Enantioselective synthesis of functionalized fluorinated cyclohexenones via Robinson annulation catalyzed by primary-secondary diamines

Article abstract of DOI:10.1021/jo902081w

(Chemical Presented) Primary-secondary diamine catalysts were used to catalyze the asymmetric Robinson annulation to synthesize multiply substituted fluorinated chiral cyclohexenones with two contiguous stereogenic centers, one of which is a fluorinated quaternary chiral center, with excellent enantioselectivities and diastereoselectivities in moderate to good yields.

Full text of DOI:10.1021/jo902081w

pubs.acs.org/joc
Enantioselective Synthesis of Functionalized Fluorinated Cyclohexenones
via Robinson Annulation Catalyzed by Primary-Secondary Diamines
Hai-Feng Cui, Ying-Quan Yang, Zhuo Chai, Peng Li, Chang-Wu Zheng, Shi-Zheng Zhu,*
and Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances and Key Laboratory of Organofluorine
Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Lu, Shanghai 200032, China
zhaog@mail.sioc.ac.cn
Received September 27, 2009
Primary-secondary diamine catalysts were used to catalyze the asymmetric Robinson annulation to
synthesize multiply substituted fluorinated chiral cyclohexenones with two contiguous stereogenic
centers, one of which is a fluorinated quaternary chiral center, with excellent enantioselectivities and
diastereoselectivities in moderate to good yields.
Introduction
Chiral cyclohexenones have been a long-standing targets
of asymmetric synthesis due to their presence as a common
structural motif of many biologically active molecules
and very important building blocks in organic synthesis.8
Fluorine-containing organic compounds play an impor-
tant role in materials, medicinal, pharmaceutical, and agro-
chemical science due to the unique properties of the fluorine
atom.1 Recently, the organocatalytic asymmetric synthesis
of fluorinated molecules has received considerable attention
among organic chemists.2 However, the enantioselective
catalytic construction of chiral fluorinated quaternary car-
bon centers, which are a class of versatile and important
monofluorinated synthons utilized in organic synthesis,2-4 is
still a very challenging subject in organic chemistry.2,3 On the
other hand, being both atom- and step-economic and envir-
onmentally friendly, asymmetric organocatalytic tandem
reactions have recently received much attention and have
become powerful and efficient tools in organic chemistry.5,6
However, applications of organocatalytic domino transfor-
mations in the asymmetric construction of fluorine-contain-
ing molecules are very limited.7
(3) Selected examples for the transition metal-based fluorination meth-
ods: (a) Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. Angew. Chem., Int. Ed. 2008, 47, 164–168. (b) Nakamura, M.;
Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem., Int. Ed. 2005, 44, 7248–
7251. (c) Shibata, N.; Kohno, J.; Takai, K.; Ishimaru, T.; Nakamura, S.;
Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2005, 44, 4204–4207.
(d) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M.
J. Am. Chem. Soc. 2005, 127, 10164–10165. (e) Hamashima, Y.; Yagi, K.;
Takano, H.; Tamas, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
14530–14531. (f) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000,
39, 4359–4362. Selected examples for organocatalytic fluorination methods:
(g) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.;
Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157–4161. (h) Brandes,
S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jøgensen, K. A. Chem.;
Eur. J. 2006, 12, 6039–6052. (i) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545–
547. Selected examples for organocatalytic methods using fluorine-contain-
ing building blocks: (j) Jiang, Z. Y.; Pan, Y. H.; Zhao, Y. J.; Ma, T.; Lee, R.;
Yang, Y. Y.; Huang, K. W.; Wang, M. W.; Tan, C. H. Angew. Chem., Int. Ed.
