Enantioselective synthesis of bicylco[3.2.1]octan-8-ones using a tandem Michael-Henry reaction

Article abstract of DOI:10.1016/j.tet.2010.04.044

Bicyclo[3.2.1]octan-8-ones have been prepared from a tandem Michael-Henry reaction between cyclohexane-1,2-diones and nitroalkenes using a quinine-derived thiourea as the catalyst. Although four stereogenic centers were created during the reaction, only two diastereomers were obtained in good diastereoselectivity and high enantioselectivity (92-99% ee). When 3-methylcyclohexane-1,2-dione (R¹=Me) was used as the substrate, only the regioisomeric product of the corresponding thermodynamic enolate was obtained.

Full text of DOI:10.1016/j.tet.2010.04.044

Tetrahedron 66 (2010) 4423e4427
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journal homepage: www.elsevier.com/locate/tet
Enantioselective synthesis of bicylco[3.2.1]octan-8-ones using a tandem
MichaeleHenry reaction
*
Derong Ding, Cong-Gui Zhao , Qunsheng Guo, Hadi Arman
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Bicyclo[3.2.1]octan-8-ones have been prepared from
a tandem MichaeleHenry reaction between
Received 10 March 2010
Received in revised form 8 April 2010
Accepted 9 April 2010
cyclohexane-1,2-diones and nitroalkenes using a quinine-derived thiourea as the catalyst. Although four
stereogenic centers were created during the reaction, only two diastereomers were obtained in good
diastereoselectivity and high enantioselectivity (92e99% ee). When 3-methylcyclohexane-1,2-dione
(R1¼Me) was used as the substrate, only the regioisomeric product of the corresponding thermodynamic
enolate was obtained.
Available online 12 May 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Bicyclo[3.2.1]octan-8-one
Tandem reaction
Organocatalysis
Enantioselective
Cyclohexane-1,2-dione
Nitroalkene
1. Introduction
alkaloid derivatives plays a crucial role.5 Herein we wish to report
a novel tandem MichaeleHenry reaction of the 1,2-dione com-
Although 1,2-diones are very reactive compounds,1 they have
been rarely studied in organocatalyzed reactions.2 In 2006, we
reported an organocatalyzed direct aldol reaction of 1,2-diones with
ketones.2c Most recently, Rueping and co-workers reported a tan-
pounds for the highly diastereoselective and enantioselective
synthesis of bicylco[3.2.1]octan-8-ones, using a quinine-derived
thiourea as the catalyst.
dem Michael-aldol reaction of cyclohexane-1,2-dione and a,b-un-
2. Results and discussion
saturated aldehydes.2d We also demonstrated that this compound
may be used for the synthesis of 8-oxo-5,6,7,8-tetrahydro-4H-
chromene derivatives through a tandem Michael addition-cycliza-
tion reaction with benzylidenemalononitriles.2e Although not well
studied in organocatalysis, it appears that the dione may behave
either as an ene-activator (for a DielseAlder reaction),2a an elec-
trophile,2b,c a nucleophile,2e or both an electrophile and a nucleo-
phile2d in organocatalytic reactions. These multiple capacities
warrant many potential applications of these interesting com-
pounds in organocatalytic reactions.
We recently demonstrated that a tandem MichaeleHenry re-
action may be achieved between 2-mercaptobezaldehydes and
trans-b
-nitrostyrenes,4a in which 2-mercaptobezaldehyde acts as
both a nucleophile and an electrophile. According to Rueping’s
results,2d such a dual role may also be played by cyclohexane-1,2-
dione. Thus, we envisioned that such a dione should be a good
substrate for a tandem MichaeleHenry reaction with trans-
nitrostyrenes. Thus, cyclohexane-1,2-dione (1a) and trans- -nitro-
styrene (2a) were adopted as the model substrates to test our
hypothesis. Since we and others6 have shown that cinchona alka-
loid-derived thioureas7 are effective catalysts for a tandem Michael-
aldol or MichaeleKnoevenagel reactions, some thiourea derivatives
(4e8) were adopted as the catalysts (Fig.1). Forcomparisonpurpose,
similar catalysts (9e11) without the thiourea moiety are also in-
cluded in the screening (Fig. 1). The results of this screening are
collected in Table 1.
