Highly enantio- and diastereoselective Michael addition of cyclohexanone to nitroolefins catalyzed by a chiral glucose-based bifunctional secondary amine-thiourea catalyst

Article abstract of DOI:10.1039/b905306a

A novel bifunctional thiourea bearing a saccharide-scaffold and a secondary amino group was synthesized, and was proven to be an effective organocatalyst for the asymmetric Michael reaction of cyclohexanone to both aryl and alkyl nitroolefins. The corresp

Full text of DOI:10.1039/b905306a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly enantio- and diastereoselective Michael addition of cyclohexanone to
nitroolefins catalyzed by a chiral glucose-based bifunctional secondary
amine-thiourea catalyst†
Aidang Lu, Peng Gao, Yang Wu, Youming Wang, Zhenghong Zhou* and Chuchi Tang
Received 19th March 2009, Accepted 7th May 2009
First published as an Advance Article on the web 11th June 2009
DOI: 10.1039/b905306a
A novel bifunctional thiourea bearing a saccharide-scaffold and a secondary amino group was
synthesized, and was proven to be an effective organocatalyst for the asymmetric Michael reaction of
cyclohexanone to both aryl and alkyl nitroolefins. The corresponding adducts were obtained with
excellent diastereo- (up to >99/1 dr) and enantioselectivities (up to 97% ee).
(ketones) and acceptors (nitroolefins) simultaneously. Moreover,
Introduction
the selectivity and activity of can be obviously tuned by a simple
The Michael addition of different nucleophiles to electron deficient
change of the thiourea motif. Carbohydrates are in general very
nitroolefins is one of the most important reactions in organic
attractive scaffolds because of their availability and well defined
synthesis that provides access to syntheticallyusefulfunctionalized
stereocenters. The introduction of a saccharide scaffold into a
nitroalkanes.1 Because of the versatile reactivity of the nitro func-
bifunctional thiourea organocatalyst has proven to be a successful
strategy to design new and efficient organocatalysts.9g,13,14 With an
interest in designing new organocatalysts for asymmetric organic
transformations, novel bifunctional thiourea based catalysts 3
bearing a saccharide-scaffold and a secondary amino group
were synthesized and their catalytic activity was evaluated in
the asymmetric direct Michael addition of cyclohexanone to
nitroolefins.
tionality, theresultingnitroalkanescanbereadilytransformedinto
a wide range of synthetically valuable compounds, such as nitrile
oxides,2 amines,3 ketones,4 carboxylic acids5 and other functional
compounds.6 Among them, the Michael addition of ketone to
nitroolefins represents a convenient access tog-nitroketones, which
are valuable building blocks in organic synthesis. Since the first
reports of an amine-catalyzed asymmetric addition of ketones to
nitroalkenes in 2001,7a–7c extraordinary progress has been made
with respect to both stereoselectivity and substrate scope using
both secondary8 and primary9 chiral amine catalysts. Recently,
chiral thiourea-based catalysts have emerged as powerful catalytic
systems since Jacobsen successfully developed an efficient chiral
Schiff base-thiourea catalyzed asymmetric Strecker reaction due
to their strong activation of carbonyl and nitro groups through
efficient double-hydrogen-bonding interactions.10 Accordingly,
some bifunctional chiral thiourea catalysts bearing a Schiff base
moiety,11 primary,9b,9c,9g,9h or secondary amino group8k,12 were
developed and functioned as efficient catalysts for the asymmetric
Michael addition of ketone to nitroolefins. The great advantage
of these types of organocatalysts is that one catalyst has two
reaction–activation sites, which can activate both Michael donors
Results and discussion
The newly designed pyrrolidine-thioureas 3, were easily pre-
pared via the coupling of (S)- or (R)-tert-butyl 2-(amino-
methyl)pyrrolidine-1-carboxylate 115 and glucosyl isothiocyanate
213 as shown in Scheme 1. Since the free bases of 3 were decom-
posed slowly on storage, we keep them in their trifluoroacetate
form and employ the in situ generated free base as the catalyst
with the addition of an organic base. In the control reactions,
it was found that the obtained result of the in situ generated
catalyst is consistent with that of directly using the free base as
the catalyst. In addition, directly using the trifluo acetic salt 3a
as the catalyst failed; no reaction occurred, even after stirring the
reaction mixture for 5 days.
State Key Laboratory of Elemento-Organic Chemistry, Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin, 300071,
P. R. China. E-mail: z.h.zhou@nankai.edu.cn; Fax: +86-22-23508939
With the catalyst in hand, the factors, such as catalyst loading,
co-catalyst, and reaction temperature, influencing the reaction
were thoroughly investigated employing the reaction between
b-nitrostyrene and cyclohexanone as the model. The results were
listed in Table 1.
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra, HRMS and IR spectra of the thiourea catalysts 3 and the new
Michael addition adducts, and HPLC data. See DOI: 10.1039/b905306a
Scheme 1 Synthesis of thiourea 3.
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Table 1 Optimization of reaction conditionsa
Entry
3 (x mol%)
Co-catalyst (10 mol%)
Temp. (◦C)
Time (h)
Yield (%)b
Dr (syn/anti)c
Ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
3a (20)
3a (20)
3a (20)
3a (20)
3a (20)
3a (20)
3a (20)
3a (10)
3a (30)
3a (20)
3a (20)
3a (20)
3b (20)
—
PrCO2H
20
20
20
20
20
20
20
20
20
36
12
12
12
16
4
10
55
2
48
60
72
72
85
>99
>99
88
>99
95
95.5/4.5
97/3
86/14
95/5
98/2
98/2
98/2
90/10
95/5
94/6
99/1
91/9
99/1
89
90
70
80
86
89
87
87
87
92
95
91
-92
CH3CO2H
PhCO2H
tBuCO2H
(S)-Mandelic acid
(R)-Mandelic acid
PrCO2H
PrCO2H
PrCO2H
PrCO2H
PrCO2H
>99
>99
>99
>99
98
0
-15
-30
-15
35e
PrCO2H
75e
a All reactions were carried out using cyclohexanone (226 mg, 2.3 mol) and 4a (0.23 mmol) in the presence of catalyst 3. b Yield of the isolated product
after chromatography on silica gel. c Determined by 1H NMR. d Determined by chiral HPLC analysis. e This refers to the conversion of b-nitrostyrene.
