Organocatalytic kinetic resolution of racemic secondary nitroallylic alcohols combined with simultaneous desymmetrization of prochiral cyclic anhydrides

Article abstract of DOI:10.1021/jo501882q

This study describes an organocatalytic kinetic resolution of racemic secondary nitroallylic alcohols (2) combined with simultaneous desymmetrization of prochiral cyclic anhydrides (1). The experimental results revealed that enantioselective alcoholysis of 3-substituted glutaric anhydrides afforded hemiesters (3) with high levels of enantioselectivities (up to 99% ee) in the presence of cinchonidine-derived thiourea catalyst (IV). The highly optical enrichment (up to 95% ee) of (S)-nitroallylic alcohols (2) was recovered.

Full text of DOI:10.1021/jo501882q

Brief Communication
pubs.acs.org/joc
Organocatalytic Kinetic Resolution of Racemic Secondary Nitroallylic
Alcohols Combined with Simultaneous Desymmetrization of
Prochiral Cyclic Anhydrides
†
†
†
,†
Suparna Roy, Kan-Fu Chen, Ramani Gurubrahamam, and Kwunmin Chen*
†Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
*
S Supporting Information
ABSTRACT: This study describes an organocatalytic kinetic resolution of racemic secondary nitroallylic alcohols (2) combined
with simultaneous desymmetrization of prochiral cyclic anhydrides (1). The experimental results revealed that enantioselective
alcoholysis of 3-substituted glutaric anhydrides afforded hemiesters (3) with high levels of enantioselectivities (up to 99% ee) in
the presence of cinchonidine-derived thiourea catalyst (IV). The highly optical enrichment (up to 95% ee) of (S)-nitroallylic
alcohols (2) was recovered.
reparing chiral nonracemic molecules with multiple stereo-
desymmetrization of prochiral cyclic anhydrides by the use of
racemic secondary nitroallylic alcohols.
P
genic centers has long been a synthetic challenge in organic
1
synthesis. Many efficient synthetic protocols have been
Initially, we attempted to desymmetrize 3-phenylglutaric
anhydride (1a) with racemic 1-phenylethanol in the presence
of various cinchona alkaloid derived organocatalysts. However,
many attempts failed to obtain promising results. We then turned
to the use of (±)-ethyl 2-hydroxy-3-nitro-4-phenylbut-3(E)-
2
developed through either metal-mediated or metal-free
3
processes. The conventional kinetic resolution (KR) that
incorporates a chiral catalyst to promote enantioselective
transformations remains a highly useful method for preparing
4
13
optically enriched materials from their racemates. The kinetic
enoate (2a). Cinchona alkaloid-based catalysts were used in the
resolution of racemic secondary alcohols has received consid-
erable attention because of functional group demonstrates
considerable synthetic value. Enantioselective acylation has
been extensively adopted in the kinetic resolution of racemic
catalysis protocol, which involved a “general base catalysis
7a,14
mechanism”.
Our initial attempt to use cinchonidine (I) as
the catalyst was not successful regarding the ee of both the
product and recovered starting substrate (Table 1, entry 1).
Thus, primary amine derivatives of cinchona alkaloids (II and
III) were used. However, these catalysts were not effective
because both the product and starting material were obtained
with inferior results (Table 1, entries 2 and 3). In contrast,
cinchonidine-derived thiourea catalysts (IV and V) were found
to be promising and equally efficient. We thus used catalyst IV in
subsequent experiments. The reaction between 3-phenylglutaric
anhydride (1a) and racemic nitroallyic alcohol (2a) in
dichloromethane (DCM) at ambient temperature afforded the
corresponding desired hemiester 3a with a chemical yield of 44%,
ee of 88%, and a diastereomeric ratio of 14:1 at a conversion rate
of approximately 50% (Table 1, entry 4). The less reactive
nitroallylic alcohol (S)-2a was recovered with a high enantio-
5
secondary alcohols. The use of a small organic catalyst in kinetic
6
resolution has been developed recently. On the other hand,
asymmetric desymmetrization is a valuable protocol in which a
simple symmetry-breaking operation is performed for accessing
7
chiral nonracemic molecules. This operation enables establish-
ing multiple stereogenic centers in the final products when meso
8
compounds were used. Desymmetrizing cyclic anhydrides
generates dense functionalized and synthetically useful hemi-
esters with multiple chiral centers. Kinetic resolution processes
are effective for the enantioselective ring opening of prochiral
7
a,9
cyclic anhydrides.
Enantioselective syntheses have been recognized as a powerful
10
strategy for asymmetric synthesis. An interesting concept that
combines kinetic resolution with asymmetric desymmetrization
to prepare optically enriched substances has been demonstra-
15
meric purity (93% ee).
Various solvents were screened for the kinetic resolution/
desymmetrization reaction (Table 1, entries 6−12). Comparable
1
1
ted. To our knowledge, functionalized racemic secondary
alcohols have not been used for enantioselective alcoholysis of
prochiral cyclic anhydrides. To extend our previous investigation
Received: August 14, 2014
Published: September 11, 2014
12
on organocatalytic kinetic resolution, we describe herein the
©
2014 American Chemical Society
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The Journal of Organic Chemistry
Brief Communication
a
Table 1. Optimization of the Organocatalytic Kinetic Resolution/Desymmetrization Process
recovered2a
product 3a
b
c
d
b
entry
cat.