2009, 48, 3627–3631. (k) Li, H.; Zhang, S. L.; Yu, C. G.; Song, X. X.; Wang,
W. Chem. Commun. 2009, 2136–2138. (l) Han, X.; Luo, J.; Liu, C.; Lu, Y. X.
Chem. Commun. 2009, 2044–2046. (m) Ding, C. H.; Maruoka, K. Synlett
2009, 664–666. (n) Zhong, G. F.; Fan, J. H.; Barbas, C. F. III Tetrahedron
Lett. 2004, 45, 5681–5684.
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320–330. (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007,
317, 1881–1886. (c) Mikami, K.; Itoh, Y.; Yamamaka, Y. M. Chem. Rev.
2004, 104, 1–16. (d) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11.
(2) For recent reviews, see: (a) Brunet, V. A.; O’Hagan, D. Angew. Chem.,
Int. Ed. 2008, 47, 1179–1182. (b) Smits, R.; Cadicamo, C. D.; Burger, K.;
Koksch, B. Chem. Soc. Rev. 2008, 37, 1727–1739. (c) Prakash, G. K. S.; Beier,
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2005, 44, 2324–2327. (f) Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147–
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(4) Selected examples: (a) Haufe, G. J. Fluorine Chem. 2004, 125, 875–
894. (b) Burchardt, A.; Takahashi, T.; Takeuchi, Y.; Haufe, G. J. Org. Chem.
2001, 66, 2078–2084. (c) Abouabdellah, A.; Boros, L.; Gyenes, F.; Welch, J.
T. J. Fluorine Chem. 1995, 72, 255–259. (d) Ihara, M.; Satoh, K.; Ishida, Y.;
Taniguchi, N.; Tokunaga, Y.; Takemura, M.; Fukumote, K. Heterocycles
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DOI: 10.1021/jo902081w
r
Published on Web 12/03/2009
J. Org. Chem. 2010, 75, 117–122 117
2009 American Chemical Society

Cui et al.
JOCArticle
SCHEME 1. Reactions of Other Substrates
FIGURE 1. Structures of catalysts studied.
multiple stereocenters, one of which is a fluorinated qua-
ternary center.
The well-known Robinson annulation, which combines
three reactions, Michael addition, intramolecular aldol reac-
tion, and dehydration, is one of the most important ways to
access various substituted cyclohexenones.9 Using a pheny-
lalanine-derived imidazolidine catalyst, Jørgensen and co-
workers were the first to realize a highly enantio- and
diastereoselective Michael-adol reaction of ketoesters and
enones to provide functionalized chiral cyclohexanes, which
after dehydration in the presence of an acid could be
converted to chiral cyclohexenones. However, a long reac-
tion time was generally required (95-240 h).10 Recently, we
have developed some primary-secondary diamine catalysts,
which were readily available from primary amino acids in
three steps, for the Michael additions of malonates to R,β-
unsaturated ketones with outstanding results (Scheme 1).11,12
Being interested in the application of organocatalysis to
the synthesis of chiral fluorinated molecules, we report
herein an asymmetric organocatalytic Robinson annulation
catalyzed by primary-secondary diamine catalysts, which
provided enantioenriched fluorinated cyclohexenones with
Results and discussion
In our previous work, we found that the acid additives
played an important role in the Michael additions of
malonates to R,β-unsaturated ketones catalyzed by pri-
mary-secondary diamines; therefore, different acid addi-
tives were first tested. Catalyzed by 1a (Figure 1) and
different acids, the reaction between R-fluoro-β-keto ester
3a, which was selected for investigation mainly due to the
easy modifiability of the vinyl group for further useful
conversion of the corresponding product, and benzylidenea-
cetone 4a gave the Robinson annulation product 5a and
Michael-aldol reaction product 6a (Table 1, entries 2-6).
Among the acids screened, PNBA (4-nitrobenzoic acid) gave
the highest yield (82%) and >99% ee value (Table 1, entry 2)
and thus was chosen for further studies.
