Thiophosphoramide catalyzed asymmetric Michael addition of acetone to functionalized nitrostyrenes: A convenient approach to optically active tetrahydropyrans

Article abstract of DOI:10.1016/j.tetasy.2010.11.019

Thiophosphoramide 5d was found to be an effective organocatalyst for the enantioselective Michael reaction of problematic acetone to various hydroxymethyl nitrostyrenes, affording the multisubstituted tetrahydropyrans with three stereogenic centers. The Michael addition products generated were obtained as a single diastereomer with enantioselectivities ranging from 46% to 74% ee.

Full text of DOI:10.1016/j.tetasy.2010.11.019

Tetrahedron: Asymmetry 21 (2010) 2988–2992
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Thiophosphoramide catalyzed asymmetric Michael addition of acetone to
functionalized nitrostyrenes: a convenient approach to optically active
tetrahydropyrans
⇑
Yang Wu , Aidang Lu , Yunfeng Liu, Xiaolei Yu, Youming Wang , Guiping Wu, Haibin Song,
Zhenghong Zhou , Chuchi Tang
⇑
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiophosphoramide 5d was found to be an effective organocatalyst for the enantioselective Michael reac-
tion of problematic acetone to various hydroxymethyl nitrostyrenes, affording the multisubstituted tetr-
ahydropyrans with three stereogenic centers. The Michael addition products generated were obtained as
a single diastereomer with enantioselectivities ranging from 46% to 74% ee.
Received 3 November 2010
Accepted 22 November 2010
Available online 12 January 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The multiple reactivities of the nitro functionality and the versa-
tile valuable building blocks that are created means that the addition
of nucleophiles to nitroolefins is recognized as one of the most
important Michael additions in organic synthesis.1 Over the past
decade, the organocatalyzed asymmetric version of this process
has attracted much attention and significant progress has been seen
in this area.2–5 In contrast to the significant amount of effort that has
been devoted to investigating the asymmetric Michael addition to
the simple b-substituted nitroolefins, the organocatalytic conju-
gated additions employing multisubstituted (functionalized) nitro-
olefins as the Michael acceptors remain rarely studied. The only
example of a Michael addition to functionalized nitroolefins is the
domino Michael-ketalization of cyclohexanone to hydroxymethyl
nitroolefins developed by Chandrasekhar.3k It is well known that
acetone is one of the most problematic substrates for the nitro-
Michael addition, and that the organocatalyzed Michael addition
reaction of nitroolefins is a continuing challenge. Therefore, the
development of organocatalyzed asymmetric Michael additions of
acetone substrates to functionalized nitroolefins would be of great
interest. Herein, we report the bifunctional thiophosphoramide
organocatalyzed asymmetric Michael addition of acetone to
hydroxymethyl nitroolefins, affording a direct and atom-economic
approach to enantiomerically enriched multisubstituted
tetrahydropyrans.
Firstly, a series of chiral pyrrolidine-based catalysts 1–5 were
chosen as the catalyst candidates (Fig. 1). In order to evaluate the
catalytic efficiency of chiral pyrrolidines, the addition of acetone
to hydroxymethyl nitroolefin 6a was first performed in neat ace-
tone in the presence of 20 mol % of each of these catalysts as well
as 10 mol % of benzoic acid as a cocatalyst (Table 1).
(S)-Diphenylprolinol 16 and (S)-diphenylprolinol trimethylsilyl
ether 2,7 which were previously reported to provide high degrees
of enantioselectivities in many asymmetric transformations ap-
peared to be not effective in this reaction (Table 1, entries 1 and 2).
Pyrrolidine-based thioureas 3,8 and 4,9 which proved to be highly
efficient catalysts for the Michael addition to nitroolefin, demon-
strated higher catalytic activities, giving the corresponding tetrahy-
dropyran 7a with enantioselectivities of 47% and 40% ee,
respectively (Table 1, entries 3 and 4). Our recently developed
bifunctional thiophosphoramide catalysts 510 also proved to be
effective for this transformation. However, the substituent on the
phosphorus atom has a marked influence on both the catalytic activ-
ityand the enantioselectivity. When O,O-diphenyl thiophosphoram-
idate 5a was employed as the catalyst, the reaction was complete in
21 h, providing 7a with an enantiomeric excess of 40%, whereas thi-
ophosphinamide 5b proved to be ineffective in this reaction (Table 1,
entry 5 vs entry 6). Comparable results were observed for thiophos-
phoramide 5c, which contains a tropos biphenyl skeleton (Table 1,
entry 7). With respect to enantioselectivity, the best result was ob-
tained with the bulky catalyst (S,aR)-5d bearing an (R)-binaphthyl
skeleton (Table 1, entry 8, 53% ee). However, under otherwise iden-
tical conditions, bifunctional thiophosphoramide (R,aR)-5d afforded
7a with an eroded enantioselectivity and reversed stereochemistry,
indicating that the configuration of the newly formed stereogenic
⇑
Corresponding authors.