solvent
CH Cl
time (h)
ee (%)
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
I
20
48
48
4
−9
20
24
93
92
45
15
14
44
42
nd
41
37
35
40
28
nd
32
42
3:1
15:1
13:1
14:1
10:1
−9
32
28
88
90
2
2
II
CH Cl
2
2
2
2
2
III
IV
V
CH Cl
2
CH Cl
2
CH Cl
4
2
IV
IV
IV
IV
IV
IV
IV
IV
IV
hexanes
toluene
CHCl3
EtOAc
THF
48
4
96
96
94
94
92
16:1
>20:1
12:1
14:1
7:1
90
90
92
90
88
4
5
10
11
12
13
14
5
MeCN
DMF
5
48
4
e
f
CHCl3
CHCl3
90
74
>20:1
>20:1
90
88
5
a
The reaction was performed using 1a (0.1 mmol, 19 mg) and 2a (0.1 mmol, 25 mg) in the presence of cat. I−V (10 mol %) in the solvent indicated
1
(
0.2 mL) at ambient temperature (25 °C). The reaction was stopped at ∼50% conversion based on the H NMR spectra of the crude reaction
b c d
1
mixtures using CH Br as an internal standard. Determined by HPLC analysis. Isolated yield of the product 3a. Determined from H NMR
2
2
e
spectra of the crude reaction mixtures. The reaction was performed with 0.8 equiv of 1a (0.08 mmol, 15.2 mg) under the same reaction conditions.
f
The reaction was carried out with 5 mol % catalyst.
results were observed regarding the enantioselectivities of the
product and recovered substrates when using various solvents
bromophenyl-derived nitroallylic alcohol was used, the product
was obtained with a high enantioselectivity (90%), but the
recovered alcohol was obtained with a moderate ee (Table 2,
entry 5). Using a 3-bromophenyl-substituted nitroallylic alcohol
yielded the recovered alcohol with promising results (95% ee) at
ambient temperature (Table 2, entry 6). The heteroaryl
substituent in 2g also worked efficiently for the enantioselective
alcoholysis (hemiester with 92% ee and recovered alcohol with
(
CH Cl , CHCl , EtOAc, THF, and MeCN). However, both
2 2 3
DMF (polar) and hexanes (nonpolar) were found to be
infeasible for the reaction, probably because of the low solubility
of the substrates in hexanes and the interruption of H-bond
formation in DMF. The most appropriate solvent was CHCl3
because the product was obtained with a high enantioselectivity
(90%) and diastereoselectivity (>20:1), exhibiting an excellent
7
4% ee) (Table 2, entry 7). Furthermore, various prochiral cyclic
enantioselectivity of the recovered alcohol (96% ee, Table 1,
entry 8). Furthermore, our results demonstrated that a low
catalyst loading (5 mol %) decreased the enantioselectivity of the
recovered alcohol to 74% ee (Table 1, entry 14).
Thus, we generalized the kinetic resolution/desymmetrization
reaction. Various racemic nitroallylic alcohols (2a−g) were used
for the enantioselective desymmetrization of 3-substituted cyclic
anhydrides. Although the optimal ambient temperature was
applied, the enantioselective alcoholysis of 3-phenylglutaric
anhydride (1a) using a 4-methylphenyl-substituted nitroallylic
alcohol (2b) yielded the hemiester (3b) only with a moderately
high enantioselectivity (83%) at approximately 50% conversion
anhydrides 1b−e were subject to the desymmetrization process.
Several 4-aryl-substituted cyclic anhydrides (1b−d) were
desymmetrized with various racemic nitroallylic alcohols
producing the desired hemiesters with high to excellent
stereoselectivites (Table 2, entries 8−13).
The less reactive (S)-substrates were consistently obtained
with acceptable to high ee. When a 4-methoxyphenyl-derived
anhydride (1b) was coupled with a 3-bromophenyl-derived
nitroallylic alcohol (2f), both the hemiester and recovered
alcohol were obtained with 92% ee (Table 2, entry 9). In
addition, the reaction between a 4-bromophenyl-derived
anhydride (1c) and a secondary alcohol (2d) yielded the
product, and the less reactive substrate of the secondary alcohols
were recovered with 92% and 94% ee, respectively (Table 2,
entry 12). The current protocol proceeded smoothly when a 3-
methylglutaric anhydride was used (Table 2, entries 14−16).
The reaction was intermittently performed at ambient temper-
ature to optimize the organocatalytic kinetic resolution/
desymmetrization process (Table 2, entries 6−7 and 14). All
of the products were obtained with high levels of diastereose-
lectivity (7:1 to >20:1).
(
Table 2, entry 1). The stereoselectivity was substantially
increased to 99% when the reaction temperature was lowered
to −20 °C under a prolonged reaction time (Table 2, entry 2).