b-
b
On the other hand, tandem reactions have been the focus of
current organic chemistry research because they can assemble
complex molecule structures from relatively simple starting ma-
terials in a very efficient manner.3 This approach has also been
widely used in organocatalysis in recent years,4,5a,g and among the
catalyst used for these organocatalyzed tandem reactions, cinchona
As shown in Table 1, when quinine-derived thiourea catalyst 4
was applied in toluene at room temperature for 26 h, a bicyclic
product was obtained (entry 1). It should be pointed out that only
* Corresponding author. E-mail address: cong.zhao@utsa.edu (C.-G. Zhao).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.044

4424
D. Ding et al. / Tetrahedron 66 (2010) 4423e4427
Table 1
S
S
Catalyst screening and reaction condition optimizationa
Ar
N
Ar
N
N
H
N
H
HN
HN
O
O
H
catalyst HO
O
Ph
N
N
+
NO2
H
H
Ph
O2N
2a
3a
1a
O
MeO
MeO
H
HO
4
5
+
S
S
Ph
3aa (minor)
O2N
Ar
Ar
N
NH
N
H
N
H
HN
drb
Yieldc (%)
eed (%)
N
Entry
Solvent
Catalyst
Time (h)
N
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Ether
CH2Cl2
CHCl3
EtOAc
CH3CN
EtOH
4
5
6
7
8
9
10
11
4
4
4
4
4
4
4
26
30
36
28
25
30
40
144
48
48
40
36
40
40
32
88:12
90:10
87:13
90:10
91:9
75
48
71
60
59
77
63
45
46
49
58
74
69
41
72
97
95
94e
95
93e
17
18
37
97
94
95
95
94
91
90
N
H
H
OMe
6
7
91:9
90:10
81:19
74:26
89:11
79:21
90:10
78:22
76:24
92:8
OH
9
S
N
10
11
12
13
14
15
Ar
N
N
H
N
N
H
H
N
MeO
a
Unless otherwise indicated, all reactions were conducted with trans-b-nitro-
styrene (0.25 mmol), 1,2-cyclohexanedione (0.30 mmol), and the catalyst (15 mmol
8
9
%) in the specified solvent (1.5 mL) at room temperature.
OH
NH2
Diastereomeric ratio was determined by 1H NMR analysis of the crude mixture.
b
c
Yield of the isolated major diastereomer after column chromatography.
Determined by HPLC analysis on a ChiralCel OJ-H column.
The opposite enantiomer was obtained as the major product.
N
N
H
d
e
H
N
HO
MeO
product are slightly lower, all the other solvents (THF, ether, CH2Cl2,
CHCl3, and EtOAc,) all lead to similar ee values of the product
(around 95% ee, entries 9e13), although the yields of the product
and/or the dr values are usually inferior to that obtained in toluene
(entry 1). Thus, toluene was identified as the best solvent for this
reaction.
10
11
Figure 1. Structure of the catalysts applied in the screening [Ar¼3,5-(CF3)2C6H3].
Next, the scope and limitation of this reaction were studied. The
results of this study are summarized in Table 2.
It is clear from the results in Table 2 that high dr values, excellent
ee values, and good yields of the desired products may be obtained
two diastereomers (3a and 3aa) are present in the crude product
according to the 1H NMR spectrum, although four stereogenic
centers are created during the reaction. The diastereomeric ratio is
88:12. Luckily the minor diastereomer 3aa may be easily removed
by column chromatography, and the major diastereomer 3a was
isolated in 75% yield and 97% ee (entry 1). Similarly, high ee values
and good dr values may also be achieved with the other cinchona
alkaloid-derived thiourea catalysts 5, 6, and 7 (entries 2e4), al-
though the product yields obtained with catalysts 5 and 7 are lower
due to the formation of some unidentified products in these cases.
