New approach to the preparation of bicyclo octane derivatives via the enantioselective cascade reaction catalyzed by chiral diamine-Ni(OAc) 2 complex

Article abstract of DOI:10.1039/c2ob25135c

A highly efficient catalyst system assembled from enantiomerically pure diaminocyclohexane and Ni(OAc)₂ is, for the first time, used to catalyze the cascade Michael-Henry reaction of various diones and substituted nitroalkenes. A series of polyfunctionalized bicyclo[3.2.1]octane derivatives containing four stereogenic centers are prepared with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to 50:1 dr) with high yields. In addition, via this chiral diamine-Ni(OAc)₂ catalyst system, the base-induced epimerization leading to the decrease of stereoselectivity can be prevented.

Full text of DOI:10.1039/c2ob25135c

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PAPER
New approach to the preparation of bicyclo octane derivatives via the
enantioselective cascade reaction catalyzed by chiral diamine-Ni(OAc)2
complex†
Wenyi Li,‡ Xiaodong Liu,‡ Zhifeng Mao, Qiao Chen and Rui Wang*
Received 18th January 2012, Accepted 17th April 2012
DOI: 10.1039/c2ob25135c
A highly efficient catalyst system assembled from enantiomerically pure diaminocyclohexane and
Ni(OAc)2 is, for the first time, used to catalyze the cascade Michael–Henry reaction of various diones
and substituted nitroalkenes. A series of polyfunctionalized bicyclo[3.2.1]octane derivatives containing
four stereogenic centers are prepared with excellent enantioselectivities (up to >99% ee) and
diastereoselectivities (up to 50 : 1 dr) with high yields. In addition, via this chiral diamine-Ni(OAc)2
catalyst system, the base-induced epimerization leading to the decrease of stereoselectivity can be
prevented.
diaminocyclohexane-Ni(OAc)2 catalyst system in the asym-
Introduction
metric conjugate addition of nitroalkenes has recently been
reported by both Sodeoka’s and Yuan’s groups separately.5
During the past few years, the cascade reaction has represented a
flourishing area within organic chemistry. Significant progress
has been made in the development of organocatalyzed asym-
metric cascade reactions using chiral secondary amines.1 These
straightforward routes—which allow two or more reactions to
occur in a single operation under the same reaction conditions—
avoid the need for costly protecting-group manipulations,
changes in the reaction conditions, or isolation of any inter-
mediates. Moreover, in this way, molecular complexities are
often achieved efficiently, accompanied by high levels of stereo-
selectivity.2 Therefore, with the significant improvement of syn-
thetic efficiency and the reduction of waste and hazardous by-
products, the exploration of catalyzed cascade reactions by
employing a single chiral secondary amine catalyst capable of
promoting each single step is one of the major topics in current
research.3
Herein, we report our recent effort in the development of
Ni(OAc)2-diamine-catalyzed cascade reaction of nitroalkenes
with 1,2-diones6 to provide a series of functionalized bicyclo-
[3.2.1]octane derivatives which are important components of
neolignan molecules. These natural compounds have been found
to exhibit significant biological activities (e.g. PAF-antagonistic
activity) and have attracted particular interest in synthesis
(Fig. 1).7
Compared to previous reports,8 our reaction produced functio-
nalized bicyclo[3.2.1]octane derivatives in a different stereo-
configuration (S,S,R,S) with higher yields, diastereo- and
enantio-selectivities and shorter reaction times. Some other sub-
stituted bicyclo[2.2.1]octane and five-membered cyclic deriva-
tives were also efficiently prepared under our Ni(OAc)2-diamine-
catalyzed system. In addition, the decrease in stereoselectivity
caused by the base-induced epimerization was prevented in this
catalyzed system.
Benzylated diaminocyclohexanes, which belong to vicinal
diamines bearing a versatile stereochemical control element,
typically combine a flexible and economically feasible syn-
thetic route, strongly binding to the metal centre, together
with excellent enantioselectivities for a variety of mechanisti-
cally diverse reactions.4 Research utilizing benzylated
Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
School of Basic Medical Science, Institute of Biochemistry and
Molecular Biology School of Life Science, Lanzhou University, Lanzhou
730000, China. E-mail: wangrui@lzu.edu.cn; Fax: (+86) 931-891-2567
†Electronic supplementary information (ESI) available. CCDC 860005.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob25135c
‡These authors contributed equally to this work.
Fig. 1 Natural products with bicyclo[3.2.1]octane core.
Org. Biomol. Chem., 2012, 10, 4767–4773 | 4767
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diastereoselective ratio was obtained when there was an ortho-
bromine substituent at the aromatic ring. The substrate 2b gave
the best result: the corresponding adduct 4b was offered in excel-
lent yield with a 50 : 1 dr and a >99% ee value. The additions of
heteroaromatic nitro-olefin derived from furyl proceeded equally
well with excellent enantioselectivity and diastereoselectivity.