After the screening of acids, a series of primary-
secondary diamines were evaluated in CHCl3 at room
temperature in the presence of 20 mol % of p-nitrobenzoic
acid as the additive (Table 2, entries 1-8). Generally, the
reaction gave two products: the desired cyclohexenone
product 5a as the major one and the undehydrated product
6a as the minor one. The absolute configurations of 5a and
6a were determined by X-ray crystallographic analysis.13
As shown in Table 2, the catalysts examined produced only
slight differences in the ratios of the two products, the yields
and ee values of 5a, while a remarkable difference in the
diastereoselectivity was observed. Taking into account all
of these factors, catalyst 2a was selected as the optimal
catalyst for further optimization (Table 2, entry 8). Nota-
bly, reducing the catalyst loading of 2a to 10 mol % still
gave the same excellent yield, albeit with a longer reaction
time (Table 2, entry 9). Replacing the solvent CHCl3 with
CH2Cl2 led to a slight drop in the product ratio and the
enantioselectivity of 5a (Table 2, entry 10). Inferior results
were observed when THF or Et2O was used (Table 2, entries
11 and 12). While the use of toluene also provided excellent
results besides a reduced product ratio, the protic solvent
ethanol was completely unsuitable for this reaction
(Table 2, entries 13 and 14). Therefore, the reaction was
best performed with 10 mol % of catalyst 2a and PNBA in
CHCl3 at room temperature (Table 2, entry 9).
(5) For recent reviews, see: (a) Yu, X.; Wang, W. Org. Biomol. Chem.
€
2008, 6, 2037–2046. (b) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570–1581. (c) Mukherjee, S.; Yang, J. W.;
€
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. (d) Erkkila, A.;
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470.
(6) For most recent examples, see: (a) Albrecht, L.; Richter, B.; Vila, C.;
Krawczyk, H.; Jøgensen, K. A. Chem.;Eur. J. 2009, 15, 3093–3102. (b) Lu,
H. H.; Liu, H.; Wu, W.; Wang, X. Y.; Lu, L. Q.; Xiao, W. J. Chem.;Eur. J.
2009, 15, 2742–2746. (c) Schrader, W.; Handayani, P. P.; Zhou, J.; List, B.
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Angew. Chem., Int. Ed. 2009, 48, 1463–1466. (d) Franzen, J.; Fisher, A.
Angew. Chem., Int. Ed. 2009, 48, 789–791. (e) Kotama, P.; Hong, B. C.; Liao,
J. H. Tetrahedron Lett. 2009, 50, 704–707.
(7) (a) Nie, J.; Zhu, H. W.; Cui, H. F.; Hua, M. Q.; Ma, J. A. Org. Lett.
2007, 9, 3053–3056. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051–15053.
(8) For reviews see: (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58,
2481–2491. (b) Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. Rev. 1999,
99, 1163–1190. (c) Varner, M. A. Tetrahedron 1999, 55, 13867–13886. (d) Ho,
T.-L. Enantioselective Synthesis: Natural Products Synthesis from Chiral
Terpenes; Wiley: New York, 1992. (e) Jung, M. E. A. Tetrahedron 1976, 32,
3–31. For recent examples, see: (f) Baran, P. S.; Ritcher, J. M.; Lin, D. W. Angew.
Chem., Int. Ed. 2005, 44, 609–612. (g) Goeke, A.; Mertl, D.; Brunner, G. Angew.
Chem., Int. Ed. 2005, 44, 99–101. (h) Lakshmi, R.; Bateman, T. D.; McIntosh, M.
C. J. Org. Chem. 2005, 70, 5313–5315. (i) Mohr, P. J.; Halcomb, R. L. J. Am.
Chem. Soc. 2003, 125, 1712–1713.
(9) For selected examples of organocatalytic Robinson annulation, see:
(a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000, 122,
2395–2396. (b) Bui, T.; Barbas, C. F. III Tetrahedron Lett. 2000, 41, 6951–
6954. (c) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
(d) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496–
497. (e) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, 1971.
(10) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2004, 43, 1272–1277.
