Stereoselective synthesis of (3S,4R)- and (3R,4S)-4-(N-substituted-amino)- 2,2-dimethyl-6-nitrochroman-3-ols via the microwave assisted regioselective ring opening of epoxides in the presence of neutral alumina

Article abstract of DOI:10.1016/j.tetasy.2012.07.002

With the aim of discovering new molecules with potassium channel activating properties, we have designed and synthesized derivatives with structural similarity to cromakalim, an important molecule which shows specific affinity toward potassium channels, based on previous structure-activity investigations by applying different C-4 substitutions. This has been accomplished by using a stereoselective Jacobsen epoxidation and microwave assisted regioselective epoxide opening with neutral alumina as the key reactions.

Full text of DOI:10.1016/j.tetasy.2012.07.002

Tetrahedron: Asymmetry 23 (2012) 1029–1037
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (3S,4R)- and (3R,4S)-4-(N-substituted-amino)-2,2-
dimethyl-6-nitrochroman-3-ols via the microwave assisted regioselective ring
opening of epoxides in the presence of neutral alumina
Li-juan Meng a, B. V. D. Vijaykumar a, Hua Zuo b, Zhu-Bo Li b, Gautam Dupati c, Kiwan Jang c,
Dong-Soo Shin a,
⇑
a Department of Chemistry, Changwon National University, Changwon, GN 641-773, South Korea
b College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
c Department of Physics, Changwon National University, Changwon, GN 641-773, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 March 2012
Accepted 4 July 2012
With the aim of discovering new molecules with potassium channel activating properties, we have
designed and synthesized derivatives with structural similarity to cromakalim, an important molecule
which shows specific affinity toward potassium channels, based on previous structure–activity investiga-
tions by applying different C-4 substitutions. This has been accomplished by using a stereoselective Jac-
obsen epoxidation and microwave assisted regioselective epoxide opening with neutral alumina as the
key reactions.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
tant for activity on smooth muscle cells15,16 was also retained. The
hydrogen bonding site at C-4 leading to the KATP channel opening
Potassium channels are exceptionally diverse both in variety
and function. They play an important and complex role in the basic
electrical and mechanical function of a wide variety of tissues,
including smooth muscle, cardiac muscle, and glands. KATP chan-
nels have been shown to be involved in several physiological pro-
cesses, such as hormone secretion, smooth muscle cell contractile
activity, myocardial protection, and neurotransmitter release.1
Since the emergence of cromakalim 1, the first benzopyran type
potassium channel activator found to be a potent antihypertensive
agent,2 many other examples of this potentially important class of
the agent have been disclosed. They include achiral EMD 52692 2,
Ro 31-6930 3, chiral SDZ PCO 400 4, BRL 38227 5, 6, and (ꢀ)-MJ-
451 7. The pharmacological potency of these agents has exten-
sively been studied and some potassium channel activators are
currently under development for therapeutic applications in vari-
ous diseases, especially in hypertension, asthma, and urinary
incontinence (Fig. 1).3–12
properties of benzopyrans13,17 has been variously substituted with
the aim of discovering more efficient molecular structures and
improving the structure–activity relationship. Moreover the stere-
ogenic C-3 and C-4 centers have been synthesized
stereospecifically.
2. Results and discussion
2.1. Retrosynthetic analysis of N-substituted (3S,4R)-4-amino-
2,2-dimethyl-6-nitrochroman-3-ol 8
Our strategy involved the use of aminolysis of an epoxide as the
key step for the construction of N-substituted (3S,4R)-4-amino-2,2-
dimethyl-6-nitrochroman-3-ols 8. The target compounds 8 could
be obtained by the aminolysis of epoxide compound (1aS,7bS)-
2,2-dimethyl-6-nitro-2,7b-dihydro-1aH-oxireno[2,3-c]chromene
9, which could be prepared by the asymmetric epoxidation of 2,2-
dimethyl-6-nitro-2H-chromene 10. The retrosynthetic route is
shown in Scheme 1.
We have synthesized analogues of cromakalim with the aim of
obtaining compounds with increased relaxant activity on smooth
muscle cells. The electron withdrawing cyano group of cromaka-
lim, favorable to the myorelaxant activity,13,14 was replaced with
a nitro group and the hydroxyl group, which appears to be impor-
2.2. Synthesis of chiral epoxides 9 and ent-9
Our synthesis started with the asymmetric epoxidation of 2,2-
dimethyl-6-nitro-2H-chromene 1018 using (S,S)-Jacobsen’s catalyst
and following the earlier reported method to obtain (1aS,7bS)-2,2-
⇑
Corresponding author.
E-mail address: dsshin@changwon.ac.kr (D.-S. Shin).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.002

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L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
O
O
O
N
N
N
O
O
OH
OH
NC
NC
NC
NC
Me
Me
CH3
CH3
Me
Me
Me
Me
O
O
O
O
EMD 52692 2
cromakalim 1
Ro 31-6930 3
SDZ PCO 400 4
N
NH
Cl
H
OH
O
N
O
N
O
O
N
NC
OH
CH3
NC
OH
S
OH
CH3
N
CH3
CH3
O
O
CH3
O
CH3
(-)-MJ 457 7
BRL 38227 5
6
Figure 1. Chemical structures of potassium channel activators with a benzopyran ring.
NHR
O
O2N
O2N
O2N
OH
O
O
O
10
8
9
Scheme 1. Retrosynthetic analysis of N-substituted (3S,4R)-4-amino-2,2-dimethyl-6-nitrochroman-3-ols 8.
dimethyl-6-nitro-2,7b-dihydro-1aH-oxireno[2,3-c]chromene 9 as
the chiral epoxide with a known enantiomeric purity (Scheme 2).19
Its antipode was obtained by the use of (R,R)-Jacobsen’s catalyst.
methods24 have also been reported. More recently, Azizi et al.
reported a method using water as solvent without any catalyst in
5–24 h.25
CH2Cl2
NaOCl, Na2HPO4·12H2O
O
O2N
O2N
O
(S,S)-Jacobsen's Catalyst
O
H
9
10
H
H
H
N
O
N
N
O
N
O
Mn
Cl
Mn
Cl
t-Bu
t-Bu
t-Bu
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
(R,R)-Jacobsen 16
Scheme 2. Synthesis of (1aS,7bS)-2,2-dimethyl-6-nitro-2,7b-dihydro-1aH-oxireno[2,3-c]chromene 9.
(S,S)-Jacobsen 15
2.3. Synthesis of the target compounds 8 by aminolysis of
epoxide 9
However, there are still some limitations to these methods; for
example, deactivated amines fail to open these epoxides or still re-
quire high temperatures. Side products are often formed by this
procedure and the reaction time is long. Furthermore, many of
the catalysts used are corrosive, stoichiometric, moisture-sensitive
or expensive, and hazardous organic solvents are often used.
