
2-thiophenyl
Ph
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
iPr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph
Ph
Ph
Ph
2s
2t
2u
2v
72
41
94/6
94/6
[a]
The reaction was carried out with 1 (0.2 mmol), precatalyst Id (0.02 mmol), AcOH (5 equiv.) in cyclic ketones (0.2 mL) at
258C for the indicated time.
Yield of isolated product.
[b]
[c]
[d]
Determined by chiral HPLC.
Determined by chiral HPLC and absolute configurations assigned to be S,R by comparison with literature data.[16]
Scheme 1. Scaled-up experiment of cyclohexanone and 1c.
entry 14). With 10 mol% loading of IIb, 10 equiv. tuted isatins and cyclic ketones to generate the corre-
AcOH were found to be suitable for the reaction sponding adducts with high yields and stereoselectivi-
(Table 3, entries 15 and 16).
ties. The isatins with electron-donating or electron-
With the optimized conditions, the substrate gener- withdrawing substituents on aromatic rings were in-
ality was investigated. As summarized in Table 4, the troduced and showed good tolerance to these condi-
reaction proceeded smoothly with a variety of substi- tions (Table 4, entries 2–7). The 5-methylindolin-3-
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In Situ Formed Bifunctional Primary Amine-Imine Catalyst
Table 3. Optimization for in situ formed primary amine-cata-
Table 4. In situ formed primary amine-catalyzed asymmetric
lyzed reaction of isatin and cyclohexanone.[a]
reaction of isatins and cyclic ketones.[a]
Entry Precat or Acid
cat
Yield
[%][b]
dr anti/
syn[c]
ee
Entry
3
Yield
[%][b]
dr anti/
syn[c]
ee
[%][d]
[%][d]
R1, R2 R5
R6
1
2
3
4
5
6
IIa
dpen
IIb
IIc
IId
IIe
IIb
IIb
IIb
IIb
IIb
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
HCOOH 94
TFA
TfOH
PhCOOH 84
92
96
90
93
94
90
88
99
81/19
65/35
83/17
75/25
80/20
74/26
84/16
78/22
86/14
85/15
76/24
82/18
92/8
70
62
79
76
76
72
77
79
78
73
65
76
88
88
93
93
1
2
-(CH2)3- H
-(CH2)3- 5-
Me
-(CH2)3- 5-F
-(CH2)3- 5-Cl
-(CH2)3- 5-Br
-(CH2)3- 4-Cl
-(CH2)3- 4-Br
-(CH2)3- H
-(CH2)3- H
H
H
95
92
93/7
91/9
93
94
3
4
5
6
7
8
9
H
H
H
H
H
97
92
98
94
95
87/13
94/6
89/11
87/13
96/4
89/11
94/6
91/9
89
89
90
94
92
84
89
89
93
7[e]
8[f]
9
10
11
93
81
Me 90
Bn 87
12[g] IIb
10[e] -(CH2)2- H
11[e] -(CH2)4- H
H
H
40
32
13[h] IIb
AcOH
AcOH
AcOH
AcOH
94
96
95
95
91/9
14[i]
15[j]
IIb
IIb
92/8
93/7
93/7
[a]
The reaction was carried out with 3 (0.2 mmol), IIb
(10 mol%), AcOH (10 equiv.) in the indicated ketone
(0.2 mL) at 258C for 24 h.
16[k] IIb
[a]
[b]
[c]
[d]
[e]
The reaction was carried out with isatin (0.2 mmol), pre-
catalyst (5 mol%), Brønsted acid (5 equiv.) in cyclohexa-
none (0.2 mL) at 258C for 24 h.
Isolated yield.
Determined by chiral HPLC.
Determined by chiral HPLC for anti product.
Reaction was carried out at 08C for 48 h.
Reaction was carried out at 408C for 12 h.
Reaction was carried out at 258C for 48 h.
With 10 mol% loading of IIb.
With 20 mol% loading of IIb.
With 10 mol% of IIb and 10 equiv. AcOH.
With 10 mol% of IIb and 20 equiv. AcOH.
Isolated yield.
Determined by chiral HPLC for anti product.
Determined by chiral HPLC for the major product.
The reaction was carried out for 48 h.
[b]
[c]
[d]
[e]
[f]
configuration, and the cyclohexanone chiral center
was assigned to be of the S-configuration.