With the optimized reaction conditions in hand, a selected
spectrum of different substrates were examined to test the
scope of this reaction and a series of useful chiral 3-alkenyl
(11) Yang, Y. Q.; Zhao, G. Chem.;Eur. J. 2008, 14, 10888–10891.
(12) For recent reviews on primary amines in organocatalysis, see: (a) Xu,
L. W.; Luo, J.; Lu, Y. X. Chem. Commun. 2009, 1807–1821. (b) Xu, L. W.;
Lu, Y. X. Org. Biomol. Chem. 2008, 6, 2047–2053. (c) Peng, F.; Shao, Z. J.
Mol. Catal. A: Chem. 2008, 285, 1–13. (d) Chen, Y. C. Synlett 2008, 1919–
1930.
(13) CCDC 728840 (5a) and 728841 (6a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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TABLE 1. Screening of Acids
entry
acid
time/h
yield of 5a/%b
5a:6ac
ee of 5a/%d
1
2
3
4
5
6
none
36
12
17
17
17
17
30
82
79
60
81
43
ND
5.4:1
5.3:1
2.3:1
5:1
ND
>99
>99
98
>99
98
p-NO2C6H4CO2H
PhCO2H
p-TsOH
CH3CO2H
CF3CO2H
5:1
aReaction conditions: 3a (1.0 equiv), 4a (1.0 equiv), 1a (20 mol %), acid (20 mol %), CHCl3 (0.5 mL). bYield of the isolated product after column
chromatography. cDetermined by 19F NMR. dDetermined by HPLC.
TABLE 2. Screening of Catalysts and Solvents a
5a
entry
solvent
cat.
t [h]
5a: 6ac
yield [%]d
drc
ee [%]e
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
THF
1a
1b
1c
1d
1e
1f
2a
2b
2a
2a
2a
2a
2a
2a
12
12
12
12
12
12
12
12
20
12
24
24
24
36
5.4:1
4:1
3.6:1
5.4:1
4.5:1
5:1
5:1
5:1
5:1
4:1
82
80
77
85
80
80
77
80
80
76
66
60
74
trace
16:1
18:1
8:1
>99
98
96
98
97
99
>99
98
>99
97
97
14:1
>99:1
30:1
30:1
24:1
30:1
>99:1
6:1
9b
10
11
12
13
14
2.6:1
2.4:1
3.6:1
ND
Et2O
Toluene
EtOH
10:1
>99:1
ND
98
>99
ND
aUnless otherwise noted, the reaction was carried out with 3a (0.1 mmol), 4a (0.1 mmol), catalyst (20 mol %), PNBA (20 mol %), and solvent (0.5 mL)
at room temperature. b2a (10 mol %) and PNBA (10 mol %) were used. cDetermined by 19F NMR. dIsolated yield after column chromatography on silica
gel. eDetermined by chiral HPLC analysis.
cyclohexen-2-ones were obtained (Table 3).14 For substrates
3a-f with different substituents on the phenyl ring of R1,
generally excellent ee and dr values were obtained irrespec-
tive of the electronic nature or positions of the substituents,
though slightly lower yields were observed for substrates
bearing electron-donating substituents (Table 3, entries
1-6). Changing the bulky tert-butyl group (R2) of 3a to a
less sterically demanding ethyl group (3g) led to diminished
dr value and yield of the desired product 5, but still with
excellent ee values (Table 3, entry 7). When R1 was a methyl
group, the product 5h was obtained in moderate yield and
excellent enantioselectivity although requiring a long reac-
tion time (Table 3, entry 8). Subsequently, the scope of the
other reaction component 4 was also examined. When R3
was an aryl group, substrates with electron-donating or -
withdrawing substituents at the para or ortho position of the
benzene ring all provided the desired products in moderate
yields, with excellent dr and ee values (Table 3, entries 8-11
and 13-18). However, substrate 4f with an o-Cl substituent
gave both significantly lower yield and dr value, but still with
an excellent ee value (Table 3, entry 12). Notably, alkyl-
substituted enone 4i also proved to be applicable to the
reaction system, giving the desired product 5t in excellent
dr and ee values and with moderate yield. Moreover, when
both reaction components were aliphatic substrates 3i and 4j,
the reaction still proceeded efficiently to give the desired
product 5u in 80% yield, 9:1 dr, and 99% ee (Scheme 1),
which provides an easy access to this kind of important
synthetic targets.15 When substrates were 3j and 4a, the
ꢀ
(14) Selected examples: (a) Henon, H.; Manduit, M.; Alexakis, A. Angew.
