The combination of domino process and kinetic resolution: Organocatalytic synthesis of functionalised cyclopentenes by sequential SN2′- Michael reaction

Article abstract of DOI:10.1016/j.tet.2012.06.085

An interesting combination of organocatalytic cascade reaction and kinetic resolution was developed for the synthesis of functionalised cyclopentenes by sequential S_N2′-Michael process. Treatment of the racemic nitroallylic acetates with glutar

Full text of DOI:10.1016/j.tet.2012.06.085

Tetrahedron 68 (2012) 7317e7321
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The combination of domino process and kinetic resolution: organocatalytic
synthesis of functionalised cyclopentenes by sequential SN20-Michael reaction
*
Lun Fu Yeh, Shaik Anwar, Kwunmin Chen
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2012
Received in revised form 12 June 2012
Accepted 21 June 2012
Available online 28 June 2012
An interesting combination of organocatalytic cascade reaction and kinetic resolution was developed for
the synthesis of functionalised cyclopentenes by sequential SN20-Michael process. Treatment of the
racemic nitroallylic acetates with glutaraldehyde in the presence of diphenylprolinol silyl ether to give
tetrasubstituted cyclopentenes with high to excellent stereoselectivities (up to 96% ee and 12:1 dr). The
less reactive enantiomeric substrates were generally recovered with good to excellent optical purities
(up to 99% ee).
Keywords:
Ó 2012 Published by Elsevier Ltd.
Kinetic resolution
Organocatalysis
Cascade
Michael reaction
Cyclopentene
1. Introduction
organocatalytic KR,12 we present here an interesting organo-
catalytic cascade reaction that involves the kinetic resolution of
The use of small molecule organocatalysts for kinetic resolution
(KR) has now become an important method for the preparation of
enantiomerically-enriched substances from its racemic starting
materials.1 Generally, the KR process generates an excess of the less
reactive substrate. In this regard, metal-mediated KR variants have
also been developed.2 On the other hand, various alcohols and
amines have been efficiently resolved via organic molecule-
mediated O/N-acylation3 and O-silylation.4 The construction of
new stereogenic carbon centers on the more reactive enantiomer of
a racemate in a KR process is potentially advantageous, but only
rare examples were reported.5
Substituted five-membered carbocycles are important structural
elements of many biologically active natural and pharmaceutical
products. Though there are numerous reports on the synthesis of
cyclopentane derivatives,6 much less attention has been directed
toward the preparation of substituted cyclopentene derivatives.
Organocatalysed [3þ2] cycloaddition routes to cyclopentene de-
rivatives have been accomplished recently via Michaelealdol,7
homoenolate Michaelealdol,8 benzoineoxyeCope,9 iminiumeen-
amine metal-catalysed enyne cycloisomerisation,10 and sequential
StettereMichaeleAldol reactions.11 However, efficient methods for
the preparation of diverse multi-substituted cyclopentenes are still
in demand. In continuation of our research efforts in the
racemic nitroallylic acetates for the synthesis of functionalized
cyclopentenes with high to excellent stereoselectivities (up to 96%
ee and 12:1 dr). The less reactive enantiomeric substrates were
recovered with good to excellent optical purities (up to 99% ee).
2. Results and discussion
We envisioned that the cyclopentene derivatives 3 could be
obtained from the reaction of functionalised nitroallylic acetates
with inexpensive glutaraldehyde,13 mediated by organocatalyst
(Scheme 1). Toward this, we initially investigated the test reaction
of rac-1a and glutaraldehyde in the presence of various organo-
catalysts (Table 1). Treatment of nitroallylic acetate 1a with glu-
taraldehyde in the presence of 20 mol % diphenylprolinol silyl ether
catalyst (Cat. I) took 6 days to reach completion. Due to the in-
stability of the dicarbonyl functionality, the isolated product was
reduced to the corresponding cyclopentene diol 3a (86% ee) di-
rectly using NaCNBH3 (Table 1, entry 1). The less reactive enantio-
meric substrate was determined as having an ee of 77%. The use of
diaryl substituted silyl ether catalyst II gave rise to poor stereo-
selectivity and yield (Table 1, entry 2). The reactivity was improved
slightly when the camphor-derived organocatalyst III was
employed. However, it gave rise to only moderate enantiose-
lectivity (57% ee) (Table 1, entry 3). The use of naphthyl-derived
amide (Cat. IV) and sulfonamide (Cat. V) catalysts failed to im-
prove the level of enantioselectivity (Table 1, entries 4 and 5). A
* Corresponding author. Tel.: þ886 2 7734 6124; fax: þ886 2 2932 4249; e-mail
address: kchen@ntnu.edu.tw (K. Chen).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2012.06.085

7318
L.F. Yeh et al. / Tetrahedron 68 (2012) 7317e7321
cinchonidine-derived organocatalyst (Cat. VI) also proved rather
ineffective at producing the product 3a (Table 1, entry 6).
substrate 1a could be recovered in 33% yield (88% ee at 48% con-
version). However, this level of reactivity diminished significantly
when only 10 mol % of the catalyst was employed (Table 1, entry
11). Decreasing the reaction temperature also failed to improve the
enantioselectivity of cyclopentene formation or the optical purity
of the resolved starting nitroallylic acetate (Table 1, entry 12). The
structure of the product 3a was fully characterised by IR, HRMS and
1H-, 13C spectroscopic data.14
With the optimised reaction conditions now identified, we next
examined substrate scope to establish the general utility of our new
domino kinetic resolution process (Table 2). It was observed that
the reaction tolerated various aryl and heteroaromatic in the
starting nitroallylic acetates (1bek). The reactivity and enantiose-
lectivity was also found to be dependent on the substituents
present in the phenyl ring of 1. The diastereoselectivity ratios varied
from 12/1 to 3/1.