The more sterically hindered nitroalkene bearing a 2-naphthyl
group was also a suitable substrate. In addition, the correspond-
ing adduct 4k was prepared smoothly when the α-bromonitro-
alkene 2k was used in the reaction.
To evaluate the effectiveness of 3b-Ni(OAc)2 catalyst
system in these reactions, several alkyl-substituted nitroalkenes
were subjected to the optimized conditions. As shown in
Table 2, excellent enantioselectivities with moderate to
high diastereoisomeric ratios were obtained for the aliphatic
nitroalkenes.
Furthermore, several different diones were evaluated and the
1,2-cyclopentanedione was found to be a good substrate for the
present method. A high enantioselectivity (97% ee value) with
an excellent diastereoselectivity (29 : 1 dr) was also obtained
while the alkyl 3,4-hexanedione was used as a substrate.
It is worth noting that a base-catalyzed isomerization was
observed in the Reuping’s report: the longer reaction time lasted,
the lower the diastereoisomeric ratio was obtained. However,
long reaction time had none of adverse effect on the stereoselec-
tivities in the benzylated diaminocyclohexane-Ni(OAc)2 cata-
lyzed system. The stereoselectivity of the reaction was
maintained when the reaction time was prolonged from 6 hours
to 48 hours. Thus, it suggested that comparing to the strong basi-
city exhibited by bifunctional thiourea catalyst, the Benzylated
diaminocyclohexane-Ni(OAc)2 catalyst system owned weaker
basicity.
Results and discussion
At the outset of the study, we chose the benzylated diaminocy-
clohexane 3a as the ligand to catalyze the reaction. To our
delight, in the presence of 5 mmol% Ni(OAc)2, the reaction
reached completion within 5 h at room temperature to afford the
desired product 4a with 66% ee and 8 : 1 diastereoselectivity in
98% yield (Table 1, entry 1). Subsequently, we examined the
reaction at a lower temperature; however, negative effects were
observed when the reaction was performed at 0 and −18 °C.
Switching the solvents had an obvious effect on the stereoselec-
tivity of the reactions, with tetrahydrofuran proving to be the
optimal solvent (Table 1, entry 4). With this promising lead in
hand, we next sought to further optimize the reaction conditions.
A series of chiral benzylated diaminocyclohexanes ligands 3b–e
were evaluated in the model reaction (Table 1, entries 7–10).
Catalyst 3b exhibited the most effective activity and afforded the
product 4a with a high diastereomeric ratio of 10 : 1 and excel-
lent enantioselectivity of 98%. Replacing the protecting group at
the nitrogen atom with a sterically bulky group (2-naphthyl)
resulted in an increase of diastereoselectivity but an obvious
decrease of enantioselectivity. Some other complexes based on
ligand 3b with various salts, such as Cu(OAc)2 and Zn(OAc)2
showed adverse inductive potential for this reaction (Table 1,
entries 11 and 12).
With the optimized reaction conditions in hand, the substrate
scope of this cascade reaction was explored by the reaction of
1,2-diones with various substituted nitroalkenes. For the reaction
with the nucleophile 1a, the majority of the reactions proceeded
smoothly to furnish the corresponding masked bicyclo[3.2.1]-
octane derivatives in high yields with excellent diastereo- and
enantio-selectivities. The aromatic ring of aromatic nitroalkenes
tolerated both electron-donating and electron-withdrawing
The relative and absolute configurations of the products were
determined by X-ray crystal structure analysis of 4k (Fig. 2).†
functionalities at any other positions, although
a 5 : 4
Table 1 Optimization of the initial reactiona
Entry
Cat./MX2
Solvent
Time (h)
Yieldb (%)
drc
eed (%)
1
3a/Ni(Oac)2
3a/Ni(Oac)2
3a/Ni(Oac)2
3a/Ni(OAc)2
3a/Ni(OAc)2
3a/Ni(OAc)2
3b/Ni(OAc)2
3c/Ni(OAc)2
3d/Ni(OAc)2
3e/Ni(OAc)2
3e/Cu(OAc)2
3e/Zn(OAc)2
iPrOH
iPrOH
iPrOH
THF
Toluene
MeOH
THF
THF
THF
THF
THF
5
8
12
6
3
3
6
5
6
5
6
6
98
86
77
78
62
78
98
73
83
79
—
—
8 : 1
6 : 1
7 : 1
7 : 1
5 : 1
8 : 1
10 : 1
4 : 1
25 : 1
25 : 1
6 : 1
3 : 1
66
62
46
99
85
87
98
88
89
87
20
89
2e
3f
4
5
6
7
8
9
10
11
12
THF
a Reaction conditions: 0.5 mL solvent, 1,2-cyclohexadione 1 (0.75 mmol), nitroalkene 2 (0.5 mmol), 5 mol% catalyst (cat. : MX2 : EtN3 = 1 : 1 : 1)
at r.t. b Yields were determined after column chromatography. c Determined by 1H NMR spectroscopy. d Enantiomeric excess was determined by
HPLC. e The reaction was performed at 0 °C. f The reaction was performed at −18 °C.