Alumina was used in different reactions, such as carbonyl
reductions and sulfonate ester elimination. Posner et al. introduced
the epoxide ring opening by weak oxygen and nitrogen nucleo-
philes at an alumina surface.26 However, the huge consumption
of alumina limited this method. The promising reactivity of alu-
The ring-opening addition reactions of 1,2-epoxides with
ammonia or amines, and their synthetic equivalents, are one of
the most widely used methods for b-amino alcohol synthesis.20 It
consists of heating an epoxide with an excess of amine at elevated
temperatures.21 Since some functional groups may be susceptible
to high temperatures, various methods using promoters or cata-
lysts in different organic solvents have been reported.22 In addi-
tion, microwave irradiation,23 and solvent-free condition

L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
1031
mina encouraged us to explore a new methodology. Herein we
used the aminolysis of epoxides in n-butanol with alumina as the
catalyst under microwave irradiation, to obtain a series of 4-
(substituted-amino)-2,2-dimethyl-6-nitrochroman-3-ol 8, with a
short reaction time and high yields.
The aminolysis of epoxide 9 was catalyzed by activated, com-
mercially available Woelm 50–200 neutral chromatographic alu-
mina under microwave irradiation (Scheme 3). In order to find
the best reaction conditions we first studied the solvent effect in
the aminolysis of epoxide 9 with benzyl amine 11a promoted by
alumina. We examined the reactions in different non-dried undis-
tilled solvents, without any precautions to exclude moisture.
The results summarized in Table 1 show that the reaction in a
high-polar solvent gave 8 in 54–92% yields. There was almost no
reaction in dichloromethane, toluene, or acetonitrile. It is notewor-
thy that the yield and the time of the reaction were dependent on
the nature of the solvent. This could probably be due to the boiling
point of the solvent. The higher the temperature applied, the short-
er the reaction time and the higher the yield (entry 7). From the
above results we concluded that butan-1-ol gave the best results
in the aminolysis of epoxides.
We next planned to evaluate the loading of the catalyst. The
reaction was carried out at different mol % of catalyst in butan-1-
ol. As shown in Table 2, the reaction time was reduced and the
yield was increased when increasing the amount of alumina from
5 to 30 mol %. Keeping the reaction time the same led only to a
slight deviation in yields when raising the catalyst above
30 mol % (entries 5–7). It should be noted that there was no prod-
uct formation without any catalyst.
R1
R2
N
O
O
O2N
R1
R2
O2N
OH
30% Al2O3
M.W.
+
N
H
O
8
9
11
R1, R2 = H, alkyl
Scheme 3. Microwave assisted aminolysis in the presence of neutral alumina.
Finally, we investigated the scope and limitations of the reac-
tion with respect to the amine. Thus, aromatic, linear, and cyclic
amines were reacted with epoxide 9 in the presence of 30 mol %
of alumina using undistilled non-dried butan-1-ol as the solvent
at 117 °C under microwave irradiation. In general, the methodol-
ogy worked well independent of the nature of the amine, to furnish
the corresponding b-amino alcohol in good yields. As can be seen
from Table 3, the process worked well for all types of amines
including aromatic, linear, cyclic, and heterocyclic amines, giving
moderate to excellent yields. Thus, anilines carrying highly deacti-
vating groups such as p-nitroaniline (entry 6) gave very reasonable
yields using a little more loading (10 mol % more) of catalyst. In the
same way, secondary hindered amines such as dimethylamine (en-
try 7), morpholine (entry 8), and 1-(4-methoxyphenyl)piperazine
(entry 9), gave products with very good yields in short reaction
times.
Similarly, (3R,4S)-4-(substituted-amino)-2,2-dimethyl-6 nit-
rochroman-3-ol ent-8 was prepared from the corresponding epox-
ide ent-9 by following the same method (Table 4). The
regioselective and stereoselective studies were carried out with
(R)-1-phenylethanamine and (S)-1-phenylethanamine (Table 5).
Of the similar kind of epoxy opening with amine27 our reaction
was completely regioselective since the only products isolated
were those deriving from the attack of the amine to the C-4 posi-
Table 1
Study of the solvent effect in the aminolysis of epoxide 9 promoted by activated
alumina
Bn
HN
O
neutral
30%
O
O2N
O2N
OH
NH2 Al2O3
+
M.W.
O
8a
9
11a
Entry
Solvent
T (°C)
ta (h)
Yieldb (%)
1
2
3
4
5
6
7
CH2C12
CH3CN
40
81
110
64
78
108
118
12
12
12
48
20
2
N.R.
N.R.
N.R.
54
67
85
Toluene
CH3OH
C2H5OH
iso-Butanol
Butan-l-ol
1
92
N.R. = No Reaction.
a
Reaction time (t) is the hold time after reaching the reaction temperature in
10 min.
b
Yields refer to isolated pure compounds after column chromatography.
Table 2
Aminolysis of epoxide 9 with different loadings of activated Al2O3
Bn
HN
O
O2N
NH2
O2N
OH
Al2O3, butan-1-ol
M.W., 117°C
+
O
O
9
11a
8a
Entry
Catalyst (mol %)
ta (h)
Yieldb (%)
1
2
3
4
5
6
7
5
10
20
30
50
100
0
12
8
4
1
1
69
78
82
92
94
1
12
87
N.R.
N.R. = No Reaction.
a
Reaction time (t) is the hold time after reaching the reaction temperature in 10 min.
Yields refer to isolated pure compounds after column chromatography.
b

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L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
Table 3
Microwave assisted alumina-catalyzed aminolysis of epoxide 9
R1
R2
N
O
O
O2N
O2N
OH
R1
R2
+
N
H
30 mol%, Al2O3
O
butan-1-ol
M.W., 117°C
11
9
8
Entry
1
Amine, 11
Amino alcohol, 8
ta (h)
Yieldb (%)
Bn
NH2
11a
HN
O2N
OH
8a
1
92
O
NH2
11b
HN
O2N
OH
8b
2
3
1
86
81
O
NH2
HN
11c
O2N
OH
8c
1.5
O
O
NH2
11d
HN
O
4
5
2
1
90
95
O2N
OH
8d
O
NH2
HN
O2N
OH
8e
11e
O
NH2
NO2
O2N
HN
6
3
65c
11f
O2N
OH
8f
O
N
H
N
O2N
OH
11g
7
8
2
3
76
80
O
8g
N
H
N
11h
O2N
OH
8h
O
NO2
HN
N
OMe
11i
9
0.2
94
O
N
N
OMe
8i
OH
a
b
c
Reaction time (t) is the hold time after reaching the reaction temperature in 10 min.