-HOAc
-HNO2
NO2
O
O
OH
HO
CO2Et
+
H
H
NO2
R
CO2Et
R
OAc
CO2Et
OAc
(R)-(+)-1
2
3
rac-1
R
Scheme 1. Organocatalysed cascade reaction for functionalized cyclopentene
derivatives.
Table 1
Optimisation of the SN20/Michael additioneelimination reactiona
1. cat. (20 mol %),
additive, solvent
NO2
2. NaCNBH3, EtOH,
O
O
OH
CO2Et
HO
CH2Cl2, HOAC
+
H
H
Ph OAc
rac-1a
Ph
CO2Et
Table 2
(R)-(+)-1a
2
3a
Substrate scope for the SN20/Michael additioneeliminationa
Me
O
Ar
1. cat.I (20 mol %),
Ar
toluene, AcOH
Me
NO2
N
O
O
OH
OTMS
2. NaCNBH3, MeOH
CH2Cl2, HOAc
N
N
H
HO
H
H
S
H
CO2Et
H
OH
N
+
H
H
N
H
N
H
cat. I: Ar = Ph
R
CO2Et
R
OAc
III
cat. II: Ar = 3,5-CF3C6H3
3a-k
2
(R)-(+)-1a-k
rac-1a-k
O
O
N
S
R:
N
H
N
N
H
N
H
VI
O
1e: X = 3-Cl
H
1a: X = H
1f: X = 4-OMe
1g: X = 3-OMe
1h: X = 4-Me
V
1b: X = 4-Br
1c: X = 3-Br
1d: X = 4-Cl
IV
S
X
1j
1i
1k
Entry
Cat.
Solvent
Time/h
Convb/drb
Yield
Yield
% ee
3a(%)c
1a(%)c
3ad/1ad
1
t/h
Convb /drb
Yield
3d,e
Yield
1d% ee
Sf
3 (%)c
(%ee)
1 (%)c
1
2
3
4
5
6
7
8
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
Toluene
Toluene
Toluene
Toluene
Toluene
6 d
4 d
3 d
4 d
6 d
3 d
6
24
6
6
76/5:1
75/1:3
84/9:1
68/35:1
91/21:1
100/15:1
83/1:1
52/5:1
48/5:1
48/9:1
47/2:1
49/2:1
15
12
28
16
10
14
42
24
27
45
24
34
10
11
13
18
5
86/77
19/78
57/67
42/28
49/11
37/nd
69/70
91/90
87/86
96/88
92/82
94/89
II
III
IV
V
VI
I
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
6
5
2
6
2
7
6
6
6
48/9:1
48/6:1
47/3:1
48/6:1
46/4:1
45/6:1
49/6:1
48/4:1
49/6:1
52/12:1
45
45
43
37
34
34
32
42
32
35
3a 96
3b 91
3c 95
3d 91
3e 94
3f 95
3g 91
3h 94
3i 90
3j 91
33
43
46
37
46
46
31
45
37
46
88
84
85
85
81
76
88
88
85
99
143
56
106
58
0
81
93
62
94
10
22
25
33
37
38
I
I
I
I
9e
10f
11f, g
12f,h
53
2 d
18
10
1j
18
111
I
a
Unless otherwise noted, all reactions were carried out with 1 (0.1 mmol) and
glutaraldehyde (0.4 mmol) with Cat. I (20 mol %) using toluene (0.5 mL) at 35 ꢀC.
a
Unless otherwise noted, all reactions were carried out with 1a (0.1 mmol) and
glutaraldehyde 2 (0.4 mmol) with Cat. (20 mol %) in the indicated solvent (0.5 mL) at
35 ꢀC.
Conversion and dr were determined by 1H NMR analysis of the crude reaction
b
mixture.
Conversion and dr were determined by 1H NMR analysis of the crude reaction
b
c
Isolated yield.
mixture.
d
Determined by chiral HPLC analyses.
Ee of the corresponding diol minor isomer was found to be >99% ee in most of
c
Isolated yield.
e
d
Determined by chiral HPLC analyses.
The reaction was carried out using 1.0 equiv of acetic acid.
The reaction was carried out using 1.5 equiv of acetic acid.
the entries.
e
f
S¼ln[(1ꢁC)(1ꢁees)/ln[(1ꢁC)(1þees)].
f
g
The reaction was carried out using 10 mol % Cat. I.
h
The reaction was carried out at 5 ꢀC.
In general, a meta-substituent outperformed a para-substituent
for generating both the products and the resolved nitroallylic ace-
tates stereoselectively. For example, product 3c was obtained in
95% ee alongside an 85% ee of recovered 1c, which compared with
a product of only 91% ee for 3b and 84% ee for 1b (Table 2, entry 2 vs
3). Comparable results were found in the case of the chloro-
substituted derivatives 1d and 1e (Table 2, entry 4 vs 5). The
electron-donating/withdrawing nature of the substituents on the
phenyl ring only affected the reactivity slightly (Table 2, entries
6e8). It was found that a 2-naphthyl substrate 1i caused a decrease
in overall reaction yield, and only moderate enantioselectivity was
seen for the product 3i (Table 2, entry 9). Heteroaromatic sub-
strates, such as 1j also took a longer time to afford the product 3j,
but they did so with very high levels of diastereoselectivity and
optical purity (99% ee) for the recovered acetate (Table 2, entry 10).