4768 | Org. Biomol. Chem., 2012, 10, 4767–4773
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Table 2 Scope of the reactiona
a Reaction conditions: 0.5 mL solvent, 1,2-cyclohexadione 1 (0.75 mmol), nitroalkene 2 (0.5 mmol), 5 mol% catalyst (3b : Ni(OAc)2 : EtN3 = 1 : 1 : 1)
at r.t. b Yields were determined after column chromatography. c Determined by 1H NMR spectroscopy. d Enantiomeric excess was determined by
HPLC.
bulky aromatic group of chiral ligand 3b. The π–π stacking inter-
action between the enolate structure of the 1,2-dione and the
double bond of nitro-olefin probably has a favorable effect on
the stereoselectivity of the reaction. The resulting adduct sub-
sequently undergoes an intramolecular Henry reaction to
form the target product and is then released. Compared to the
hydrogen bond interaction in the bifunctional thiourea catalyst, a
strong complexation between the nickel and nitronate anion also
induced the high stereoselectivity.
Conclusion
In summary, for the first time we are able to report a simple cata-
lyst system assembled from enantiomerically pure diaminocyclo-
Fig. 2 X-ray Structure of the adduct 4k.
hexane and Ni(OAc)2 which has efficiently catalyzed the
On the basis of our experimental results and related studies, a
possible model to account for the high stereoselectivity of the
present reaction is shown in Scheme 1. We assume that at the
beginning of the transition state the nitronate anion is stabilized
by interaction at the open apical position on the nickel ion. A
Michael addition then occurs with the activated metal enolate
structure of the 1,2-diones. In the favored transition state, the
substituted group of the nitro-olefin is oriented away from the
cascade Michael–Henry reaction of various 1,2-diones with sub-
stituted nitroalkenes. A series of polyfunctionalized bicyclo
octane derivatives containing four consecutive stereogenic
centers were obtained in excellent enantioselectivities (up to
>99% ee) and diastereoselectivities (up to 50 : 1 dr) with high
yields. Furthermore, via this catalyzed system, the base-induced
epimerization leading to the decrease of stereoselectivity can be
prevented.
This journal is © The Royal Society of Chemistry 2012
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Scheme 1 Proposed reaction transition state.
Found: 279.1335; [α]Drt = +16 (c = 1.0 in CHCl3); HPLC:
DAICEL CHIRALCEL OJ-H, n-hexane/i-PrOH = 90/10, flow
rate = 1.0 mL min−1, retention time: tmajor = 17.4, tminor = 22.6,
98% ee.
Experimental
Materials
All reactions were monitored by thin layer chromatography
(TLC) and column chromatography purifications were carried
out using silica gel. All substrates were prepared according to the
literature. 1H NMR and 13C NMR spectra were recorded
(300 MHz and 75 MHz, respectively) using tetramethylsilane as
(1S,5S,6R,7S)-6-(4-Fluorophenyl)-1-hydroxy-7-nitrobicyclo-
[3.2.1]octan-8-one (4b). A single diastereoisomer in 98% yield
(diastereomeric ratio
=
50 : 1). Colorless oil. 1H NMR
1
internal reference. Data for H NMR are recorded as follows:
(300 MHz, CDCl3): δ 7.16–7.12 (m, 2H), 7.06–7.01 (m, 2H),
4.71 (d, J = 6 Hz, 1H), 4.17 (d, J = 6 Hz, 1H), 3.27 (s, 1H), 2.78
(s, 1H), 2.44–2.32 (m, 2H), 2.17–2.08 (m, 1H), 2.01–1.90 (m,
2H), 1.79–1.72 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 212.3,
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet,
t = triplet, m = multiplet, q = quartet, hept = heptet, coupling
constant(s) in Hz, integration). Data for 13C NMR are reported
in terms of chemical shift (δ, ppm). IR spectra were recorded on
a FTIR spectrometer. Optical rotations were reported as follows:
[α]2D0 (c: g 100 mL−1, in solvent). HR-MS was measured with an
APEX II 47e mass spectrometer. The ee value determination was
carried out using chiral HPLC with Daicel Chiralcel AD-H, IA,
OJ-H, AS column on Waters with a 996 UV-detector.