E-mail address: z.h.zhou@nankai.edu.cn (Z. Zhou).
These two authors contributed equally to this work.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.019

Y. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2988–2992
2989
OAc
Ph
Ph
Ph
O
OAc
H
N
H
N
Ph
AcO
N
H
N
H
AcO
N
OTMS
OH
H.CF3CO2H
S
2
1
3
H
N
H
N
H
N
H
OPh
OPh
Ph
CF3
N
Ph
N
H
P
S
P
S
N
N
H2
CF3CO2
H2
S
−
−
CF3CO2
CF3
4
5b
5a
O
P
O
O
P
O
O
P
O
S
S
O
N
N
N
H
H
H
NH2
CF3CO2
NH2
CF3CO2
NH2
CF3CO2
−
−
−
5c
(R,aR)-5d
(S,aR)-5d
Figure 1. Different pyrrolidine-based organocatalysts.
Table 1
Table 2
Catalyst evaluationa
Optimization of reaction conditionsa
OH
O
OH
(S,aR)-5d (20 mol%)
NO2
OH
NO2
OH
O
O
Et3N (20 mol%)
O
cat. (20 mol%)
Ph
Ph
+
+
cocatalyst (10 mol%)
PhCO2H (10 mol%)
Ph
Ph
Solvent, 20 °C
NO2
NO2
7a
6a
7a
6a
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
Entry
Cocatalyst
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1
2
48
48
48
48
21
72
12
8
Trace
Trace
51
49
66
Trace
34
48
NDd
NDd
47
1
2
3
4
5
6
7
8
—
Neat
Neat
Neat
Neat
Neat
PhCH3
THF
CHCl3
EtOAc
CH3OH
Neat
Neat
Neat
NRd
8
—
—
PhCO2H
CH3CO2H
tBuCO2H
48
43
34
55
40
47
30
51
Trace
65
75
75
53
50
49
53
34
47
34
53
NDd
53
54
57
3/Et3N
4
5a/Et3N
5b/Et3N
5c/Et3N
48
48
10
48
48
84
36
120
14
30
72
40
40
Nicotinic acid
Nicotinic acid
Nicotinic acid
Nicotinic acid
Nicotinic acid
Nicotinic acid
Nicotinic acid
Nicotinic acid
Nicotinic acid
NDd
31
(S,aR)-5d/Et3N
(R,aR)-5d/Et3N
53
ꢀ11
36
43
9
10
11e
12f
13g
a
Reaction conditions: acetone (0.5 mL, 6.8 mmol), nitroolefin 7a (0.2 mmol),
20 °C.
b
Yield of the isolated product after chromatography on silica gel.
Determined by Chiral HPLC analysis.
ND means not determined.
c
d
a
Reaction conditions: acetone (0.5 mL, 6.8 mmol) or acetone (116 mg, 10 equiv)
and 0.5 mL of solvent, nitroolefin 7a (0.2 mmol), 20 °C.
b
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC analysis.
ND means not determined.
The reaction was carried out at 10 °C.
The reaction was performed at 0 °C.
The reaction was conducted at ꢀ10 °C.
centers was determined by the chirality of pyrrolidine, rather than
that of binaphthol and that (R,aR)-5d was a mismatched catalyst
(Table 1, entry 9, ꢀ11% ee). It is worth noting that this reaction
was highly diastereoselective, and only a single diastereomer was
formed although three stereogenic centers were generated in this
reaction.
c
d
e
f
g
Then, in order to further improve the enantioselectivity other
factors, such as cocatalyst, solvent, and reaction temperature, influ-
encing the reaction were thoroughly investigated in the presence
of 20 mol % (S,aR)-5d. The results are summarized in Table 2.