Aliphatic substrates, such as 1k reacted sluggishly with glutaral-
dehyde, with the latter requiring 2 days to furnish the product 3k in
Next, we varied the solvents, the reaction concentration, the
reaction temperature and incorporated various additives (Table 1,
entries 7e12). Unsatisfactory results were observed when the re-
action was carried out in methyl tert-butyl ether (MTBE) (Table 1
entry 7). However, the level of enantioselectivity could be consid-
erably improved to 91% ee, when the reaction was conducted in
toluene, which led to a 52% conversion, following an overnight run
(Table 1, entry 8). We next investigated whether an acidic additive
might enhance reactivity, and initially observed that when
1.0 equiv of acetic acid was added to the reaction mixture, it gave
rise to a comparable stereochemical outcome (Table 1, entry 9).
However, when 1.5 equiv of HOAc was included, the chemical yield
and overall stereoselectivity of the products markedly improved
(Table 1, entry 10). Thus the product 3a could now be isolated in
45% yield with an enantioselectivity of 96% ee, while the unreacted

L.F. Yeh et al. / Tetrahedron 68 (2012) 7317e7321
7319
a rather low chemical yield of 27% (data not shown). The range of S
factors for these unusual reactions ranged from 53e143.15
Domino reactions that involve a kinetic reaction are interesting
and might have many applications in organic reaction.16 Formation
of the functionalised cyclopentenes 3 can potentially be rational-
ised by the mechanistic sequence shown in Fig. 1. It is presumed
that the enamine A, formed from glutaraldehyde 2 and Cat. I, at-
tacks the more reactive nitroallylic acetate (S)-1 in an SN20 fashion
leading to intermediate B. The less reactive (R)-enantiomer then
sits in the reaction mixture undisturbed. Subsequently, in-
termediate B re-enters the catalytic cycle to generate second en-
amine species C, which reacts preferentially via a 5-exo-trig
addition17 to give D with the release of the organocatalyst. Cycli-
sation might readily arise from the spatial proximity of the tri-
substituted alkene in C, which looks energetically conducive to the
formation of cyclopentene ring system. Deprotonation and elimi-
nation of nitrous acid in D then finally affords the desired cyclo-
pentene products E.18
a JASCO P-1010 polarimeter. HRMS spectra were recorded on JEOL
SX-102A. Routine monitoring of reactions was performed using
silica gel, glass-backed TLC plates (Merck Kieselgel 60 F254) and
visualized by UV light (254 nm). Solutions were evaporated to
dryness under reduced pressure on a rotary evaporator and the
residues purified by flash column chromatography on silica gel
(230e400 mesh) with the indicated eluents. Air and/or moisture
sensitive reactions were performed under the usual inert atmo-
sphere conditions.
4.2. Typical reaction procedure
To a solution of racemic nitroallylic acetate 1aej (0.1 mmol),
glutaraldehyde (0.4 mmol) and HOAc (0.15 mmol) in toluene
(0.5 mL) was added organocatalyst I (20 mol %) in one portion at
35 ꢀC. The reaction mixture was allowed to stir for a needful time
(monitored by TLC and crude 1H NMR analysis). The reaction
mixture was stopped at w50% conversion and subject directly to
flash column chromatography (silica gel with ethyl acetate/
hexanes¼1:4) to give cyclopentendialdehyde and the less reactive
enantiomeric substrates 1aej. The isolated cyclopentendialdehyde
was dissolved in CH2Cl2 (1.0 mL), EtOH (1.0 mL), HOAc (0.5 equiv)
and sodium cyanoborohydride (4.0 equiv) was added portionwise.
The mixture was stirred for 3 h and subject directly to flash column
chromatography (silica gel with ethyl acetate/hexanes¼3:1) to af-
ford cyclopentenediols 3aej.
H
OHC
CHO
OHC
CHO
- HNO2
H2O
R
R
CO2Et
CO2Et
NO2
E
D
O
O
H
H
H
2
N
H
cat. I
H2O
O
H
N
4.2.1. Ethyl 2-(2,4-bis(hydroxymethyl)-5-phenylcyclopent-1-en-1-yl)
SN2' -Michael
Cascade Process
N
O
H
acetate (3a). Purification: EA/hexanes¼3:1 (Rf¼0.28) to give 3a as
a colorless oil. ½a D24
ꢂ
þ79.2 (c¼0.5, CH2Cl2); IR (CH2Cl2):
n
3300, 2915,
1H NMR
NO2
H
R
A
2847, 1731, 1552, 1450, 1368, 1258, 1193, 1028 cmꢁ1
;
CO2Et
C
cat. I
rac 1
(500 MHz, CDCl3):
d
¼7.29 (dd, J¼7.5 and 7.5 Hz, 2H), 7.24e7.19 (m,
O
R
O
1H), 7.14 (m, 2H), 4.24 (s, 2H), 4.05e3.93 (m, 2H), 3.69 (d, J¼5.8 Hz,
2H), 3.65 (s, 1H), 3.10 (d, J¼15.6, 1H), 2.88e2.81 (m, 2H), 2.43e2.39
(m, 2H), 1.15 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
(R)-(+)-1
H
H
NO2
CO2Et
Fig. 1. Proposed catalytic cycle.