[g]
[h]
[i]
Similar to our previous studies, the in situ formed
primary amine-imine catalyst from chiral diimine Id
and its enamine intermediates formed with cyclohexa-
none could be detected significantly from the ESI-MS
analysis (Figure 5), and similar results could be ob-
tained for chiral diimine IIb (see the Supporting In-
[j]
[k]
one and 4-chloroindoline-2,3-dione gave the best formation for more details).
enantioselectivity (94% ee) and 4-bromoindoline-2,3-
dione gave the best diastereoselectivity (Table 4, en-
tries 2, 6 and 7). The methyl and benzyl 1-substituted Conclusions
isatins were shown to be also good aldol acceptors
(Table 4, entries 8 and 9). Other cyclic ketones were In conclusion, the aldol-type asymmetric reaction of
also investigated and provided the products with high cyclic ketones with other activated ketone com-
enantioselectivities despite much losses in yields pounds, i.e., b,g-unsaturated a-keto esters and isatins,
(Table 2, entries 10 and 11). The absolute configura- could be catalyzed by an in situ formed primary
tion of the major anti diastereoisomer was determined amine-imine catalyst in high yields and good to excel-
to be S,R by comparing its HPLC profile with report- lent enantioselectivities to give biologically valuable
ed results[17] and a single-X-ray structural analysis of chiral tertiary alcohols successfully. Given the easy
4a (Figure 4).[18] The newly formed carbon center con- synthetic accessible of chiral diimines and their stabil-
taining the hydroxy group was found to be of the R ity for storage, this method provides a new alternative
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Zhijie Mao et al.
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for the synthesis of chiral tertiary alcohols through or-
ganocatalytic asymmetric reactions. Efforts aimed at
further applications of the catalyst system are ongoing
in our laboratory.
Experimental Section
Typical Procedure for the Preparation of 2 using
Precatalyst Id
To the mixture of diimine Id (7.8 mg, 0.02 mmol), b,g-unsa-
turated a-keto ester 1a (38 mg, 0.2 mmol) in cyclohexanone
(0.2 mL) was added AcOH (57.0 mL, 1 mmol) at 258C. The
reaction mixture was stirred at 258C for 30 h. After a simple
treatment, purification by flash chromatography (ethyl ace-
tate/petroleum ether=1/8) afforded the desired product 2a
1
Figure 4. X-ray crystal structure of compound 4a.
as a white solid. H NMR (400 MHz, CDCl3): d=7.39–7.37
(m, 2H), 7.32–7.29 (m, 2H), 7.26–7.22 (m, 1H), 6.88 (d, J=
15.6 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 3.77 (s, 3H), 3.63 (s,
1H), 3.13–3.09 (m, 1H), 2.44–2.34 (m, 2H), 2.15–2.08 (m,
2H), 1.95–1.90 (m, 1H), 1.73–1.62 (m, 3H); 13C NMR
(100 MHz, CDCl3): d=211.8, 174.9, 136.1, 131.6, 128.6,
127.9, 127.6, 126.7, 76.9, 57.1, 53.0, 42.2, 27.3, 27.1, 24.8; HR-
MS: m/z=311.1253, calculated for C17H20O4Na: 311.1259
[M+Na]+; HPLC (Chiralpak AS-H, hexane/i-PrOH=90:10,
flow rate 1.0 mLminÀ1, l=254 nm): retention time=
12.32 min (major), 19.47 min (minor); [a]2D3:3: À107.3 (c=
0.80, CHCl3, 92% ee).
Typical Procedure for the Preparation of 4 using
Precatalyst IIb
To a stirred solution of precatalyst IIb (4.2 mg, 0.01 mmol)
in cyclohexanone (0.2 mL) was added isatin (14.7 mg,
0.1 mmol) and then AcOH (10 equiv.) at 258C. The resulting
mixture was stirred at 258C for 24 h, and then was directly
purified through flash column chromatography on a silica
gel (CH2Cl2/CH3OH=20/1) to afford the product 4a as
1
a white solid. H NMR (400 MHz, DMSO-d6): d=10.18 (s,
1H), 7.22–7.14 (m, 2H), 6.87–6.78 (m, 2H), 5.80 (s, 1H),
3.07 (dd, J=13.2, 4.8 Hz, 1H), 2.61–2.56 (m, 1H), 2.36–2.27
(m, 1H), 1.97–1.64 (m, 5H), 1.49–1.44ACTHNUTRGNEUNG
(m, 1H); 13C NMR
(100 MHz, DMSO-d6): d=209.0, 178.7, 143.4, 130.8, 128.5,
124.7, 120.7, 109.3, 73.8, 57.3, 41.4, 26.6, 26.5, 24.4; HR-MS:
m/z=268.0949, calculated for C14H15NNaO3: 268.0950 [M+
Na]+; HPLC (Chiralcel OJ-H, hexane/i-PrOH=80:20, flow
rate 1.0 mLminÀ1, l=210 nm): retention time=11.2 min
(major), 13.8 min (minor). [a]2D5: À31.2 (c=0.11, CHCl3,
93% ee).