Yields refer to isolated pure compounds after column chromatography.
10 mol % more catalyst used.

L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
1033
Table 4
Microwave assisted alumina-catalyzed aminolysis of epoxide ent-9
R1
R2
N
O
O
O2N
OH
O2N
R1
R2
30 mol%, Al2O3
N
H
+
butan-1-ol
M.W., 117°C
O
ent-8
11
ent-9
Entry
1
Amine, 11
Amino alcohol, ent-8
ta (h)
Yieldb (%)
Bn
NH2
11a
HN
O2N
O2N
OH
ent-8a
1
92
86
O
NH2
11b
HN
OH
ent-8b
2
3
1
O
NH2
HN
11c
O2N
OH
1.5
81
ent-8c
O
O
NH2
11d
HN
O
4
5
2
1
90
95
O2N
O2N
OH
ent-8d
O
NH2
HN
OH
11e
ent-8e
NO2
O
NH2
O2N
HN
6
3
65c
11f
O2N
O2N
OH
ent-8f
O
N
N
H
OH
11g
7
8
2
3
76
80
O
N
ent-8g
N
H
11h
O2N
OH
ent-8h
O
NO2
HN
N
OMe
11i
9
0.2
94
O
N
N
OMe
ent-8i
OH
a
b
c
Reaction time (t) is the hold time after reaching the reaction temperature in 10 min.
Yields refer to isolated pure compounds after column chromatography.
10 mol % more catalyst.

1034
L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
Table 5
Aminolysis of epoxide, 9 with (R)-1-phenylethanamine and (S)-1-phenylethanamine
Me
*
Me
*
O
*
O2N
HN
*
Ph
30 mol%, Al2O3
*
+
NH2
O2N
OH
*
butan-1-ol
M.W., 117°C
O
O
9/ent-9
11/ent-11
8/ent-8
Entry
Epoxide
Amine
Product
ta (h)
Yieldb (%)
O
Me
Me
O2N
NH2
HN
Ph
O
O2N
OH
1
1.2
72
11j
9
O
8j
Me
Me
NH2
ent-11j
HN
Ph
2
3
4
9
1.2
71
85
80
O2N
OH
O
8k
O
Me
Me
O2N
HN
Ph
11j
1
O2N
OH
O
ent-9
ent-8k
ent-8j
O
HN
Ph
ent-9
ent-11j
1
O2N
OH
O
a
Reaction time (t) is the hold time after reaching the reaction temperature in 10 min.
Yields refer to isolated pure compounds after column chromatography.
b
tion of the pyran ring.28 This selectivity could be explained by the
fact that an unsaturated aryl group helps to promote the positively
charged C-4 carbon atom of the epoxide ring in the presence of a
nucleophilic reagent, owing to its high degree of resonance stabil-
ization29 and the effect of two methyl groups at the C-2 position,
which enhanced the steric hindrance of the C-3 position greatly.
Due to the configuration of the substrate, the amine only attacked
the opposite side of the epoxide, which resulted in the enantiome-
rically pure products. The relative stereochemistry was also deter-
mined based on the coupling constants of the peaks (CHNHPh; d,
J = 9.6 Hz) and (CHOH; d, J = 9.6 Hz) in their 1H NMR spectra.
tuted-amino)-2,2-dimethyl-6-nitrochroman-3-ol ent-8 in n-
butanol by microwave irradiation. This method offers high yields,
very short reaction time, uses a simple procedure, and environ-
mentally friendly conditions with commercially available alumina
as the catalyst, compared with the existing methods.
4. Experimental
4.1. General
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus and were uncorrected. Optical rotations
were measured with a Rudolph AUTOPOL IV digital polarimeter.
Nuclear magnetic resonance (1H and 13C NMR spectra) were re-
corded in CDCl3 (400 MHz for 1H and 100 MHz for 13C, respec-
tively) with TMS as the internal reference on a Bruker Advance
400 FT spectrometer. Chemicals shifts are reported in parts per
million. Mass spectra (MS) were measured by the EI method. Silica
gel (Merck D-6100, 70–230 mesh, ASTM) was used for flash col-
umn chromatography. All reactions were monitored by TLC using
0.25 mm silica gel plates (Merck 60F-254) with or without a UV
indicator. All other reagents were commercially available (Acros,
Aldrich) and used without further purification. All microwave-as-
sisted reactions were carried out on KMIC-1.5KW creator from Kor-
ea Microwave Instrument Company. The microwave-assisted
3. Conclusion
On the basis of our investigation of the structure–activity rela-
tionship, we have designed and synthesized a series of potential
antihypertensive agents by applying different C-4 substitutions
with the aim of discovering more efficient molecular structures
and improving the structure–activity relationship. The C-3 and C-
4 positions were functionalized stereoselectively using an asym-
metric Jacobsen epoxidation and microwave assisted regioselective
epoxide opening.
A practical and efficient epoxide ring opening method was
introduced for the preparation of (3S,4R)-4-(N-substituted-ami-
no)-2,2-dimethyl-6-nitro chroman-3-ol 8 and (3R,4S)-4-(N-substi-

L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
1035
reaction time is the hold time at the final temperature after reach-
ing it in 10 min (RAMP).
4.2.1.5. (3S,4R)-4-(Hexylamino)-2,2-dimethyl-6-nitrochroman-
3-ol 8e.
A yellow oil; ½a 2D0
¼ þ101:5 (c 1.0, CH2Cl2); IR (KBr)
ꢁ
m
/cmꢀ1: 3525, 3083, 2928, 2863, 1726, 1582, 1517, 1472, 1331,
4.2. Experimental procedures
1270, 1133, 1069, 940, 833, 746, 688; 1H NMR (400 MHz, CDCl3)
d 0.89 (t, J = 6.8 Hz, 3H), 1.26–1.38 (m, 9H), 1.51–1.57 (m, 5H),
2.53–2.59 (m, 1H), 2.66–2.73 (m, 1H), 3.60 (d, J = 6.0 Hz, 1H),
3.76 (d, J = 6.0 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 8.05 (dd, J = 9.2,
2.8 Hz, 1H), 8.26–8.27 (m, 1H); 13C NMR (100 MHz, CDCl3) d
14.11, 19.14, 22.67, 28.93, 27.00, 30.96, 31.73, 44.34, 56.58,
70.84, 80.10, 117.98, 123.85, 123.70, 124.70, 141.37, 159.30; MS
(EI) m/z: 251 (M+-71, 100%), 221 (47), 207 (9), 193 (20), 180 (19),
167 (7).