Moreover, 0.6 equiv of cyclic anhydride was determined to be
sufficient for the reaction to proceed. The desymmetrization of
1a was performed using 4-halophenyl-substituted nitroallylic
alcohols (2c and 2d), and the hemiesters 3c and 3d were
obtained with high enantiomeric purities (>99% and 96% ee,
respectively), along with a considerably high ee of the unreacted
alcohols at −20 °C (Table 2, entries 3 and 4). When a 2-
8
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The Journal of Organic Chemistry
Brief Communication
a
Table 2. Substrate Scope of Desymmetrization/Kinetic Resolution Process
recov sub (S)-2a−g
products 3b−p
b
c
b
d
c
entry
R (1a−e)
Ph (1a)
Ar (2a−g)
time (days)
yield (%)
ee (%)
yield (%)
dr
ee (%)
e
1
4-MeC H (2b)
4 h
5
44
47
49
42
52
53
37
49
45
49
40
36
41
49
45
55
86
86
82
79
61
95
74
79
92
82
87
94
84
94
88
83
3b
3b
3c
3d
3e
3f
37
42
43
51
34
43
39
39
42
40
53
54
50
39
47
36
>20:1
>20:1
13:1
8:1
83
99
>99
96
90
84
92
94
92
96
93
92
95
92
83
82
6
4
2
3
4
5
Ph (1a)
4-MeC H (2b)
6 4
Ph (1a)
4-ClC H (2c)
6
6
4
Ph (1a)
4-BrC H (2d)
5
6
4
Ph (1a)
2-BrC H (2e)
5
7:1
6
4
e
6
e
Ph (1a)
3-BrC H (2f)
4 h
4 h
3
11:1
10:1
20:1
10:1
>20:1
15:1
9:1
6
4
7
Ph (1a)
2-thienyl (2g)
Ph (2a)
3g
3h
3i
8
9
4-OMeC H (1b)
6
4
4-OMeC H (1b)
3-BrC H (2f)
5
6
4
6
4
10
11
12
13
14
15
16
4-OMeC H (1b)
4-MeC H (2b)
5
3j
6
4
6
4
4-BrC H (1c)
Ph (2a)
4
3k
3l
6
4
4-BrC H (1c)
4-BrC H (2d)
5
6
4
6
4
4-MeC H (1d)
4-Br C H (2d)
5
3m
3n
3o
3p
10:1
9:1
6
4
6
4
e
Me (1e)
Ph (2a)
6 h
4
Me (1e)
Me (1e)
4-MeC H (2b)
11:1
>20:1
6
4
2-thienyl (2g)
3
a
The reaction was performed using 1a−e (0.12 mmol) and 2a−g (0.2 mmol) in the presence of cat. IV (20 mol %, 17.1 mg) in CHCl (0.4 mL) at
3
1
−
20 °C. The reaction was stopped at ∼50% conversion from H NMR of the crude reaction mixture using CH Br as an internal standard. For
2
2
b c
absolute stereochemistry determination of the products, see the Supporting Information. Isolated yield. Determined by HPLC analysis.
d
1
e
Determined from H NMR spectra of the crude reaction mixtures. Reaction performed at ambient temperature (25 °C) with 10 mol % of
organocatalyst IV.
It is widely assumed that the reaction proceeds through an
acid/base catalysis mechanism and that the bifunctional
organocatalyst IV simultaneously activates the nucleophile and
mixture using CH Br as an internal standard. Then, the reaction
2 2
mixture was subjected directly to flash column chromatography (silica
gel with ethyl acetate/hexanes = 1:3) to afford the unreacted substrates
2a−g first and then the hemiesters of 3a−p. Racemic products of 3a−p
were prepared following the general procedure using DABCO (30 mol
1
6,17
electrophile.
The tertiary amine moiety of the organocatalyst
IV deprotonates alcohol, whereas the appropriately seated
thiourea moiety activates the cyclic anhydride through H-bond
formation. Thus, the kinetic resolution of the nucleophile and
desymmetrization of the electrophilic component occurs
concomitantly in a stereocontrolled manner.
%
) as a catalyst.
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-phenylbut-3-en-2-yl)oxy)-5-oxo-
-phenylpentanoic Acid (3a). Reaction time: 4 h. Yield: 37% (33 mg).
5
3
1
Viscous liquid. H NMR (400 MHz, CDCl ): δ 8.34 (s, 1H), 7.49−7.40
3
(m, 3H), 7.29−7.23 (m, 4H), 7.21−7.15 (m, 3H), 6.46 (s, 1H), 4.15 (q,
J = 7.2 Hz, 2H), 3.70−3.62 (m, 1H), 2.97−2.66 (m, 4H), 1.16 (t, J = 7.2
In conclusion, we demonstrated an example that combine the
kinetic resolution of functionalized nitroallylic secondary
alcohols with desymmetrization of cyclic anhydrides. The
synthesis is interesting that no reactive chemistry is involved at
either of the resulting stereogenic centers in the product. The
hemiesters were obtained with high diastereoselectivities and
enantioselectivities (up to >20:1 dr and 99% ee). The less
reactive nucleophilic (S)-nitroallylic alcohols were resolved with
high levels of enantioselectivity (up to 95% ee). The protocol
tolerates various starting substrates including cyclic anhydrides
and nitroallylic alcohols. The bifunctional behavior of the
cinchonidine-derived thiourea catalyst has proven to be useful in
organocatalysis and further studies are ongoing in our laboratory.
Hz, 3H). 13C NMR (100 MHz, CDCl
): δ 176.7, 169.6, 165.7, 144.6,
3
1
4
1
41.7, 140.6, 131.3, 130.2, 129.6, 129.2, 128.7, 127.2, 127.1, 65.5, 62.6,
−1
0.1, 39.8, 37.6, 13.8 ppm. IR (ν/cm ): 2977, 2924, 1745, 1730, 1649,
531, 1295. HRMS (ESI-TOF): m/z calcd for C H NO Na [M +
23
23
8
+
Na] 464.1321, found 464.1317; ee 90%. HPLC [Chiralcel AD-H, 2-
propanol/hexanes = 20/80, 0.2 mL/min, λ = 254 nm, retention time
6
6.2 min (major), 86.0 min (minor)].