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21172106, 21074054), the National
Basic Research Program of China (2010CB923303) and the
Research Fund for the Doctoral Program of Higher Educa-
tion of China (20120091110010) for their financial support.
Figure 5. ESI-MS analysis of a mixture of Id with AcOH; a)
in CH2Cl2, b) in cyclohexanone.
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In Situ Formed Bifunctional Primary Amine-Imine Catalyst
References
[5] For some selected reviews, see: a) B. List, Tetrahedron
2002, 58, 5573; b) B. List, Acc. Chem. Res. 2004, 37,
548; c) W. Notz, F. Tanaka, C. F. Barbas III, Acc.
Chem. Res. 2004, 37, 580; d) H. Pellissier, Tetrahedron
2007, 63, 9267; e) M. Bhanushali, C.-G. Zhao, Synthesis
2011, 1815; f) M. M. Heravi, S. Asadi, Tetrahedron:
Asymmetry 2012, 23, 1431.
[1] a) K. Narasaka, T. Sakakura, T. Uchimaru, D. Guedin-
vuong, J. Am. Chem. Soc. 1984, 106, 2954; b) A. N.
Cuzzupe, R. Di Florio, J. M. White, M. A. Rizzacasa,
Org. Biomol. Chem. 2003, 1, 3572; c) D. A. Nicewicz,
A. D. Satterfield, D. C. Schmitt, J. S. Johnson, J. Am.
Chem. Soc. 2008, 130, 17281; d) Y. Hayashi, H. Yama-
guchi, M. Toyoshima, K. Okado, T. Toyo, M. Shoji,
Chem. Eur. J. 2010, 16, 10150; e) P. Li, J. Zhao, F. Li,
A. S. C. Chan, F. Y. Kwong, Org. Lett. 2010, 12, 5616;
f) C. Liu, X. Dou, Y. Lu, Org. Lett. 2011, 13, 5248;
g) H. Yang, M. Sun, S. Zhao, M. Zhu, Y. Xie, C. Niu,
C. Li, J. Org. Chem. 2013, 78, 339; h) Y.-H. Deng, J.-Q.
Chen, L. He, T.-R. Kang, Q.-Z. Liu, S.-W. Luo, W.-C.
Yuan, Chem. Eur. J. 2013, DOI: 10.1002/
chem.201300478.
[2] a) C. H. Senanayake, K. Fang, P. Grover, R. P. Bakale,
C. P. Vandenbossche, S. A. Wald, Tetrahedron Lett.
1999, 40, 819; b) P. T. Grover, N. N. Bhongle, S. A.
Wald, C. H. Senanayake, J. Org. Chem. 2000, 65, 6283;
c) S. Masumoto, M. Suzuki, M. Kanai, M. Shibasaki,
Tetrahedron Lett. 2002, 43, 8647; d) P. Gupta, R. A. Fer-
nandes, P. Kumar, Tetrahedron Lett. 2003, 44, 4231;
e) S. Masumoto, M. Suzuki, M. Kanai, M. Shibasaki,
Tetrahedron 2004, 60, 10497; f) M. Hatano, K. Ishihara,
Synthesis 2008, 1647; g) S. Kong, W. Fan, G. Wu, Z.
Miao, Angew. Chem. 2012, 124, 8994; Angew. Chem.
Int. Ed. 2012, 51, 8864.
[3] a) R. R. Goehring, Y. P. Sachdeva, J. S. Pisipati, M. C.
Sleevi, J. F. Wolfe, J. Am. Chem. Soc. 1985, 107, 435;
b) R. B. Labroo, L. A. Cohen, J. Org. Chem. 1990, 55,
4901; c) H. B. Rasmussen, J. K. MacLeod, J. Nat. Prod.
1997, 60, 1152; d) J. Jimenez, U. Huber, R. Moore, G.