Table 2 Substrate scope of 3a catalyzed asymmetric Michael addition of
As shown in Table 1, the acidic co-catalyst has an important
influence on the reaction. The addition of 10 mol% of carboxylic
acid as co-catalyst significantly accelerated the reaction rate
relative to that of the catalyst in the absence of acidic co-catalyst.
Among the employed carboxylic acids (Table 1, entries 2–7),
butyric acid afforded the best result in terms of selectivity (Table 1,
entry 2, 97/3 dr and 90% ee). Moreover, the reaction temperature
was found to be an essential factor to the enantioselectivity of
this reaction. The stereoselectivity was gradually increased by
cyclohexanone to nitroolefins
Time Yield Dr
(h)
Ee
Entry
R
(%)a
(syn/anti)b (%)c
◦
decreasing the reaction temperature from 20 to -15 C (Table 1,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph (a)
60
49
80
80
49
49
96
120
47
72
49
120
61
52
49
98
76
95
71
86
78
87
98
82
96
81
90
>99
>99
88
81
87
99/1
97/3
98.5/1.5
97/3
98/2
95
97
93
95
94
95
94
97
94
92
93
93
92
96
94
92
94
93
entries 2, 10 and 11, 90–95% ee). However, further lowering
the temperature to -30 ◦C resulted in a slight decrease of the
enantiomeric excess of the adduct as well as the reaction rate
(Table 1, entry 12, 91% ee). In addition, catalyst loading proved to
be particularly important. For example, the use of both more or
less thiourea organocatalyst led to a small loss of stereo-control
(Table 1, entry 9, 87% ee and entry 8, 87% ee). Under the optimal
reaction conditions (20 mol% of catalyst, 10 mol% of butyric
acid as the co-catalyst, at -15 ◦C), bifunctional amine-thiourea 3b
derived from D-proline demonstrated much lower catalytic activity.
Although the desired adduct was obtained with almost the same
selectivity, the reaction became quite sluggish; only a conversion
of 75% of the b-nitrostyrene was observed at a prolonged reaction
time (Table 1, entry 11 versus entry 13). This indicates that the
(S)-configuration of 1,2-diaminocyclohexane matched the a-D-
glucopyranose to enhance the catalytic activity of the catalyst.
Encouraged by these results, we next probed the scope of the
reaction with a variety of nitroolefins under the optimal reaction
conditions. The results were summarized in Table 2.
2-CF3C6H4 (b)
3-CF3C6H4 (c)
4-CF3C6H4 (d)
4-ClC6H4 (e)
4-FC6H4 (f)
>99/1
2,4-Cl2C6H3 (g)
2-NO2-5-ClC6H3 (h)
2-MeOC6H4 (i)
4-MeOC6H4 (j)
4-MeC6H4 (k)
2,4-(MeO)2C6H3 (l)
4-Benzyloxy (m)
Benzo[d][1,3]dioxol-5-yl (n)
1-Naphthyl (o)
2-Furyl (p)
>99/1
98/2
98/2
98/2
98/2
97/3
97/3
>99/1
99/1
92/8
95/5
76/24
52
(E)-Cinnamyl (q)
Phenylethyl (r)
48
35d
73
a Yield of the isolated product after chromatography on silica gel.
1
b Determined by H NMR. c Determined by chiral HPLC analysis. d The
reaction was carried out at room temperature (25 ◦C).
For example, ortho substituted nitroolefins 4b, 4g, 4h, 4i and 4l still
go smoothly to afford the corresponding adducts in good yields as
well as excellent enantioselectivities. Moreover, alkenyl substituted
nitroolefin can also be employed successfully; the same high levels
of diastereo- and enantioselectivity were observed as those found
in the aryl substituted ones. Notably, aliphatic aldehyde derived
nitroolefin also appeared to be a good candidate at an elevated
temperature (Table 2, entry 18, syn/anti = 76/24, 93% ee for syn
As shown in Table 2, the reaction has broad applicability
with respect to the niroolefins. The corresponding adducts were
obtained in high enantioselectivity and with excellent syn di-
astereoselectivity in all the cases examined. Not only phenyl,
but also electron-rich and electron-deficient aryl groups and
heteroaromatic substituents can be present on the nitroolefin.
Sterically demanding substrates are tolerated well in this reaction.
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isomer), which clearly demonstrated the broad generality of this
asymmetric Michael addition reaction.
Conclusions
We have developed a novel pyrrolidine-based thiourea catalyst
bearing a saccharide-scaffold and a secondary amino group, which
worked well as a bifunctional organocatalyst to promote the
asymmetric Michael reaction of cyclohexanone to both aryl and
alkyl nitroolefins. In these transformations, the prepared catalyst
exhibits a high catalytic activity, and the reaction takes place
with excellent diastereo- (up to >99/1 dr) and enantioselectivity
(up to 97% ee), which may be potentially useful for preparing
enantiomerically enriched g-nitroketones. Further investigations
on the application of this catalyst in asymmetric catalysis are in
progress.
The relative and absolute configurations of the Michael addition
products are shown in Table 2. The relative configurations were
assigned by comparison of 1H and 13C NMR of the products with
the known compounds. The absolute configuration of the major
isomer was established by comparison to the literature value of
optical rotation.
The asymmetric addition of other ketones to nitrostyrene 4a
using 3a as a catalyst was also preliminarily investigated at room
temperature. As shown in Scheme 2, acetone worked well to
provide the desired product 6 in 75% yield with 40% ee. By
performing the reaction of cyclopentanone and cycloheptanone,
it was found that there is a dramatic dependence on ring size.
Cyclopentanone resulted in a decrease in both diastereoselectivity
and enantioselectivity, which gave the desired products 7 in
fair yield with moderate selectivity (syn/anti = 75/25, 79% ee
for syn-7 and 77% ee for anti-7, respectively). The reaction of
cycloheptanone is very sluggish under identical conditions, and
failed to provide the corresponding adduct. This effect may be
attributed to the difference of the barriers for the attack of
pyrrolidine on the carbonyl group of the respective ketones to
form the enamine transition state.16
Experimental
General methods
All reagents and solvents were commercial grade and purified
prior to use when necessary. NMR spectra were acquired on either
a Bruker AMX-300 or Varian 400 MHz instrument. Chemical
shifts are measured relative to residual solvent peaks as an internal
standard set to d 7.26 and d 77.0 (CDCl3). Specific rotations were
measured on a Perkin-Elmer 341MC polarimeter. Enantiomeric
excesses were determined on a HP-1100 instrument (chiral col-
umn; mobile phase: hexane/i-PrOH). Elemental analyses were
conducted on a Yanaco CHN Corder MT-3 automatic analyzer.