A trans-cyclohexane-1,2-diamine-derived thiourea catalyst 8 also
leads to 59% yield of the product with excellent dr (91:9) and ee
value (93%, entry 5). In contrast, similar cinchona alkaloid-derived
catalysts without the thiourea moiety (9e11) all give very low ee
values of the product, although the dr values remain high (entries
6e8). These results hint that the thiourea group is indeed essential
for maintaining the high enantioselectivity of this reaction, most
for the reaction of cyclohexane-1,2-dione and trans-b-nitrostyrenes
with different substituents on the phenyl ring. For example, both
electron-donating and electron-withdrawing groups at the para
position of the phenyl ring do not lead to major differences in the dr
values, the product yields, or the ee values (entries 1e7). Even with
the strong electron-withdrawing nitro group, an excellent ee value
of 93% and a high dr of 94:6 were obtained (entry 7). Similarly,
substituents at the ortho (entries 8e9) or meta (entry 10) positions
show no influence on the enantioselectivity, either. The lower dr
value obtained with ortho-bromo-substituted nitrostyrene (entry
9) is probably due to steric reasons. A heteroarene-substituted
nitroalkene (entry 11) is also a good substrate for this reaction: the
reaction of trans-2-(2-nitrovinyl)thiophene with cyclohexane-1,2-
dione produce the expected product in 89% yield and 99% ee. The
original dr value was 92:8 in this case. Excellent ee value (97%),
good dr value (88:12) and yield (77%) may also be obtained for
a trans-nitroalkene with an alkyl substituent (entry 12).
likely through hydrogen-bonding with trans-b-nitrostyrene. It
should be pointed out that the major enantiomer obtained with
catalysts 6 and 8 is opposite that of the rest of the catalysts.
Because catalyst 4 leads to the highest ee value of the product
with a high dr value, it was adopted as the catalyst of choice in our
further screening. Besides toluene, several other common organic
solvents were screened. In fact, except for acetonitrile (entry 14)
and ethanol (entry 15), in which the ee values obtained for the
3-Methylcyclohexane-1,2-dione (1b) is also a good substrate
for this reaction (entry 13). Since this compound is not symmetric,
it may enolize both at the less substituted 6-position (to give
a kinetic enolate) or the more substituted 3-position (to give

D. Ding et al. / Tetrahedron 66 (2010) 4423e4427
4425
Table 2
stereochemistry of the other products was similarly assigned on the
basis of the reaction mechanism.
Tandem MichaeleHenry reaction between 1,2-diones and nitroalkenesa
To show the practical utility of the current method, the reaction
of compounds 1a and 2a was also carried out with a much larger
scale (Eq. 1). As shown in Eq. 1, the reaction with 4 mmol (0.60 g) of
2a and 4.8 mmol (0.54 g) of 1a under the optimized conditions gave
0.77 g (74% yield) of 3a with an ee value of 96%, which is almost
identical to the results obtained under the microscale conditions
(Table 2, entry 1).
O
R1
O
O
R1
HO
R2
R3
R4
4
NO2
R2
+
R4
toluene, rt
R3
1
O2N
3
2
Entry R1
R2
R3
R4
Ph(3a)
4-MeC6H4(3b)
drb
Yield (%)c ee d (%)
O
1
2
3
4
5
6
7
8
9
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
H
H
H
H
H
H
H
H
H
H
88:12
92:8
75
83
82
68
89
79
90
87
66
77
97
97
97
96
4 (15 mmol%)
O
Ph
+
3a (Eq. 1)
NO2
toluene (20 mL)
4-MeO C6H4(3c) 88:12
rt, 26 h, 74%
4-ClC6H4(3d)
4-BrC6H4(3e)
4-CNC6H4(3f)
4-NO2C6H4(3g)
86:14
94:6
91:9
94:6
97
97e
93e
94
1a
2a
dr: 88:12
ee: 96%
2-MeOC6H4(3h) 95:5
ð1Þ
2-BrC6H4(3i)
3-ClC6H4(3j)
72:28
88:12
92
10
96e
11
e(CH2)3e
H
92:8
89
99e
3. Conclusions
S
12
13
14
15
e(CH2)3e
e(CH2)3e
H
n-C6H13(3l)
88:12
77
97
97
d
d
We have demonstrated that bicyclo[3.2.1]otan-8-ones may be
prepared in excellent enantioselectivity, high diastereoselectivity,
and regioselectivity from a tandem MichaeleHenry reaction be-
tween cyclohexane-1,2-diones and nitroalkenes by using a quinine-
derived thiourea as the catalyst. However, cyclopentan-1,2-diones
and enolizable acyclic 1,2-diones fail to give similar products.
