Highly enantioselective synthesis of α-fluoro-α-nitro esters via organocatalyzed asymmetric Michael addition

Article abstract of DOI:10.1016/j.tet.2010.11.041

Primary amines catalyzed the asymmetric Michael addition of ethyl 2-fluoro-2-nitroacetate to enones to provide chiral α-fluoro-α-nitro ester ketones with two contiguous stereogenic centers, one of which is a fluorinated quaternary chiral center, with exce

Full text of DOI:10.1016/j.tet.2010.11.041

Tetrahedron 67 (2011) 312e317
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective synthesis of
asymmetric Michael addition
a-fluoro-a-nitro esters via organocatalyzed
,
b
,
,
b
,
,
b
,
,
b
,
,
b
,
,
z
Hai-Feng Cui a y, Peng Li a y, Xiao-Wei Wang a y, Zhuo Chai a y, Ying-Quan Yang a y, Yue-Peng Cai c
,
Shi-Zheng Zhu a
y, Gang Zhao a
,
b
, ,
,
b
, ,
y
*
*
a Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
c School of Chemistry and Environment, Key Lab of Technology on Electrochemical Energy Storage and Power Generation in Guangdong Universities, South China Normal University,
Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2010
Received in revised form 30 October 2010
Accepted 9 November 2010
Available online 12 November 2010
Primary amines catalyzed the asymmetric Michael addition of ethyl 2-fluoro-2-nitroacetate to enones to
provide chiral a-fluoro-a-nitro ester ketones with two contiguous stereogenic centers, one of which is
a fluorinated quaternary chiral center, with excellent enantioselectivities and in moderate to good yields.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Primary amine
Asymmetric Michael addition
Fluorinated
Enantioselectivities
1. Introduction
et al.4c independently reported asymmetric Michael and Mannich
addition using racemic a-fluoro-b-keto esters as nucleophiles with
Due to the unique properties of the fluorine atom, fluorine-
containingorganiccompoundshavemanyimportant applicationsin
materials, medicinal, pharmaceutical and agrochemical science.1
There are two common strategies for the introduction of the fluo-
rine atom:2e4 (a) direct fluorination of organic compounds with
kinds of electrophilic or nucleophilic fluorinating reagents and (b)
the use of easily available simple fluorine-containing building
blocks. Recently, with the rapid development of organocatalysis,
organocatalytic asymmetric synthesis of chiral fluorinated mole-
cules with both strategies has received considerable attentions
among organic chemists.3gem,4 Particularly, the catalytic construc-
tion of chiral fluorinated quaternary carbon centers using simple
monofluorinated building blocks, which could provide a class of
versatile monofluorinated synthons utilized in organic synthesis,5
has recently gained significant progress, is still a very challenging
subject in organic chemistry.4,5 For examples, Lu et al.4d and Wang
good to excellent enantioselectivities; Tan et al. reported the con-
struction of chiral quaternarycarbon centers bearing a fluorine atom
via enantio- and diastereo-selective guanidine-catalyzed additions
of fluorocarbon nucleophiles to N-alkyl maleimides or imines.4b
Nitro compounds are also valuable synthons due to the rich
chemistry involved with the nitro group6 and many of them have
also shown important biological activity.7 Therefore, it would be
interesting to have compounds containing both the nitro group and
fluorine atom. Togni et al. firstly reported asymmetric electrophilic
fluorination of
fluoro-
-nitro esters with up to 40% ee.8 As an alternative way, the
direct use of racemic -fluoro- -nitro esters as nucleophiles in
organocatalytic asymmetric Michael addition reactions would also
provide the desired chiral -fluoro- -nitro esters. Surprisingly, to
a-nitro esters with Selectfluor to synthesize chiral a-
a
a
a
a
a
our best knowledge, there has been no precedent with this strategy.
During the preparation of this manuscript, Wang et al. reported
a primary amine-catalyzed Michael addition of nitro esters to
enones and they also provided an example of the preparation of
a chiral
a-fluoro-a-nitro ester via electrophilic fluorination of the
* Corresponding authors. Tel.: þ86 21 54925182; fax: þ86 21 64166128; e-mail
addresses: ypcai8@yahoo.com (Y.-P. Cai), zhusz@mail.sioc.ac.cn (S.-Z. Zhu), zhaog@
mail.sioc.ac.cn (G. Zhao).
Michael adduct, but the conjugate addition could not proceed cat-
alyzed by primary amine/(þ)-CSA Salt when
a-fluorinated nitro-
acetate was used,9 fortunately, in our research when other organic
acids were employed, good results were gained. So we report herein
y
Tel.: þ86 21 54925182; fax: þ86 21 64166128.
z
Tel.: þ86 20 33033475; fax: þ86 20 85215865.
0040-4020/$ e see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.041

H.-F. Cui et al. / Tetrahedron 67 (2011) 312e317
313
an asymmetric Michael addition reaction of
to enones catalyzed by chiral primary amine catalysts.
a
-fluoro-
a-nitro esters
results than the initially used PNBA (entries 12e14). The different
representations between (þ)-CSA and PNBA may due to their dif-
ferent acidic ability and stereo effect. Therefore, the reaction was
best performed with 10 mol % of catalyst 1b and PNBA in toluene at
room temperature (Table 1, entry 11).
2. Results and discussion
With the optimized reaction conditions in hand, a selected
spectrum of different substrates was examined to test the scope of
this reaction. For substrates 2 with different substituents on the
phenyl ring (R¼aryl), generally excellent ee values and yields with
1.8:1 to 2.4:1 dr values were obtained irrespective of the electronic
nature or positions of the substituents (Table 2, entries 1e9),
though slightly lower yields were observed for substrates bearing
We have recently developed a series of novel amino acid-derived
primaryamine catalystsfor the Michael reaction ofenones.10,11 Here,
catalyst 1a of this type (Fig. 1) catalyzed the model reaction with an
excellent yield while the enantioselectivities of the products were
not very satisfactory (Table 1, entry 1). Notably, the two di-
Table 2
NH2
Investigation of reaction scopea
N
N
H
NH2
N
N
1b
1c
Ph
N
H
O
O
NH2
NH2
N
H
1a
N
Entry
R
Product
Time/h
Yield
Ratio of
(2S, 3R)
/(2R, 3R)c
ee of 4/%d
NH2
of 4/%b
N
N
1e
1d
Fig. 1. Structures of catalysts studied.
1
2
3
4
5
6
7
8
Ph
p-FC6H4
4a
4b
4c
4d
4e
4f
4 g
4 h
4i
24
36
36
36
36
36
36
36
36
36
36
36
90
95
95
93
86
85
95
85
90
90
75
80
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
2.4:1.0
2.2:1.0
1.8:1.0
1.5:1.0
1.2:1.0
99, 99
99, 99
98, 99
99, 99
98, 99
98, 99
97, 98
99, 99
99, 99
99, 97
98, 99
93, 98
p-ClC6H4
p-BrC6H4
p-CH3C6H4
p-CH3OC6H4
p-NO2C6H4
o-ClC6H4
m-ClC6H4
1-Naphthyl
2-Furyl
Table 1
The optimization of reaction conditiona
9
10
11
12
4j
4 k
4l
n-Butyl
a
Unless otherwise noted, the reaction was carried out with 1b (10 mol %), PNBA
(10 mol %).
b
c
Isolated yield.