138.2 (JC–F = 3.75 Hz), 128.4 (JC–F = 8.25 Hz), 116.3(JC–F
=
21.75 Hz), 93.7, 81.6, 51.7, 43.3, 39.8, 36.0, 17.9; IR (CHCl3):
3444, 2954, 2927, 1763, 1550, 1511, 1452, 1370, 1335, 1231,
1138, 1100, 930, 835, 803, 672 cm−1
;
HRMS (ESI):
C14H14NFO4 + NH4, Calc: 297.1245, Found: 297.1242; [α]Drt
=
+9 (c = 1.0 in CHCl3); HPLC: DAICEL CHIRALCEL OJ-H,
n-hexane/i-PrOH = 95/5, flow rate = 1.0 mL min−1, retention
time: tmajor = 60.6, tminor = 70.2, >99% ee.
General procedure for the preparation of 4
(1S,5S,6R,7S)-6-(4-Bromophenyl)-1-hydroxy-7-nitrobicyclo-
[3.2.1]octan-8-one (4c). A single diastereoisomer in 77% yield
(diastereomeric ratio = 40 : 1). White solid. m.p. 148–152 °C.
1H NMR (300 MHz, CDCl3): δ 7.50–7.45 (m, 2H), 7.06–7.02
(m, 2H), 4.70 (d, J = 6 Hz, 1H), 4.14 (d, J = 5.7 Hz, 1H), 3.24
(s, 1H), 2.79–2.76 (m, 1H), 2.45–2.30 (m, 2H), 2.18–2.07
(m, 1H), 2.03–1.86 (m, 2H), 1.81–1.72 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 212.1, 141.2, 132.5, 128.5, 121.9, 93.3,
81.5, 51.5, 43.4, 39.8, 36.0, 17.9; IR (CHCl3): 3429, 2925,
Reaction conditions: 0.5 mL solvent, 1,2-cyclohexadione 1
(0.75 mmol), nitroalkene 2 (0.5 mmol), 5 mol% catalyst (3b : Ni-
(OAc)2 : EtN3 = 1 : 1 : 1) at R.T. After the reaction was complete
(as determined by TLC); the reaction mixture was concentrated,
and the residue was purified by flash chromatography (petroleum
ether–ethyl acetate, 5 : 1) to afford the product 4.
(1S,5S,6R,7S)-1-Hydroxy-7-nitro-6-phenylbicyclo[3.2.1]octan-
8-one (4a). A single diastereoisomer in 98% yield (diastereo-
meric ratio = 10 : 1). White solid. m.p. 143–150 °C. H NMR
(300 MHz, CDCl3): δ 7.37–7.28 (m, 3H), 7.17–7.14 (m, 2H),
4.77 (d, J = 5.7 Hz, 1H), 4.18 (d, J = 6 Hz, 1H), 3.28 (s, 1H),
2.81 (d, J = 2.1 Hz, 1H), 2.43–2.32 (m, 2H), 2.19–2.05 (m, 1H),
2.01–1.93 (m, 2H), 1.83–1.76 (m, 1H);
1763, 1549, 1490, 1371, 1138, 1074, 1010, 825, 732 cm−1
;
HRMS (ESI): C14H14NBrO4 + NH4, Calc: 357.0444, Found:
357.0439; [α]rDt = +12 (c = 1.0 in CHCl3); HPLC: DAICEL
CHIRALCEL OJ-H, n-hexane/i-PrOH = 90/10, flow rate =
1.0 mL min−1, retention time: tminor = 17.3, tmajor = 22.4, 97% ee.
13C NMR (75 MHz, CDCl3): δ 212.5, 142.3, 129.4, 127.9,
126.8, 93.7, 81.6, 51.6, 43.9, 39.9, 36.1, 18.0; IR (CHCl3):
3444, 2952, 1763, 1549, 1451, 1370, 1334, 1137, 754, 701,
678 cm−1; HRMS (ESI): C14H15NO4 + NH4, Calc: 279.1339,
(1S,5S,6R,7S)-6-(2-Bromophenyl)-1-hydroxy-7-nitrobicyclo-
[3.2.1]octan-8-one (4d). Both diastereoisomers in 99% yield
(diastereomeric ratio = 5 : 4). White solid. m.p. 139–144 °C.