4.2.1. Typical procedure for the aminolysis of epoxide under
microwave irradiation in the presence of neutral alumina
To a solution of epoxide, 9 (0.44 g, 2 mmol) in n-butan-1-ol
(10 mL) were added amine (0.43 g, 4 mmol) and Al2O3 (61.0 mg,
0.6 mmol). The resulting mixture was placed into a microwave
oven (KMIC-1.5 kW) at 117 °C and irradiated for the period listed
in Table 3. The solvent was evaporated under reduced pressure.
The crude product was purified by short column chromatography
using ethyl acetate as the eluting solvent to afford the pure
compound.
4.2.1.6. (3S,4R)-2,2-Dimethyl-6-nitro-4-(4-nitrophenylamino)
chroman-3-ol 8f.
A
yellow solid, mp 166–168 °C;
½
a 2D0
ꢁ
¼ þ102:8 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3529, 3342, 3075,
4.2.1.1. (3S,4R)-4-(Benzylamino)-2,2-dimethyl-6-nitrochroman-
2981, 1586, 1513, 1476, 1327, 1270, 1122, 1069, 936, 836, 742,
692; 1H NMR (400 MHz, CDCl3) d 1.48 (s, 3H), 2.13 (s, 3H), 5.22
(d, J = 10.0 Hz, 1H), 5.55 (s, 1H), 6.60–6.61 (dd, J = 2.4, 0.8 Hz,
1H), 6.75 (d, J = 8.8 Hz, 1H), 6.97–7.01 (m, 1H), 7.40–7.43 (dd,
J = 8.8, 1.2 Hz, 2H) 8.04 (d, J = 2.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 23.58, 25.98, 71.70, 78.63, 84.95, 121.73, 122.42, 128.44,
132.11, 139.06, 148.29, 148.98, 154.24, 160.13, 167.51; MS (EI)
m/z: 288 (M+-71, 100%), 238 (46), 238 (11), 222 (23), 204 (13),
137 (56).
3-ol 8a.
1.0, CH2Cl2); IR (KBr)
A light-yellow solid, mp 93–94 °C; ½a D20
¼ þ67:7 (c
ꢁ
m
/cmꢀ1: 3529, 3342, 3075, 2981, 1586,
1513, 1476, 1327, 1270, 1122, 1069, 936, 836, 742, 692; 1H NMR
(400 MHz, CDCl3) d 1.29 (s, 3H), 1.60 (s, 3H), 3.71–3.91 (m, 4H),
6.93 (d, J = 8.4 Hz, 1H), 7.31–7.42 (m, 5H), 8.11 (d, J = 8.4 Hz, 1H),
8.40 (s, 1H); 13C NMR (100 MHz, CDCl3) d 19.16, 26.95, 48.70,
56.52, 71.13, 80.15, 118.13, 123.49, 123.85, 124.88, 127.59,
128.25, 128.84, 139.83, 141.52, 159.35; MS (EI) m/z: 257 (M+-71,
70%), 91 (100).
4.2.1.2. (3S,4R)-4-(Cyclohexylmethylamino)-2,2-dimethyl-6-nit-
4.2.1.7. (3S,4R)-4-(Dimethylamino)-2,2-dimethyl-6-nitrochro-
rochroman-3-ol 8b.
A
light-yellow solid, mp 88–89 °C;
man-3-ol 8g.
A
light-yellow solid, mp 111–113 °C;
a 2D0
ꢁ
¼ þ134:5 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3327, 3075, 2928,
½
a 2D0
ꢁ
¼ þ55:9 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3437, 2969, 2928,
½
2852, 1590, 1513, 1476, 1270, 1122, 1069, 940, 840, 795, 753; 1H
NMR (400 MHz, CDCl3) d 0.93–1.03 (m, 2H), 1.21–1.32 (m, 6H),
1.42–1.48 (m, 1H), 1.59 (s, 3H), 1.70–1.85 (m, 5H), 2.40–2.55 (m,
2H), 3.62 (d, J = 6.0 Hz, 1H), 3.78 (d, J = 6.0 Hz, 1H), 6.89 (d,
J = 8.8 Hz, 1H), 8.07 (dd, J = 8.8, 2.8 Hz, 1H), 8.26 (d, J = 1.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 19.18, 26.04, 26.63, 27.02,
31.35, 31.45, 39.12, 50.87, 56.64, 70.77, 80.07, 117.95, 123.76,
124.86, 141.35, 159.31; MS (EI) m/z: 263 (M+-71, 100%), 219 (3),
180 (44), 167 (13).
2874, 2813, 1586, 1521, 1472, 1331, 1267, 1091, 1057, 928, 836,
750, 685; 1H NMR (400 MHz, CDCl3) d 1.18 (s, 6H), 1.27 (s, 3H),
1.57 (s, 3H), 3.49 (d, J = 6.0 Hz, 1H), 3.83 (d, J = 6.0 Hz, 1H), 6.87
(d, J = 8.8 Hz, 1H), 8.04–8.06 (dd, J = 8.8, 1.6 Hz, 1H), 8.20 (dd,
J = 2.8, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 16.50, 19.08,
27.21, 60.65, 70.58, 80.15, 118.16, 122.87, 124.05, 124.55, 140.85,
159.81; MS (EI) m/z: 223 (M+-43, 96%), 205 (100), 193 (97), 177
(19), 165 (13), 147 (15), 119 (8), 70 (8).
4.2.1.8.
man-3-ol 8h.
¼ þ145:6 (c 1.0, CH2Cl2); IR (KBr)
(3S,4R)-2,2-dimethyl-6-nitro-4-(piperidin-1-yl)chro-
light-yellow solid, mp 120–121 °C;
/cmꢀ1: 3486, 3437, 2935,
4.2.1.3. (3S,4R)-4-(Cyclohexylamino)-2,2-dimethyl-6-nitrochro-
A
man-3-ol 8c.
A
light-yellow solid, mp 164–165 °C;
a 2D0
ꢁ
¼ þ32:3 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3312, 3079, 2935,
½
a 2D0
ꢁ
m
½
2809, 1582, 1513, 1472, 1335, 1270, 1118, 1069, 1034, 924, 833,
753, 688; 1H NMR (400 MHz, CDCl3) d 1.24 (s, 3H), 1.55–1.62 (m,
9H), 2.77–2.96 (m, 5H), 3.66–3.73 (m, 2H), 6.85 (d, J = 8.0 Hz,
1H), 8.02–8.05 (dd, J = 8.0, 2.8 Hz, 1H), 8.37–8.38 (dd, J = 2.8,
0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) 18.75, 24.69, 26.91,
27.35, 64.15, 70.26, 79.90, 117.91, 122.99, 124.45, 124.80, 141.12,
159.46; MS (EI) m/z: 234 (M+-72, 100%), 217 (49), 200 (30), 187
(11), 82 (9).