Determined by 19F NMR.
Determined by HPLC analysis.
Entry
Cat.
Sol.
Additive
Yield 4a/%b
drc
ee of 4a/%d
d
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1b
1b
1b
1b
1b
1b
1b
1b
1b
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CCl4
DCE
Xylene
Et2O
PNBAe
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
TsOH
TfOH
TFA
95
95
93
70
95
80
85
89
90
95
90
92
93
10
1.2:1.0
1.5:1.0
1.5:1.0
1.5:1.0
1.2:1.0
1.4:1.0
2.0:1.0
1.5:1.0
1.8:1.0
1.7:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
ꢀ93, ꢀ90
99, 99
ꢀ99, ꢀ99
99, 99
ꢀ99, ꢀ99
99, 98
94, 97
98, 99
99, 98
98, 98
99, 99
96, 92
96, 86
ND
electron-donating substituents (Table 2, entries 5 and 6). Excellent
results were also obtained when R was a heterocyclic 2-furyl or an
aliphatic n-butyl (Table 2, entries 11 and 12). Notably, as 4a, all of
diastereoisomers of the product 4 could be easily separated by flash
column chromatography on silica gel. The absolute configurations
of two isomers of 4 were determined by X-ray crystallographic
analysis.12
To our delight, besides open chain enones, cyclohexenone also
performed well as an acceptor of the Michael addition and excel-
lent enantioselectivities were achieved (Scheme 1).
9
10
11
12
13
14
Toluene
Toluene
Toluene
Toluene
a
Unless otherwise noted, the reaction was carried out with 1 (10 mol %), additive
(10 mol %) in solvent (1.0 mL) at rt.
b
Isolated yield.
c
Determined by 19F NMR.
d
Determined by HPLC analysis.
PNBA (4-nitrobenzoic acid), TfOH (trifluoromethanesulfonic acid), TFA (tri-
e
fluoroacetic acid).
Scheme 1. Michael addition of 5 to cyclohexenone.
astereoisomers of the product 4a were easily separated by flash
column chromatography on silica gel. Further catalysts screening
proved that primary amines 1bee derived from cinchona alkaloids
excelled in this reaction, with quinidine-derived 1b being the best
one (Table 1, entries 2e5). Then, some other solvents were screened
(entries 6e11) and toluene was selected as the optimal solvent for
that a slightly better diastereoselectivity was obtained (entry 11).
Furthermore, three other acid additives examined all gave inferior
The products obtained from Michael additions are easily
transformed into corresponding
a-fluorinated esters or nitro
compounds following the procedures reported.13 Otherwise, (2R,
3R)-4d could be inverted to 7 quantitatively in excellent stereo-
selectivity (Scheme 2).

314
H.-F. Cui et al. / Tetrahedron 67 (2011) 312e317
Scheme 2. Conversion of (2R, 3R)-4d to 7.
3. Conclusion
(d, J¼28.3 Hz), 133.7 (d, J¼1.2 Hz), 129.0 (d, J¼1.9 Hz), 128.4, 128.2,
115.3 (d, J¼254.9 Hz), 63.7, 44.0 (d, J¼17.9 Hz), 42.4 (d, J¼3.0 Hz),
29.9, 13.0; IR (film)
2986, 1767, 1723, 1577, 1251 cmꢀ1; EIMS (m/z):
In summary, we have developed an asymmetric Michael addition
n
system to synthesize multiply substituted
a
-fluoro-
a
-nitro ester
43 (100), 205 (31), 115 (26), 251 (23), 84 (20), 208 (19), 133 (17), 86
(13); HRMS (EI): m/z: calcd for C14H16FNO5: 297.1013; found:
297.1010 [M]þ. HPLC separation conditions: Chiralcel ODH, 20 ꢁC,
254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼10.7 min (minor en-
antiomer), 13.1 min (major enantiomer).
with two contiguous stereogenic centers, one of which is a fluori-
nated quaternary chiral center. Using readily available primary
amines as the catalysts, the desired products were obtained with
excellent enantioselectivities in moderate to good yields.
25
4. Experimental
4.1. General
4.2.3. Compound (2S,3R)-4b. Colorless oil. [
a
]
68.1 (c 1.03 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.29e7.25 (m, 2H), 7.02e6.96
(m, 2H), 4.70e4.55 (m, 1H), 4.38 (q, J¼7.4, 14.6 Hz, 2H), 3.04 (d,
J¼6.7 Hz, 2H), 2.09 (s, 3H), 1.35 (t, J¼7.4 Hz, 3H); 19F NMR (282 MHz,
Unless otherwise indicated, chemicals and solvents were pur-
chased from commercial suppliers and purified by standard tech-
niques. Flash column chromatography was performed using silica
gel. For thin-layer chromatography (TLC), and compounds were vi-
sualized by irradiation with UV light or by treatment with a solution
of phosphomolybdic acid in ethanol followed by heating. For NMR
spectroscopy, samples were dissolved in CDCl3 and run in room
CDCl3)
d
ꢀ113.51 (s, 1F), ꢀ135.30 (d, J¼33.1 Hz, 1F); 13C NMR
(75 MHz, CDCl3)
d
203.0, 162.7 (d, J¼247.9 Hz), 160.6 (d, J¼27.7 Hz),
131.0 (dd, J¼1.6, 8.4 Hz), 129.7 (d, J¼3.5 Hz), 115.8 (d, J¼21.6 Hz),
115.2 (d, J¼256.1 Hz), 64.7, 43.9, 43.5 (d, J¼18.2 Hz), 30.1, 13.6; IR
(film)
n
3020, 1765, 1724, 1583, 1512, 1216 cmꢀ1; EIMS (m/z): 315
(Mþ, 1), 43 (100), 226 (24), 223 (13), 133 (13), 151 (9), 181 (8), 227
(7), 269 (7); HRMS (EI): m/z: calcd for C14H15NF2O5: 315.0918;
found: 315.0924 [M]þ. HPLC separation conditions: Chiralcel ODH,
20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼10.4 min (major
enantiomer), 14.9 min (minor enantiomer).
temperature. The 1H NMR (300 MHz), 13C NMR (100 MHz), and 19
NMR (282 MHz) were recorded on 300, 400 MHz spectrometer.
F
4.2. General procedure for the synthesis of compound 4a
27
4.2.4. Compound (2R,3R)-4b. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a]
8.0 (c 1.10 in
D
d
7.38e7.27 (m, 2H), 7.04e6.99
To a solution of 2a (58 mg, 0.4 mmol) and 3 (67 mg, 0.44 mmol)
in 2 mL toluene, 1b (12 mg, 0.04 mmol, 10 mol %) and PNBA (7 mg,
0.04 mmol, 10 mol %) were added. The mixture was stirred at room
temperature and monitored by TLC. After completion (24 h), the
mixture was concentrated by rotary evaporation and the residue
was purified by flash chromatography (dichloromethane/pet.
ether: 1/1) to provide 4a as a mixture of two isomers, 107 mg, 90%,
then the mixture was further purified by flash chromatography
(ethyl acetate/pet. ether: 1/4) to provide pure (2S,3R)-4a 71 mg as
colorless oil and (2R,3R)-4a 36 mg as colorless oil.