Me Ph (3m)
Ph
Me Ph
88:12 67f
Me
H
H
d
0
e(CH2)2e
d
0g
a
All reactions were conducted with trans-nitroalkenes (0.25 mmol), 1,2-diones
(0.30 mmol), and catalyst 4 (15 mmol %) in toluene (1.5 mL) at room temperature for
26 to 32 h (TLC monitoring).
b
Diastereomeric ratio was determined by 1H NMR analysis of the crude mixture.
Yield of the isolated major diastereomer after column chromatography.
Unless otherwise specified, ee values were determined by HPLC analysis on
c
d
4. Experimental
4.1. General
a ChiralCel OJ-H column.
e
Determined by HPLC analysis on a ChiralPak AD-H column.
The reaction time was 72 h.
A complex mixture of unidentified products was obtained.
f
g
Unless otherwise specified, all compounds used in this study
were purchased from commercial sources and were used as re-
ceived. Catalysts 4,9 5, 9 6,9 7,9 10,7d and 119 were prepared by using
the reported procedures from quinine or quinidine. THF and ether
were freshly distilled from benzophenone and sodium metal. Tol-
uene, CH2Cl2, CHCl3, and CH3CN were distilled from CaH2. HPLC
grade EtOH and EtOAC were used directly. All reactions were car-
ried out at ambient temperature in oven-dried glassware. Optical
rotation was measured at room temperature (23 ꢀC).
a thermodynamic enolate). However, only the thermodynamic
enolate participates in the reaction to give a single regioisomer 3m
with a dr of 88:12 as revealed by the NMR spectrum of the crude
product. The major diastereomer may be isolated in 97% ee and
67% yield.
Nevertheless, this reaction seems to be limited to cyclohexane-
1,2-diones, because the attempted reactions of both butane-2,
3-dione and 3-methylcyclopentane-1,2-dione failed under the
optimized conditions, with the former giving no sign of reaction at
all (entry 14) and the latter being too complex to be useful (entry 15).
To determine the absolute configuration of the major enantio-
mer obtained in this reaction, crystals of compound 3f were ana-
lyzed by X-ray crystallography (Fig. 2).8 On the basis of the X-ray
analysis, its stereochemistry was assigned to be (1R,5R,6S,7S). The
4.2. General procedure for the tandem MichaeleHenry
reaction
To a solution of the 1,2-cycloalkanedione (0.30 mmol) and the
catalyst (0.038 mmol, 15 mol %) in toluene (1.5 mL) was added the
nitroalkene (0.25 mmol). The mixture was stirred at room tem-
perature for the time as indicated in the Tables. The solvent was
then removed under reduced pressure and the residue was purified
by chromatography on silica gel to afford the product.
4.2.1. (1R,5R,6S,7S)-1-Hydroxy-7-nitro-6-phenylbicyclo[3.2.1]-oc-
tan-8-one (3a). Colorless oil, 75% yield, [
a
]
ꢁ16.2 (c 0.455,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.13e7.16 (m, 2H), 7.24e7.36
(m, 3H), 4.78 (d, J¼6.0 Hz, 1H), 4.18 (d, J¼6.0 Hz, 1H), 3.34 (s, 1H),
2.81 (d, J¼2.7 Hz, 1H), 2.32e2.43 (m, 2H), 1.94e2.14 (m, 3H),
1.76e1.79 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 212.6, 142.5, 129.6,
128.1, 127.0, 93.9, 82.0, 52.0, 44.3, 40.2, 36.4, 18.4; nmax (cmꢁ1):
3424, 1760, 1545; HRMS calcd for C14H15NO4: 261.1001; found:
261.1006. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane
20:80, flow rate 1.0 mL/min, UV detection at 240 nm.