4770 | Org. Biomol. Chem., 2012, 10, 4767–4773
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1H NMR (300 MHz, CDCl3): δ 7.62–7.59 (m, 1H), 7.34–7.29
(m, 1H), 7.18–7.13 (m, 1H), 7.02–6.99 (m, 1H), 5.09 (d, J = 6.3
Hz, 1H), 4.80 (d, J = 6.6 Hz, 1H), 3.31 (s, 1H), 2.63 (d, J = 3.9
Hz, 1H), 2.52–2.42 (m, 2H), 2.18–1.99 (m, 3H), 1.83–1.76 (m,
1H); 13C NMR (75 MHz, CDCl3): δ 212.4, 140.7, 133.7, 129.4,
128.6, 128.2, 123.7, 91.8, 81.8, 52.5, 43.1, 40.4, 36.4, 17.9;
IR (CHCl3): 3428, 2928, 1763, 1551, 1471, 1445, 1369, 1139,
1027, 929, 753 cm−1; HRMS (ESI): C14H14NBrO4 + NH4, Calc:
357.0444, Found: 357.0434; [α]rDt = −14 (c = 1.0 in CHCl3);
HPLC: DAICEL CHIRALCEL OJ-H, n-hexane/i-PrOH = 90/10,
(1S,5S,6R,7S)-6-(3,4-Dimethylphenyl)-1-hydroxy-7-nitrobicyclo-
[3.2.1]octan-8-one (4h). Both diastereoisomers in 91% yield
(diastereomeric ratio = 7 : 1). Yellow solid. m.p. 123–126 °C.
1H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 7.7 Hz, 1H),
6.91–6.86 (m, 2H), 4.78 (d, J = 5.9 Hz, 1H), 4.11 (d, J = 5.9 Hz,
1H), 3.42 (s, 1H), 2.76 (d, J = 2.8 Hz, 1H), 2.41–2.31 (m, 2H),
2.22 (s, 6H), 2.11–1.93 (m, 3H), 1.81–1.74 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 212.9, 139.9, 137.8, 136.3, 130.5, 127.8,
124.1, 93.8, 81.7, 51.8, 43.5, 39.8, 36.1, 19.8, 19.4, 17.9; IR
(CHCl3): 3381, 2924, 2855, 2023, 1758, 1546, 1455, 1371,
1232, 1135, 1058, 933, 801, 715, 668 cm−1; HRMS (ESI):
C15H17NO4 + Na, Calc: 312.1206, Found: 312.1217; [α]rDt = +12
(c = 1.0 in CHCl3); HPLC: DAICEL CHIRALCEL IA,
n-hexane/i-PrOH = 90/10, flow rate = 1.0 mL min−1, retention
time: tmajor = 13.0, tminor = 20.6, >97% ee.
flow rate = 1.0 mL min−1, retention time: tmajor = 28.7, tminor
34.1, 90% ee, tmajor = 58.5, tminor = 79.4, 91% ee.
=
(1S,5S,6R,7S)-1-Hydroxy-6-(4-methoxyphenyl)-7-nitrobicyclo-
[3.2.1]octan-8-one (4e). A single diastereoisomer in 74% yield
(diastereomeric ratio
=
50 : 1). Colorless oil. 1H NMR
(1S,5S,6S,7S)-6-(Furan-2-yl)-1-hydroxy-7-nitrobicyclo[3.2.1]-
octan-8-one (4i). Both diastereoisomers in 70% yield (diastereo-
meric ratio = 30 : 1). Colorless oil. 1H NMR (300 MHz, CDCl3):
δ 7.35 (d, J = 1.2 Hz, 1H), 6.31–6.30 (m, 1H), 6.19 (d, J = 3.3
Hz, 1H), 4.94 (d, J = 6 Hz, 1H), 4.30 (d, J = 5.7 Hz, 1H), 3.28
(s, 1H), 2.83 (d, J = 2.4 Hz, 1H), 2.43–2.29 (m, 2H), 2.15–2.05
(m, 1H), 2.02–1.86 (m, 2H), 1.78–1.70 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 211.1, 152.7, 143.1, 110.5, 106.5, 90.2,
81.2, 49.5, 39.8, 37.8, 35.5, 17.9; IR (CHCl3): 3431, 2926, 1766,
1551, 1453, 1371, 1335, 1141, 1070, 934, 743 cm−1; HRMS
(ESI): C12H13NO5 + NH4, Calc: 269.1132, Found: 269.1138;
[α]rDt = +48 (c = 1.0 in CHCl3); HPLC: DAICEL CHIRALCEL
OJ-H, n-hexane/i-PrOH = 95/5, flow rate = 1.0 mL min−1, reten-
tion time: tmajor = 33.5, tminor = 40.0, >99% ee.
(300 MHz, CDCl3): δ 7.10–7.05 (m, 2H), 6.88–6.83 (m, 2H),
4.73 (d, J = 5.7 Hz, 1H), 4.13 (d, J = 5.7 Hz, 1H), 3.79 (s, 3H),
3.27 (s, 1H), 2.77 (d, J = 2.7 Hz, 1H), 2.42–2.32 (m, 2H),
2.16–2.04 (m, 1H), 2.02–1.92 (m, 2H), 1.77–1.75 (m, 1H);
13C NMR (75 MHz, CDCl3): δ 212.6, 159.1, 134.5, 127.8,
114.7, 94.1, 81.6, 55.3, 51.8, 43.2, 39.8, 36.0, 17.9; IR (CHCl3):
3439, 2925, 1762, 1612, 1549, 1515, 1457, 1070, 1253, 1182,
1030, 831 cm−1; HRMS (ESI): C15H17NO4 + NH4, Calc:
309.1445, Found: 309.1447; [α]rDt = +10 (c = 1.0 in CHCl3);
HPLC: DAICEL CHIRALCEL AD-H, n-hexane/i-PrOH =
80/20, flow rate = 1.0 mL min−1, retention time: tmajor = 56.7,
tminor = 65.4, 98% ee.