(m, 2H), 4.76e4.60 (m, 1H), 4.13 (q, J¼6.8 Hz, 2H), 3.13e3.03 (m,
1H), 2.79e2.72 (m, 1H), 2.07 (s, 3H), 1.12 (t, J¼6.8 Hz, 3H); 19F NMR
(282 MHz, CDCl3)
d
ꢀ113.45 (s, 1F), ꢀ135.89 (d, J¼28.3 Hz, 1F); 13C
NMR (75 MHz, CDCl3)
d
202.5, 162.2 (d, J¼248.0 Hz), 159.3
(d, J¼28.0 Hz), 130.8 (dd, J¼2.2, 8.4 Hz), 129.7 (d, J¼8.6 Hz), 129.6
(dd, J¼0.9, 3.4 Hz), 115.7 (d, J¼22.1 Hz), 115.4 (d, J¼21.5 Hz), 114.8 (d,
J¼254.1 Hz), 63.8, 43.3 (d, J¼18.2 Hz), 42.4 (d, J¼2.8 Hz), 29.8, 13.1;
EIMS (m/z): 43 (100), 223 (19), 133 (16), 269 (14), 226 (13), 151 (10),
149 (10), 227 (8); HRMS (EI): m/z: calcd for C14H15NF2O5: 315.0918;
found: 315.0907 [M]þ. HPLC separation conditions: Chiralcel ODH-
ASH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼19.9 min
(major enantiomer), 23.6 min (minor enantiomer).
26
4.2.1. Compound (2S,3R)-4a. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a
]
75.6 (c 0.90 in
D
d
7.32e7.26 (m, 5H), 4.72e4.55
(m,1H), 4.37 (q, J¼7.0 Hz, 2H), 3.11e3.06 (m, 2H), 2.08 (s, 3H),1.35 (t,
4.2.5. Compound (2S,3R)-4c. White solid. Mp: 92e93 ꢁC; [
a]
26 63.6
D
J¼7.0 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ134.08 (d, J¼32.5 Hz,
(c 1.00 in CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.29e7.21 (m, 4H),
1F); 13C NMR (75 MHz, CDCl3)
d
202.8, 160.4 (d, J¼27.9 Hz), 134.5,
4.69e4.54 (m, 1H), 4.37 (q, J¼6.8 Hz, 2H), 3.10e2.98 (m, 2H), 2.09 (s,
128.8 (d, J¼1.7 Hz), 128.3, 128.2, 114.9 (d, J¼255.3 Hz), 64.2, 43.7 (d,
3H), 1.35 (t, J¼7.5, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ135.07 (d,
J¼18.2 Hz), 43.4 (d, J¼1.9 Hz), 29.7, 13.2; IR (film)
n
2987, 1764, 1723,
J¼27.3 Hz,1F); 13C NMR (75 MHz, CDCl3)
202.9,160.5 (d, J¼28.1 Hz),
d
1580, 1456, 1356, 1249 cmꢀ1; EIMS (m/z): 43 (100), 208 (31), 163
(24), 115 (20), 205 (17), 133 (13), 251 (12), 162 (11); HRMS (EI): m/z:
calcd for C14H16FNO5: 297.1013; found: 297.1011 [M]þ. HPLC sepa-
ration conditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH,
0.7 mL/min; tR¼15.6 min (minor enantiomer), 17.5 min (major
enantiomer).
134.7, 132.5, 130.6, 129.0, 115.1 (d, J¼254.5 Hz), 64.7, 43.7, 43.5 (d,
J¼18.2 Hz), 30.1, 13.6; IR (KBr)
n 2993, 1768, 1724, 1578, 1512,
1251 cmꢀ1;EIMS(m/z): 331 (Mþ,1), 43(100), 242(17), 239(9),197(7),
133 (7), 244 (6), 243 (5), 285 (5); HRMS (EI): m/z: calcd for
C14H15ClFNO5: 331.0623; found: 331.0624 [M]þ. HPLC separation
conditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/
min; tR¼11.9 min (major enantiomer), 16.5 min (minor enantiomer).
26
4.2.2. Compound (2R,3R)-4a. Colorless oil. [
a
]
6.8 (c 0.55 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.50e7.26 (m, 5H), 4.77e4.63
26
4.2.6. Compound (2R,3R)-4c. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
(m,1H), 4.14 (q, J¼7.5 Hz, 2H), 3.12e3.03 (m,1H), 2.80e2.73 (m,1H),
a
]
6.0 (c 0.90 in
(m,1H), 4.10 (q, J¼7.3 Hz, 2H), 3.18e3.05 (m,1H), 2.83e2.70 (m,1H),
D
2.05 (s, 3H), 1.08 (t, J¼7.3 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
7.33e7.27 (m, 4H), 4.77e4.61
d
ꢀ134.68 (d, J¼27.1 Hz, 1F); 13C NMR (75 MHz, CDCl3)
d 202.7, 159.4

H.-F. Cui et al. / Tetrahedron 67 (2011) 312e317
315
2.07 (s, 3H), 1.13 (t, J¼7.5 Hz, 3H); 19F NMR (282 MHz, CDCl3)
20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.6 mL/min; tR¼12.9 min (minor
d
ꢀ135.57 (d, J¼70.9 Hz,1F); 13C NMR (75 MHz, CDCl3)
d
202.7,159.8
enantiomer), 14.2 min (major enantiomer).
(d, J¼18.0 Hz), 134.8, 132.8, 130.9, 129.1, 115.4 (d, J¼254.6 Hz), 64.3,
26
43.8 (d, J¼18.6 Hz), 42.8 (d, J¼2.7 Hz), 30.3, 13.5; IR (film)
n
2987,
4.2.11. Compound (2S,3R)-4f. Colorless oil. [
a
]
60.6 (c 1.12 in
D
1766, 1723, 1579, 1494, 1351, 1251, 1095 cmꢀ1; ESI-MS (m/z): 354.0
[Mþ1]þ; HRMS (ESI): m/z: calcd for C14H15ClFNO5Na: 354.0515;
found: 354.0509 [M]þ. HPLC separation conditions: Chiralcel ASH,
20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼20.5 min (minor
enantiomer), 24.0 min (major enantiomer).