4.2.2. (1R,5R,6S,7S)-1-Hydroxy-6-(4-methylphenyl)-7-nitrobicyclo
Figure 2. ORTEP drawing of compound 3f.
[3.2.1]octan-8-one (3b). Colorless oil, 83% yield, [
a
]D ꢁ17.4 (c 0.465,

4426
D. Ding et al. / Tetrahedron 66 (2010) 4423e4427
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.11e7.13 (dd, J1¼6.0 Hz,
18.2; nmax (cmꢁ1): 1757, 1599, 1546; HRMS calcd for C14H14N2O6:
306.0852; found: 306.0863. HPLC conditions: ChiralPak AD-H col-
umn, i-PrOH/hexane 35:65, flow rate 1.0 mL/min, UV detection at
254 nm.
J2¼1.8 Hz, 2H), 7.01e7.04 (dd, J1¼6.0 Hz, J2¼1.8 Hz, 2H), 4.75 (d,
J¼5.7 Hz, 1H), 4.13 (d, J¼5.7 Hz, 1H), 3.31 (s, 1H), 2.78 (d, J¼3.0 Hz,
1H), 2.32e2.42 (m, 2H), 2.30 (s, 3H), 1.95e2.14 (m, 3H), 1.74e1.77
(m,1H); 13C NMR (75 MHz, CDCl3):
d 212.7,139.6, 137.8,130.2, 126.8,
94.1, 81.9, 52.0, 43.9, 40.2, 36.4, 21.4, 18.3; nmax (cmꢁ1): 3374, 2937,
1758, 1542; HRMS calcd for C15H17NO4: 275.1158; found: 275.1165.
HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80,
flow rate 1.0 mL/min, UV detection at 240 nm.
4.2.8. (1R,5R,6S,7S)-1-Hydroxy-6-(2-methoxyphenyl)-7-nitro-bicy-
clo[3.2.1]octan-8-one (3h). Colorless oil, 87% yield, [
a
]
ꢁ13.8 (c
D
0.505, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d7.25e7.30 (m, 2H),
6.84e6.94 (m, 2H), 5.10 (d, J¼5.7 Hz, 1H), 4.06 (d, J¼5.7 Hz, 1H),
3.67e3.69 (m, 3H), 3.28 (s, 1H), 2.60(d, J¼3.9 Hz, 1H), 2.24e2.38 (m,
4.2.3. (1R,5R,6S,7S)-1-Hydroxy-6-(4-methoxyphenyl)-7-nitrobicyclo
2H), 1.92e2.08 (m, 4H); 13C NMR (75 MHz, CDCl3):
d 212.5, 156.0,
[3.2.1]octan-8-one (3c). Colorless oil, 82% yield, [
a
]
ꢁ18.7 (c 1.58,
130.1, 129.4, 129.1, 120.7, 111.0, 91.9, 81.3, 54.2, 51.3, 43.7, 40.6, 36.5,
17.8; nmax (cmꢁ1): 3451, 2937, 1761, 1543; HRMS calcd for C15H17NO5:
291.1107; found 291.1103. HPLC conditions: ChiralCel OJ-H column, i-
PrOH/hexane 30:70, flow rate 1.0 mL/min, UV detection at 240 nm.