5
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(p-tolyl)but-3-en-2-yl)oxy)-5-
oxo-3-phenylpentanoic Acid (3b). Reaction time: 5 d. Yield: 42% (38
1
mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ 8.32 (s, 1H), 7.27−
3
7.25 (m, 2H), 7.23−7.20 (m, 5H), 7.19−7.17 (m, 2H), 6.50 (s, 1H),
4.18−4.12 (m, 2H), 3.70−3.62 (m, 1H), 2.96−2.66 (m, 4H), 2.39 (s,
3H), 1.16 (t, J = 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl
): δ 176.0,
3
1
69.7, 165.8, 143.9, 142.3, 141.8, 140.8, 130.1, 129.9, 128.7, 127.4, 127.2
−1
(
×2), 65.7, 62.6, 40.0, 39.9, 37.7, 21.6, 13.9 ppm. IR (ν/cm ): 2924,
EXPERIMENTAL SECTION
■
1764, 1741, 1710, 1527, 1367, 1333, 1295. HRMS: (ESI-TOF) m/z
+
General Procedure. To a solution of cyclic anhydrides (1a−e, 0.12
calcd for C H NO Na [M + Na] 478.1478, found 478.1476; ee 99%.
24
25
8
mmol) in CHCl was added sequentially racemic nitroallylic alcohols
HPLC [Chiralcel AD-H, 2-propanol/hexanes = 22/78, 0.2 mL/min, λ =
254 nm, retention time 47.1 min (major), 50.9 min (minor)].
5-(((E)-4-(4-Chlorophenyl)-1-ethoxy-3-nitro-1-oxobut-3-en-2-yl)-
3
(
2a−g, 0.2 mmol) and organocatalyst (IV, 20 mol %, 17.1 mg) at −20
°
C. The reaction mixture was stirred at the same temperature for the
reaction period indicated in Table 2. The reaction was monitored at
oxy)-5-oxo-3-phenylpentanoic Acid (3c). Reaction time: 6 d. Yield:
1
1
∼
50% conversion by using H NMR data analyses of the crude reaction
43% (41 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ 8.26 (s,
3
8
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Brief Communication
1
6
4
1
1
1
H), 7.38 (d, J = 8.4 Hz, 2H), 7.28−7.24 (m, 3H), 7.21−7.18 (m, 4H),
1736, 1710, 1524, 1249. HRMS (ESI-TOF): m/z calcd for
+
.40 (s, 1H), 4.19−4.13 (m, 2H), 3.67−3.63 (m, 1H), 2.97−2.66 (m,
C H NO Na [M + Na] 494.1427, found 494.1418; ee 94%. HPLC
24
25
9
H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 175.9,
[Chiralcel AD-H, 2-propanol/hexanes = 10/90, 1 mL/min, λ = 220 nm,
retention time 35.9 min (major), 46.0 min (minor)].
3
69.6, 165.6, 145.0, 141.7, 139.2, 137.8, 130.9, 129.6, 128.7, 128.6, 127.3,
−1
27.2, 65.3, 62.7, 40.0, 39.8, 37.7, 13.8 ppm. FTIR (ν/cm ): 2924,
5-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(3-bromophenyl-2-yl)but-3-en-
768, 1745, 1714, 1528, 1333, 1229. HRMS (ESI-TOF): m/z calcd for
2-yl)oxy)-5-oxo-3-(4-methoxyphenyl)pentanoic Acid (3i). Reaction
+
1
C H ClNO Na [M + Na] 498.0932, found 498.0936; ee >99%.
time: 5 d. Yield: 42% (46 mg). Viscous liquid. H NMR (400 MHz,
23
22
8
HPLC [Chiralcel AD-H, 2-propanol/hexanes = 25/75, 0.2 mL/min, λ =
54 nm, retention time 46.3 min (major).
-(((E)-4-(4-bromophenyl)-1-ethoxy-3-nitro-1-oxobut-3-en-2-yl)-
oxy)-5-oxo-3-phenylpentanoic acid (3d). Reaction time: 5 d; Yield:
CDCl ): δ 8.23 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.32−7.24
3
2
(m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.77 (d, J =
8.4 Hz, 2H), 6.38 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.67−
3.53 (m, 1H), 2.92 (dd, J = 16.0 and 6.8 Hz, 1H), 2.81 (dd, J = 14.4 and
8.4 Hz, 1H), 2.75 (dd, J = 14.8 and 6.8 Hz, 1H), 2.64 (dd, J = 16.0 and 8.0
5
1
5
1
7
1% (53 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ 8.23 (s,
3
13
H), 7.53 (d, J = 8.4 Hz, 2H), 7.25−7.22 (m, 2H), 7.19−7.17 (m, 3H),
Hz, 1H), 1.19 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl ): δ 176.3,
3
.12 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 4.18−4.13 (m, 2H), 3.67−3.60
169.6, 165.5, 158.6, 145.7, 138.7, 134.1, 133.7, 132.4, 132.2, 130.7, 128.2,
13
(
m, 1H), 2.96−2.64 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H). C NMR (100
127.8, 123.2, 114.1, 65.2, 62.8, 55.2, 40.3, 40.0, 36.9, 13.9 ppm. IR (ν/
−
1
MHz, CDCl ): δ 177.1, 169.6, 165.5, 144.9, 141.6, 139.2, 132.5, 130.9,
cm ): 2933, 1763, 1743, 1714, 1514, 1249. HRMS (ESI-TOF): m/z
3
+
1
29.0, 128.7, 127.1, 126.1, 65.2, 62.7, 40.2, 39.7, 37.5, 13.8 ppm; IR (ν/
calcd for C H NO BrNa [M + Na] 572.0532, found 572.0532; ee
24
24
9
−1
cm ): 2977, 1730, 1710, 1535, 1371, 1280, 1215. HRMS (ESI-TOF):
m/z calcd for C H BrNO Na [M + Na] 542.0426, found 542.0425;
ee 96%. HPLC [Chiralcel AD-H, 2-propanol/hexanes = 10/90, 0.5 mL/
min, λ = 254 nm, retention time: 62.8 min (major), 68.8 min (minor)].