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.19 (AB, J¼9.0 Hz, 2H), 6.87 (AB,
J¼9.0 Hz, 2H), 4.65e4.50 (m, 1H), 4.36 (q, J¼6.9, 14.1 Hz, 2H), 3.76 (s,
3H), 3.11e2.95 (m, 2H), 2.08 (s, 3H), 1.35 (t, J¼6.9 Hz, 3H); 19F NMR
(282 MHz, CDCl3)
CDCl3)
d
ꢀ135.41 (d, J¼30.3 Hz, 1F); 13C NMR (75 MHz,
d
203.4, 160.8 (d, J¼27.9 Hz), 159.7, 130.4, 125.6, 115.5 (d,
J¼254.5 Hz), 114.2, 64.5, 55.1, 43.9 (d, J¼1.8 Hz), 43.6 (d, J¼18.2 Hz),
30.2, 13.7; IR (film)
2938, 1764, 1722, 1611, 1580, 1515, 1254 cmꢀ1
EIMS (m/z): 327 (Mþ, 7), 43 (100), 238 (29), 145 (27), 193 (20), 239
26
4.2.7. Compound (2S,3R)-4d. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a]
56.2 (c 1.23 in
n
;
D
d
7.43 (AB, J¼8.9 Hz, 2H), 7.16
(AB, J¼8.9 Hz, 2H), 4.68e4.53 (m, 1H), 4.37 (q, J¼6.8 Hz, 2H),
(16), 280 (14), 133 (10), 163 (9); HRMS (EI): m/z: calcd for C15H18F
3.09e3.00 (m, 2H), 2.09 (s, 3H), 1.35 (t, J¼7.3 Hz, 3H); 19F NMR
NO6: 327.1118; found: 327.1122 [M]þ. HPLC separation conditions:
Chiralcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min;
tR¼13.6 min (major enantiomer), 16.7 min (minor enantiomer).
(282 MHz, CDCl3)
CDCl3)
d
ꢀ135.01 (d, J¼29.5 Hz, 1F); 13C NMR (75 MHz,
d
202.9, 160.5 (d, J¼27.7 Hz), 133.0, 132.0, 130.9, 123.0, 115.0
(d, J¼255.2 Hz), 64.7, 43.7, 43.6 (d, J¼19.6 Hz), 30.2, 13.7; IR (KBr)
n
26
2987, 1764, 1723, 1580, 1491, 1356, 1249 cmꢀ1; EIMS (m/z): 43 (100),
296 (10), 288 (10), 133 (8), 134 (6), 285 (6), 283 (5), 120 (4); HRMS
(EI): m/z: calcd for C14H15BrFNO5: 375.0118; found: 375.0115 [M]þ.
HPLC separation conditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1
hexane/i-PrOH, 0.7 mL/min; tR¼13.2 min (major enantiomer),
17.7 min (minor enantiomer).
4.2.12. Compound (2R,3R)-4f. Colorless oil. [
a
]
10.8 (c 1.35 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.25 (AB, J¼8.6 Hz, 2H), 6.83
(AB, J¼8.6 Hz, 2H), 4.71e4.57 (m, 1H), 4.07 (q, J¼7.2, 14.3 Hz, 2H),
3.78 (s, 3H), 3.13e3.04 (m, 1H), 2.75e2.68 (m, 1H), 2.05 (s, 3H), 1.13
(t, J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3)
ꢀ136.17 (d, J¼28.3 Hz,
d
1F); 13C NMR (75 MHz, CDCl3)
d
202.8, 159.4 (d, J¼28.3 Hz), 159.2,
130.1, 125.3, 115.4 (d, J¼254.4 Hz), 113.7, 63.7, 54.8, 43.3 (d,
2938, 1767, 1723,
26
4.2.8. Compound (2R,3R)-4d. White solid. Mp: 45e46 ꢁC; [
(c 5.15 in CHCl3); 1H NMR (300 MHz, CDCl3)
a
]
9.1
J¼18.2 Hz), 42.4 (d, J¼3.0 Hz), 29.9, 13.1; IR (film)
n
D
d
7.46 (AB, J¼8.7 Hz,
1611, 1576, 1515, 1253 cmꢀ1; EIMS (m/z): 327 (Mþ, 4), 43 (100), 238
(29), 145 (47), 239 (29), 281 (27), 193 (19), 238 (18), 235 (18), 163
(17); HRMS (EI): m/z: calcd for C15H18F NO6: 327.1118; found:
327.1121 [M]þ. HPLC separation conditions: Chiralcel ASH, 20 ꢁC,
254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼29.0 min (minor en-
antiomer), 30.8 min (major enantiomer).
2H), 7.23 (AB, J¼8.7 Hz, 2H), 4.75e4.59 (m, 1H), 4.14 (q, J¼6.8 Hz,
2H), 3.12e3.03 (m, 1H), 2.79e2.72 (m, 1H), 2.06 (s, 3H), 1.13 (t,
J¼6.8 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ135.52 (d, J¼28.7 Hz,
1F); 13C NMR (75 MHz, CDCl3)
d
202.3, 159.3 (d, J¼28.0 Hz), 132.8,
131.5, 130.7 (d, J¼2.0 Hz), 122.5, 114.8 (d, J¼255.9 Hz), 63.9, 43.4 (d,
J¼18.0 Hz), 42.3 (d, J¼1.9 Hz), 29.8, 13.1; IR (KBr)
n
3054, 1766, 1724,
26
1580, 1491, 1265, 1217 cmꢀ1; EIMS (m/z): 43 (100), 285 (12), 283
(11), 133 (11), 286 (10), 288 (8), 329 (8), 331 (8); HRMS (EI): m/z:
calcd for C14H15BrFNO5: 375.0118; found: 375.0119 [M]þ. HPLC
separation conditions: Chiralcel ASH, 20 ꢁC, 254 nm, 9:1 hexane/i-
PrOH, 0.7 mL/min; tR¼21.0 min (minor enantiomer), 28.4 min
(major enantiomer).
4.2.13. Compound (2S,3R)-4g. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a]
75.3 (c 1.18 in
D
d
8.16 (AB, J¼9.7 Hz, 2H), 7.50
(AB, J¼9.7 Hz, 2H), 4.83e4.68 (m, 1H), 4.39 (q, J¼7.3, 14.0 Hz, 2H),
3.21e3.04 (m, 2H), 2.12 (s, 3H), 1.36 (t, J¼6.7 Hz, 3H); 19F NMR
(282 MHz, CDCl3)
CDCl3)
d
ꢀ134.46 (d, J¼28.8 Hz, 1F); 13C NMR (75 MHz,
d
202.5, 160.2 (d, J¼27.4 Hz), 147.9, 141.4, 130.4, 123.8, 114.7
(d, J¼256.4 Hz), 65.0, 43.7 (d, J¼18.1 Hz), 43.6 (d, J¼1.2 Hz), 30.0,
26
4.2.9. Compound (2S,3R)-4e. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a]
74.1 (c 1.00 in
13.6; IR (KBr) 2987, 1765, 1723, 1581, 1525, 1421, 1351, 1299,
n
D
d
7.16 (AB, J¼8.4 Hz, 2H), 7.09
1250 cmꢀ1; EIMS (m/z): 43 (100), 250 (20), 253 (10), 296 (7), 133
(7), 134 (4), 254 (3), 251 (3); HRMS (EI): m/z: calcd for C14H15FN2O7:
342.0863; found: 342.0861 [M]þ. HPLC separation conditions:
Chiralcel AD, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.85 mL/min;
tR¼22.0 min (minor enantiomer), 30.5 min (major enantiomer).