B
d
¼172.2, 143.6, 140.8, 133.3, 128.7, 127.9, 126.7, 66.4, 61.1, 59.5, 58.7,
48.5, 36.9, 32.7, 14.0 ppm; HRMS (ESI) m/z calcd for C17H22O4
(MþþNa) 313.1418, found 313.1416. The enantiomeric excess (96%
ee) of 3a was determined by HPLC with AD-H column (i-PrOH/
3. Conclusions
hexanes: 5/95; flow rate: 1.0 mL/min;
51.23 min; tR (minor)¼57.96 min.
l
¼220 nm); tR (major)¼
In conclusion, we have successfully developed an interesting
organocatalytic reaction for the synthesis of functionalised cyclo-
pentene derivatives. The protocol exploits the reaction of racemic
nitroallylic acetates and glutaraldehyde and is accompanied by
a kinetic resolution. The more reactive enantiomeric nitroallylic
acetates are typically converted into multi-substituted cyclo-
pentene derivatives 3 with high enantiomeric excess (up to 96% ee).
The less reactive enantiomeric starting nitroallylic acetates are re-
covered with good to excellent optical purity (up to 99% ee). To the
best of our knowledge, this is the first organocatalytic process for
preparing cyclopentenes via an SN20/Michael conjugate addi-
tioneelimination process catalysed by the popular diphenylproli-
nol silyl ether catalyst. More studies are under investigation.
For recovery acetate (1a): Spectroscopic data are in agreement
with racemic substrate 1a. isolated yield: 33% (10 mg). The enan-
tiomeric excess (88% ee) was determined by HPLC with AD-H col-
umn (i-PrOH/hexanes: 5/95; flow rate: 0.5 mL/min;
(major)¼25.92 min; tR (minor)¼22.54 min.
l¼254 nm); tR
4.2.2. Ethyl 2-(5-(4-bromophenyl)-2,4-bis(hydroxymethyl)cyclopent-
1-en-1-yl)acetate (3b). purification: CH2Cl2/MeOH¼20:1 (Rf¼0.19)
to give 3b as a colorless oil. ½a D25
ꢂ
þ71.0 (c¼0.6, CH2Cl2); IR (CH2Cl2):
n
3290, 2920, 2847, 1728, 1552, 1462, 1371, 1172, 1075, 1045 cmꢁ1; 1H
NMR (500 MHz, CDCl3)
d
¼7.41 (d, J¼8.4 Hz, 2H), 7.02 (d, J¼8.3 Hz,
2H), 4.23 (s, 2H), 4.05e3.94 (m, 2H), 3.67e3.64 (m, 3H), 3.08 (d,
J¼15.5 Hz, 1H), 2.86e2.79 (m, 2H), 2.42e2.32 (m, 2H), 1.16 (t,
J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
¼172.0, 142.7,
d
4. Experimental
141.3, 132.6, 131.7, 129.7, 120.4, 66.1, 61.2, 59.4, 58.1, 48.5, 36.8, 32.6,
14.0 ppm; HRMS (ESI) m/z calcd for C17H21BrO4 (MþþNa) 391.0527,
found 391.0521. The enantiomeric excess (91% ee) of 3b was de-
termined by HPLC with AD-H column (i-PrOH/hexanes: 8/92; flow
4.1. General remarks
All reagents were used as purchased from commercial suppliers
without further purification. IR spectra were recorded on a Perkin
Elmer 500 spectrometer. NMR spectra were recorded on a Bruker
Avance 500 NMR spectrometer (500 MHz for 1H and 125 MHz for
rate: 1.0 mL/min;
32.12 min.
For recovery acetate (1b): Spectroscopic data are in agreement
with recemic substrate 1b. Yield: 43% (16 mg). The enantiomeric
excess (84% ee) was determined by HPLC with OD-H column (i-
PrOH/hexanes: 5/95; flow rate: 0.5 mL/min;
(major)¼20.27 min; tR (minor)¼24.51 min.
l
¼220 nm); tR (major)¼19.40 min; tR (minor)¼
13C). Chemical shifts are reported in
d parts per million referenced
to an internal TMS standard for 1H NMR and chloroform-
l¼220 nm); tR
d (77.0 ppm) for 13C NMR. Optical rotations were measured on

7320
L.F. Yeh et al. / Tetrahedron 68 (2012) 7317e7321
4.2.3. Ethyl 2-(5-(3-bromophenyl)-2,4-bis(hydroxymethyl)cyclopent-
3.60 (d, J¼4.1 Hz, 1H), 3.09 (d, J¼15.8 Hz, 1H), 2.86e2.80 (m, 2H),
2.43e2.35 (m, 2H), 1.17 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz,
1-en-1-yl)acetate (3c). Purification: EA/hexane¼3:1 (Rf¼0.33) to
give 3c as a colorless oil. ½a D20
ꢂ
þ80.4 (c¼1.3, CH2Cl2); IR (CH2Cl2):
n
CDCl3):
d
¼172.4, 158.4, 140.4, 135.6, 133.8, 128.9, 114.1, 66.4, 61.2,
3307, 2920, 2847, 1643, 1470, 1261, 1065 cmꢁ1; 1H NMR (500 MHz,
59.4, 57.9, 55.3, 48.5, 36.8, 32.6, 14.0 ppm; HRMS (ESI) m/z calcd for
C18H24O5 (MþþNa) 343.1516, found 343.1521. The enantiomeric
excess (95% ee) was determined by HPLC with AD-H column (i-
CDCl3)
d
¼7.34 (d, J¼8.2 Hz, 1H), 7.28 (s, 1H), 7.16 (dd, J¼7.8 and
7.8 Hz, 1H), 7.07 (d, J¼7.7 Hz, 1H), 4.24 (dd, J¼19.7 and 13.0 Hz, 2H),
4.07e3.96 (m, 2H), 3.67e3.65 (m, 3H), 3.10 (d, J¼15.7 Hz, 1H),
2.86e2.79 (m, 2H), 2.44e2.34 (m, 2H), 1.17 (t, J¼7.2 Hz, 3H) ppm;
PrOH/hexanes: 5/95; flow rate: 1.0 mL/min;
(major)¼60.99 min; tR (minor)¼82.05 min.