As shown in Table 2, the acidic cocatalyst played an important
role in the reaction. No reaction occurred without the presence
of acidic cocatalysts (Table 2, entry 1 vs entries 2–5). Although
almost the same enantioselectivity was obtained for all the cocat-
alysts tested, the acid strength of the cocatalyst also seemed to
have some effect on the catalytic activity. For example, more acidic
benzoic acid and nicotinic acid afforded product 7a within a short-
er reaction time (Table 2, entries 2 and 5). Moreover, the use of nic-
otinic acid as a cocatalyst led to a slightly higher yield than that of
benzoic acid. Solvent evaluation revealed that the reaction was
best carried out in neat acetone. Generally, the performing of the
reaction in different solvents resulted in some loss of stereocontrol
(Table 2, entry 5 vs entries 6–9). The reaction was quite sluggish in
a protic solvent, such as methanol (Table 2, entry 10). The
enantiomeric excess of 7a was slightly increased by decreasing
the reaction temperature from 20 to ꢀ10 °C (Table 2, entries 11–
13). An enantioselectivity of 57% ee was obtained at the expense
of reaction time (Table 2, entry 13).
With the optimized reaction conditions in hand, we next stud-
ied the generality of the reaction with a variety of hydroxymethyl
nitroolefins. The results are listed in Table 3.
As shown in Table 3, the reaction has a broad applicability with
respect to the hydroxymethyl nitroolefins. Moderate to good
enantioselectivities (ranging from 46% to 74% ee) were observed

2990
Y. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2988–2992
Table 3
the aid of nicotinic acid. Subsequently, the acidic hydrogen acti-
vates and orientates the nitro group through hydrogen-bonding
interactions so that the enamine acts as a nucleophile and enanti-
oselectively attacks the nitroolefin, which triggers the second
tandem ketalization to afford tetrahydropyrans 7a–j in an intramo-
lecular fashion.
Substrate scope of (S,aR)-5d catalyzed asymmetric Michael addition of acetone to
functionalized nitroolefinsa
OH
(S,aR)-5d (20 mol%)
NO2
OH
O
Et3N (20 mol%)
O
R
+
nicotinic acid (10 mol%)
R
neat, −10 °C
NO2
7a−j
3. Conclusions
6a−j
Entry
R
Time (h)
Yieldb (%)
eec (%)
We have developed a highly diastereoselective as well as enan-
tioselective Michael addition of acetone to functionalized nitrosty-
renes to provide a direct and atom-economic asymmetric synthetic
route toward optically active tetrahydropyrans. This protocol is of
considerable interest since this six-membered heterocyclic compo-
nent is widely found in biologically active molecules and natural
products.
1
2
3
4
5
6
7
8
9
Ph a
72
60
96
68
36
72
84
84
68
84
75
55
66
40
44
82
50
63
41
68
56
67
46
71
63
74
52
57
52
50
4-ClC6H4
2-BrC6H4
4-BrC6H4
b
c
d
3-FC6H4 e
2-NO2C6H4
2-MeOC6H4
4-MeOC6H4
2-Furyl i
f
g
h
4. Experimental
10
2-Thienyl j
a
Reaction conditions: acetone (0.5 mL, 6.8 mmol), nitroolefin 7a (0.2 mmol),
20 °C.
4.1. General procedure for thiophosphoramide (S,aR)-5d
catalyzed asymmetric tandem Michael-ketalizations
b
Yield of the isolated product after chromatography on silica gel.
c
Determined by chiral HPLC analysis.
A
mixture of thiophosphoramide (S,aR)-5d (22.4 mg,
with various hydroxymethyl substituted styrene-type nitroolefins
bearing either electron-donating or electron-withdrawing substit-
uents on the benzene ring (Table 3, entries 2–8). Moreover, the
reaction also tolerated sterically hindered ortho-substituted
nitroolefins 6c, 6f, and 6g, providing the corresponding o-bromo,
o-nitro, and o-methoxyl-substituted product with 46%, 74%, and
52% ee, respectively. In addition, not only aromatic groups but also
electron-rich heteroaromatic groups, such as furyl and thienyl
were suitable substituents (Table 2, entries 9 and 10).
0.04 mmol) and triethylamine (4.0 mg, 0.04 mmol) in acetone
(0.5 mL, 6.8 mmol) was stirred at room temperature for 30 min.
Then, nicotinic acid (2.5 mg, 0.02 mmol) was added, and the
reaction mixture was stirred for 15 min. To the resulting mixture
was added functionalized nitroolefin 6 (0.2 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 3:1) to afford the desired tetra-
hydropyran 7.
In order to determine the relative and absolute configuration of
the three newly generated stereogenic centers, single crystals suit-
able for X-ray crystallographic analysis were obtained from com-
pound 7h bearing a methoxy group.11 As shown in Figure 2, the
six-membered tetrahydropyran ring is in the chair form, the rela-
tive larger methoxyphenyl, methyl, and nitro groups occupy equa-
torial positions. The absolute configuration of 7h was assigned to
be (2R,4R,5R). The stereochemistry of the other products was
assigned by analogy.