(AB, J¼8.4 Hz, 2H), 4.66e4.51 (m, 1H), 4.37 (q, J¼7.1 Hz, 2H),
3.13e2.96 (m, 2H), 2.29 (s, 3H), 2.11 (s, 3H), 1.35 (t, J¼7.1 Hz, 3H); 19F
NMR (282 MHz, CDCl3)
d
ꢀ135.17 (d, J¼31.4 Hz, 1F); 13C NMR
(75 MHz, CDCl3)
d
203.4, 160.8 (d, J¼28.0 Hz), 138.5, 130.6, 129.5,
129.1, 115.4 (d, J¼254.9 Hz), 64.5, 43.9 (d, J¼18.5 Hz), 43.8 (d,
3026, 2924, 1764, 1723, 1581,
27
J¼1.9 Hz), 30.2, 21.0, 13.7; IR (film)
n
4.2.14. Compound (2R,3R)-4g. Colorless oil. [
a
]
10.7 (c 0.52 in
D
1516, 1355, 1249, 756 cmꢀ1; EIMS (m/z): 311 (Mþ, 1), 43 (100), 222
(34), 177 (30), 129 (21), 223 (13), 219 (11), 133 (11), 176 (10); HRMS
(EI): m/z: calcd for C15H18FNO5: 311.1169; found: 311.1165 [M]þ.
HPLC separation conditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1
hexane/i-PrOH, 0.7 mL/min; tR¼10.7 min (major enantiomer),
12.0 min (minor enantiomer).
CHCl3); 1H NMR (300 MHz, CDCl3)
d
8.19 (AB, J¼8.7 Hz, 2H), 7.56
(AB, J¼8.7 Hz, 2H), 4.89e4.74 (m, 1H), 4.15 (q, J¼7.5, 14.2 Hz, 2H),
3.18e3.09 (m, 1H), 2.90e2.82 (m, 1H), 2.09 (s, 3H), 1.14 (t, J¼7.5 Hz,
3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ134.41 (d, J¼29.0 Hz, 1F); 13C
NMR (75 MHz, CDCl3)
d
201.9, 159.0 (d, J¼27.7 Hz), 147.5, 141.3,
130.2, 123.4, 114.3 (d, J¼255.9 Hz), 64.2, 43.5 (d, J¼18.0 Hz), 42.3 (d,
J¼3.2 Hz), 29.7, 13.1; IR (film)
n
2922, 1767, 1723, 1580, 1526 cmꢀ1
;
27
4.2.10. Compound (2R,3R)-4e. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a
]
10.2 (c 0.37 in
EIMS (m/z): 43 (100), 250 (29), 296 (10), 133 (8), 253 (8), 251 (4),
204 (4), 134 (4); HRMS (EI): m/z: calcd for C14H15FN2O7: 342.0863;
found: 342.0866 [M]þ. HPLC separation conditions: Chiralcel AD,
20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.85 mL/min; tR¼22.1 min
(minor enantiomer), 27.0 min (major enantiomer).
D
d
7.22e7.20 (AB, J¼7.7 Hz, 2H),
7.13e7.10 (AB, J¼7.7 Hz, 2H), 4.81e4.57 (m, 1H), 4.11 (q, J¼7.1,
14.0 Hz, 2H), 3.15e3.06 (m,1H), 2.78e2.70 (m,1H), 2.30 (s, 3H), 2.05
(s, 3H), 1.11 (t, J¼7.1 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ135.74
(d, J¼33.0 Hz, 1F); 13C NMR (75 MHz, CDCl3)
d 202.8, 159.5 (d,
26
J¼28.3 Hz),138.1, 130.4 (d, J¼0.9 Hz),129.0, 128.8 (d, J¼1.9 Hz),115.3
(d, J¼254.3 Hz), 63.6, 43.7 (d, J¼17.9 Hz), 42.4 (d, J¼3.0 Hz), 29.9,
4.2.15. Compound (2S,3R)-4h. Colorless oil. [
a
]
66.6 (c 0.90 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.45e7.35 (m, 2H), 7.27e7.19 (m,
20.6, 13.1; IR (film)
n
2923, 1765, 1723, 1578, 1516, 1250 cmꢀ1; EIMS
2H), 5.45e5.25 (m,1H), 4.47e4.32 (m, 2H), 3.19e2.95 (m, 2H), 2.11 (s,
(m/z): 43 (100), 129 (33), 265 (30), 219 (26), 222 (24), 223 (20), 177
(19), 147 (17); HRMS (EI): m/z: calcd for C15H18FNO5: 311.1169;
found: 311.1168 [M]þ. HPLC separation conditions: Chiralcel ADH,
3H), 1.36 (t, J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ134.06 (d,
J¼25.6 Hz,1F); 13C NMR (75 MHz, CDCl3)
203.0,160.6 (d, J¼27.9 Hz),
d
135.2, 132.5, 130.4, 129.7, 128.5, 127.3, 114.5 (d, J¼256.0 Hz), 64.7,

316
H.-F. Cui et al. / Tetrahedron 67 (2011) 312e317
44.5, 39.5 (d, J¼18.1 Hz), 29.8, 13.7; IR (film)
n
2924, 1767, 1724, 1581,
3H); 19F NMR (282 MHz, CDCl3)
(75 MHz, CDCl3)
d
ꢀ135.36 (d, J¼28.7 Hz,1F); 13C NMR
1478 cmꢀ1; EIMS (m/z): 43 (100), 145 (54), 296 (16), 165 (12), 239 (9),
133 (9), 146 (7), 193 (6); HRMS (EI): m/z: calcd for C14H15ClFNO5:
331.0623; found: 331.0619 [M]þ. HPLC separation conditions: Chir-
alcel ADH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min;
tR¼15.3 min (minor enantiomer), 17.1 min (major enantiomer).
d
202.6,159.4 (d, J¼28.2 Hz),132.6 (d, J¼1.3 Hz),131.2
(d, J¼1.0 Hz),128.6 (d, J¼1.9 Hz),128.2,127.6,127.2,126.3 (d, J¼2.1 Hz),
126.2, 126.1, 115.4 (d, J¼254.8 Hz), 63.7, 44.1 (d, J¼17.9 Hz), 42.5 (d,
J¼3.0 Hz), 29.9,13.0; IR (KBr)
n
2921,1767,1723,1577,1251 cmꢀ1; EIMS
(m/z):347 (Mþ,17), 43(100),165(59),183(29), 259 (26), 255 (23), 258
(21), 213 (19), 152 (19); HRMS (EI): m/z: calcd for C18H18NFO5:
347.1169;found:347.1164[M]þ. HPLCseparationconditions:Chiralcel
ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼15.4 min
(minor enantiomer), 22.7 min (major enantiomer).
25
4.2.16. Compound (2R,3R)-4h. Colorless oil. [
a]
15.5 (c 0.98 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.44e7.24 (m, 4H), 5.43e5.30 (m,
1H), 4.22e4.06 (m, 2H), 3.10e2.89 (m, 2H), 2.09 (s, 3H), 1.12 (t,
J¼7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3)
ꢀ136.09 (d, J¼28.5 Hz,1F);
d
13C NMR (75 MHz, CDCl3)
d
202.3,159.3 (d, J¼28.7 Hz),135.0,132.1 (d,
4.2.21. Compound (2S,3R)-4k. Brown oil. [
1H NMR (300 MHz, CDCl3)
7.38e7.32 (m, 1H), 6.32e6.24 (m, 2H),
a]
26 33.0 (c 0.10 in CHCl3);
D
J¼1.5 Hz),129.8,129.3,128.3,127.0,114.6 (d, J¼253.9 Hz), 63.9, 42.8 (d
2987, 1767, 1725,
d
J¼3.3 Hz), 39.4 (d, J¼17.6 Hz), 29.5, 12.9; IR (film)
n
4.86e4.73 (m, 1H), 4.36 (q, J¼7.4, 14.3 Hz, 2H), 3.25e3.16 (m, 1H),
1580, 1254 cmꢀ1; EIMS (m/z): 43 (100), 145 (54), 296 (20), 165 (15),
239 (12), 133 (10), 195 (8), 193 (8); HRMS (EI): m/z: calcd for
C14H15ClFNO5: 331.0623; found: 331.0617 [M]þ. HPLC separation
conditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/
min; tR¼12.6 min (minor enantiomer),14.9 min (major enantiomer).