l
¼220 nm); tR
13C NMR (125 MHz, CDCl3):
d
¼172.0,146.2, 141.6,132.3, 130.9, 130.2,
For recovery acetate (1f): spectroscopic data are in agreement
with racemic substrate 1f. Yield: 46% (15 mg). The enantiomeric
excess (76% ee) was determined by HPLC with AD-H column (i-
129.8, 126.7, 122.8, 65.9, 61.2, 59.3, 58.2, 48.4, 36.7, 32.6, 14.0 ppm;
HRMS (ESI) m/z calcd for C17H21BrO4 (MþþNa) 391.0518, found
391.0521. The enantiomeric excess (95% ee) was determined by
HPLC with AD-H column (i-PrOH/hexanes: 5/95; flow rate: 1.0 mL/
PrOH/hexanes: 10/90; flow rate: 1.0 mL/min;
(major)¼12.43 min; tR (minor)¼10.82 min.
l¼254 nm); tR
min;
l
¼220 nm); tR (major)¼42.98 min; tR (minor)¼47.78 min.
For recovery acetate (1c): spectroscopic data are in agreement
with racemic substrate 1c. Yield: 46% (17 mg). The enantiomeric
excess (85% ee) was determined by HPLC with OD-H column (i-
4.2.7. Ethyl 2-(2,4-bis(hydroxymethyl)-5-(3-methoxyphenyl)cyclo-
pent-1-en-1-yl)acetate (3g). Purification: EA/hexane¼3:1 (Rf¼0.32)
to give 3g as a colorless oil. ½a D21
ꢂ
þ90.2 (c¼0.3, CH2Cl2); IR (CH2Cl2):
n
PrOH/hexanes: 5/95; flow rate: 0.5 mL/min;
(major)¼23.75 min; tR (minor)¼27.89 min.
l¼220 nm); tR
3380, 2920, 2847,1725,1601,1584,1552,1487,1261,1181,1034 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
¼7.21 (dd, J¼7.9 Hz, 1H), 6.76e6.73 (m,
2H), 6.68 (s,1H), 4.23 (s, 2H), 4.05e3.96 (m, 2H), 3.79 (s, 3H), 3.68 (d,
J¼5.7 Hz, 2H), 3.62 (s,1H), 3.09 (d, J¼15.6 Hz,1H), 2.89e2.80 (m, 2H),
2.43e2.39 (m, 2H), 1.16 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz,
4.2.4. Ethyl 2-(5-(4-chlorophenyl)-2,4-bis(hydroxymethyl)cyclopent-
1-en-1-yl)acetate (3d). Purification: EA/hexane¼3:1 (Rf¼0.35) to
3d give as a colorless oil. ½a D25
ꢂ
þ96.4 (c¼0.5, CH2Cl2); IR (CH2Cl2):
n
CDCl3):
d¼172.3, 159.9, 145.3, 141.0, 133.1, 129.6, 120.4, 113.7, 111.8,
3432, 2955, 2920, 2852, 1710, 1649, 1555, 1490, 1365, 1255, 1193,
66.4, 61.1, 59.4, 58.7, 55.2, 48.5, 36.9, 32.6,14.0 ppm; HRMS (ESI) m/z
calcd for C18H24O5 (MþþNa) 343.1529, found 343.1521. The enan-
tiomeric excess (91% ee) was determined by HPLC with AD-H col-
1088, 1028 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d¼7.26 (d, J¼8.3 Hz,
2H), 7.08 (d, J¼8.4 Hz, 2H), 4.24 (s, 2H), 4.05e3.94 (m, 2H),
3.67e3.66 (m, 3H), 3.08 (d, J¼15.6 Hz, 1H), 2.86e2.79 (m, 2H),
2.42e2.33 (m, 2H), 1.16 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz,
umn (i-PrOH/hexanes: 5/95; flow rate: 1.0 mL/min;
(major)¼66.82 min; tR (minor)¼76.62 min.
l
¼220 nm); tR
CDCl3):
d
¼172.0, 142.2, 141.3, 132.7, 132.4, 129.3, 128.8, 66.1, 61.2,
For recovery acetate (1g): spectroscopic data are in agreement
with racemic substrate 1g. Yield: 31% (10 mg). The enantiomeric
excess (88% ee) was determined by HPLC with AD-H column (i-
59.4, 58.0, 48.6, 36.8, 32.6, 14.0 ppm; HRMS (ESI) m/z calcd for
C17H21ClO4 (MþþNa) 347.1030, found 347.1026. The enantiomeric
excess (91% ee) was determined by HPLC with IA column (i-PrOH/
PrOH/hexanes: 5/95; flow rate: 0.3 mL/min;
(major)¼43.26 min; tR (minor)¼39.36 min.