2856, 1582, 1509, 1472, 1376, 1323, 1263, 1216, 1118, 1069,
932, 803, 750; 1H NMR (400 MHz, CDCl3) d 1.14–1.43 (m, 8H),
1.56 (s, 3H), 1.65–1.69 (m, 1H), 1.77–1.84 (m, 2H), 2.00–2.03 (m,
2H), 2.88–2.93 (m, 1H), 3.37 (d, J = 10.0 Hz, 1H), 3.69 (d,
J = 10.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 8.03 (dd, J = 9.2, 2.8 Hz,
1H), 8.27 (d, J = 2.8, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
19.63, 24.71, 25.06, 25.90, 27.06, 35.04, 35.08, 54.84, 55.87,
73.64, 80.30, 117.65, 123.30, 124.62, 126.25, 141.39, 158.79; MS
(EI) m/z: 249 (M+-71, 100%), 231 (8), 219 (30), 205 (18), 193 (11),
180 (8), 167 (23), 55 (9).
4.2.1.9.
(3S,4R)-4-(4-(4-Methoxyphenyl)piperazin-1-yl)-2,2-
A light-yellow solid, mp
¼ þ167:8 (c 1.0, CH2Cl2); IR (KBr)
/cmꢀ1: 3336,
dimethyl-6-nitrochroman-3-ol 8i.
181–182 °C; ½a 2D0
ꢁ
m
4.2.1.4.
(3S,4R)-2,2-Dimethyl-6-nitro-4-((tetrahydrofuran-2-
3073, 3038, 2979, 2948, 2930, 2896, 2833, 1613, 1584, 1509,
1463, 1407, 1370, 1348, 1333, 1292, 1270, 1251, 1220, 1178,
1165, 1137, 1062, 1033, 1016, 993, 945, 927, 914, 827, 747, 712,
691; 1H NMR (400 MHz, CDCl3) d 1.24 (s, 3H), 1.50 (s, 3H), 2.86
(s, 1H), 3.00–3.06 (m, 4H), 3.11–3.13 (m, 4H), 3.78 (s, 3H), 3.81–
3.85 (m, 2H), 6.84–6.94 (m, 5H), 8.04 (dd, J = 9.2, 2.0 Hz, 1H),
8.48 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 18.64, 26.79,
49.94, 52.15, 55.61, 63.09, 70.25, 79.99, 114.46, 118.08, 118.73,
122.84, 124.71, 124.97, 141.45, 145.65, 154.08, 159.48; MS (EI)
m/z: 413 (M+, 43%), 342 (10), 191 (21), 162 (100), 148 (22), 134
(21), 120 (16), 56 (10).
yl)methylamino)chroman-3-ol 8d.
A light-yellow solid, mp
145–146 °C; ½a 2D0
ꢁ
¼ þ121:6 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3331,
3083, 2977, 2874, 1586, 1509, 1482, 1331, 1267, 1077, 940, 818,
753; 1H NMR (400 MHz, CDCl3) d 1.26 (s, 3H), 1.53–1.61 (m, 4H),
1.89–2.03 (m, 3H), 2.56–2.91 (m, 2H), 3.57–3.63 (m, 1H), 3.78–
3.86 (m, 2H), 3.89–4.08 (m, 2H), 6.84 (dd, J = 8.8, 3.2 Hz, 1H),
8.03 (d, J = 8.8 Hz, 1H), 8.38 (dd, J = 2.8, 1.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 19.10, 25.82, 26.99, 28.88, 48.90, 56.74,
68.05, 71.87, 79.50, 80.31, 117.77, 124.12, 124.57, 124.69, 141.48,
159.23; MS (EI) m/z: 251 (M+-71, 100%), 222 (17), 207 (8), 180
(56), 164 (10), 152 (6), 84 (7), 71 (36), 59 (8).

1036
L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
4.2.1.10.
(3S,4R)-2,2-Dimethyl-6-nitro-4-((S)-1-phenylethyl
An off-white solid, mp 125–
¼ þ51:5 (c 1.0, CH2Cl2); IR (KBr)
/cmꢀ1: 3513, 3345,
4.2.1.15. (3R,4S)-2,2-Dimethyl-6-nitro-4-((tetrahydrofuran-2-
amino)chroman-3-ol 8j.
yl)methylamino)chroman-3-ol ent-8d.
A light-yellow solid,
126 °C; ½a 2D0
ꢁ
m
mp 147–148 °C; ½a D20
ꢁ
¼ ꢀ121:8 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1
:
3072, 3030, 2973, 2932, 2867, 1582, 1509, 1331, 1270, 1126,
1065, 981, 943, 905, 829, 750; 1H NMR (400 MHz, CDCl3) d 1.08
(s, 3H), 1.48 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 3.39 (d, J = 9.6 Hz,
1H), 3.54 (d, J = 9.6 Hz, 1H), 4.36–4.41 (q, J = 6.8 Hz, 1H), 6.84 (d,
J = 9.2 Hz, 1H), 7.33 (m, 1H), 7.38–7.43 (m, 4H), 8.05–8.07 (dd,
J = 9.2, 2.4 Hz, 1H), 8.34–8.35 (dd, J = 2.4, 1.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 19.27, 24.80, 26.85, 55.25, 58.34, 73.79,
80.22, 117.78, 123.38, 124.81, 126.89, 127.94, 129.12, 141.33,
158.71; MS (EI) m/z: 271 (M+-71, 59%), 166 (19), 105 (100), 79 (9).
3334, 3083, 2979, 2878, 1586, 1502, 1468, 1334, 1268, 1079,
932, 818, 752; 1H NMR (400 MHz, CDCl3) d 1.27 (s, 3H), 1.53–
1.61 (m, 4H), 1.89–2.02 (m, 3H), 2.57–2.92 (m, 2H), 3.56–3.63
(m, 1H), 3.77–3.85 (m, 2H), 3.89–4.08 (m, 2H), 6.80 (dd, J = 8.8,
3.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.35 (dd, J = 2.8, 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 19.21, 25.92, 26.99, 28.97, 48.99,
56.94, 68.19, 71.89, 79.64, 80.43, 117.98, 124.22, 124.64, 124.75,
141.40, 159.22; MS (EI) m/z: 251 (M+-71, 100%), 222 (17), 207
(11), 180 (55), 164 (8), 152 (6), 84 (7), 71 (38), 59 (7).
4.2.1.16. (3R,4S)-4-(Hexylamino)-2,2-dimethyl-6-nitrochroman-
4.2.1.11.
(3S,4R)-2,2-Dimethyl-6-nitro-4-((R)-1-phenylethyl
An off-white solid, mp 122–
¼ þ91:2 (c 1.0, CH2Cl2); IR (KBr)
/cmꢀ1: 3490, 3345,
3-ol ent-8e.