Chem., Int. Ed. 2008, 47, 9122–9124. (b) Schachtschabel, D.; Boland, W. J.
Org. Chem. 2007, 72, 1366–1372. (c) Luo, J. D.; Huang, S.; Cheng, Y. J.; Kim,
T. D.; Shi, Z. W.; Zhou, X. H.; Jen, A. K. Y. Org. Lett. 2007, 9, 4471–4474.
(d) Luo, J. D.; Cheng, Y. J.; Kim, T. D.; Hau, S.; Jang, S. H.; Shi, Z. W.;
Zhou, X. H.; Jen, A. K. Y. Org. Lett. 2006, 8, 1387–1390. (e) Akai, S.;
Tanimoto, K.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43, 1407–1410.
(15) (a) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int.
Ed. 2008, 47, 7656–7658. (b) Letizia, C. S.; Cocchiara, J.; Wellington, G. A.;
Funk, C.; Api, A. M. Food Chem. Toxicol. 2000, 38, 5153–5155.
(c) Yamamoto, H.; Sham, H. L. J. Am. Chem. Soc. 1979, 101, 1609–1611.
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J. Org. Chem. Vol. 75, No. 1, 2010 119

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TABLE 3. Investigation of Reaction Scopea
5
entry
R1
R3
t [h]
5:6c
yield [%]b
drc
ee [%]d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
p-BrC6H4 (3a)
m-BrC6H4 (3b)
o-BrC6H4 (3c)
p-NO2C6H4 (3d)
p-MeOC6H4 (3e)
Ph (3f)
3g
Me (3h)
Ph (3f)
Ph (3f)
Ph (3f)
Ph (3f)
Ph (3f)
Ph (3f)
Ph (3f)
Ph (3f)
p-MeOC6H4 (3e)
p-MeOC6H4 (3e)
p-BrC6H4 (3a)
Ph (3f)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
20
19
26
24
24
27
20
48
20
29
20
19
48
24
40
23
29
29
19
24
5:1
5:1
6:1
5:1
5:1
4:1
3:1
ND
4:1
5:1
4:1
4:1
1:1
5:1
4:1
5:1
6:1
5:1
5:1
5:1
80 (5a)
78 (5b)
80 (5c)
80 (5d)
68 (5e)
67 (5f)
61 (5g)
60 (5h)
60 (5i)
74 (5j)
67 (5k)
63 (5l)
44 (5m)
70 (5n)
68 (5o)
77 (5p)
60 (5q)
65 (5r)
70 (5s)
62 (5t)
30:1
25:1
>99:1
>99:1
30:1
>99:1
10:1
10:1
35:1
46:1
20:1
20:1
6:1
47:1
36:1
44:1
24:1
34:1
>99
>99
>99
>99
>99
>99
99
>99
99
99
p-FC6H4 (4b)
p-ClC6H4 (4c)
p-BrC6H4 (4d)
m-ClC6H4 (4e)
o-ClC6H4 (4f)
p-MeOC6H4 (4g)
p-NO2C6H4 (4h)
p-MeC6H4 (4b)
p-MeOC6H4 (4g)
p-NO2C6H4 (4h)
p-BrC6H4 (4d)
n-C4H9 (4i)
>99
99
98
99
>99
>99
>99
>99
>99
99
50:1
>99:1
aReaction conditions: 3 (1.0 equiv), 4 (1.0 equiv), 2a (10 mol %), PNBA (10 mol %), CHCl3 (0.5 mL). bIsolated yield after column chromatography on
silica gel. cDetermined by 19F NMR. dDetermined by chiral HPLC analysis.