92%. HPLC [Chiralcel AD-H, 2-propanol/hexanes = 10/90, 1 mL/min,
λ = 220 nm, retention time 48.4 min (major), 74.5 min (minor)].
5-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(4-methylphenyl-2-yl)but-3-en-
2-yl)oxy)-5-oxo-3-(4-methoxyphenyl)pentanoic Acid (3j). Reaction
+
23
22
8
1
5
-(((E)-4-(2-Bromophenyl)-1-ethoxy-3-nitro-1-oxobut-3-en-2-yl)-
time: 5 d. Yield: 40% (39 mg). Viscous liquid. H NMR (400 MHz,
oxy)-5-oxo-3-phenylpentanoic Acid (3e). Reaction time: 5 d. Yield:
CDCl ): δ 8.32 (s, 1H), 7.23−7.15 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H),
3
1
3
1
7
1
4% (35 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ 8.36 (s,
6.76 (d, J = 8.4 Hz, 2H), 6.48 (s, 1H), 4.21−4.10 (m, 2H), 3.70 (s, 3H),
3.66−3.55 (m, 1H), 2.91 (dd, J = 15.6 and 7.2 Hz, 1H), 2.86−2.73 (m,
3
H), 7.66−7.64 (m, 1H), 7.31−7.25 (m, 5H), 7.23−7.18 (m, 3H),
.06−7.03 (m, 1H), 6.26 (s, 1H), 4.17−4.10 (m, 2H), 3.67−3.60 (m,
2H), 2.64 (dd, J = 10.0 and 8.4 Hz, 1H), 2.38 (s, 3H), 1.16 (t, J = 7.2 Hz,
13
13
H), 2.94−2.63 (m, 4H), 1,18 (t, J = 7.1 Hz, 3H). C NMR (100 MHz,
3H). C NMR (100 MHz, CDCl ): δ 176.3, 169.8, 165.8, 158.5, 143.8,
3
CDCl ): δ 176.6, 169.4, 165.5, 145.8, 141.7, 139.7, 133.2, 132.2, 131.3,
142.3, 140.8, 133.7, 130.0, 129.9, 128.2, 127.3, 114.1, 65.6, 62.6, 55.1,
3
−1
130.1, 128.7, 127.9, 127.2 (×2), 124.3, 65.3, 62.7, 40.1, 39.8, 37.6, 13.8
40.3, 40.1, 37.0, 21.5, 13.8 ppm. IR (ν/cm ): 2931, 1763, 1742, 1710,
1514, 1249. HRMS (ESI-TOF): m/z calcd for C H NO Na [M +
−1
ppm; IR (ν/cm ): 2916, 1744, 1729, 1710, 1535, 1340, 1280, 1223.
HRMS (EI-ion trap): m/z calcd for C H BrNO [M + H] 520.0607,
2
5
27
9
+
+
Na] 508.1584, found 508.1577; ee 96%. HPLC [Chiralcel AD-H, 2-
propanol/hexanes = 10/90, 1 mL/min, λ = 220 nm, retention time 33.7
min (major), 40.8 min (minor)].
23
23
8
found 520.0602; ee 90%. HPLC [Chiralcel AD-H, 2-propanol/hexanes
25/75, 0.2 mL/min, λ = 254 nm, retention time 38.1 min (major), 52.4
min (minor)].
=
5-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(phenyl-2-yl)but-3-en-2-yl)oxy)-
5
-(((E)-4-(3-Bromophenyl)-1-ethoxy-3-nitro-1-oxobut-3-en-2-yl)-
5-oxo-3-(4-bromophenyl)pentanoic Acid (3k). Reaction time: 4 d.
1
oxy)-5-oxo-3-phenylpentanoic Acid (3f). Reaction time: 4 h. Yield:
Yield: 53% (55 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ
3
1
4
1
7
3
3% (44 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ 8.22 (s,
8.34 (s, 1H), 7.55−7.35 (m, 5H), 7.30 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 8.4
3
H), 7.59 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.29−7.28 (m, 2H), 7.25−
Hz, 2H), 6.47 (s, 1H), 4.22−4.10 (m, 2H), 3.70−3.52 (m, 1H), 2.99−
.23 (m, 2H), 7.21−7.17 (m, 3H), 6.38 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H),
2.53 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ
3
13
.68−3.61 (m, 1H), 2.98−2.64 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H).
C
176.1, 169.4, 165.7, 144.6, 140.7, 140.6, 131.8, 131.4, 130.2, 129.6, 129.3,
−1
NMR (100 MHz, CDCl ): δ 175.7, 169.5, 165.5, 145.7, 141.7, 138.6,
129.1, 121.1, 65.6, 62.7, 39.8, 39.7, 37.2, 13.8 ppm; IR (ν/cm ): 2977,
1760, 1743, 1714, 1530, 1222. HRMS (ESI-TOF) m/z calcd for
3
1
4
1
34.1, 132.3, 132.2, 130.7, 128.8, 128.6, 127.8, 127.2, 123.2, 65.2, 62.8,
0.0, 39.8, 37.7, 13.9 ppm. IR (ν/cm ): 2985, 1741, 1730, 1710, 1539,
531, 1337, 1227. HRMS (ESI-TOF): m/z calcd for C H BrNO Na
−1
+
C H NO BrNa [M + Na] 542.0426, found 542.0417; ee 93%. HPLC
23
22
8
[Chiralcel AD-H, 2-propanol/hexanes = 10/90, 1 mL/min, λ = 220 nm,
retention time: 35.3 min (major), 45.7 min (minor)].