HRMS was performed on a Varian QFT-ESI instrument. Melting
points were determined on a T-4 melting point apparatus. IR
spectra were measured on Bruker FT-IR Equinox 55 and Bruker
TENSOR 27 instruments. All temperatures were uncorrected.
Preparation of (S)- and (R)-1-glucosyl-3-(N-tert-butoxy-carbonyl-
pyrrolidin-2-ylmethyl)thiourea
To a stirred solution of (S)- or (R)-tert-butyl 2-(aminomethyl)-
pyrrolidine-1-carboxylate 1 (501 mg, 2.5 mmol) in dry CH2Cl2
(5 mL) was added a solution of glucosyl isothiocyanate 2 (941 mg,
2.5 mmol) in dry CH2Cl2 (5 mL) at room temperature. The
reaction mixture was allowed to stir for complete consumption
of 2 (monitored by TLC, about 6 h). After removal of solvent, the
crude product was purified by column chromatography on silica
gel (200–300 mesh, petroleum ether/ethyl acetate = 2/1) to afford
the title compound as a white solid.
Scheme 2 Reaction of other ketones.
Based on the experimental results, a possible transition state
for this reaction was proposed to account for the observed high
diastereo- and enantioselectivity. As shown in Fig. 1, the free base
of 3a functioned as a bifunctional catalyst. The pyrrolidine part of
the catalyst reacted with carbonyl compounds to form an enamine
with the aid of acidic co-catalyst, and at the same time, nitroolefin
was activated via hydrogen-bonding interaction with the thiourea
moiety as well as the Brønsted acid additive. Then, nucleophilic
attack of the enamine to the nitroolefin from the re-face resulted
in the formation of the desired product, which was consistent with
the experimental results.
(S)-1-Glucosyl-3-(N-tert-butoxy-carbonyl-pyrrolidin-2-ylmethyl)-
◦
thiourea. 1.41 g, 96% yield, m.p. 79–81 C, [a]2D0 -5.2 (c 1.0,
1
CHCl3). H NMR (CDCl3, 300 MHz): d 1.45 (s, 9 H), 1.70–1.87
(m, 4 H), 1.99 (s, 3 H), 2.00 (s, 3 H), 2.01 (s, 3 H), 2.05 (s, 3 H),
3.27–3.36 (m, 3 H), 3.74–3.87 (m, 2 H), 4.00–4.12 (m, 2 H), 4.29
(dd, J = 4.2 and 12.3 Hz, 1 H), 4.96 (t, J = 9.6 Hz, 1 H), 5.07 (t,
J = 9.6 Hz, 1 H), 5.32 (t, J = 9.6 Hz, 1 H), 5.53–5.56 (m, 1 H),
6.32 (br. s, 1 H), 8.61 (br. s, 1 H). 13C NMR (CDCl3, 75.0 MHz):
20.5, 20.6, 20.7, 23.9, 28.4, 47.4, 52.7, 56.5, 61.7, 68.3, 70.6, 73.0,
80.6, 82.3, 157.2, 169.5, 169.9, 170.6, 183.0. IR (KBr): n 3315,
1748, 1668, 1551, 1413, 1369, 1223, 1070 cm-1. HRMS (ESI) m/z
calc’d for C25H39N3O11S [M + H]+: 532.2323, found 532.2333.
(R)-1-Glucosyl-3-(N -tert-butoxy-carbonyl-pyrrolidin-2-yl-
◦
14
406
methyl)-thiourea. 1.45g, 99% yield, m.p. 70–71 C, [a] -18.4
1
Fig. 1 Possible transition state of the present reaction.
(c 1.0, CHCl3). H NMR (CDCl3, 300 MHz): d 1.40 (s, 9 H),
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1.61–1.81 (m, 4 H), 1.92 (s, 3 H), 1.94 (s, 3 H), 1.97 (s, 3 H), 1.98
(s, 3 H), 3.25–3.33 (m, 3 H), 3.60 (d, J = 7.2 Hz, 1 H), 3.94–4.20
(m, 4 H), 4.89 (t, J = 9.0 Hz, 1 H), 5.00 (t, J = 9.0 Hz, 1 H), 5.15
(t, J = 9.0 Hz, 1 H), 6.65 (br. s, 1 H), 8.47 (br. s, 1 H). 13C NMR
(CDCl3, 100.6 MHz): 20.3, 20.4, 20.5, 23.7, 28.3, 29.4, 47.2, 52.7,
55.7, 61.2, 67.7, 70.2, 72.4, 72.7, 77.2, 80.2, 80.9, 156.9, 169.2,
169.7, 170.4, 170.5, 181.8. IR (KBr): n 3322, 3265, 1751, 1666,
1549, 1367, 1226, 1038 cm-1. Anal. calc’d for C25H39N3O11S: C,
50.92; H, 6.67; N, 7.13; Found: C, 50.74; H, 6.40; N, 7.08.
1.22 (m, 1 H), 1.47–1,73 (m, 4 H), 1.98–2.04 (m, 1 H), 2.26–2.44 (m,
2 H), 2.61 (m, 1 H), 3.69 (dt, J = 4.5 and 9.9 Hz, 1 H), 4.56 (dd, J =
9.9 and 12.6 Hz, 1 H), 4.87 (dd, J = 4.5 and 12.6 Hz, 1 H), 7.08–
7.11 (m, 2 Harom), 7.19–7.27 (m, 3 Harom). 13C NMR (CDCl3,
100.6 MHz): 25.1, 28.5, 33.2, 42.8, 44.0, 52.6, 78.9, 127.8, 128.2,
128.9, 137.8, 211.9. HPLC analysis (Chiralpak AD-H column,
hexane:2-propanol=85:15, flowrate=1.0mL/min, wavelength=
254 nm): Rt = 8.25 (minor) and 9.94 min (major).