D
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.03e7.08 (dd, J1¼5.1 Hz,
J2¼2.7 Hz, 2H), 6.82e6.87 (dd, J1¼5.1 Hz, J2¼2.7 Hz, 2H), 4.73 (d,
J¼6.0 Hz, 1H), 4.12 (d, J¼6.0 Hz, 1H), 3.78 (s, 3H), 3.34 (s, 1H), 2.76
(d, J¼2.1 Hz, 1H), 2.31e2.42 (m, 2H), 1.92e2.12 (m, 3H), 1.74e1.77
(m, 1H); 13C NMR (75 MHz, CDCl3):
d
212.9, 159.3, 135.7, 128.1, 115.0,
4.2.9. (1R,5R,6S,7S)-6-(2-Bromophenyl)-1-hydroxy-7-nitrobicyclo
94.3, 81.9, 55.6, 52.1, 43.5, 40.0, 36.3, 18.2; nmax (cmꢁ1): 3448, 2962,
1759; HRMS calcd for C15H17NO5: 291.1107; found: 291.1098. HPLC
conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate
1.0 mL/min, UV detection at 220 nm.
[3.2.1]octan-8-one (3i). Viscous liquid, 66% yield, [
a
]
D ꢁ11.6 (c 0.69,
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.58e7.61 (m, 1H), 7.28e7.33
(m, 1H), 7.12e7.17 (m, 1H), 6.98e7.02 (m, 1H), 5.08 (d, J¼6.0 Hz, 1H),
4.80 (d, J¼6.0 Hz, 1H), 3.28 (s, 1H), 2.64 (d, J¼3.9 Hz, 1H), 2.41e2.50
(m, 2H), 1.95e2.19 (m, 3H), 1.76e1.81 (m, 1H); 13C NMR (75 MHz,
4.2.4. (1R,5R,6S,7S)-6-(4-Chlorophenyl)-1-hydroxy-7-nitrobicyclo
CDCl3): d 212.4, 140.9, 133.9, 129.6, 128.8, 128.4, 123.9, 92.1, 82.1,
[3.2.1]octan-8-one (3d). Viscous liquid, 68% yield, [
a
]
D ꢁ18.4 (c 0.46,
52.8, 43.5, 40.6, 36.7, 18.3; nmax (cmꢁ1): 3424, 2923, 1746, 1550;
HRMS calcd for C14H14BrNO4: 339.0106; found: 339.0120. HPLC
conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate
1.0 mL/min, UV detection at 220 nm.
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.01e7.08 (dd, J1¼6.6 Hz,
J2¼1.8 Hz, 2H), 6.84e6.86 (dd, J1¼6.6 Hz, J2¼1.8 Hz, 2H), 4.46 (d,
J¼6.0 Hz, 1H), 3.92 (d, J¼6.0 Hz, 1H), 3.04 (s, 1H), 2.54 (s, 1H),
2.08e2.20 (m, 2H), 1.68e1.91 (m, 3H), 1.51e1.57 (m, 1H); 13C NMR
(75 MHz, CDCl3):
d
212.2, 140.9, 134.1, 129.7, 128.3, 93.6, 81.9, 51.9,
4.2.10. (1R,5R,6S,7S)-6-(3-Chlorophenyl)-1-hydroxy-7-nitrobicyclo
43.7, 40.1, 36.4, 18.3; nmax (cmꢁ1): 3440, 2938, 1745, 1544; HRMS
calcd for C14H14ClNO4: 295.0611; found: 295.0619. HPLC condi-
tions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate
1.0 mL/min, UV detection at 240 nm.
[3.2.1]octan-8-one (3j). Colorless oil, 77% yield, [
a
]
D ꢁ12.0 (c 0.755,
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.24e7.31 (m, 2H), 7.16 (s,
1H), 7.01e7.04 (m, 1H), 4.74 (d, J¼6.0 Hz, 1H), 4.16 (d, J¼6.0 Hz, 1H),
3.30 (s, 1H), 2.80 (d, J¼2.1 Hz, 1H), 2.30e2.45 (m, 2H), 2.10e2.19 (m,
1H), 1.90e2.08 (m, 2H), 1.75e1.81 (m, 1H); 13C NMR (75 MHz,
4.2.5. (1R,5R,6S,7S)-6-(4-Bromophenyl)-1-hydroxy-7-nitrobicyclo
CDCl3): d 212.0, 144.2, 135.4, 131.0, 128.4, 127.4, 125.0, 93.4, 81.9,
[3.2.1]octan-8-one (3e). White solid, 89% yield, mp: 139e140 ꢀC,
51.7, 44.0, 40.2, 36.4,18.3; nmax (cmꢁ1): 3418, 2961,1759,1596,1544;
HRMS calcd for C14H14ClNO4: 295.0611; found: 295.0616. HPLC
conditions: ChiralPak AD-H column, i-PrOH/hexane 35:65, flow
rate 1.0 mL/min, UV detection at 254 nm.