23
22
8
+
[
M + Na] 542.0426, found 542.0428; ee 84%. HPLC [Chiralcel AD-H,
2
5
-propanol/hexanes =25/75, 0.2 mL/min, λ = 254 nm, retention time
1.7 min (major), 72.3 min (minor)].
5-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(4-bromophenyl-2-yl)but-3-en-
2-yl)oxy)-5-oxo-3-(4-bromophenyl)pentanoic Acid (3l). Reaction
time: 5 d. Yield: 54% (65 mg). Viscous liquid. H NMR (400 MHz,
1
5
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(thiophen-2-yl)but-3-en-2-yl)-
oxy)-5-oxo-3-phenylpentanoic Acid (3g). Reaction time: 4 h. Yield:
CDCl ): δ 8.24 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H),
3
1
3
1
1
9% (32 mg). Viscous liquid; H NMR (400 MHz, CDCl ): δ 8.43 (s,
7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 4.24−4.10
3
H), 7.69 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.26−7.22 (m,
(m, 2H), 3.69−3.51 (m, 1H), 3.20−2.87 (m, 1H), 2.86−2.70 (m, 2H),
13
H), 7.21−7.19 (m, 4H), 7.18−7.16 (m, 1H), 6.72 (s, 1H), 4.23−4.15
2.69−2.56 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H). C NMR (100 MHz,
(
m, 2H), 3.70−3.62 (m, 1H), 2.96−2.63 (m, 4H), 1.17 (t, J = 7.2 Hz,
CDCl ): δ 176.0, 169.3, 165.5, 144.8, 140.6, 139.3, 132.7, 131.8, 131.7,
3
3
1
3
1
H). 13C NMR (100 MHz, CDCl ): δ 176.8, 170.1, 165.4, 141.7, 140.8,
131.0, 129.0, 126.4, 121.1, 65.3, 62.8, 39.9, 39.6, 37.1, 13.8 ppm. IR (ν/
3
−
1
36.8, 134.4, 133.1, 132.5, 128.8, 128.6, 127.1, 127.0, 65.7, 62.6, 40.0,
cm ): 2931, 1767, 1743, 1714, 1535, 1224. HRMS (ESI-TOF) m/z
−1
+
9.9, 37.6, 13.8 ppm. FTIR (ν/cm ): 2977, 1764, 1737, 1710, 1634,
calcd for C H NO Br Na [M + Na] 619.9536, found 619.9532; ee
23
21
8
2
524, 1333, 1310, 1215. HRMS (ESI-TOF): m/z calcd for
92%. HPLC [Chiralcel AD-H, 2-propanol/hexanes = 10/90, 1 mL/min,
λ = 220 nm, retention time 38.8 min (major), 44.4 min (minor)].
5-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(4-bromophenyl-2-yl)but-3-en-
2-yl)oxy)-5-oxo-3-(4-methylphenyl)pentanoic Acid (3m). Reaction
+
C H NO SNa [M + Na] 470.0886, found 470.0884; ee 92%.
HPLC [Chiralcel AD-H, 2-propanol/hexanes = 22/78, 0.2 mL/min, λ =
2
21
21
8
54 nm, retention time 78.5 min (major), 88.8 min (minor)].
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(phenyl-2-yl)but-3-en-2-yl)oxy)-
-oxo-3-(4-methoxyphenyl)pentanoic Acid (3h). Reaction time: 3 d.
1
5
time: 5 d. Yield: 50% (53 mg). Viscous liquid. H NMR (400 MHz,
5
CDCl ): δ 8.25 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.14−7.01 (m, 6H),
3
1
Yield: 39% (37 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ
6.37 (s, 1H), 4.25−4.10 (m, 2H), 3.70−3.55 (m, 1H), 2.94 (dd, J = 16.0
and 6.8 Hz, 1H), 2.83 (dd, J = 15.6 and 8.8 Hz, 1H), 2.76 (dd, J = 16.0
and 6.8 Hz, 1H), 2.67 (dd, J = 16.0 and 8.0 Hz, 1H), 2.24 (s, 3H), 1.17 (t,
3
8
.34 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.44−7.37 (m, 2H), 7.27 (d, J = 8.8
Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.46 (s, 1H),
.23−4.13 (m, 2H), 3.70 (s, 3H), 3.69−3.55 (m, 1H), 2.92 (dd, J = 18.0
4
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 176.7, 169.6, 165.6,
3
and 7.2 Hz, 1H), 2.89−2.72 (m, 2H), 2.65 (dd, J = 16.0 and 8.4 Hz, 1H),
144.9, 139.2, 138.6, 136.8, 132.5, 131.0, 129.4, 129.0, 127.1, 126.1, 65.3,
.17 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 175.8, 169.6,
65.8, 158.6, 144.7, 140.6, 133.7, 131.3, 130.2, 129.7, 129.3, 128.2, 114.1,
5.5, 62.6, 55.1, 40.2, 40.1, 37.0, 13.8 ppm. IR (ν/cm ): 2931, 1760,
62.7, 40.3, 39.9, 37.3, 20.9, 13.8 ppm. IR (ν/cm ): 2925, 1763, 1741,
−1
1
1
6
3
1714, 1535, 1223. HRMS (ESI-TOF): m/z calcd for C H NO BrNa
2
4
24
8
−1
+
[M + Na] 556.0583, found 556.0592; ee 95%. HPLC [Chiralcel AS-H,
8
958
dx.doi.org/10.1021/jo501882q | J. Org. Chem. 2014, 79, 8955−8959

The Journal of Organic Chemistry
Brief Communication
2
2
-propanol/hexanes = 10/90, 1 mL/min, λ = 220 nm, retention time
3.0 min (major), 30.1 min (minor)].