(S)-2-((R)-2-Nitro-1-(2-trifluoromethylphenyl)ethyl)-cyclohexa-
none (5b).17 Brown oil, 76% yield, [a]D20 -26.2 (c 1.3, CHCl3),
syn/anti = 97/3, 97% ee. 1H NMR (CDCl3, 400 MHz): d 1.29–1.36
(m, 1H), 1.57–1.80 (m, 4 H), 2.11–2.14 (m, 1 H), 2.39–2.50 (m, 2
H), 2.96–3.02 (m, 1 H), 4.09 (s, 1H), 4.76 (dd, J = 3.2 and 12.0 Hz,
1 H), 5.00 (dd, J = 7.6 and 11.6 Hz, 1 H), 7.36 (d, J = 7.6 Hz,
1 Harom), 7.39 (t, J = 7.6 Hz, 1 Harom), 7.55 (t, J = 7.6 Hz,
1 Harom), 7.68 (d, J = 8.0 Hz, 1 Harom). 13C NMR (CDCl3,
100.6 MHz): 25.5, 28.8, 33. 6, 39.2, 43.0, 52.6, 78.5, 122.8, 125.5,
126.7 (q, J = 5.8 Hz), 127.8, 128.1, 132.5, 137.2, 133.7, 211.6.
HPLC analysis (Chiralpak AS-H column, hexane:2-propanol =
90:10, flow rate = 0.7 mL/min, wavelength = 254 nm): Rt = 10.71
(minor) and 12.16 min (major).
Preparation of (S)- and (R)-1-glucosyl-3-(pyrrolidin-2-ylmethyl)-
thiourea trifluoroacetate (3a,b). The N-Boc-derivative (590 mg,
1.0 mmol) was dissolved in a mixture of trifluoroacetic acid and
dichloromethane (4 mL, V/V = 1:1) and the resulting solution
was stirred for 2 h at room temperature. After removal of solvent,
the crude product was purified through column chromatography
on silica gel (200–300 mesh, ethyl acetate) to afford the target
compound as a white solid.
(S)-1-Glucosyl-3-(pyrrolidin-2-ylmethyl)-thiourea trifluoroace-
◦
tate (3a). 543 mg, 90% yield, m.p. 86–89 C, [a]2D0 -4.1 (c 1.4,
CHCl3). 1H NMR (CDCl3, 300 MHz): d 1.78–1.82 (m, 1 H), 1.99
(s, 6 H), 2.00 (s, 3 H), 2.04 (s, 3 H), 2.10–2.13 (m, 3 H), 3.33 (s, 2
H), 3.82–3.85 (m, 2 H), 3.99 (s, 2 H), 4.10–4.14 (m, 1 H), 4.21 (dd,
J = 3.9 and 12.0 Hz, 1 H), 4.96 (t, J = 9.3 Hz, 1 H), 5.05 (t, J =
9.6 Hz, 1 H), 5.28 (t, J = 9.3 Hz, 1 H), 5.60–5.62 (m, 1 H), 7.53
(S)-2-((R)-2-Nitro-1-(3-trifluoromethylphenyl)ethyl)-cyclohexa-
none (5c). Pale yellow oil, 95% yield, [a]2D0 -15.6 (c 0.9, CHCl3),
syn/anti = 98.5/1.5, 93% ee. 1H NMR (CDCl3, 300 MHz): d 1.56–
1.83 (m, 5 H), 2.04–2.13 (m, 1 H), 2.33–2.51 (m, 2 H), 2.70 (m, 1 H),
3.86 (dt, J = 4.8 and 9.6 Hz, 1 H), 4.67 (dd, J = 9.6 and 12.9 Hz, 1
H), 4.96 (dd, J = 4.5 and 12.9 Hz, 1 H), 7.38–7.55 (m, 4 Harom).
13C NMR (CDCl3, 75.0 MHz): 25.1, 28.3, 33.2, 42.7, 43.8, 52.4,
78.3, 124.7, 124.7, 124.8, 124.8, 124.9, 124.9, 124.9, 125.0, 129.5,
131.7, 139.1, 211.1. HRMS (ESI) m/z calc’d for C15H16F3NO3
[M + Na]+: 338.0974, found 338.0979. C15H16F3NO3 (315.28):
calcd. C 57.14, H 5.12, N 4.44; found C 57.01, H 4.97, N 4.33.
HPLC analysis (Chiralpak AS-H column, Hexane:2-propanol =
90:10, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 11.71
(minor) and 21.06 min (major).
(br. s, 1 H), 8.49 (br. s, 1 H), 9.09 (br. s, 1 H), 9.96 (br. s, 1 H). 13
C
NMR (CDCl3, 75.0 MHz): 20.5, 20.5, 20.6, 20.7, 24.0, 27. 8, 45.3,
45.4, 61.0, 61.6, 68.2, 70.7, 73.1, 73.2, 82.4, 114.6, 169.5, 169.9,
170.7, 170.8, 185.3. IR (KBr): n 3279, 1748, 1675, 1537, 1369,
1231, 1063 cm-1. HRMS (ESI) m/z calc’d for C22H32F3N3O11S
[M - CF3CO2H + H]+: 490.1854, found 490.1845.
(R)-1-Glucosyl-3-(pyrrolidin-2-ylmethyl)-thiourea trifluoroace-
◦
14
406
tate (3b). 597 mg, 99% yield, m.p. 90–92 C, [a] -25.0 (c 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): d 1.69–1.73 (m, 1 H), 1.92
(s, 3 H), 1.95 (s, 3 H), 1.96 (s, 3 H), 1.98 (s, 3 H), 2.10–2.13 (m, 3 H),
3.28 (s, 2 H), 3.80–4.12 (m, 5 H), 4.90–5.01 (m, 4 H), 5.24 (t, J =
9.3 Hz, 1 H), 7.60 (br. s, 1 H), 8.30 (br. s, 1 H), 8.88 (br. s, 1 H), 9.23
(br. s, 1 H). 13C NMR (CDCl3, 100.6 MHz): 20.3, 20.4, 20.4, 23.7,
27.6, 45.3, 60.8, 61.5, 67.8, 70.5, 72.8, 73.0, 82.3, 114.8, 169.5,
169.9, 170.1, 170.2, 185.4. IR (KBr): n 3686, 3063, 1749, 1681,
1553, 1371, 1207, 1038 cm-1. Anal. calc’d for C22H32F3N3O11S: C,
43.78; H, 5.34; N, 6.96; Found: C, 43.52; H, 5.12; N, 7.03.