2.98e2.90 (m, 1H), 2.16 (s, 3H), 1.34 (t, J¼7.4 Hz, 3H); 19F NMR
(282 MHz, CDCl3)
CDCl3)
d
ꢀ132.95 (d, J¼28.6 Hz, 1F); 13C NMR (75 MHz,
d
203.0,160.3 (d, J¼26.9 Hz),146.8,143.3,113.2 (d, J¼255.7Hz),
110.7, 110.2, 64.6, 41.1, 38.6 (d, J¼19.9 Hz), 29.9, 13.6; IR (film)
n 3020,
1764, 1721, 1583, 1216 cmꢀ1; EIMS (m/z): 43 (100), 83 (16), 198 (16),
195 (10), 55 (10), 84 (9), 240 (8), 199 (8); HRMS (EI): m/z: calcd for
C12H14NFO6: 287.0805; found: 287.0810 [M]þ. HPLC separation
conditions: Chiralcel OD, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/
min; tR¼11.6 min (major enantiomer), 14.3 min (minor enantiomer).
26
4.2.17. Compound (2S,3R)-4i. Colorless oil. [
a]
38.6 (c 0.45 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.32e7.13 (m, 4H), 4.69e4.54 (m,
1H), 4.37 (q, J¼6.8,14.2 Hz, 2H), 3.12e2.98 (m, 2H), 2.11 (s, 3H),1.35 (t,
J¼6.8 Hz, 3H); 19FNMR (282MHz, CDCl3)
ꢀ134.76 (d, J¼30.2 Hz,1F);
d
13C NMR (75 MHz, CDCl3)
d
202.8, 160.4 (d, J¼27.5 Hz), 136.0, 134.5,
4.2.22. Compound (2R,3R)-4k. Brown oil. [
1H NMR (300 MHz, CDCl3)
7.36e7.35 (m, 1H), 6.33e6.30 (m, 2H),
a]
27 5.6 (c 1.20 in CHCl3);
D
130.0, 129.2 (d, J¼2.0 Hz), 128.9, 127.6 (d, J¼1.8 Hz), 115.0 (d,
J¼255.5 Hz), 64.8, 43.8 (d, J¼18.3 Hz), 43.7 (d, J¼1.8 Hz), 30.1,13.6; IR
d
4.91e4.78 (m, 1H), 4.27 (q, J¼7.4, 14.8 Hz, 2H), 3.26e3.17 (m, 1H),
(film)
n
3022, 1765, 1722, 1581, 1478, 1434, 1358, 1249 cmꢀ1; EIMS
2.75e2.68 (m, 1H), 2.13 (s, 3H), 1.25 (t, J¼7.4 Hz, 3H); 19F NMR
(m/z): 331 (Mþ, 1), 43 (100), 242 (15), 239 (14), 197 (9), 133 (7), 285
(6), 241 (5), 244 (5); HRMS (EI): m/z: calcd for C14H15ClFNO5:
331.0623; found: 331.0614 [M]þ. HPLC separation conditions: Chir-
alcel ASH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min; tR¼
21.5 min (major enantiomer), 36.1 min (minor enantiomer).
(282 MHz, CDCl3)
CDCl3)
d
ꢀ133.30 (d, J¼25.1 Hz, 1F); 13C NMR (75 MHz,
d
202.4,159.4 (d, J¼27.7 Hz),146.6,142.7,113.6 (d, J¼255.5 Hz),
110.3,109.8, 64.0, 40.0, 38.2 (d, J¼19.6 Hz), 29.6,13.2; IR (film)
n 1765,
1721,1580 cmꢀ1; EIMS (m/z): 43 (100),198 (19),195 (18),199 (18), 241
(14), 170 (9), 151 (9), 83 (9); HRMS (EI): m/z: calcd for C12H14NFO6:
287.0805; found: 287.0807 [M]þ. HPLC separation conditions: Chir-
alcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min;
tR¼13.0 min (minor enantiomer), 14.3 min (major enantiomer).
26
4.2.18. Compound (2R,3R)-4i. Colorless oil. [
a]
8.8 (c 1.30 in
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.34e7.20 (m, 4H), 4.76e4.60 (m,
1H), 4.15 (q, J¼7.4,14.3 Hz, 2H), 3.14e3.04 (m,1H), 2.81e2.73 (m,1H),
26
2.08 (s, 3H), 1.13 (t, J¼7.4 Hz, 3H); 19F NMR (282 MHz, CDCl3)
4.2.23. Compound (2S,3R)-4l. Colorless oil. [
a]
39.6 (c 0.45 in
D
d
ꢀ135.33 (d, J¼28.7 Hz,1F); 13C NMR (75 MHz, CDCl3)
d
202.2,159.2
CHCl3); 1H NMR (300 MHz, CDCl3)
d
4.31 (q, J¼7.4 Hz, 2H), 3.50e3.34
(d, J¼27.5 Hz), 135.8 (d, J¼1.2 Hz), 134.1, 129.6, 129.2 (d, J¼2.1 Hz),
128.5, 127.2 (d, J¼2.0 Hz), 114.8 (d, J¼255.1 Hz), 63.9, 43.6 (d,
(m, 1H), 2.82e2.46 (m, 2H), 2.19 (s, 3H), 1.49e1.14 (m, 9H), 0.87 (t,
J¼7.4 Hz, 3H); 19F NMR (282MHz, CDCl3)
ꢀ133.06 (d, J¼29.7 Hz,1F);
d
J¼17.9 Hz), 42.2 (d, J¼2.8 Hz), 29.8, 13.1; IR (film)
n
2985, 1767, 1723,
13C NMR (75 MHz, CDCl3)
d
204.5, 161.0 (d, J¼28.0 Hz), 116.3 (d,
1576, 1478 cmꢀ1; EIMS (m/z): 43 (100), 239 (24), 285 (13), 242 (12),
133 (9), 241 (8), 197 (7), 149 (7); HRMS (EI): m/z: calcd for
C14H15ClFNO5: 331.0623; found: 331.0627 [M]þ. HPLC separation
conditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/
min; tR¼12.0 min (minor enantiomer),14.0 min (major enantiomer).