l¼254 nm); tR
hexanes: 5/95; flow rate: 1.0 mL/min;
35.08 min; tR (minor)¼41.41 min.
l
¼220 nm); tR (major)¼
For recovery acetate (1d): spectroscopic data are in agreement
with racemic substrate 1d. Yield: 37% (12 mg). The enantiomeric
excess (85% ee) was determined by HPLC with OD-H column (i-
4.2.8. Ethyl 2-(2,4-bis(hydroxymethyl)-5-(p-tolyl)cyclopent-1-en-1-
yl)acetate (3h). Purification: EA/hexane¼3:1 (Rf¼0.41) to give 3h
as a colorless oil. ½a D24
ꢂ
þ81.5 (c¼0.5, CH2Cl2); IR (CH2Cl2):
n
3210,
PrOH/hexanes: 10/90; flow rate: 1.0 mL/min;
(major)¼6.76 min; tR (minor)¼7.62 min.
l¼254 nm); tR
2920, 2852, 1731, 1552, 1510, 1258, 1178, 1025 cmꢁ1 1H NMR
;
(500 MHz, CDCl3)
d
¼7.10 (d, J¼8.0 Hz, 2H), 7.02 (d, J¼8.0 Hz, 2H),
4.26e4.20 (m, 2H), 4.05e3.94 (m, 2H), 3.67 (d, J¼5.8 Hz, 2H), 3.61
(d, J¼4.2 Hz, 1H), 3.10 (d, J¼15.6 Hz, 1H), 2.86e2.80 (m, 2H),
2.41e2.35 (m, 2H), 2.32 (s, 3H), 1.15 (t, J¼7.2 Hz, 3H) ppm; 13C NMR
4.2.5. Ethyl 2-(5-(3-chlorophenyl)-2,4-bis(hydroxymethyl)cyclopent-
1-en-1-yl)acetate (3e). Purification: EA/hexane¼3:1 (Rf¼0.35) to
give 3e as a colorless oil. ½a D21
ꢂ
þ82.7 (c¼0.5, CH2Cl2); IR (CH2Cl2):
n
(125 MHz, CDCl3):
d
¼172.6, 140.8, 140.7, 136.4, 133.7, 129.6, 128.0,
3460, 2920, 2858, 1640, 1473, 1365, 1076, 1023 cmꢁ1
;
1H NMR
66.6, 61.4, 59.6, 58.4, 48.7, 37.0, 32.8, 21.2, 14.1 ppm; HRMS (ESI) m/z
calcd for C18H24O4 (MþþNa) 327.1570, found 327.1572. The enan-
tiomeric excess (94% ee) was determined by HPLC with AD-H col-
(500 MHz, CDCl3)
d
¼7.24e7.18 (m, 2H), 7.12 (s,1H), 7.03 (d, J¼7.2 Hz,
1H), 4.27e4.22 (m, 2H), 4.07e3.96 (m, 2H), 3.68e3.66 (m, 3H), 3.10
(d, J¼15.7 Hz, 1H), 2.87e2.80 (m, 2H), 2.42e2.35 (m, 2H), 1.17 (t,
umn (i-PrOH/hexanes: 10/90; flow rate: 1.0 mL/min;
(major)¼13.77 min; tR (minor)¼17.71 min.
l
¼220 nm); tR
J¼7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
¼172.0, 145.9,
d
141.5, 134.5, 132.4, 129.9, 128.0, 126.9, 126.2, 66.1, 61.2, 59.4, 58.3,
48.5, 36.7, 32.7, 14.0 ppm; HRMS (ESI) m/z calculated for C17H21ClO4
(MþþNa) 347.1024, found 347.1026. The enantiomeric excess (94%
ee) was determined by HPLC with AD-H column (i-PrOH/hexanes:
For recovery acetate (1h): spectroscopic data are in agreement
with racemic substrate 1h. Yield: 45% (14 mg). The enantiomeric
excess (79% ee) was determined by HPLC with AD-H column (i-
PrOH/hexanes: 5/95; flow rate: 0.5 mL/min;
(major)¼21.46 min; tR (minor)¼18.44 min.
l¼254 nm); tR
5/95; flow rate: 0.5 mL/min;
(minor)¼92.78 min.
l
¼220 nm); tR (major)¼81.56 min; tR
For recovery acetate (1e): spectroscopic data are in agreement
with racemic substrate 1e. Yield: 46% (15 mg). The enantiomeric
excess (81% ee) was determined by HPLC with AD-H column (i-
4.2.9. Ethyl 2-(2,4-bis(hydroxymethyl)-5-(naphthalen-2-yl)cyclopent-
1-en-1-yl)acetate (3i). Purification: EA/hexanes¼3:1 (Rf¼0.38) to
give as a colorless oil. ½a D25
ꢂ
þ98.6 (c¼0.6, CH2Cl2); IR (CH2Cl2):
n
PrOH/hexanes: 5/95; flow rate: 0.5 mL/min;
(major)¼23.82 min; tR (minor)¼18.85 min.