(S)-2-((R)-2-Nitro-1-(4-trifluoromethylphenyl)ethyl)-cyclohexa-
◦
17
none (5d). Yellow solid, 71% yield, m.p. 79–81 C, [a]2D0 -21.4
(c 1.4, CHCl3), syn/anti = 97/3, 95% ee. 1H NMR (CDCl3,
300 MHz): d 1.22–1.30 (m, 1H), 1.59–1.82 (m, 4 H), 2.06–2.10
(m, 1 H), 2.32–2.50 (m, 2 H), 2.65–2.74 (m, 1 H), 3.86 (dt, J = 4.5
and 9.6 Hz, 1H), 4.66 (dd, J = 9.9 and 12.6 Hz, 1 H), 4.96 (dd, J =
4.5 and 12.6 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 2 Harom), 7.58 (d, J =
8.1 Hz, 2 Harom). 13C NMR (CDCl3, 75.0 MHz): 25.1, 28.3, 33.2,
42.7, 43.8, 52.4, 78.3, 125.9 (q, J = 3.8 Hz), 128.7, 129.9, 130.3,
142.1, 211.1. HPLC analysis (Chiralpak AS-H column, Hexane:2-
propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 11.03 (minor) and 16.63 min (major).
General procedure for thiourea 3 catalyzed asymmetric Michael
addition to nitroolefins
A mixture of the catalyst 3 (0.046 mmol) and triethylamine
(0.046 mmol) in cyclohexanone (226 mg, 2.3 mmol) was stirred
at room temperature for 30 min. Then, n-butyric acid (2 mg,
0.023 mmol) was added, and the reaction mixture was stirred
for 15 min. To the resulting mixture was added nitroolefin
(0.23 mmol) at the required temperature. After the reaction was
complete (monitored by TLC), the mixture was purified by column
chromatography on silica gel (200–300 mesh, PE/EtOAc =
15 : 1–10 : 1) to afford the product.
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)-cyclohexanone
◦
18
(5e). Pale yellow solid, 86% yield, m.p. 93–96 C, [a]2D0 -28.1
(c 1.6, CHCl3), syn/anti = 98/2, 94% ee. 1H NMR (CDCl3,
400 MHz): d 1.17–1.23 (m, 1H), 1.55–1.81 (m, 4 H), 2.06–2.11
(m, 1 H), 2.33–2.48 (m, 2 H), 2.61–2.68 (m, 1 H), 3.75 (dt, J = 4.4
and 10.0 Hz, 1 H), 4.60 (dd, J = 10.4 and 12.4 Hz, 1 H), 4.93 (dd,
J = 4.4 and 12.4 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2 Harom), 7.29 (d,
J = 8.0 Hz, 2 Harom). 13C NMR (CDCl3, 75.0 MHz): 25.0, 28.4,
33.1, 42.7, 43.4, 52.4, 78.6, 129.1, 129.6, 133.6, 136.4, 211.4. HPLC
analysis (Chiralpak AS-H column, hexane:2-propanol = 90:10,
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (5a).12b White
◦
solid, 98% yield, m.p. 124–126 C, [a]2D0 -31.5 (c 1.3, CHCl3),
1
syn/anti = 99/1, 95% ee. H NMR (CDCl3, 300 MHz): d 1.10–
3144 | Org. Biomol. Chem., 2009, 7, 3141–3147
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flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 16.25
2.34–2.46 (m, 2 H), 2.57–2.67 (m, 1 H), 3.66–3.72 (m, 1H), 3.75
(s, 3 H), 4.56 (dd, J = 9.9 and 12.3 Hz, 1 H), 4.89 (dd, J =
4.5 and 12.3 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 2 Harom), 7.06 (d,
J = 8.7 Hz, 2 Harom). 13C NMR (CDCl3, 75.0 MHz): 25.0, 28.5,
33.1, 42.7, 43.2, 52.7, 55.2, 79.1, 114.3, 129.2, 129.6, 159.0, 212.0.
HPLC analysis (Chiralpak AS-H column, Hexane:2-propanol =
90:10, flow rate = 0.7 mL/min, wavelength = 254 nm): Rt = 27.43
(minor) and 35.48 min (major).
(minor) and 26.15 min (major).
(S)-2-((R)-1–4-Fluorophenyl-2-nitroethyl)cyclohexanone (5f).
◦
Pale yellow solid, 78% yield, m.p. 64–66 C, [a]2D0 -18.9 (c 1.8,
CHCl3), syn/anti = >99/1, 95% ee. 1H NMR (CDCl3, 400 MHz):
d 1.10–1.25 (m, 1 H), 1.56–1.82 (m, 4 H), 2.01–2.10 (m, 1 H),
2.34–2.49 (m, 2 H), 2.65 (m, 1 H), 3.77 (dt, J = 4.0 and 9.6 Hz, 1
H), 4.60 (t, J = 11.2 Hz, 1 H), 4.93 (dd, J = 4.0 and 12.4 Hz, 1
H), 7.01 (dd, J = 8.0 and 8.4 Hz, 2 Harom), 7.15 (dd, J = 5.6 and
6.8 Hz, 2 Harom). 13C NMR (CDCl3, 100.6 MHz): 24.0, 27.4,
32.1, 41.7, 42.3, 51.5, 77.8, 114.9 (d, J = 21.4 Hz), 128.8 (d, J =
8.0 Hz), 132.5 (d, J = 3.2 Hz), 161.1 (d, J = 246.7 Hz), 210.7.
HPLC analysis (Chiralpak AS-H column, hexane:2-propanol =
90:10, flow rate = 0.7 mL/min, wavelength = 238 nm): Rt =
26.01 (minor) and 37.87 min (major).