J¼252.0 Hz), 64.2, 42.5 (d, J¼1.9 Hz), 37.4 (d, J¼19.8 Hz), 29.9, 28.7,
28.5 (d, J¼12.5 Hz), 22.4, 13.7, 13.6; IR (film)
n 2962, 1766, 1722, 1579,
1358 cmꢀ1; ESI-MS (m/z): 300.2 [MþNa]þ; HRMS (ESI): m/z: calcd for
C12H20NFO5Na: 300.1218; found: 300.1212 [M]þ. HPLC separation
conditions: Chiralcel OD, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/
min; tR¼6.9 min (major enantiomer), 8.0 min (minor enantiomer).
26
4.2.19. Compound (2S,3R)-4j. Colorless oil. [
a]
59.8 (c 1.00 in
D
26
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.83e7.76 (m, 4H), 7.50e7.39 (m,
4.2.24. Compound (2R,3R)-4l. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a]
3.0 (c 1.10 in
D
3H), 4.88e4.74 (m, 1H), 4.38 (q, J¼8.7 Hz, 2H), 3.25e3.08 (m, 2H),
d
4.36 (q, J¼6.7 Hz, 2H), 3.52e3.35
2.07 (s, 3H), 1.36 (t, J¼8.7 Hz, 3H); 19F NMR (282 MHz, CDCl3)
(m, 1H), 2.74e2.46 (m, 2H), 2.17 (s, 3H), 1.60e1.18 (m, 9H), 0.87 (t,
d
ꢀ134.61 (d, J¼28.2 Hz, 1F); 13C NMR (75 MHz, CDCl3)
d
203.2, 160.8
J¼6.7 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ132.41 (d, J¼22.2 Hz,
(d, J¼28.0 Hz), 133.1, 133.0(7), 131.4, 128.9, 128.6, 128.1, 127.6, 126.4,
126.3 (d, J¼1.9 Hz), 115.5 (d, J¼254.8 Hz), 64.7, 44.3 (d, J¼18.1 Hz),
1F); 13C NMR (75 MHz, CDCl3)
d
203.7, 160.4 (d, J¼27.7 Hz), 116.1 (d,
J¼252.4 Hz), 63.8, 41.8 (d, J¼2.8 Hz), 36.9 (d, J¼19.4 Hz), 29.5, 28.7 (d,
44.0 (d, J¼1.8 Hz), 30.2, 13.7; IR (film)
n
3020, 1764, 1722, 1581, 1357,
J¼1.7 Hz), 28.3, 22.1, 13.3, 13.2(7); IR (film)
n
2960, 1765, 1721,
1216 cmꢀ1; EIMS (m/z): 347 (Mþ,19), 43 (100),165 (41), 258 (31), 213
(26), 183 (21), 152 (13), 259 (13); HRMS (EI): m/z: calcd for
C18H18NFO5: 347.1169; found: 347.1176 [M]þ. HPLC separation con-
ditions: Chiralcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/
min; tR¼18.1 min (minor enantiomer), 23.1 min (major enantiomer).
1578 cmꢀ1; EIMS (m/z): 43 (100), 173 (15), 147 (15), 95 (13), 55 (11),
58 (11), 41 (10), 129 (9); HRMS (EI): m/z: calcd for C12H20NFO5:
277.1326; found: 277.1322 [M]þ. HPLC separation conditions: Chir-
alcel ODH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.7 mL/min;
tR¼7.9 min (major enantiomer), 8.9 min (minor enantiomer).
27
4.2.20. Compound (2R,3R)-4j. Whitesolid.Mp:77e78ꢁC;[
a]
26 9.2 (c
4.2.25. Compound (2S,3R)-4m. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a]
50.7 (c 0.64 in
D
D
1.40 in CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.84e7.78 (m, 4H),
d
4.39 (q, J¼7.0 Hz, 2H),
7.52e7.44 (m, 3H), 4.95e4.81 (m, 1H), 4.05 (q, J¼7.2 Hz, 2H),
3.28e3.19 (m, 1H), 2.87e2.81 (m, 1H), 2.05 (s, 3H), 1.01 (t, J¼7.2 Hz,
3.24e3.06 (m, 1H), 2.54e2.02 (m, 6H), 1.81e1.60 (m, 2H), 1.36 (t,
J¼7.0 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ138.62 (d, J¼21.0 Hz,

H.-F. Cui et al. / Tetrahedron 67 (2011) 312e317
317
1F); 13C NMR (75 MHz, CDCl3)
J¼254.9 Hz), 64.1, 41.3 (d, J¼21.2 Hz), 40.1, 39.0 (d, J¼2.3 Hz), 24.1 (d,
2961, 1765, 1720, 1579, 1255 cmꢀ1
d
206.2, 159.7 (d, J¼27.5 Hz), 114.7 (d,
References and notes
1. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320; (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (c) Mikami, K.;
Itoh, Y.; Yamamaka, Y. M. Chem. Rev. 2004, 104, 1; (d) Smart, B. E. J. Fluorine
Chem. 2001, 109, 3.
2. For recent reviews, see: (a) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int. Ed.
2008, 47, 1179; (b) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc.
Rev. 2008, 37, 1727; (c) Prakash, G. K. S.; Beier, P. Angew. Chem., Int. Ed. 2006, 45,
2172; (d) Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544; (e) Oestreich, M.
Angew. Chem., Int. Ed. 2005, 44, 2324; (f) Ibrahim, H.; Togni, A. Chem. Commun.
2004, 1147; (g) Ma, J. A.; Cahard, D. Chem. Rev. 2004, 104, 6119.
3. Selected examples for the transition metal-based fluorination methods: (a)
Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew.
Chem., Int. Ed. 2008, 47, 164; (b) Nakamura, M.; Hajra, A.; Endo, K.; Naka-
mura, E. Angew. Chem., Int. Ed. 2005, 44, 7248; (c) Shibata, N.; Kohno, J.;
Takai, K.; Ishimaru, T.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew.
Chem., Int. Ed. 2005, 44, 4204; (d) Hamashima, Y.; Suzuki, T.; Takano, H.;
Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164; (e) Ha-
mashima, Y.; Yagi, K.; Takano, H.; Tamas, L.; Sodeoka, M. J. Am. Chem.
Soc. 2002, 124, 14530; (f) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed.
2000, 39, 4359 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;
(h) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jøgensen, K. A. Chem.
dEur. J. 2006,12, 6039; (i) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545; (j)Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jøgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703;
(k) Steiner, D. D.; Mase, N.; Babars, C. F., III. Angew. Chem., Int. Ed. 2005, 44, 3706; (l)
Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826; (m) Jiang, H.;
J¼2.3 Hz), 23.3, 13.7; IR (film)
n
;
EIMS (m/z): 247 (Mþ, 5), 55 (100), 79 (66), 41 (58), 81 (51), 42 (44),
97 (43), 68 (41), 155 (38); HRMS (EI): m/z: calcd for C10H14NFO5:
247.0856; found: 247.0860 [M]þ. HPLC separation conditions:
Chiralcel ADH, 20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.6 mL/min;
tR¼22.9 min (major enantiomer), 31.6 min (minor enantiomer).