4.1.1. (2R,4R,5R)-2-Methyl-5-nitro-4-phenyltetrahydro-2H-
pyran-2-ol 7a
White solid, 75% yield, mp 94–96 °C. ½a D20
¼ þ23:2 (c 1.0, CHCl3),
ꢁ
56% ee. 1H NMR (CDCl3, 400 MHz): d = 1.50 (s, 3H, CH3), 1.82 (t, 1H,
J = 13.6 Hz), 2.12 (dd, J = 3.6 and 13.6 Hz, 1H), 2.18 (br s, 1H, OH),
3.83 (dt, J = 4.0 and 12.8 Hz, 1H), 4.08 (dd, J = 4.4 and 10.4 Hz, 1H),
4.37 (t, J = 10.4 Hz, 1H), 4.84 (dt, J = 4.4 and 11.2 Hz, 1H), 7.20–7.32
(m, 5H arom). 13C NMR (CDCl3, 100.6 MHz): 29.3, 41.0, 62.0, 86.5,
95.5, 127.2, 127.8, 129.0, 138.8. HRMS (ESI) m/z calcd for
C
12H15NO4 [M+Na]+: 260.0893, found 260.0892. HPLC analysis
(Chiralpak AD-H column, Hexane/2-propanol = 90:10, flow rate =
1.0 mL/min, wavelength = 225 nm): Rt = 10.39 (major) and
27.99 min (minor).
4.1.2. (2R,4R,5R)-4-(4-Chlorophenyl)-2-methyl-5-nitro-
tetrahydro-2H-pyran-2-ol 7b
White solid, 55% yield, mp 84–86 °C. ½a D20
¼ þ18:8 (c 1.0, CHCl3),
ꢁ
67% ee. 1H NMR (CDCl3, 400 MHz): d 1.50 (s, 3H, CH3), 1.79 (t,
J = 13.6 Hz, 1H), 2.05 (s, 1H, OH), 2.11 (dd, J = 4.0 and 13.6 Hz, 1H),
3.84 (dt, J = 4.0 and 12.4 Hz, 1H), 4.07–4.13 (m, 1H), 4.37 (t,
J = 10.4 Hz, 1H), 4.79 (dt, J = 4.8 and 11.2 Hz, 1H), 7.17 (d,
J = 8.4 Hz, 2H arom), 7.30 (d, J = 8.4 Hz, 2H arom). 13C NMR (CDCl3,
100.6 MHz): d 29.2, 40.5, 41.0, 61.9, 86.4, 95.4, 128.6, 129.2, 133.7,
137.4. HRMS (ESI) m/z calcd for C12H14ClNO4, [MꢀH]ꢀ: 270.0539,
found 270.0533. HPLC analysis (Chiralpak AD-H column, Hexane/
2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 225 nm):
Rt = 13.14 (major) and 21.63 min (minor).
Figure 2. X-ray structure tetrahydropyran 7h. Most of the hydrogen atoms have
been omitted for clarity.
Even though the exact mechanism is still unclear for this reac-
tion, based on our previous report,10a it is believed that thiophos-
phoramide 5d functions as a bifunctional organocatalyst. The
pyrrolidine ring first reacts with acetone to form an enamine with
4.1.3. (2R,4R,5R)-4-(2-Bromophenyl)-2-methyl-5-nitro-
tetrahydro-2H-pyran-2-ol 7c
Yellow oil, 66% yield, ½a D20
ꢁ
¼ ꢀ8:2 (c 1.0, CHCl3), 46% ee. 1H NMR
(CDCl3, 400 MHz): d 1.49 (s, 3H), 2.08–2.24 (m, 2H), 2.30 (br s, 1H),

Y. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2988–2992
2991
4.15 (dd, J = 8.8 and 10.8 Hz, 1H), 4.43 (t, J = 10.8 Hz, 1H), 4.52 (dd,
J = 2.8 and 13.2 Hz, 1H), 5.00–5.13 (m, 1H), 7.09–7.13 (m, 1H arom),
7.27–7.32 (m, 2H arom), 7.57 (d, J = 8.0 Hz, 1H arom). 13C NMR
(CDCl3, 100.6 MHz): d 29.1, 33.4, 37.2, 62.0, 81.5, 95.5, 124.8,
128.1, 129.0, 133.0, 133.8, 136.9. HRMS (ESI) m/z calcd for
rate = 1.0 mL/min, wavelength = 225 nm): Rt = 10.41 (major) and
11.79 min (minor).