8a
(S)-2-((R)-1-(4-Methylphenyl)-2-nitroe◦thyl)-cyclohexanone
(5k). 18 White solid, 81% yield, m.p. 123–126 C, [a]2D0 -23.8 (c 1.3,
CHCl3), syn/anti = 98/2, 93% ee. 1H NMR (CDCl3, 400 MHz):
d 1.19–1.26 (m, 1H), 1.54–1.80 (m, 4 H), 2.05–2.09 (m, 1 H), 2.31
(s, 3 H), 2.34–2.49 (m, 2 H), 2.63–2.70 (m, 1 H), 3.71 (dt, J = 4.4
and 10.0 Hz, 1 H), 4.60 (dd, J = 10.4 and 12.0 Hz, 1 H), 4.91 (dd,
J = 4.4 and 12.4 Hz, 1 H), 7.04 (d, J = 7.6 Hz, 2 Harom), 7.12 (d,
J = 7.6 Hz, 2 Harom). 13C NMR (CDCl3, 100.6 MHz): 20.0, 24.0,
27.5, 32.2, 41.7, 42.6, 51.6, 78.0, 127.0, 128.6, 133.6, 136.4, 211.1.
HPLC analysis (Chiralpak AS-H column, hexane:2-propanol =
90:10, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.78
(minor) and 17.96 min (major).
(S)-2-((R)-1-(2,4-Dichlorophenyl)-2-nitroethyl)-◦cyclohexanone
12b
(5g).
Colorless crystal, 87% yield, m.p. 98–99 C, [a]2D0 -27.0
1
(c 1.0, CHCl3), syn/anti = >99/1, 94% ee. H NMR (CDCl3,
400 MHz): d 1.25–1.34 (m, 1H), 1.65–1.83 (m, 4 H), 2.11 (s, 1 H),
2.38–2.46 (m, 2 H), 2.87 (s, 1 H), 4.25 (s, 1 H), 4.88 (s, 2 H),
7.18–7.24 (m, 2 Harom), 7.40 (s, 1 Harom). 13C NMR (CDCl3,
75.0 MHz): 25.2, 28.4, 33.0, 40.6, 42.8, 51.6, 76.9, 127.7, 130.1,
130.3, 134.1, 134.2, 135.2, 211.2. HPLC analysis (Chiralpak AS-H
column, hexane:2-propanol = 90:10, flow rate = 0.8 mL/min,
wavelength = 238 nm): Rt = 13.69 (minor) and 22.87 min (major).
(S)-2-((R)-1-(2,4-Dimethoxyphenyl)-2-nitroethyl)-cyclohexa-
none (5l). 18 Yellow oil, 90% yield, [a]D20 -30.0 (c 1.2, CHCl3),
1
syn/anti = 97/3, 93% ee. H NMR (CDCl3, 300 MHz): d 1.12–
1.21 (m, 1H), 1.54–1.79 (m, 4 H), 2.03–2.07 (m, 1 H), 2.31–2.48 (m,
2 H), 2.92 (dt, J = 5.1 and 11.4 Hz, 1 H), 3.76 (s, 3 H), 3.80 (s, 3 H),
3.85–3.91 (m, 1H), 4.77–4.79 (m, 2 H), 6.37–6.43 (m, 2 Harom),
6.96 (d, J = 8.1 Hz, 1 Harom). 13C NMR (CDCl3, 75.0 MHz):
25.1, 28.5, 29.6, 33.2, 40.8, 42.6, 50.8, 55.2, 55.4, 77.7, 99.1, 104.4,
117.7, 131.4, 158.6, 160.4, 212.6. HPLC analysis (Chiralpak AS-
H column, hexane:2-propanol = 2:98, flow rate = 1.0 mL/min,
wavelength = 254 nm): Rt = 38.05 (minor) and 55.05 min (major).
(S)-2-((R)-1-(5-Chloro-2-nitrophenyl)-2-nitroethyl)-cyclohexa-
none (5h). Brown oil, 98% yield, [a]2D0 -137.9 (c 0.95, CHCl3),
syn/anti = 98/2, 97% ee. 1H NMR (CDCl3, 400 MHz): d 1.50–1.55
(m, 1H), 1.67 (broad s, 2 H), 1.6 (broad s, 2 H), 2.12 (broad s, 1 H),
2.36–2.49 (m, 2 H), 2.89 (broad s, 1 H), 4.37 (broad s, 1 H), 4.90
(broad s, 1 H), 7.39 (d, J = 8.4 Hz, 1 Harom), 7.47 (s, 1 Harom),
7.82 (d J = 8.4 Hz, 1 Harom). 13C NMR (CDCl3, 100.6 MHz):
25.3, 28.2, 29.6, 33.2, 42.8, 52.2, 77.1, 126.5, 128.8, 129.5, 135.3,
139.5, 149.0, 210.7. HRMS (ESI) m/z calc’d for C14H15ClN2O5
[M + Na]+: 349.0562, found 349.0567. C14H15ClN2O5 (326.73):
calcd. C 51.46, H 4.63, N 8.57; found C 51.28, H 4.57, N 8.37.
HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol =
95:5, flow rate = 0.7 mL/min, wavelength = 220 nm): Rt = 59.75
(major) and 87.55 min (minor).
(S)-2-((R)-1-(4-Benzyloxyphenyl)-2-nitroethyl)◦-cyclohexanone
(5m). White solid, >99% yield, m.p. 167–168 C, [a]2D0 -18.4
(c 1.1, CHCl3), syn/anti = 97/3, 92% ee. 1H NMR (CDCl3,
400 MHz): d 1.42–1.81 (m, 5 H), 2.06–2.09 (m, 1 H), 2.34–2.49
(m, 2 H), 2.62–2.68 (m, 1 H), 3.72 (dt, J = 4.4 and 9.6 Hz, 1 H),
4.59 (dd, J = 10.4 and 11.6 Hz, 1 H), 4.91 (dd, J = 4.4 and
12.4 Hz, 1 H), 6.93 (d, 2 Harom), 7.09 (d, 2 Harom), 7.33–7.43 (m,
5 Harom). 13C NMR (CDCl3, 75.0 MHz): 25.0, 28.5, 33.1, 42.7,
43.3, 52.7, 70.1, 79.1, 115.2, 127.5, 128.0, 128.6, 129.2, 130.0, 136.9,
158.4, 211.9. HRMS (ESI) m/z calc’d for C21H23NO4 [M + Na]+:
376.1519, found 376.1522. C21H23NO4 (353.40): calcd. C 71.37,
H 6.56, N 3.96; found C 71.09, H 6.43, N 3.76. HPLC analysis
(Chiralpak AD-H column, Hexane:2-propanol = 98:2, flow rate =
1.0 mL/min, wavelength = 254 nm): Rt = 45.67 (minor) and
56.00 min (major).