l¼254 nm); tR
3205, 2920, 2847, 1728, 1711, 1598, 1550, 1368, 1176, 1025 cmꢁ1; 1H
NMR (500 MHz, CDCl3)
d
¼7.81e7.75 (m, 3H), 7.59 (s, 1H), 7.48e7.42
(m, 2H), 7.27 (dd, J¼6.8 and 1.6 Hz, 1H), 4.28 (s, 2H), 3.99e3.84 (m,
3H), 3.73 (d, J¼6.0 Hz, 2H), 3.11 (d, J¼15.6 Hz, 1H), 2.92e2.87 (m,
2H), 2.53e2.44 (m, 2H), 1.02 (t, J¼7.2 Hz, 3H) ppm; 13C NMR
4.2.6. Ethyl 2-(2,4-bis(hydroxymethyl)-5-(4-methoxyphenyl)cyclo-
pent-1-en-1-yl)acetate (3f). Purification: EA/hexane¼3:1 (Rf¼0.32)
to give 3f as a colorless oil. ½a D24
ꢂ
þ62.4 (c¼0.7, CH2Cl2); IR (CH2Cl2):
n
(125 MHz, CDCl3):
d
¼172.2, 141.1, 141.0, 133.5, 133.1, 132.5, 128.5,
3210, 2915, 2847, 1728, 1552, 1510, 1246, 1176, 1028 cmꢁ1; 1H NMR
127.6,127.6,126.6, 126.1,126.1,125.5, 66.3, 61.1, 59.5, 58.8, 48.5, 37.0,
32.7, 13.8 ppm; HRMS (ESI) m/z calcd for C21H24O4 (MþþNa)
363.1574, found 363.1572. The enantiomeric excess (90% ee) was
(500 MHz, CDCl3)
4.23 (s, 2H), 4.05e3.96 (m, 2H), 3.79 (s, 3H), 3.69 (d, J¼5.6 Hz, 2H),
d
¼7.05 (d, J¼8.7 Hz, 2H), 6.8 (d, J¼8.7 Hz, 2H),

L.F. Yeh et al. / Tetrahedron 68 (2012) 7317e7321
7321
1998, 120, 1629; (f) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613; (g) Pellissier,
H. Adv. Synth. Catal. 2011, 353, 659.
determined by HPLC with AD-H column (i-PrOH/hexanes: 10/90;
flow rate: 1.0 mL/min;
(minor)¼23.39 min.
l
¼220 nm); tR (major)¼19.47 min; tR
2. For selected references on metal-mediated kinetic resolution, see: (a) Morken,
J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123;
(b) Ramdeehul, S.; Dierkes, P.; Aguado, R.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M.; Osborn, J. A. Angew. Chem., Int. Ed. 1998, 37, 3118; (c) Tanaka, K.; Fu, G. C. J.
For recovery acetate (1i): spectroscopic data are in agreement
with racemic substrate 1i. Yield: 37% (13 mg). The enantiomeric
excess (85% ee) was determined by HPLC with OD-H column
€
Am. Chem. Soc. 2002, 124, 10296; (d) Lussem, B. J.; Gais, H.-J. J. Am. Chem. Soc.
2003, 125, 6066; (e) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628; (f) Hou, X. L.; Zheng, B. H. Org. Lett. 2009, 11, 1789.
3. For selected O-acylation reactions, see: (a) Shiina, I.; Nakata, K.; Ono, K.;
(i-PrOH/hexanes: 5/95; flow rate: 1.0 mL/min;
(major)¼14.26 min; tR (minor)¼17.48 min.
l¼254 nm); tR
€
Sugimoto, M.; Sekiguchi, A. Chem.dEur. J. 2010, 16, 167; (b) Muller, C. E.; Wanka,
L.; Jewell, K.; Schreiner, P. R. Angew. Chem., Int. Ed. 2008, 47, 6180; (c) Li, X.; Liu,
P.; Houk, K. N.; Birman, V. B. J. Am. Chem. Soc. 2008, 130, 13836; (d) Birman, V.
B.; Guo, L. Org. Lett. 2006, 8, 4859; (e) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji,
K. J. Am. Chem. Soc. 1997, 119, 3169 For selected N-acylation reactions, see: (f)
Arseniyadis, S.; Valleix, A.; Wagner, A.; Mioskowski, C. Angew. Chem., Int. Ed.
2004, 43, 3314; (g) Kanta De, C.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 17060.
4. For selected catalytic silylation, see: (a) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.;
Snapper, M. L. Angew. Chem., Int. Ed. 2007, 46, 8471; (b) Isobe, T.; Fukuda, K.;
Araki, Y.; Ishikawa, T. Chem. Commun. 2001, 243.
5. (a) Xie, J.-W.; Fan, L.-P.; Su, H.; Li, X.-S.; Xu, D.-C. Org. Biomol. Chem. 2010, 8,
2117; (b) Yu, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett. 2010, 12, 4050; (c) Shimada, N.;
Ashburn, B. O.; Basak, A. K.; Bow, W. F.; Vicic, D. A.; Tius, M. A. Chem. Commun.
2010, 3774; (d) Yu, C.; Zhang, Y.; Song, A.; Ji, Y.; Wang, W. Chem.dEur. J. 2011,
770.
6. For selected synthesis of cyclopentane derivatives, see (a) Zu, L.; Li, H.; Xie, H.;
Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732; (b)
Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sunden, H.; Dziedzic, P.; Cordova, A.
Chem.dEur. J. 2008, 14, 7867; (c) Zhao, G.-L.; Ibrahem, I.; Dziedzic, P.; Sun, J.;
Bonneau, C.; Cordova, A. Chem.dEur. J. 2008, 14, 10007; (d) Tan, B.; Shi, Z.; Chua,
P. J.; Zhong, G. Org. Lett. 2008, 10, 3425; (e) Tan, B.; Chua, P. J.; Zeng, X.; Min, L.;
Zhong, G. Org. Lett. 2008, 10, 3489; (f) Hong, B. C.; Dange, N. S.; Hsu, C.-S.; Liao,
J.-H.; Lee, G.-H. Org. Lett. 2011, 1338.