(3) For recent reviews on organocatalytic processes, see: (a) Moyano,
A.; Rios, R. Chem. Rev. 2011, 111, 4703. (b) Graaff, C.; Ruijter, E.; Orru,
R. V. A. Chem. Soc. Rev. 2012, 41, 3969. (c) Pellissier, H. Adv. Synth.
Catal. 2012, 354, 237. (d) Jensen, K. L.; Dickmeiss, G.; Jiang, H.;
Albrecht, Ł.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
(4) (a) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L.,
Ed.; John Wiley and Sons: New York, 1988; Chapter 4, p 249. For
review articles, see:. (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv.
Synth. Catal. 2001, 343, 5. (c) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
5
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(4-phenyl-2-yl)but-3-en-2-yl)-
oxy)-5-oxo-3-(4-methyl)pentanoic Acid (3n). Reaction time: 6 h.
Yield: 39% (30 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ
1
3
8
.40 (s, 1H), 7.55−7.43 (m, 5H), 6.60 (s, 1H), 4.30−4.10 (m, 2H),
2
.65−2.40 (m, 4H), 2.39−2.20 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.10
13
(
d, J = 5.6 Hz, 3H). C NMR (100 MHz, CDCl ): δ 177.8, 170.5, 165.8,
3
1
1
44.8, 140.5, 131.4, 130.3, 129.7, 129.3, 65.5, 62.7, 40.1, 40.0, 27.1, 19.6,
3.9 ppm. IR (ν/cm ): 2970, 1763, 1744, 1710, 1532, 1339, 1214.
−1
2
005, 44, 3974.
(5) Muller, C. E.; Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50, 6012.
6) (a) Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew. Chem., Int.
+
HRMS (ESI-TOF) m/z calcd for C H NO Na [M + Na] 402.1165,
18
21
8
found 402.1174; ee 92%. HPLC [Chiralcel AD-H, 2-propanol/hexanes
10/90, 0.5 mL/min, λ = 220 nm, retention time: 34.2 min (major),
9.8 min (minor)].
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(4-methylphenyl-2-yl)but-3-en-
-yl)oxy)-5-oxo-3-(4-methyl)pentanoic Acid (3o). Reaction time: 4 d.
(
=
3
Ed. 2005, 44, 7466. (b) Chen, L.; Luo, S.; Li, J.; Li, X.; Cheng, J.-P. Org.
Biomol. Chem. 2010, 8, 2627. (c) Yu, J.; Chen, W.-J.; Gong, L.-Z. Org.
Lett. 2010, 12, 4050. (d) Xie, J.-W.; Fan, L.-P.; Su, H.; Li, X.-S.; Xu, D.-C.
Org. Biomol. Chem. 2010, 8, 2117. (e) McGarraugh, P. G.; Brenner-
Moyer, S. E. Org. Lett. 2011, 13, 6460.
5
2
1
Yield: 47% (37 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ
3
8
.38 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.62 (s,
H), 4.30−4.10 (m, 2H), 2.62−2.45 (m, 4H), 2.41 (s, 3H), 2.40−2.30
(7) For review article, see: (a) Chen, Y.; McDaid, P.; Deng, L. Chem.
1
Rev. 2003, 103, 2965. (b) García-Urdiales, E.; Alfonso, I.; Goto, V. Chem.
Rev. 2005, 105, 313. (c) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev.
(
(
m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 5.6 Hz, 3H). 13C NMR
100 MHz, CDCl ): δ 176.6, 170.7, 165.9, 144.0, 142.4, 140.8, 130.1,
3
2
007, 107, 5683. (d) Diaz-de-Villegas, M. D.; Galvez, J. A.; Etayo, P.;
Badorrey, R.; Lopez-Ram-de-Viu, M. P. Chem. Soc. Rev. 2011, 40, 5564.
8) For recent reviews, see: (a) Diaz-de-Villegas, M. D.; Galvez, J. A.;
1
30.0, 127.5, 65.7, 62.7, 40.1, 39.9, 27.2, 21.6, 19.6, 13.9 ppm. IR (ν/
−1
cm ): 2968, 1767, 1742, 1710, 1532, 1335, 1219. HRMS (ESI-TOF):
m/z calcd for C H NO Na [M + Na] 416.1321, found 416.1328; ee
(
+
19
23
8
Badorrey, R.; Lopez-Ram-de-Viu, M. P. Chem.Eur. J. 2012, 18, 13920.
8
3%. HPLC [Chiralcel AD-H, 2-propanol/hexanes = 10/90, 1 mL/min,
(
(
(
b) Enriquez-Garcia, A.; Kundig, E. P. Chem. Soc. Rev. 2012, 41, 7803.
c) Rodriguez-Docampo, Z.; Connon, S. J. ChemCatChem. 2012, 4, 151.
d) Fernandez-Perez, H.; Etayo, P.; Lao, J. R.; Nunez-Rico, J. L.; Vidal-
́ ́
́
̃
λ = 220 nm, retention time 12.2 min (major), 14.1 min (minor)].