(S)-2-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)-cyclohexanone
19
(5i).
White solid, 82% yield, m.p. 97–100 ◦C, [a]D20 -28.5 (c 1.3,
CHCl3), syn/anti = 98/2, 94% ee. 1H NMR (CDCl3, 400 MHz):
d 1.19–1.22 (m, 1H), 1.56–1.79 (m, 4 H), 2.05–2.08 (m, 1 H),
2.34–2.49 (m, 2 H), 2.97 (dt, J = 4.8 and 11.2 Hz, 1 H), 3.84
(s, 3 H), 3.93–3.99 (m, 1H), 4.78–4.87 (m, 2 H), 6.87 (d, J =
8.4 Hz, 1 Harom), 6.88 (t, J = 8.4 Hz, 1 Harom), 7.08 (d,
J = 7.2 Hz, 1 Harom), 7.24 (t, J = 8.0 Hz, 1 Harom). 13C
NMR (CDCl3, 100.6 MHz): 25.2, 28.6, 33.3, 41.3, 42.7, 50.7,
55.4, 77.5, 111.0, 120.9, 125.4, 128.9, 131.0, 157.6, 212.5. HPLC
analysis (Chiralpak AS-H column, Hexane:2-propanol = 90:10,
flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 13.52
(minor) and 15.32 min (major).
(S)-2-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)-cyclohexa-
12b
none (5n).
Pale brown solid, >99% yield, m.p. 144–145 ◦C,
[a]2D0 -19.2 (c 1.3, CHCl3), syn/anti = >99/1, 96% ee. H NMR
(CDCl3, 400 MHz): d 1.19–1.22 (m, 1H), 1.56–1.69 (m, 2 H), 1.78
(br. s, 2 H), 2.06 (br. s, 1 H), 2.33–2.48 (m, 2 H), 2.58–2.62 (m,
1 H), 3.65–3.68 (m, 1H), 4.54 (t, J = 11.2 Hz, 1 H), 4.89 (dd,
J = 2.8 and 12.0 Hz, 1 H), 5.94 (s, 2 H), 6.61 (d, J = 7.6 Hz,
1 Harom), 6.64 (s, 1 Harom), 6.73 (d, J = 7.6 Hz, 1 Harom).
13C NMR (CDCl3, 100.6 MHz): 25.0, 28.5, 33.1, 42.7, 43.7, 52.7,
79.0, 101.2, 108.0, 108.6, 121.7, 131.3, 147.1, 148.1, 211.9. HPLC
analysis (Chiralpak AD-H column, hexane:2-propanol = 85:15,
1
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitro◦ethyl)-cyclohexanone
(5j). 12b White solid, 96% yield, m.p. 115–117 C, [a]2D0 -224.4 (c 1.2,
CHCl3), syn/anti = 98/2, 92% ee. 1H NMR (CDCl3, 300 MHz):
d 1.19–1.25 (m, 1H), 1.53–1.74 (m, 4 H), 2.04–2.08 (m, 1 H),
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flow rate = 0.5 mL/min, wavelength = 254 nm): Rt = 27.71
(major, syn), 43.17 (minor, syn), 40.05 (major, anti) and 46.92 min
(minor, anti).
(minor) and 29.02 min (major).
12b
(R)-5-Nitro-4-phenylpentan-2-one (6).
White solid, 75%
(S)-2-((R)-1-(Naphthalen-1-yl)-2-nitroethyl)-cyclohexanone
(5o).
yield, m.p. 90–92 ◦C, [a]D20 -3.4 (c 1.7, CHCl3), 40% ee. 1H NMR
(CDCl3, 400 MHz): d 2.10 s, 3H), 2.91 (d, J = 6.8 Hz, 2 H), 4.00 (t,
J = 6.8 Hz, 1 H), 4.56–4.71 (m, 2 H), 7.20–7.22 (m, 2 Harom), 7.26–
7.32 (m, 3 Harom). 13C NMR (CDCl3, 100.6 MHz): 30.3, 39.0,
46.1, 79.4, 109.0, 127.3, 127.8, 129.0, 138.8, 205.4. HPLC analysis
(Chiralpak AD-H column, hexane:2-propanol = 99:1, flow rate =
0.5 mL/min, wavelength = 254 nm): Rt = 19.70 (minor) and
29.55 min (major).
◦
12b
Pale brown solid, 88% yield, m.p. 116–119 C, [a]D20
-101.4 (c 1.1, CHCl3), syn/anti = 99/1, 94% ee. 1H NMR (CDCl3,
400 MHz): d 1.20–1.30 (m, 1H), 1.50–1.69 (m, 4 H), 2.06–2.09 (m,
1 H), 2.37–2.52 (m, 2 H), 2.87 (s, 1 H), 4.77 (s, 1H), 4.91 (dd, J =
9.2 and 12.4 Hz, 1 H), 5.07 (dd, J = 4.0 and 12.4 Hz, 1 H), 7.38
(d, J = 7.6 Hz, 1 Harom), 7.44–7.58 (m, 3 Harom), 7.78 (d, J =
8.0 Hz, 1 Harom), 7.86 (d, J = 8.0 Hz, 1 Harom), 8.17 (s, 1 Harom).
13C NMR (CDCl3, 100.6 MHz): 24.3, 27.7, 32.3, 35.8, 41.9, 52.8,
77.7, 121.8, 122.6, 124.4, 124.9, 125.6, 127.2, 128.0, 131.4, 133.0,
133.7, 211.3. HPLC analysis (Chiralpak AS-H column, hexane:2-
propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 238
nm): Rt = 11.48 (minor) and 16.16 min (major).
12b
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclopentanone (7).