4.2.10. Ethyl 2-(2,4-bis(hydroxymethyl)-5-(thiophen-3-yl)cyclopent-
1-en-1-yl)acetate (3j). Purification: EA/hexanes¼3:1 (Rf¼0.43) to
give as a colorless oil. ½a D24
ꢂ
þ59.5 (c¼0.5, CH2Cl2); IR (CH2Cl2):
n
3443, 2920, 2847, 1640, 1442, 1365, 1190, 1020 cmꢁ1 1H NMR
;
(500 MHz, CDCl3)
d
¼7.16 (d, J¼5 Hz, 1H), 6.92 (dd, J¼5 and 3.4 Hz,
1H), 6.83 (d, J¼3.4 Hz, 1H), 4.22 (dd, J¼21.3 and 13.6 Hz, 2H),
4.09e4.00 (m, 2H), 3.70 (d, J¼5.9 Hz, 2H), 3.70 (d, J¼5.9 Hz, 2H),
3.18 (d, J¼15.9 Hz, 1H), 2.95 (d, J¼15.9 Hz, 1H), 2.83 (dd, J¼16.3 and
8.4 Hz, 1H), 2.39 (dd, J¼16.3 and 5.2 Hz, 2H), 1.20 (t, J¼7.2 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3):
d¼172.1, 147.4, 140.5, 133.0, 126.9,
124.7, 124.0, 66.0, 61.2, 59.5, 53.1, 49.3, 36.2, 32.4, 14.1 ppm; HRMS
(ESI) m/z calcd for C15H20O4S (MþþNa) 319.0986, found 319.0980.
The enantiomeric excess (91% ee) was determined by HPLC with
AD-H column (i-PrOH/hexanes: 10/90; flow rate: 1.0 mL/min;
l
¼220 nm); tR (major)¼15.98 min; tR (minor)¼18.12 min.
For recovery acetate (1j): spectroscopic data are in agreement
with racemic substrate 1j. Yield: 46% (14 mg). The enantiomeric
excess (99% ee) was determined by HPLC with AD-H column (i-
7. (a) Wang, J.; Li, H.; Xie, H.; Zu, L.; Shen, X.; Wang, W. Angew. Chem., Int. Ed. 2007,
46, 9050; (b) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed.
2009, 48, 3699.
PrOH/hexanes: 10/90; flow rate: 0.5 mL/min;
(major)¼24.04 min; tR (minor)¼26.47 min.
l¼254 nm); tR
8. (a) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006, 128,
8736; (b) Nair, V.; Babu, B. P.; Vellalath, S.; Suresh, E. Chem. Commun. 2008, 747.
9. (a) Chiang, P. C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520;
(b) Chiang, P. C.; Rommel, M.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 8714.
10. (a) Zhao, G. L.; Ullah, F.; Deiana, L.; Lin, S.; Zhang, Q.; Sun, J.; Ibrahem, I.;
Dziedzic, P.; Cordova, A. Chem.dEur. J. 2010, 16, 1585; (b) Jensen, K. L.; Franke, P.
T.; Arroniz, C.; Kobbelgaard, S.; Jørgensen, K. A. Chem.dEur. J. 2010, 16, 1750.
11. Hong, B. C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H. Org. Lett. 2010, 12, 4812.
12. (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.
Acknowledgements
We thank the National Science Council of the Republic of China
(NSC 99-2113-M-003-002-MY3 and NSC 99-2119-M-003-001-
MY2) and National Taiwan Normal University (100-D-06) for
financial support of this work.
13. For the use of glutaraldehyde in organocatalysis, see: (a) He, Z.-Q.; Han, B.; Li,
R.; Wu, L.; Chen, Y.-C. Org. Biomol. Chem. 2010, 8, 755; (b) Hong, B. C.; Nimje, R.
Y.; Sadani, A. A.; Liao, J.-H. Org. Lett. 2008, 10, 2345; (c) Hazelard, D.; Ishikawa,
H.; Hashizume, D.; Koshino, H.; Hayashi, Y. Org. Lett. 2008, 10, 1445; (d) Hayashi,
Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922.
14. Many attempts to derivatize 3a for the absolute stereochemistry determination
failed. Tentative assignment was made according to our previous observation
(Ref. 12) and Hayashi paper Ref. 13(d).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.085.
References and notes
15. Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Fiaud, J. C., Eds.;
Wiley: New York, NY, 1988; vol. 18, p 249.
16. For the first example of organocascade kinetic resolution, see: McGarraugh, P.
G.; Brenner-Moyer, S. E. Org. Lett. 2011, 13, 6460.
17. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
1. (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809; (b) Hori, Y.; Imai, K.;
Sasaki, R. Tetrahedron Lett. 1996, 37, 8543; (c) Matsumura, Y.; Maki, T.;
Murakami, S.; Onomura, O. J. Am. Chem. Soc. 2003, 125, 2052; (d) Kawabata, T.;
Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169; (e) Miller, S. J.;
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc.
18. (a) Rueping, M.; Parra, A. Org. Lett. 2010, 12, 5281; (b) Huang, W.-Y.; Chen, Y.-C.;
Chen, K. Chem.dAsian J. 2012, 7, 688.