Patterson, J. Nat. Prod. 1999, 62, 569; e) T. Tokunaga,
W. E. Hume, T. Umezome, K. Okazaki, Y. Ueki, K.
Kumagai, S. Hourai, J. Nagamine, H. Seki, M. Taiji, H.
Noguchi, R. Nagata, J. Med. Chem. 2001, 44, 4641; f) T.
Tokunaga, W. E. Hume, J. Nagamine, T. Kawamura, M.
Taiji, R. Nagata, Bioorg. Med. Chem. Lett. 2005, 15,
1789; g) A. V. Malkov, M. A. Kabeshov, M. Bella, O.
[6] For some selected references, see: a) A. Bassan, W.
Zou, E. Reyes, F. Himo, A. Cꢃrdova, Angew. Chem.
2005, 117, 7190; Angew. Chem. Int. Ed. 2005, 44, 7028;
b) A. Cꢃrdova, W. Zou, P. Dziedzic, I. Ibrahem, E.
Reyes, Y. Xu, Chem. Eur. J. 2006, 12, 5383; c) X. Wu,
Z. Jiang, H.-M. Shen, Y. Lu, Adv. Synth. Catal. 2007,
349, 812; d) S. S. V. Ramasastry, H. Zhang, F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2007, 129, 288;
e) X.-Y. Xu, Y.-Z. Wang, L.-Z. Gong, Org. Lett. 2007,
9, 4247; f) L.-W. Xu, Y.-D. Ju, L. Li, H.-Y. Qiu, J.-X.
Jiang, G.-Q. Lai, Tetrahedron Lett. 2008, 49, 7037; g) J.
Zhou, V. Wakchaure, P. Kraft, B. List, Angew. Chem.
2008, 120, 7768; Angew. Chem. Int. Ed. 2008, 47, 7656.
[7] a) D. A. Yalalov, S. B. Tsogoeva, S. Schmatz, Adv.
Synth. Catal. 2006, 348, 826; b) K. Liu, H.-F. Cui, J.
Nie, K.-Y. Dong, X.-J. Li, J.-A. Ma, Org. Lett. 2007, 9,
923; c) S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9,
599; d) Z. Yang, J. Liu, X. Liu, Z. Wang, X. Feng, Z.
Su, C. Hu, Adv. Synth. Catal. 2008, 350, 2001.
[8] T.-Y. Liu, H.-L. Cui, Y. Zhang, K. Jiang, W. Du, Z.-Q.
He, Y.-C. Chen, Org. Lett. 2007, 9, 3671.
[9] a) A. Sakakura, K. Suzuki, K. Ishihara, Adv. Synth.
Catal. 2006, 348, 2457; b) W. Chen, W. Du, Y.-Z. Duan,
Y. Wu, S.-Y. Yang, Y.-C. Chen, Angew. Chem. 2007,
119, 7811; Angew. Chem. Int. Ed. 2007, 46, 7667; c) Y.
Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman, L.
Deng, J. Am. Chem. Soc. 2007, 129, 6364; d) R. P.
Singh, K. Bartelson, Y. Wang, H. Su, X. Lu, L. Deng, J.
Am. Chem. Soc. 2008, 130, 2422.
[10] a) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew.
Chem. 2006, 118, 6514; Angew. Chem. Int. Ed. 2006, 45,
6366; b) H. Huang, E. N. Jacobsen, J. Am. Chem. Soc.
2006, 128, 7170; c) S. B. Tsogoeva, S. Wei, Chem.
Commun. 2006, 1451; d) P. Li, Y. Wang, X. Liang, J. Ye,
Chem. Commun. 2008, 3302; e) P. Li, S. Wen, F. Yu, Q.
Liu, W. Li, Y. Wang, X. Liang, J. Ye, Org. Lett. 2009,
11, 753.
´
Kysilka, D. A. Malyshev, K. Pluhꢂckovꢂ, P. Kocovsky,
Org. Lett. 2007, 9, 5473; h) S. Nakamura, N. Hara, H.
Nakashima, K. Kubo, N. Shibata, T. Toru, Chem. Eur. J.
2008, 14, 8079; i) Q. Guo, M. Bhanushali, C.-G. Zhao,
Angew. Chem. 2010, 122, 9650; Angew. Chem. Int. Ed.
2010, 49, 9460; j) Q. Guo, J. C.-G. Zhao, Tetrahedron
Lett. 2012, 53, 1768.
[11] a) S. Luo, H. Xu, J. Li, L. Zhang, J.-P. Cheng, J. Am.
Chem. Soc. 2007, 129, 3074.