5
-(((E)-1-Ethoxy-3-nitro-1-oxo-4-(2-thienyl-2-yl)but-3-en-2-yl)-
oxy)-5-oxo-3-(4-methyl)pentanoic Acid (3p). Reaction time: 3 d.
Yield: 36% (28 mg). Viscous liquid. H NMR (400 MHz, CDCl ): δ
1
Ferran, A. Chem. Commun. 2013, 49, 10666.
9) (a) Seebach, D.; Jaeschke, G.; Gottwald, K.; Matsuda, K.;
3
(
8
.49 (s, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.58 (d, J = 3.6 Hz, 1H), 7.25−7.20
Formisano, R.; Chaplin, D. A.; Breuning, M.; Bringmann, G.
Tetrahedron 1997, 53, 7539. For parallel kinetic resolution (PKR),
see: (b) Chen, Y.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302.
(10) (a) Lee, J. Y.; You, Y. S.; Kang, S. H. J. Am. Chem. Soc. 2011, 133,
(
m, 1H), 6.84 (s, 1H), 4.39−4.13 (m, 2H), 2.70−2.41 (m, 4H), 2.40−
.25 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H). C NMR
13
2
(
100 MHz, CDCl ): δ 177.7, 171.0, 165.6, 141.1, 137.0, 134.4, 133.1,
3
−1
1
32.5, 129.0, 65.8, 62.7, 40.1, 40.1, 27.1, 19.6, 13.9 ppm. IR (ν/cm ):
1
772. (b) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc.
2968, 1767, 1744, 1706, 1636, 1524, 1312, 1220. HRMS (ESI-TOF): m/
+
2011, 133, 8834. (c) Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.;
Feng, X. J. Am. Chem. Soc. 2012, 134, 17023. (d) Zhou, F.; Guo, J.; Liu,
J.; Ding, K.; Yu, S.; Cai, Q. J. Am. Chem. Soc. 2012, 134, 14326.
z calcd for C H NO SNa [M + Na] 408.0729, found 408.0736; ee
16
19
8
8
2%. HPLC [Chiralcel AD-H, 2-propanol/hexanes = 10/90, 1 mL/min,
λ = 220 nm, retention time 24.0 min (major), 27.8 min (minor)].
(e) Aikawa, K.; Okamoto, T.; Mikami, K. J. Am. Chem. Soc. 2012, 134,
1
0329. (f) Gopinath, P.; Watanabe, T.; Shibasaki, M. Org. Lett. 2012, 14,
ASSOCIATED CONTENT
■
1358.
*
S
Supporting Information
(11) For the only report on organocatalytic KR of secondary thiols,
see: Peschiulli, A.; Procuranti, B.; O’ Connor, C. J.; Connon, S. J. Nat.
Chem. 2010, 2, 380.
1
13
H and C NMR spectra and HPLC chromatograms for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) For our previous reports on organocatalytic KR, see: (a) Reddy, R.
J.; Chen, K. Org. Lett. 2011, 13, 1458. (b) Reddy, R. J.; Lee, P.-H.; Magar,
D. R.; Chen, J.-H.; Chen, K. Eur. J. Org. Chem. 2012, 353. (c) Roy, S.;
Chen, K. Org. Lett. 2012, 14, 2496.
AUTHOR INFORMATION
■
(
13) For the preparation of compound 2a, see: Deb, I.; Shanbhag, P.;
Mobin, S. M.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2009, 4091.
14) (a) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Chem.
Corresponding Author
*
Tel: +886-2-77346124. Fax: +886-2-29324249. E-mail:
(
kchen@ntnu.edu.tw.
Commun. 1985, 1717. (b) Hang, J.; Tian, S.-K.; Tang, L.; Deng, L. J. Am.
Chem. Soc. 2001, 123, 12696.
Notes
The authors declare no competing financial interest.
(15) For absolute configuration determination of (S)-2, see the
Supporting Information.
(
16) For selected recent review aricles on bifunctional catalysis, see:
ACKNOWLEDGMENTS
■
(
a) Connon, S. J. Chem. Commun. 2008, 2499. (b) Takemoto, Y. Chem.
Pharm. Bull. 2010, 58, 593. (c) Lu, L.-Q.; An, X.-L.; Chen, J.-R.; Xiao,
W.- J. Synlett 2012, 490.
(17) For reports on asymmetric additions to anhydrides using
bifunctional catalysis, see: (a) Peschiulli, A.; Gun’ko, Y. K.; Connon,
S. J. J. Org. Chem. 2008, 73, 2454. (b) Rho, H. S.; Oh, S. H.; Lee, J. W.;
Chin, J.; Song, C. E. Chem. Commun. 2008, 1208. (c) Oh, S. H.; Rho, H.
S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem.,
Int. Ed. 2008, 47, 7872.
We thank the Ministry of Science and Technology of the
Republic of China (MOST 102-2113-M-003-005-MY3) for
financial support of our work.
REFERENCES
■
(
1) For reviews on natural products, see: (a) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
b) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109,
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Further Targets, Strategies, Methods; Wiley-VCH: New York, 2011.
2) For recent reviews on metal-catalysis processes, see: (a) Claviera,
(
3
NOTE ADDED AFTER ASAP PUBLICATION
■
(
An author (R.G.) was inadvertently omitted from the original
author list. The correct version reposted September 16, 2014.
H.; Pellissier, H. Adv. Synth. Catal. 2012, 354, 3347. (b) Pellissier, H.
Chem. Rev. 2013, 113, 442.
8
959
dx.doi.org/10.1021/jo501882q | J. Org. Chem. 2014, 79, 8955−8959