(KBr)
A yellow oil; ½a 2D0
¼ ꢀ100:5 (c 1.0, CH2Cl2); IR
ꢁ
amino)chroman-3-ol 8k.
m
/cmꢀ1: 3525, 3083, 2933, 2863, 1729, 1588, 1514, 1470,
124 °C; ½a 2D0
ꢁ
m
1334, 1273, 1137, 1064, 940, 832, 744, 689; 1H NMR (400 MHz,
CDCl3) d 0.89 (t, J = 6.8 Hz, 3H), 1.27–1.38 (m, 9H), 1.52–1.59 (m,
5H), 2.55–2.61 (m, 1H), 2.66–2.74 (m, 1H), 3.61 (d, J = 6.0 Hz,
1H), 3.77 (d, J = 6.0 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 8.07 (dd,
J = 9.2, 2.8 Hz, 1H), 8.26–8.28 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 14.19, 19.17, 22.57, 29.10, 27.05, 31.13, 31.81, 44.39, 56.57,
70.85, 80.12, 118.07, 123.97, 123.77, 124.74, 141.39, 159.34; MS
(EI) m/z: 251 (M+-71, 100%), 221 (45), 207 (9), 193 (25), 180 (20),
167 (7).
3072, 2985, 2920, 2863, 1582, 1513, 1472, 1331, 1274, 1130,
1061, 985, 947, 913, 829, 756, 696; 1H NMR (400 MHz, CDCl3) d
1.24 (s, 3H), 1.46–1.49 (m, 6H), 3.39 (d, J = 9.6 Hz, 1H), 3.75 (d,
J = 9.6 Hz, 1H), 4.11–4.16 (q, J = 6.8 Hz, 1H), 6.85 (d, J = 9.2 Hz,
1H), 7.31 (m, 1H), 7.39–7.47 (m, 4H), 8.04–8.07 (dd, J = 8.8,
2.8 Hz, 1H), 8.34–8.35 (dd, J = 2.8, 1.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 19.47, 25.27, 26.75, 55.64, 55.80, 73.25,
80.12, 117.82, 124.10, 124.70, 126.50, 127.66, 129.05, 141.42,
145.91, 159.02; MS (EI) m/z: 271 (M+-71, 55%), 166 (15), 105
(100), 79 (9).
4.2.1.17.
(3R,4S)-2,2-Dimethyl-6-nitro-4-(4-nitrophenyl
A light-yellow solid, mp 171–
/cmꢀ1: 3528,
amino)chroman-3-ol ent-8f.
172 °C; ½a 2D0
ꢁ
¼ ꢀ102:1 (c 1.0, CH2Cl2);); IR (KBr)
m
4.2.1.12.
man-3-ol ent-8a.
¼ ꢀ67:5 (c 1.0, CH2Cl2); IR (KBr)
(3R,4S)-4-(Benzylamino)-2,2-dimethyl-6-nitrochro-
light-yellow solid, mp 103–104 °C;
/cmꢀ1: 3527, 3340, 3075,
3340, 3076, 2985, 1588, 1503, 1468, 1320, 1263, 1121, 1063,
935, 833, 745, 698; 1H NMR (400 MHz, CDCl3) d 1.48 (s, 3H), 2.13
(s, 3H), 5.20 (d, J = 10.0 Hz, 1H), 5.54 (s, 1H), 6.63–6.64 (dd,
J = 2.4, 0.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.98–7.02 (m, 1H),
7.41–7.44 (dd, J = 8.8, 1.2 Hz, 2H), 8.04 (d, J = 2.4 Hz, 2H); 13C
A
½
a 2D0
ꢁ
m
2976, 1582, 1510, 1471, 1320, 1265, 1117, 1063, 939, 843, 746,
690; 1H NMR (400 MHz, CDCl3) d 1.29 (s, 3H), 1.60 (s, 3H), 3.72–
3.92 (m, 4H), 6.94 (d, J = 8.4 Hz, 1H), 7.33–7.43 (m, 5H), 8.12 (d,
J = 8.4 Hz, 1H), 8.40 (s, 1H); 13C13C NMR (100 MHz, CDCl3) d
19.26, 27.03, 48.62, 56.57, 71.19, 80.21, 118.20, 123.48, 123.85,
124.98, 127.79, 128.32, 128.95, 139.89, 141.46, 159.53; MS (EI)
m/z: 257 (M+-71, 72%), 91 (100).
NMR (100 MHz, CDCl3)
d 23.65, 26.06, 71.79, 78.73, 84.98,
121.91, 122.62, 128.59, 132.25, 139.09, 148.32, 149.03, 154.27,
160.16, 167.56; MS (EI) m/z: 288 (M+-71, 100%), 238 (46), 238
(11), 222 (23), 204 (13), 137 (56).
4.2.1.18. (3R,4S)-4-(Dimethylamino)-2,2-dimethyl-6-nitrochro-
4.2.1.13.
(3R,4S)-4-(Cyclohexylmethylamino)-2,2-dimethyl-6-
A light-yellow solid, mp 92–
¼ ꢀ134:9 (c 1.0, CH2Cl2); IR (KBr)
/cmꢀ1: 3327, 3073,
man-3-ol ent-8g.
A
light-yellow solid, mp 115–116 °C;
a 2D0
ꢁ
¼ ꢀ55:9 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3437, 2969, 2928,
nitrochroman-3-ol ent-8b.
½
93 °C; ½a 2D0
ꢁ
m
2874, 2813, 1585, 1528, 1472, 1331, 1267, 1091, 1057, 928, 836,
756, 685; 1H NMR (400 MHz, CDCl3) d 1.19 (s, 6H), 1.28 (s, 3H),
1.58 (s, 3H), 3.51 (d, J = 6.0 Hz, 1H), 3.84 (d, J = 6.0 Hz, 1H), 6.87
(d, J = 8.8 Hz, 1H), 8.04–8.06 (dd, J = 8.8, 1.6 Hz, 1H), 8.19 (dd,
J = 2.8, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 16.50, 19.08,
27.12, 60.83, 70.48, 80.21, 118.16, 122.86, 124.03, 124.59, 140.84,
159.83; MS (EI) m/z: 223 (M+-43, 97%), 205 (100), 193 (94), 177
(19), 165 (20), 147 (15), 119 (10), 70 (6).
2925, 2850, 1586, 1523, 1472, 1269, 1127, 1052, 944, 847, 802,
758; 1H NMR (400 MHz, CDCl3) d 0.92–1.03 (m, 2H), 1.20–1.31
(m, 6H), 1.40–1.47 (m, 1H), 1.55 (s, 3H), 1.68–1.83 (m, 5H), 2.43–
2.57 (m, 2H), 3.65 (d, J = 6.0 Hz, 1H), 3.78 (d, J = 6.0 Hz, 1H), 6.89
(d, J = 8.8 Hz, 1H), 8.08 (dd, J = 8.8, 2.8 Hz, 1H), 8.27 (d, J = 1.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 19.25, 26.16, 26.73, 27.13,
31.47, 31.45, 39.10, 50.81, 56.62, 70.87, 80.15, 118.00, 123.79,
124.91, 141.43, 159.31; MS (EI) m/z: 263 (M+-71, 100%), 219 (5),
180 (42), 167 (13).