[
a]
D ꢁ15.7 (c 1.545, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.44e7.48
(m, 2H), 7.01e7.05 (m, 2H), 4.70 (d, J¼5.7 Hz, 1H), 4.14 (d, J¼5.7 Hz,
1H), 3.29 (s,1H), 2.77 (d, J¼2.1 Hz,1H), 2.30e2.43 (m, 2H), 2.11e2.17
(m, 1H), 1.91e2.09 (m, 2H), 1.74e1.80 (m, 1H); 13C NMR (75 MHz,
CDCl3):
d
212.2, 141.4, 132.7, 128.7, 122.1, 93.5, 81.9, 51.8, 43.8, 40.1,
4.2.11. (1R,5R,6R,7S)-1-Hydroxy-7-nitro-6-(thiophen-2-yl)bicyclo-
36.4, 18.3; nmax (cmꢁ1): 3490, 3387, 1749, 1541; HRMS calcd for
C14H14BrNO4: 339.0106; found: 339.0103. HPLC conditions: Chir-
alCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV
detection at 220 nm.
[3.2.1]octan-8-one (3k). Viscous oil, 89% yield, [
a
]
ꢁ6.2 (c 1.30,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
7.20e7.26 (m, 1H), 6.93e6.96
(m, 1H), 6.86e6.87 (m, 1H), 4.81 (d, J¼5.4 Hz, 1H), 4.48 (d, J¼5.4 Hz,
1H), 3.29 (s, 1H), 2.91e2.93 (m, 1H), 2.32e2.44 (m, 2H), 2.07e2.18
(m, 1H), 1.94e2.04 (m, 2H), 1.72e1.92 (m, 1H); 13C NMR (75 MHz,
4.2.6. (1R,5R,6S,7S)-6-(4-Cyanophenyl)-1-hydroxy-7-nitrobicyclo
CDCl3): d 211.4, 144.8, 127.7, 125.3, 124.5, 94.1, 81.7, 52.4, 40.0, 39.7,
[3.2.1]octan-8-one (3f). White solid, 79% yield, mp: 207e209 ꢀC, [
a
]
36.2, 18.3; nmax (cmꢁ1): 3424, 2948, 1760, 1544; HRMS calcd for
C12H13NO4S: 267.0565; found: 267.0556. HPLC conditions: Chir-
alPak AD-H column, i-PrOH/hexane 40:60, flow rate 1.0 mL/min, UV
detection at 254 nm.
D
ꢁ16.9 (c 0.53, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.66e7.67 (dd,
J1¼6.6 Hz, J2¼1.2 Hz, 2H), 7.28e7.32 (dd, J1¼6.6 Hz, J2¼1.2 Hz, 2H),
4.71 (d, J¼6.0 Hz, 1H), 4.24 (d, J¼6.0 Hz, 1H), 3.33 (s, 1H), 2.80e2.81
(m, 1H), 2.34e2.47 (m, 2H), 2.13e2.19 (m, 1H), 1.90e2.05 (m, 2H),
1.79e1.83 (m, 1H); 13C NMR (125 MHz, CDCl3): 211.8, 147.4, 133.5,
128.0, 118.3, 112.3, 92.9, 81.8, 51.5, 44.2, 40.0, 36.2, 18.1; nmax (cmꢁ1):
3517, 2231,1766,1609; HRMS calcd for C15H14N2O4:286.0954; found:
286.0965. HPLC conditions: ChiralPak AD-H column, i-PrOH/hexane
35:65, flow rate 1.0 mL/min, UV detection at 254 nm.