(1S,5S,6R,7S)-1-Hydroxy-6-(3-methoxyphenyl)-7-nitrobicyclo-
[3.2.1]octan-8-one (4f). A single diastereoisomer in 98% yield
(diastereomeric ratio = 50 : 1). White solid. m.p. 144–149 °C.
1H NMR (300 MHz, CDCl3): δ 7.26 (t, J = 8.1 Hz, 1H),
6.83–6.79 (m, 1H), 6.72–6.70 (m, 2H), 4.78 (d, J = 6 Hz, 1H),
4.15 (d, J = 6 Hz, 1H), 3.79 (s, 3H), 3.27 (s, 1H), 2.81 (d, J =
2.4 Hz, 1H), 2.43–2.32 (m, 2H), 2.17–2.05 (m, 1H), 2.00–1.91
(m, 2H), 1.80–1.73 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
212.4, 160.2, 143.8, 130.6, 118.7, 112.9, 112.8, 93.5, 81.6, 55.3,
51.5, 43.9, 39.8, 36.0, 17.9; IR (CHCl3): 3439, 2937, 1763,
1602, 1549, 1454, 1370, 1267, 1050, 783, 699 cm−1; HRMS
(ESI): C15H17NO4 + NH4, Calc: 309.1445, Found: 309.1451;
[α]rDt = +10 (c = 1.0 in CHCl3); HPLC: DAICEL CHIRALCEL
(1S,5S,6R,7S)-1-Hydroxy-6-(naphthalen-2-yl)-7-nitrobicyclo-
[3.2.1]octan-8-one (4j). As both diastereoisomer in 99% yield
1
(diastereomeric ratio = 8 : 1). Yellow oil. H NMR (300 MHz,
CDCl3): δ 7.85–7.79 (m, 3H), 7.65 (s, 1H), 7.53–7.46 (m, 2H),
7.23–7.20 (m, 1H), 4.87 (d, J = 5.7 Hz, 1H), 4.36 (d, J = 6 Hz,
1H), 3.32 (s, 1H), 2.92 (d, J = 2.4 Hz, 1H), 2.46–2.37 (m, 2H),
2.21–2.01 (m, 3H), 1.86–1.75 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ 212.5, 139.3, 133.3, 132.6, 129.7, 127.8, 127.7,
126.8, 126.4, 125.7, 124.2, 93.5, 81.7, 51.6, 44.1, 39.9, 36.1,
18.0; IR (CHCl3): 3433, 2928, 1762, 1548, 1451, 1369, 1237,
1136, 1056, 818, 734, 478 cm−1; HRMS (ESI): C18H17NO4 +
NH4, Calc: 329.1496, Found: 329.1492; [α]rDt = +11 (c = 1.0 in
CHCl3); HPLC: DAICEL CHIRALCEL OJ-H, n-hexane/i-PrOH
= 90/10, flow rate = 1.0 mL min−1, retention time: tmajor = 52.3,
AD-H, n-hexane/i-PrOH = 80/20, flow rate = 1.0 mL min−1
retention time: tmajor = 33.6, tminor = 45.2, 98% ee.
,
(1S,5S,6R,7S)-1-Hydroxy-7-nitro-6-p-tolylbicyclo[3.2.1]octan-
8-one (4g). A single diastereoisomer in 80% yield (diastereo-
tminor = 69.6, 92% ee.