4.2.1.19. (3R,4S)-2,2-Dimethyl-6-nitro-4-(piperidin-1-yl)chro-
man-3-ol ent-8h.
A
light-yellow solid, mp 122–123 °C;
a 2D0
ꢁ
¼ ꢀ146:2 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3486, 3437, 2934,
4.2.1.14. (3R,4S)-4-(Cyclohexylamino)-2,2-dimethyl-6-nitroch-
½
roman-3-ol ent-8c.
A light-yellow solid, mp 174–175 °C;
2808, 1582, 1513, 1472, 1337, 1275, 1120, 1069, 1037, 922, 835,
751, 687; 1H NMR (400 MHz, CDCl3) d 1.25 (s, 3H), 1.59–1.66 (m,
9H), 2.79–2.98 (m, 5H), 3.67–3.74 (m, 2H), 6.88 (d, J = 8.0 Hz,
1H), 8.03–8.06 (dd, J = 8.0, 2.8 Hz, 1H), 8.37–8.38 (dd, J = 2.8,
0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) 18.55, 24.47, 26.80,
27.18, 64.02, 70.17, 79.79, 117.93, 122.95, 124.25, 124.80, 141.15,
159.49; MS (EI) m/z: 234 (M+-72, 100%), 217 (47), 200 (35), 187
(13), 82 (10).
½
a 2D0
ꢁ
¼ ꢀ32:1 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1: 3312, 3078, 2936,
2852, 1580, 1506, 1470, 1379, 1326, 1264, 1218, 1120, 1060,
938, 809, 756; 1H NMR (400 MHz, CDCl3) d 1.15–1.43 (m, 8H),
1.56 (s, 3H), 1.66–1.71 (m, 1H), 1.78–1.86 (m, 2H), 2.01–2.04 (m,
2H), 2.86–2.93 (m, 1H), 3.36 (d, J = 10.0 Hz, 1H), 3.68 (d,
J = 10.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 8.04 (dd, J = 9.2, 2.8 Hz,
1H), 8.26 (d, J = 2.8, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
19.73, 24.79, 25.09, 25.92, 27.26, 35.18, 35.21, 54.74, 55.79,
73.60, 80.20, 117.66, 123.33, 124.66, 126.24, 141.37, 158.86; MS
(EI) m/z: 249 (M+-71, 100%), 231 (10), 219 (38), 205 (18), 193
(13), 180 (7), 167 (22), 55 (11).
4.2.1.20.
(3R,4S)-4-(4-(4-Methoxyphenyl)piperazin-1-yl)-2,2-
dimethyl-6-nitrochroman-3-ol ent-8i.
An off-white solid,
mp 183–184 °C; ½a D20
ꢁ
¼ ꢀ170:2 (c 1.0, CH2Cl2); IR (KBr)
m
/cmꢀ1
:

L.-j. Meng et al. / Tetrahedron: Asymmetry 23 (2012) 1029–1037
1037
2. (a) Hamilton, T. C.; Weir, S. W.; Weston, A. H. Br. J. Pharmacol. 1986, 88, 103; (b)
Ashwood, V. A.; Buckingham, R. E.; Cassidy, F.; Evans, J. M.; Faruk, E. A.;
Hamilton, T. C.; Nash, D. J.; Stemp, G.; Willcocks, K. J. Med. Chem. 1986, 29, 2194.
3. Andersson, K. E. Pharmacol. Toxicol. 1992, 70, 244.
4. Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492.
5. Smith, D. G. J. Chem. Soc. Perkin Trans. 1 1990, 3187.
6. Burrell, G.; Cassidy, F.; Evans, J. M.; Lightowler, D.; Stemp, G. J. Med. Chem. 1990,
33, 3023.
7. Buckle, D. R.; Arch, J. R. S.; Edge, C.; Foster, K. A.; Houge-Frydrych, C. S. V.; Pinto,
I. L.; Smith, D. G.; Taylor, J. F.; Taylor, S. G.; Tedder, J. M.; Webster, R. A. B. J. Med.
Chem. 1991, 34, 919.
8. Ashwood, V. A.; Cassidy, F.; Evans, J. M.; Gagliardi, S.; Stemp, G. J. Med. Chem.
1991, 34, 3261.
9. Sanfilippo, P. J.; McNally, J. J.; Press, J. B.; Fitzpatrick, L. J.; Urbanski, M. J.; Katz,
L. B.; Giardino, E.; Falotico, R.; Salata, J.; Moore, J. B., Jr.; Miller, W. J. Med. Chem.
1992, 35, 4425.
3390, 3074, 3039, 2978, 2948, 2895, 2948, 2833, 1614, 1585, 1510,
1463, 1406, 1379, 1370, 1348, 1334, 1270, 1251, 1221, 1179, 1166,
1137, 1077, 1063, 1034, 1016, 993, 945, 927, 914, 827, 747, 729,
712, 692, 633; 1H NMR (400 MHz, CDCl3) d 1.24 (s, 3H), 1.49 (s,
3H), 2.86 (s, 1H), 3.02–3.06 (m, 4H), 3.11–3.13 (m, 4H), 3.78 (s,
3H), 3.81–3.85 (m, 2H), 6.84–6.94 (m, 5H), 8.04 (dd, J = 8.8,
2.8 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
18.63, 26.81, 49.94, 52.15, 55.61, 63.10, 70.26, 80.02, 114.48,
118.09, 118.73, 122.84, 124.71, 124.96, 141.44, 145.65, 154.10,
159.48; MS (EI) m/z: 413 (M+, 32%), 355 (8), 341 (7), 327 (8), 281
(47), 267 (7), 253 (18), 207 (100), 191 (24), 162 (62), 152 (15),
135 (22), 120 (12), 96 (11), 73 (10), 59 (10), 44 (31).
10. Almansa, C.; Gómez, L. A.; Cavalcanti, F. L.; Rodriguez, R.; Carceller, E.; Bartrolí,
J.; García-Rafanell, J.; Forn, J. J. Med. Chem. 1993, 36, 2121.
11. Atwal, K.-S. Med. Res. Rev. 1992, 12, 569.
12. Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.; Yoden, T.; Uchida, W.;
Asano, M.; Fujita, S.; Yanagisawa, I.; Fujikura, T. Chem. Pharm. Bull. 1996, 44,
103.