4.2.12. (1R,5R,6R,7S)-6-Hexyl-1-hydroxy-7-nitrobicyclo[3.2.1]-oc-
tan-8-one (3l). Colorless oil, 77% yield, [
a
]
D ꢁ43.5 (c 0.66, CH2Cl2);
1H NMR (300 MHz, CDCl3):
d
4.40 (d, J¼5.4 Hz, 1H), 3.22 (s, 1H),
2.91e2.98 (m, 1H), 2.32e2.40 (m, 2H), 2.14e2.18 (m, 1H), 1.70e2.07
(m, 3H), 1.61e1.67 (m, 1H), 1.40e1.50 (m, 2H), 1.20e1.29 (m, 8H),
0.86e0.90 (m, 3H); 13C NMR (75 MHz, CDCl3):
d 212.6, 92.2, 81.7,
4.2.7. (1R,5R,6S,7S)-1-Hydroxy-7-nitro-6-(4-nitrophenyl)bicyclo
50.0, 40.1, 39.0, 36.2, 36.0, 31.9, 29.3, 26.9, 22.9, 18.4, 14.4; nmax
(cmꢁ1): 3420, 2926, 2857, 1760, 1544; HRMS calcd for C14H23NO4:
269.1627; found: 269.1616. HPLC conditions: ChiralCel OJ-H column,
i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV detection at 220 nm.
[3.2.1]octan-8-one (3g). White solid, 90% yield, mp: 170e171 ꢀC, [
a]
D
ꢁ11.3 (c 0.515, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 8.22e8.24 (dd,
J1¼5.4 Hz, J2¼1.5 Hz, 2H), 7.36e7.38 (dd, J1¼5.4 Hz, J2¼1.5 Hz, 2H),
4.72 (d, J¼6.0 Hz, 1H), 4.31 (d, J¼6.0 Hz, 1H), 3.28 (s, 1H), 2.84 (d,
J¼2.0 Hz, 1H), 2.45e2.49 (m, 1H), 2.36e2.39 (m, 1H), 2.14e2.21 (m,
1H), 1.90e2.05 (m, 2H), 1.81e1.85 (m, 1H); 13C NMR (125 MHz,
CDCl3):211.7,149.3,147.8,128.2,124.9, 92.8, 81.7, 51.5, 44.0, 40.0, 36.2,
4.2.13. (1R,5R,6R,7S)-1-Hydroxy-5-methyl-7-nitro-6-phenyl-bicyclo
[3.2.1]octan-8-one (3m). Colorless oil, 67% yield, [
a
]
ꢁ6.5 (c 0.94,
D
CH2Cl2); 1H NMR (300 MHz,CDCl3):
d
7.26e7.35 (m, 3H), 6.70e7.03

D. Ding et al. / Tetrahedron 66 (2010) 4423e4427
4427
E. Org. Lett. 2006, 8, 507e509; (c) Samanta, S.; Zhao, C.-G. Tetrahedron Lett. 2006,
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(m, 2H), 4.99 (d, J¼6.0 Hz, 1H), 4.13 (d, J¼6.0 Hz, 1H), 3.43 (s, 1H),
2.43e2.47 (m, 1H), 2.14e2.17 (m, 1H), 1.92e2.00 (m, 3H), 1.68e1.74
(m, 1H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3):
d214.0, 139.9, 129.3,
128.6, 128.1, 93.7, 81.3, 51.5, 49.8, 45.5, 39.8, 18.4, 17.4; nmax (cmꢁ1):
3426, 2931, 1756, 1545; HRMS calcd for C15H17NO4: 275.1158;
found: 275.1155. HPLC conditions: ChiralCel OJ-H column, i-PrOH/
hexane 30:70, flow rate 1.0 mL/min, UV detection at 240 nm.
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Acknowledgements
This research was financially supported by the Welch Founda-
tion (Grant No. AX-1593) and partially by the NIH-NIGMS (Grant
No. SC1GM082718), for which the authors are very grateful.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.04.044. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
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