1
meric ratio = 6 : 1). Yellow solid. m.p. 135–143 °C. H NMR
(1R,5S,6R,7R)-7-Bromo-1-hydroxy-7-nitro-6-phenylbicyclo[3.2.1]-
(300 MHz, CDCl3): δ 7.14 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.1
Hz, 2H), 4.75 (d, J = 5.9 Hz, 1H), 4.14 (d, J = 5.9 Hz, 1H), 3.34
(s, 1H), 2.78 (d, J = 2.5 Hz, 1H), 2.43–2.35 (m, 2H), 2.32
(s, 3H), 2.17–1.92 (m, 3H), 1.77–1.73 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 212.7, 139.3, 137.6, 130.0, 126.6, 93.8,
81.6, 51.7, 43.5, 39.8, 36.0, 21.0, 17.9; IR (CHCl3): 3358, 2929,
2860, 2024, 1754, 1550, 1369, 1234, 1135, 1057, 930, 814, 672,
572, 513 cm−1; HRMS (ESI): C15H17NO4 + Na, Calc:
298.1050, Found: 298.1055; [α]rDt = +20 (c = 1.0 in CHCl3);
HPLC: DAICEL CHIRALCEL IA, n-hexane/i-PrOH = 90/10,
octan-8-one (4k). Both diastereoisomers in 99% yield (diastereo-
meric ratio = 20 : 1). Yellow solid. m.p. 178–188 °C. H NMR
1
(300 MHz, CDCl3): δ 7.34–7.28 (m, 5H), 4.23 (d, J = 1.5 Hz,
1H), 3.28 (s, 1H), 3.25–3.23 (m, 1H), 2.60–2.55 (m, 1H),
2.27–2.11 (m, 4H), 1.88–1.79 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ 210.8, 134.5, 128.8, 128.6, 128.5, 108.2, 85.2, 57.2,
48.7, 43.9, 36.6, 17.4; IR (CHCl3): 3394, 2957, 1767, 1568,
1447, 1343, 1151, 1087, 1075, 1028, 918, 742, 730, 700 cm−1
;
HRMS (ESI): C14H14NBrO4 + NH4, Calc: 357.0444, Found:
357.0439; [α]rDt = +8 (c = 1.0 in CHCl3); HPLC: DAICEL CHIR-
ALCEL AD-H, n-hexane/i-PrOH = 90/10, flow rate = 1.0 mL
min−1, retention time: tminor = 21.1, tmajor = 24.4, 82% ee.
flow rate = 1.0 mL min−1, retention time: tmajor = 20.4, tminor
=
30.0, >99% ee.
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(1S,5S,6S,7S)-6-Cyclohexyl-1-hydroxy-7-nitrobicyclo[3.2.1]-
octan-8-one (4l). Both diastereoisomers in 51% yield (diastereo-
meric ratio = 8 : 1). Yellow oil. H NMR (300 MHz, CDCl3): δ
(2S,3S,4R,5R)-2-Ethyl-2-hydroxy-5-methyl-3-nitro-4-phenyl-
cyclopentanone (4p). Both diastereoisomers in 91% yield (dia-
stereomeric ratio = 29 : 1). White solid. m.p. 166–170 °C.
1H NMR (300 MHz, CDCl3): δ 7.44–7.30 (m, 5H), 5.05 (d,
J = 9.6 Hz, 1H), 3.79 (dd, J = 12.4, 9.6 Hz, 1H), 2.72 (s, 1H),
2.62 (dq, J = 13.4, 6.7 Hz, 1H), 2.05–1.91 (m, 2H), 1.20 (d,
J = 6.7 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 211.8, 137.2, 129.3, 128.2, 127.3, 90.7, 79.2, 49.1,
47.8, 28.9, 12.2, 7.7; IR (CHCl3): 3499, 2979, 2361, 2022,
1
4.62 (d, J = 6.3 Hz, 1H), 3.18 (s, 1H), 2.85 (t, J = 6.6 Hz, 1H),
2.56 (d, J = 3.9 Hz, 1H), 2.30–2.25 (m, 1H), 2.17–2.03 (m, 2H),
1.96–1.86 (m, 2H), 1.78–1.60 (m, 6H), 1.43–1.31 (m, 1H),
1.25–1.14 (m, 3H), 1.00–0.85 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 213.1, 89.5, 81.5, 47.1, 43.9, 41.7, 39.9, 36.1, 29.8,
29.3, 26.1, 25.9, 17.9; IR (CHCl3): 3429, 2927, 2854, 1763,
1548, 1449, 1369, 1335, 1238, 1137, 1052, 932, 687 cm−1
;
1754, 1555, 1457, 1379, 1306, 1116, 753, 699 495 cm−1
;
HRMS (ESI): C14H21NO4 + NH4, Calc: 285.1809, Found:
285.1817; [α]rDt = +52 (c = 1.0 in CHCl3); HPLC: DAICEL
CHIRALCEL OJ-H, n-hexane/i-PrOH = 90/10, flow rate =
1.0 mL min−1, retention time: tminor = 12.6, tmajor = 16.5, 97% ee.
HRMS (ESI): C14H21NO4 + Na, Calc: 286.1055, Found:
286.1049; [α]rDt = +111 (c = 1.0 in CHCl3); HPLC: DAICEL
CHIRALCEL AS, n-hexane/i-PrOH = 90/10, flow rate = 1.0 mL
min−1, retention time: tminor = 14.3, tmajor = 19.2, 97% ee.