Brown
oil, 70% yield, [a]2D0 -26.0 (c 1.0, CHCl3), syn/anti = 72.5/27.5,
79% ee (syn), 77% ee (anti). 1H NMR (CDCl3, 400 MHz): d 1.43–
1.53 (m, 1H), 1.68–1.73 (m, 1 H), 1.86–1.90 (m, 2 H), 2.08–2.17
(m, 1 H), 2.25–2.26 (m, 0.27 H, anti), 2.36–2.42 (m, 1 H), 2.51–2.53
(m, 0.31 H, anti), 3.68–3.70 (m, 0.70 H, syn), 3.82–3.83 (m, 0.30
H, anti), 4.08–4.09 (m, 0.26 H, anti), 4.71 (t, J = 11.2 Hz, 0.71
H, syn), 5.01 (d, J = 7.2 Hz, 0.71 H, syn), 5.33 (d, J = 12.8 Hz,
1 H, syn), 7.15–7.19 (m, 2 Harom), 7.26–7.31 (m, 3 Harom). 13C
NMR (CDCl3, 100.6 MHz): 20.3 (syn), 20.6 (anti), 28.3 (syn), 29.7
(anti), 38.7 (syn), 39.3 (anti), 44.0 (anti), 44.2 (syn), 50.5 (syn),
51.4 (anti), 77.2 (anti), 78.3 (syn), 127.9 (anti), 128.0 (anti), 128.0
(syn), 128.5 (syn), 128.8 (syn), 128.9 (syn), 129.0 (anti), 130.9 (anti),
137.4 (anti), 137.5 (syn), 218.5 (syn), 219.1 (anti). HPLC analysis
(Chiralpak AD-H column, Hexane:2-propanol = 95:5, flow rate =
1.0 mL/min, wavelength = 220 nm): Rt = 12.29 (major, anti), 14.20
(minor, anti), 15.87 (minor, syn) and 21.09 min (major, syn).
(S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl)cyclohexanone
(5p).
Brown oil, 81% yield, [a]D20 -8.23 (c 0.85, CHCl3), syn/anti =
12b
92/8, 92% ee. 1H NMR (CDCl3, 400 MHz): d 1.29–1.32 (m,
1H), 1.61–1.84 (m, 4 H), 2.08–2.09 (m, 1 H), 2.32–2.47 (m, 2
H), 2.71–2.77 (m, 1 H), 3.93–3.99 (m, 1 H), 4.63–4.69 (m, 1 H),
4.78 (dd, J = 4.0 and 12.4 Hz, 1 H), 6.17 (s, 1 Harom), 6.27 (s, 1
Harom), 7.37 (s, 1 Harom). 13C NMR (CDCl3, 100.6 MHz): 25.1,
27.2, 32.5, 37.6, 42.6, 51.1, 76.7, 109.0, 110.3, 142.3, 151.0, 211.0.
HPLC analysis (Chiralpak AD-H column, hexane:2-propanol =
98:2, flow rate = 0.7 mL/min, wavelength = 254 nm): Rt = 31.34
(major) and 40.84 min (minor).
(S)-2-((S,E)-1-Nitro-4-phenylbut-3-en-2-yl)-cyclohexanone
◦
(5q). Pale yellow solid, 92% yield, m.p. 78–81 C, [a]2D0 -40.0
(c 1.1, CHCl3), syn/anti = 95/5, 94% ee. 1H NMR (CDCl3,
400 MHz): d 1.42–1.51 (m, 1H), 1.66–1.71 (m, 3 H), 2.16–2.20
(m, 2 H), 2.33–2.48 (m, 2 H), 3.35–3.38 (m, 1H), 4.56–4.76 (m, 2
H), 6.03 (dd, J = 9.6, 15.6 Hz, 1 H), 6.50 (d, J = 15.6 Hz, 1 H),
7.25–7.34 (m, 5 Harom). 13C NMR (CDCl3, 100.6 MHz): 25.0,
28.1, 32.5, 41.9, 42.6, 51.7, 78.0, 125.7, 126.4, 127.9, 128.6, 134.4,
136.3, 211.2. HRMS (ESI) m/z calc’d for C16H19NO3 [M + Na]+:
296.1257, found 296.1263. C16H19NO3 (273.32): calcd. C 70.31,
H 7.01, N 5.12; found C 70.27, H 6.95, N 5.02. HPLC analysis
(Chiralpak AD-H column, hexane:2-propanol = 99:1, flow rate =
0.5 mL/min, wavelength = 254 nm): Rt = 84.23 (minor) and
87.01 min (major).
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 20772058) for generous financial support for our
programs.
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(S)-2-((S)-1-Nitro-4-phenylbutan-2-yl)cyclohexanone
(5r).
Colorless oil, 92% yield, [a]2D0 -15.1 (c 1.7, CHCl3), syn/anti =
76/24, 93% ee (syn), 88% ee (anti). 1H NMR (CDCl3, 400 MHz):
d 1.43–1.53 (m, 1H), 1.64–1.70 (m, 3 H), 1.81–1.86 (m, 1 H),
1.93–1.95 (m, 1 H), 2.09–2.14 (m, 2 H), 2.28–2.39 (m, 2 H),
2.51–2.55 (m, 1 H), 2.63–2.72 (m, 3 H), 4.36 (dd, J = 6.0 and
12.4 Hz, 0.21 H, anti), 4.46 (dd, J = 6.0 and 12.4 Hz, 0.71 H, syn),
4.62 (dd, J = 6.0 and 12.4 Hz, 1 H), 7.17–7.22 (m, 3 Harom),
7.28–7.31 (m, 2 Harom). 13C NMR (CDCl3, 100.6 MHz): 25.1
(anti), 25.2 (syn), 27.3 (anti), 27.6 (syn), 29.8 (anti), 30.2 (syn),
30.8 (anti), 31.3 (syn), 33.5 (syn), 33.7 (anti), 36.9 (anti), 37.0
(syn), 42.4 (anti), 42.5 (syn), 51.1 (anti), 51.4 (syn), 76.9, 126.1,
128.2, 128.5, 141.1, 211.1. HRMS (ESI) m/z calc’d for C16H21NO3
[M + Na]+: 298.1414, found 298.1411. C16H21NO3 (275.34): calcd.
C 69.79, H 7.69, N 5.09; found C 69.54, H 7.45, N 4.88. HPLC
analysis (Chiralpak AD-H column, Hexane:2-propanol = 99:1,
flow rate = 0.5 mL/min, wavelength = 254 nm): Rt = 38.39
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