4.2.1.21.
(3R,4S)-2,2-Dimethyl-6-nitro-4-((S)-1-phenylethyl
An off-white solid, mp 124–
¼ ꢀ91:3 (c 1.0, CH2Cl2); IR (KBr)
/cmꢀ1: 3486, 3344,
amino)chroman-3-ol ent-8k.
125 °C; ½a 2D0
ꢁ
m
3072, 2985, 2920, 2863, 1582, 1513, 1472, 1327, 1274, 1130,
1061, 980, 943, 913, 829, 756, 693; 1H NMR (400 MHz, CDCl3) d
1.23 (s, 3H), 1.45 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 3.39 (d,
J = 9.6 Hz, 1H), 3.76 (d, J = 9.6 Hz, 1H), 4.12–4.17 (q, J = 6.8 Hz,
1H), 6.85 (d, J = 9.2 Hz, 1H), 7.29–7.34 (m, 1H), 7.39–7.47 (m,
4H), 8.05–8.08 (dd, J = 8.8, 2.8 Hz, 1H), 8.34–8.35 (dd, J = 2.8,
1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 19.40, 25.12, 26.75,
55.75, 55.92, 73.10, 80.11, 117.86, 124.07, 124.76, 126.54, 127.75,
129.08, 141.43, 159.00; MS (EI) m/z: 271 (M+-71, 59%), 166 (19),
105 (100), 79 (9).
13. Atwal, K.-S. Med. Res. Rev. 1992, 12, 569.
14. Edwards, G.; Weston, A.-H. Trends Pharmacol. 1990, 11, 417.
15. Ashwood, V. A.; Buckingham, R. E.; Cassidy, F.; Evans, J. M.; Faruk, E. A.;
Hamilton, T. C.; Nash, D. J.; Stemp, G.; Wilcocks, K. J. Med. Chem. 1986, 29, 2194.
16. Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492.
17. Atwal, K.-S. J. Cardiovasc. Pharmacol. 1994, 24, S12.
18. Zuo, H.; Li, Z. B.; Zhao, B.-X.; Miao, J.-Y.; Meng, L.-J.; Jang, K.; Ahn, C.; Lee, D.-H.;
Shin, D.-S. Bull. Korean. Chem. Soc. 2011, 32, 2965.
19. Lee, N. H.; Muci, A. R.; Jacobsen, E. R. Tetrahedron Lett. 1991, 32, 5055.
20. (a) Möller, F. In Methoden der Organischen Chemie (Houben-Weyl), 4th ed.;
Müller, E., Ed.; Thieme Verlag: Stuttgart, 1957; Vol.11/1, pp 311–326.; (b)
Mousseron, M.; Jullien, J.; Jolchine, Y. Bull. Soc. Chim. Fr. 1952, 757.
21. Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1969, 34, 175.
22. (a) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31, 4661; (b)
Yamamoto, Y.; Asao, N.; Meguro, M.; Tsukade, N.; Nemoto, H.; Adayari, N.;
Wilson, J. G.; Nakamura, H. J. Chem. Soc., Chem. Commun. 1993, 1201; (c)
Meguro, M.; Asao, N.; Yamamoto, Y. J. Chem. Soc. Perkin Trans. 1 1994, 2597; (d)
Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287; (e) Sagava, S.; Abe, H.; Hase,
Y.; Inaba, T. J. Org. Chem. 1999, 64, 4962; (f) Curini, M.; Epifano, F.; Marcotullio,
M. C.; Rosati, O. Eur. J. Org. Chem. 2001, 4149; (g) Fagnou, K.; Lautens, M. Org.
Lett. 2000, 2, 2319; (h) Pacho’n, L. D.; Gamez, P.; van Bassel, J. J. M.; Reedijk, J.
Tetrahedron Lett. 2003, 44, 6025; (i) Chakraborti, A. K.; Kondaskar, A.
Tetrahedron Lett. 2003, 44, 8315; (j) Zhao, P.-Q.; Xu, L.-W.; Xia, C.-G. Synlett
2004, 846; (k) Fan, R.-H.; Hou, X.-L. J. Org. Chem. 2003, 68, 726; (l) Kamal, A.;
Ramu, R.; Amerudin Azhar, M.; Ramesh Khanna, G. B. Tetrahedron Lett. 2005,
46, 2675; (m) Carree, F.; Gil, R.; Collin, J. Tetrahedron Lett. 2004, 45, 7749; (n)
Sundrarajan, G.; Vijayakrishna, K.; Varghese, B. Tetrahedron Lett. 2004, 45,
8253; (o) Rodriquez, J. R.; Navarro, A. Tetrahedron Lett. 2004, 45, 7495.
23. Mojtahedi, M. M.; Saidi, M. R.; Bolourtchian, M. J. Chem. Res. Synop. 1999, 128.
24. (a) Swamy, N. R.; Goud, T. V.; Reddy, S. M.; Krishnaiah, P.; Venkateswarlu, Y.
Synth. Commun. 2004, 34, 727; (b) Chakraborti, A. K.; Rudrawar, S.; Kondaskar,
A. Org. Biomol. Chem. 2004, 2, 1277.
4.2.1.22.
(3R,4S)-2,2-Dimethyl-6-nitro-4-((R)-1-phenylethyl
A light-yellow solid, mp 129–
¼ ꢀ51:6 (c 1.0, CH2Cl2); IR (KBr)
/cmꢀ1: 3510, 3345,
amino)chroman-3-ol ent-8j.
130 °C; ½a 2D0
ꢁ
m
3072, 3030, 2977, 2935, 2870, 1582, 1509, 1334, 1274, 1126,
1065, 980, 943, 905, 829, 752; 1H NMR (400 MHz, CDCl3) d 1.08
(s, 3H), 1.48 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 3.43 (d, J = 9.6 Hz,
1H), 3.57 (d, J = 9.6 Hz, 1H), 4.38–4.32 (q, J = 6.8 Hz, 1H), 6.84 (d,
J = 9.2 Hz, 1H), 7.30–7.40 (m, 1H), 7.42–7.44 (m, 4H), 8.06–8.09
(dd, J = 8.8, 2.8 Hz, 1H), 8.34–8.35 (dd, J = 2.8, 1.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 19.18, 24.63, 26.83, 55.35, 58.41, 73.57,
73.59, 80.21, 117.86, 123.42, 124.92, 126.94, 128.06, 129.17,
141.34, 158.71; MS (EI) m/z: 271 (M+-71, 57%), 166 (17), 105
(100), 79 (15).
Acknowledgements
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This work was partially supported by grants from the Korea
Ministry of Environment (KME, 412-111-008) and the National Re-
search Foundation of Korea (NRF-2010-0029634) and the Ministry
of Knowledge Economy (MKE, R0000495).
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