(1S,5S,6S,7S)-6-Butyl-1-hydroxy-7-nitrobicyclo[3.2.1]octan-8-
one (4m). Both diastereoisomers in 87% yield (diastereomeric
ratio = 43 : 1). Colorless oil. H NMR (300 MHz, CDCl3): δ 4.4
Acknowledgements
1
We are grateful for the grants from the NSFC of China
(20932003 and 90813012), the Key National S & T Major
Project and Major New Drugs Development of China
(2012ZX09504-001-003) and Young Scholar of Distinction for
Doctoral Candidate of Lanzhou University.
(d, J = 5.4 Hz, 1H), 3.15 (s, 1H), 2.95 (q, J = 7.5, 13.5 Hz, 1H),
2.42–2.40 (m, 1H), 2.37–2.33 (m, 1H), 2.21–2.13 (m, 1H),
2.07–1.96 (m, 1H), 1.90–1.85 (m, 2H), 1.71–1.63 (m, 1H),
1.53–1.43 (m, 2H), 1.39–1.29 (m, 4H), 0.90 (t, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 212.5, 92.0, 81.4, 49.6, 39.8,
38.6, 35.7, 35.5, 28.6, 22.3, 18.1, 13.8; IR (CHCl3): 3426, 2956,
2929, 2862, 1764, 1548, 1453, 1371, 1337, 1239, 1145, 1095,
1055, 678 cm−1 ; HRMS (ESI): C12H19NO4 + NH4, Calc:
259.1652, Found: 259.1648; [α]rDt = +41 (c = 1.0 in CHCl3);
HPLC: DAICEL CHIRALCEL OJ-H, n-hexane/i-PrOH = 90/10,
Notes and references
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flow rate = 1.0 mL min−1, retention time: tminor = 12.1, tmajor
=
15.7, 97% ee.
2 Selected reviews for domino reaction: (a) C. Grondal, M. Jeanty and
D. Enders, Nat. Chem., 2010, 2, 167; (b) H. M. L. Davies and
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(1S,2S,3R,4S)-1-Hydroxy-2-nitro-3-phenylbicyclo[2.2.1]heptan-
7-one (4n). Both diastereoisomers in 67% yield (diastereomeric
ratio = 10 : 1). White solid. m.p. 170–175 °C. 1H NMR
(300 MHz, CDCl3): δ 7.39–7.26 (m, 5H), 6.57 (s, 1H), 5.31 (dd,
J = 13.8, 8.5 Hz, 1H), 4.92 (dd, J = 13.8, 7.4 Hz, 1H), 4.49 (t,
J = 8.0 Hz, 1H), 2.50–2.35 (m, 4H); 13C NMR (75 MHz,
CDCl3): δ 203.3, 148.9, 141.8, 136.7, 129.3, 128.3, 127.9, 76.5,
45.4, 31.7, 24.7; IR (CHCl3): 3313, 2919, 1696, 1655, 1546,
1407, 1348, 1304, 1230, 1220, 910, 758, 683 cm−1; HRMS
(ESI): C14H21NO4 + Na, Calc: 270.0737, Found: 270.0741;
[α]rDt = +75 (c = 1.0 in CHCl3); HPLC: DAICEL CHIRALCEL
IA, n-hexane/i-PrOH = 90/10, flow rate = 1.0 mL min−1, reten-
tion time: tminor = 24.0, tmajor = 28.9, 50% ee.
(2S,3S,4R,5R)-5-Ethyl-2-hydroxy-2-methyl-3-nitro-4-phenyl-
cyclopentanone (4o). Both diastereoisomers in 86% yield (dia-
stereomeric ratio = 4 : 1). White solid. m.p. 164–169 °C.
1H NMR (300 MHz, CDCl3): δ 7.41–7.31 (m, 5H), 4.86 (d, J =
10.5 Hz, 1H), 4.00 (t, J = 10.8 Hz, 1H), 2.71 (s, 1H), 2.66–2.58
(m, 1H), 1.74 (m, 3H), 1.61 (s, 3H), 0.89 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 210.7, 137.5, 129.2, 128.1,
127.5 93.8 76.1 53.7, 46.3, 21.8, 20.9, 10.8; IR (CHCl3):
3305,3031, 2920, 2024, 1688, 1653, 1548, 1409, 1377, 1351,
1126, 914, 763, 698, 642 cm−1; HRMS (ESI): C14H21NO4 + Na,
Calc: 286.1050, Found: 286.1055; [α]rDt = +54 (c = 1.0 in
CHCl3); HPLC: DAICEL CHIRALCEL IA, n-hexane/i-PrOH =
90/10, flow rate = 1.0 mL min−1, retention time: tminor = 11.4,
6 For selected examples of utilization of 1,2-dicarbonyl compounds as
electrophiles in the reaction, see: (a) V. B. Gondi, K. Hagihara and
V. H. Rawal, Chem. Commun., 2010, 46, 904; (b) Y. Xu, G. Lu,
tmajor = 23.5, 90% ee.
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This journal is © The Royal Society of Chemistry 2012

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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4767–4773 | 4773