[12] F. Xue, S. Zhang, W. Duan, W. Wang, Adv. Synth.
Catal. 2008, 350, 2194.
[13] a) S. B. Tsogoeva, S. W. Wei, Tetrahedron: Asymmetry
2005, 16, 1947; b) D. A. Yalalov, S. B. Tsogoeva, T. E.
Shubina, I. M. Martynova, T. Clark, Angew. Chem.
2008, 120, 6726; Angew. Chem. Int. Ed. 2008, 47, 6624;
c) F.-Z. Peng, Z.-H. Shao, X.-W. Pu, H.-B. Zhang, Adv.
Synth. Catal. 2008, 350, 2199; d) R.-Q. Mei, X.-Y. Xu,
Y.-C. Li, J.-Y. Fu, Q.-C. Huang, L.-X. Wang, Tetrahe-
[4] a) S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2002, 124,
4233; b) O. Tokuda, T. Kano, W.-G. Gao, T. Ikemoto,
K. Maruoka, Org. Lett. 2005, 7, 5103; c) S. E. Denmark,
Y. Fan, M. D. Eastgate, J. Org. Chem. 2005, 70, 5235;
d) Z. Tang, L.-F. Cun, X. Cui, A.-Q. Mi, Y.-Z. Jiang, L.-
Z. Gong, Org. Lett. 2006, 8, 1263; e) S. Samanta, C.-G.
Zhao, J. Am. Chem. Soc. 2006, 128, 7442; f) T. Wang,
G.-W. Zhang, Y. Teng, J. Nie, Y. Zheng, J.-A. Ma, Adv.
Synth. Catal. 2010, 352, 2773; g) J. Luo, H. Wang, X.
Han, L.-W. Xu, J. Kwiatkowski, K.-W. Huang, Y. Lu,
Angew. Chem. 2011, 123, 1901; Angew. Chem. Int. Ed.
2011, 50, 1861; h) F. Zhong, G.-Y. Chen, Y. Lu, Org.
Lett. 2011, 13, 82.
´
dron Lett. 2011, 52, 1566; e) K. Dudzinski, A. M. Pak-
ulska, P. Kwiatkowski, Org. Lett. 2012, 14, 4222.
[14] a) X. Zhu, A. Lin, L. Fang, W. Li, C. Zhu, Y. Cheng,
Chem. Eur. J. 2011, 17, 8281; b) X. Zhu, A. Lin, Y. Shi,
J. Guo, C. Zhu, Y. Cheng, Org. Lett. 2011, 13, 4382.
[15] a) W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacob-
sen, J. Am. Chem. Soc. 1990, 112, 2801; b) J. Sun, C.
Adv. Synth. Catal. 2013, 355, 2029 – 2036
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2035

Zhijie Mao et al.
FULL PAPERS
Zhu, Z. Dai, M. Yang, Y. Pan, H. Hu, J. Org. Chem.
2004, 69, 8500; c) Y. Huang, F. Yang, C. Zhu, J. Am.
Chem. Soc. 2005, 127, 16386; d) M. Yang, C. Zhu, F.
Yuan, Y. Huang, Y. Pan, Org. Lett. 2005, 7, 1927; e) C.
Baleiz¼o, H. Garcia, Chem. Rev. 2006, 106, 3987; f) S. J.
Wezenberg, A. W. Kleij, Angew. Chem. 2008, 120,
2388; Angew. Chem. Int. Ed. 2008, 47, 2354; g) J. Sun,
M. Yang, F. Yuan, X. Jia, X. Yang, Y. Pan, C. J. Zhu,
Adv. Synth. Catal. 2009, 351, 920.
[17] a) A. Ricci, L. Bernardi, C. Gioia, S. Vierucci, M. Ro-
bitzerb, F. Quignard, Chem. Commun. 2010, 6288; b) Y.
Liu, P. Gao, J. Wang, Q. Sun, Z. Ge, R. Li, Synlett 2012,
1031.
[18] CCDC 877875 [for 4a, C14H15NO3, unit cell parameters:
a=25.184(4), b=25.184(4), c=10.113(4), space group
rhombohedra, R-3] contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[16] a) C. Zheng, Y. Wu, X. Wang, G. Zhao, Adv. Synth.
Catal. 2008, 350, 2690; b) P. Li, S. H. Chan, A. S. C.
Chan, F. Y. Kwonga, Adv. Synth. Catal. 2011, 353, 1179.
2036
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2029 – 2036