27
4.2.26. Compound (2R,3R)-4m. Colorless oil. [
CHCl3); 1H NMR (300 MHz, CDCl3)
a
]
D
ꢀ6.7 (c 0.96 in
d
4.37 (q, J¼7.4 Hz, 2H), 3.27e3.09
(m,1H), 2.59e2.09 (m, 5H),1.80e1.65 (m, 3H),1.35 (t, J¼6.8 Hz, 3H);
19F NMR (282 MHz, CDCl3)
(75 MHz, CDCl3)
d
ꢀ139.00 (d, J¼24.6 Hz, 1F); 13C NMR
d
206.3, 159.4 (d, J¼27.7 Hz), 114.4 (d, J¼254.3 Hz),
64.1, 41.3 (d, J¼20.2 Hz), 40.0 (d, J¼1.9 Hz), 39.9, 23.0 (d, J¼2.5 Hz),
22.9, 13.2; IR (film) n
2958, 1767, 1720, 1579, 1260 cmꢀ1; EIMS (m/z):
247 (Mþ, 3), 55 (100), 79 (76), 81 (59), 41 (55), 127 (52), 97 (50), 155
(48), 200 (48); HRMS (EI): m/z: calcd for C10H14NFO5: 247.0856;
found: 247.0850 [M]þ. HPLC separation conditions: Chiralcel ADH,
20 ꢁC, 254 nm, 9:1 hexane/i-PrOH, 0.6 mL/min; tR¼19.0 min (minor
enantiomer), 22.4 min (major enantiomer).
4.3. General procedure for the synthesis of compound 7
~
Falcicchio, A.; Jensen, K. L.; Paixao, M. W.; Bertelsen, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2009, 131, 7153.
4.3.1. Compound (2R, 3R)-4d. Compound (2R, 3R)-4d (90 mg,
0.24 mmol) and 6 (93 mg, 0.50 mmol) were dissolved in dry tet-
rahydrofuran (5 mL). The mixture was stirred at room temperature
and monitored by TLC. After completion (53 h), the mixture was
concentrated by rotary evaporation and the residue was purified by
flash chromatography (ethyl acetate/pet. ether: 1/3) to provide
pure product 7 130 mg in quantitative yield as white solid.
4. Selected examples for organocatalytic methods using fluorine-containing
building blocks: (a) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K. W.; Lu, Y. X.
Angew. Chem., Int. Ed. 2009, 48, 7604; (b) 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; (c) Li, H.; Zhang, S. L.; Yu, C. G.; Song, X. X.; Wang, W. Chem.
Commun. 2009, 2136; (d) Han, X.; Luo, J.; Liu, C.; Lu, Y. X. Chem. Commun. 2009,
2044; (e) Ding, C. H.; Maruoka, K. Synlett 2009, 664; (f) Prakash, G. K. S.; Wang,
F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4090;
(g) Prakash, G. K. S.; Zhao, X. M.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A.
Beilstein J. Org. Chem. 2008, 4, 17; (h) Zhong, G. F.; Fan, J. H.; Barbas, C. F., III.
Tetrahedron Lett. 2004, 45, 5681.
5. Selected examples: (a) Haufe, G. J. Fluorine Chem. 2004, 125, 875; (b) Burch-
ardt, A.; Takahashi, T.; Takeuchi, Y.; Haufe, G. J. Org. Chem. 2001, 66, 2078; (c)
Abouabdellah, A.; Boros, L.; Gyenes, F.; Welch, J. T. J. Fluorine Chem. 1995, 72,
255; (d) Ihara, M.; Satoh, K.; Ishida, Y.; Taniguchi, N.; Tokunaga, Y.; Takemura,
M.; Fukumote, K. Heterocycles 1999, 18, 537; (e) Okutani, T.; Ukawa, K.; Ya-
mamoto, H.; Amano, T.; Nombra, H.; Ootsu, K.; Kozai, Y. Chem. Pharm. Bull.
1986, 34, 713.
Mp: 55e56 ꢁC; [
CDCl3)
a
]
26 ꢀ31.5 (c 1.35 in CHCl3); 1H NMR (300 MHz,
D
d
7.96e7.84 (m, 1H), 7.68 (AB, J¼8.3 Hz, 2H), 7.31 (AB,
J¼7.7 Hz, 2H), 7.24 (AB, J¼8.3 Hz, 1H), 7.02 (AB, J¼7.7 Hz, 2H),
4.55e4.42 (m, 1H), 4.09 (q, J¼7.3 Hz, 2H), 2.78e2.69 (m, 1H),
2.57e2.41 (m, 4H), 1.63 (s, 3H), 1.09 (t, J¼7.3 Hz, 3H); 19F NMR
(282 MHz, CDCl3)
CDCl3)
d
ꢀ137.06 (d, J¼29.4 Hz, 1F); 13C NMR (100 MHz,
d
159.8 (d, J¼27.8 Hz), 151.8 (d, J¼5.2 Hz), 144.2, 135.4, 132.6,
6. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, NY, 2001.
7. (a) Metcalf, R. L. Organic Insecticides: Their Chemistry and Mode of Action; In-
terscience: New York, NY, 1955; 134; (b) Ivanov, Y. Y.; Brell, B. K.; Postnova, L. B.;
Martinov, B. Khim. Pharm. J. 1986, 968; (c) Cartwright, D. In Recent Developments
in Fluorine-Containing Agrochemicals, In Organofluorine Chemistry: Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum:
New York, NY, 1996; p 237.
131.7, 131.3 (d, J¼1.4 Hz), 129.7, 127.8, 122.6, 115.5 (d, J¼256.9 Hz),
64.3, 45.5 (d, J¼18.2 Hz), 37.7 (d, J¼4.5 Hz), 21.7, 16.3 (d, J¼2.1 Hz),
13.5; IR (film) n
2926, 1768, 1579, 1490, 1338, 1255, 1167 cmꢀ1; ESI-
MS (m/z): 544.1 (Mþ1)þ.
Acknowledgements
8. Ramírez, J.; Huber, D. P.; Togni, A. Synlett 2007, 1143.
9. Liu, C.; Lu, Y. X. Org. Lett. 2010, 12, 2278.
The generous financial support from the National Natural Sci-
ence Foundation of China (No. 21032006), Excellent Young Scholars
Foundation of National Natural Science Foundation of China
(20525208) is gratefully acknowledged.
10. For recent reviews on primary amines in organocatalysis, see: (a) Xu, L. W.; Luo,
J.; Lu, Y. X. Chem. Commun. 2009, 1807; (b) Xu, L. W.; Lu, Y. X. Org. Biomol. Chem.
2008, 6, 2047; (c) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1; (d) Chen,
Y. C. Synlett 2008, 1919.
11. (a) Cui, H. F.; Yang, Y. Q.; Chai, Z.; Li, P.; Zheng, C. W.; Zhu, S. Z.; Zhao, G. J. Org.
Chem. 2010, 75, 117; (b) Yang, Y. Q.; Chai, Z.; Wang, H. F.; Chen, X. K.; Cui, H. F.;
Zheng, C. W.; Xiao, H.; Li, P.; Zhao, G. Chem.dEur. J. 2009, 15, 13295; (c) Yang, Y.
Q.; Zhao, G. Chem.dEur. J. 2008, 14, 10888; (d) Yang, Y. Q.; Chen, X. K.; Xiao, H.;
Liu, W.; Zhao, G. Chem. Commun. 2010, 4130.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.041.
12. See Supplementary data for details.
13. Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54, 5453.