SCHEME 2. Possible Mechanism for the Robinson Annulation
120 J. Org. Chem. Vol. 75, No. 1, 2010

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JOCArticle
FIGURE 2. Monitoring the reaction of 3a with 4a by 19F NMR
reaction performed slow and product 5v was gained in 70%
yield, 9:1 dr, and 99% ee (Scheme 1).
reaction time was prolonged to 96 h, the ratio of 5a decreased
as the signal of 6a almost disappeared.
In accord with the above experimental results and pre-
vious related studies, a probable mechanism for the current
transformation was proposed (Scheme 2). First, the Michael
reaction between 3 and 4 provided intermediates I (trans)
and II (cis) as a mixture, which then underwent intramole-
cular aldol reactions to form I0 and 6, respectively. The
intermediate I0 underwent the dehydration step quickly to
deliver the desired product 5. However, the dehydration
of 6 was so sluggish that it could be detected after the reac-
tion time, which may be attributed to the stabilization
of this compound structure resulting from the intramolecu-
lar hydrogen bond interaction between the hydroxyl group
and the ester carbonyl group as revealed by the X-ray
structure of 6a.
In an effort to gain an insight into the mechanism of the
reaction, the reaction between 3a and 4a was monitored by
19F NMR (Figure 2). As expected, the dehydration of the
intermediate I0 was almost complete after the reaction time
indicated in Table 3, entry 1 (20 h), while the dehydration of
6a was very slow. In addition, no signals assignable to the
assumed diastereoisomers of the intermediate I0 and 6a was
observed, which might imply that the intramolecular aldol
reaction also proceeded in a highly diastereoselective way.
The 19F NMR also showed that the diastereomeric ratio of
5a was dependent on the dehydration rates of 6a: when the
Conclusion
In summary, we have developed an asymmetric Robinson
annulation system to synthesize multiply substituted fluori-
nated chiral cyclohexenones with two contiguous stereogenic
centers, one of which is a fluorinated quaternary chiral
center. With use of readily available primary-secondary
diamines as the catalysts, the desired products were obtained
with excellent enantioselectivities and diastereoselectivities
in moderate to good yields.
Experimental Section
General Procedure for the Preparation of r-Fluoro-β-keto
Esters: (E)-tert-Butyl 5-(4-Bromophenyl)-2-fluoro-3-oxopent-4-
enoate, 3a. To a solution of 7a (972 mg, 3.0 mmol) in
acetonitrile (4 mL) was added Selectfluor (1.6 g, 4.5 mmol) at
room temperature and the mixture was stirred for 10 h. Upon
completion of the reaction (monitored by TLC), the solvent was
removed in vacuum, the residue was mixed with 20 mL of ethyl
ether, and the mixture was then filtered through a pad of Celite.
The filtrate was then concentrated under vacuum to provide a
white solid. After recrystallization from petroleum ether and
ethyl acetate at -10 °C, 3a (875 mg, 85% yield) was obtained as
white solid: mp 67-68 °C; 1H NMR (300 MHz, CDCl3)
δ 7.75 (d, J = 15.9 Hz, 1H), 7.51 (AB, J = 28.1 Hz, 4H), 7.07
J. Org. Chem. Vol. 75, No. 1, 2010 121

Cui et al.
JOCArticle
(dd, J = 2.2, 15.9 Hz, 1H), 5.31 (d, J = 49.2 Hz, 1H), 1.51 (s,
9H); 19F NMR (282 MHz, CDCl3) δ -194.13 (d, J = 49.5 Hz,
1F); 13C NMR (75 MHz, CDCl3) δ 189.3 (d, J = 21.8 Hz), 163.3
(d, J = 24.1 Hz), 144.8 (d, J = 3.2 Hz), 132.8, 132.3, 130.1,
125.8, 120.0, 91.3 (d, J = 197.6 Hz), 84.5, 27.9; IR (KBr) ν 1758,
1703, 1611 cm-1; EI-MS (m/z) 342 (Mþ, 3.2%), 57 (100), 209
(75), 211 (73), 102 (54), 41 (20), 133 (13), 75 (12), 286 (12);
HRMS (EI) m/z calcd for C15H16BrFO3 342.0267, found
342.0266 [M]þ.
(75 MHz, CDCl3) δ 197.4 (d, J = 2.1 Hz), 166.0 (d, J =14.5 Hz),
151.8 (d, J = 21.1 Hz), 137.2 (d, J = 6.1 Hz), 135.4 (d, J = 0.8
Hz), 134.8 (d, J = 0.9 Hz), 132.1, 128.8 (d, J = 1.1 Hz), 128.7,
128.5 (d, J = 4.4 Hz), 128.4, 128.2, 123.9 (d, J = 1.8 Hz), 123.6,
94.4 (d, J = 193.5 Hz), 84.4, 47.8 (d, J = 21.9 Hz), 39.2 (d,
J = 8.8 Hz), 27.7; IR (KBr) ν 1721, 1676, 1664, 1596, 1584 cm-1
;
ESI-MS (m/z) 493 (M þ 23), 471 (M þ 1); HRMS (EI) m/z calcd
for C25H24Br(81)FO3 472.0872, found 472.0869 [M]þ. HPLC
separation conditions: Chiralcel AD, 20 °C, 254 nm, 9:1 hexane:
i-PrOH, 0.8 mL/min; tR = 19.2 min (minor enantiomer), 25.4
min (major enantiomer).
General Procedure for the Enantioselective Robinson Annula-
tion: (1S,6S,E)-tert-Butyl 2-(4-Bromostyryl)-1-fluoro-4-oxo-
6-phenylcyclohex-2-enecarboxylate, 5a. To a solution of 3a
(34 mg, 0.1 mmol) and 4a (15 mg, 0.1 mmol) in 0.5 mL of
chloroform were added 2a (2 mg, 0.01 mmol, 10 mol %) and
4-nitrobenzoic acid (2 mg, 0.01 mmol, 10 mol %). The mixture
was stirred at room temperature and monitored by TLC. After
completion (20 h), the mixture was concentrated by rotary
evaporation and the residue was purified by flash chromato-
graphy (ethyl acetate/petroleum ether: 1/10) to provide pure 5a
Acknowledgment. The authors are grateful for research
support from the National Natural Science Foundation of
China (No.20172064, 203900502, 20532040), 973 Program,
Shanghai Natural Science Council, and Excellent Young
Scholars Foundation of National Natural Science Founda-
tion of China (20525208).
(38 mg, 80% yield) as a white solid: mp 101-102 °C; [R]25
D
-205.8 (c 0.400 in CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.40
(AB, J = 41.9 Hz, 4H), 7.39-7.33 (m, 5H), 7.26 (d, J = 16.5 Hz,
1H), 6.76 (d, J = 16.5 Hz, 1H), 6.35 (s, 1H), 3.96-3.84 (m, 1H),
3.54-3.43 (m, 1H), 2.80-2.72 (m, 1H), 1.29 (s, 9H); 19F NMR
(282 MHz, CDCl3) δ -150.78 (d, J = 15.9 Hz, 1F); 13C NMR
Supporting Information Available: Experimental proce-
dures, 1H and 13C NMR and HRMS data for substrates 3 and
product 5 and 6a, and X-ray crystal data in CIF format for 5a
and 6a. This material is available free of charge via the Internet
at http://pubs.acs.org.
122 J. Org. Chem. Vol. 75, No. 1, 2010