4.1.8. (2R,4R,5R)-4-(4-Methoxyphenyl)-2-methyl-5-nitro-
tetrahydro-2H-pyran-2-ol 7h
C
12H14BrNO4, [M+Na]+: 337.9998, found 338.0003. HPLC analysis
White solid, 53% yield, mp105–108 °C. ½a D20
¼ þ21:0 (c 1.0,
ꢁ
(Chiralpak AD-H column, Hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, wavelength = 225 nm): Rt = 11.36 (major) and
12.65 min (minor).
CHCl3), 57% ee. 1H NMR (CDCl3, 400 MHz): d 1.51 (s, 3H, CH3),
1.81 (t, J = 13.6 Hz, 1H), 2.11 (dd, J = 4.0 and 13.6 Hz, 1H), 2.18
(br s, 1H), 3.78 (s, 3H, OCH3), 3.80–3.83 (m, 1H), 4.07 (dd, J = 4.4
and 10.4 Hz, 1H), 4.38 (t, J = 10.4 Hz, 1H), 4.79 (dt, J = 4.0 and
10.8 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H arom), 7.14 (d, J = 8.4 Hz, 2H
arom). 13C NMR (CDCl3, 100.6 MHz): d 29.4, 40.3, 41.1, 55.2, 62.1,
86.9, 95.6, 114.3, 128.2, 130.8, 159.1. HRMS (ESI) m/z calcd for
4.1.4. (2R,4R,5R)-4-(4-Bromophenyl)-2-methyl-5-nitro-
tetrahydro-2H-pyran-2-ol 7d
White solid, 40% yield, mp 95–97 °C. ½a D20
¼ þ16:8 (c 1.0, CHCl3),
ꢁ
71% ee. 1H NMR (CDCl3, 400 MHz): d 1.51 (s, 3H, CH3), 1.79 (t,
J = 13.6 Hz, 1H), 2.11 (dd, J = 4.0 and 13.6 Hz, 1H), 2.17 (br s, 1H),
3.83 (dt, J = 4.0 and 12.8 Hz, 1H), 4.09 (dd, J = 4.8 and 10.8 Hz, 1H),
4.37 (t, J = 10.8 Hz, 1H), 4.79 (dt, J = 4.8 and 11.2 Hz, 1H), 7.11 (d,
J = 8.4 Hz, 2H arom), 7.45 (d, J = 8.4 Hz, 2H arom). 13C NMR (CDCl3,
100.6 MHz): d 29.3, 40.5, 40.9, 61.9, 86.3, 95.4, 121.7, 129.0, 132.1,
137.9. HRMS (ESI) m/z calcd for C12H14BrNO4, [M+Na]+: 337.9998,
found 338.0005. HPLC analysis (Chiralpak AD-H column, Hexane/
2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 225 nm):
Rt = 14.00 (major) and 21.67 min (minor).
C
13H17NO5, [M+Na]+: 290.0999, found 290.1000. HPLC analysis
(Chiralpak AD-H column, Hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, wavelength = 225 nm): Rt = 16.09 (major) and
21.81 min (minor).
4.1.9. (2R,4S,5R)-4-(Furan-2-yl)-2-methyl-5-nitrotetrahydro-
2H-pyran-2-ol 7i
White solid, 41% yield, mp75–78 °C. ½a D20
¼ þ8:2 (c 1.0, CHCl3),
ꢁ
52% ee. 1H NMR (CDCl3, 400 MHz): d 1.51 (s, 3H, CH3), 1.92 (t,
J = 13.2 Hz, 1H), 2.13 (br s, 1H, OH), 2.18–2.22 (m, 1H), 3.0–4.08
(m, 2H), 4.34 (t, J = 10.8 Hz, 1H), 4.81 (dt, J = 4.8 and 11.2 Hz, 1H),
6.12 (d, J = 3.2 Hz, 1H arom), 6.28 (s, 1H arom), 7.33 (s, 1H arom).
13C NMR (CDCl3, 100.6 MHz): d 29.3, 34.7, 38.0, 61.6, 84.7, 95.2,
106.8, 110.3, 142.3, 152.1. HRMS (ESI) m/z calcd for C10H13NO5,
[M+Na]+: 250.0686, found 250.0690. HPLC analysis (Chiralpak
AD-H column, Hexane/2-propanol = 90:10, flow rate = 1.0 mL/
min, wavelength = 225 nm): Rt = 11.05 (major) and 43.14 min
(minor).
4.1.5. (2R,4R,5R)-4-(3-Fluorophenyl)-2-methyl-5-nitro-
tetrahydro-2H-pyran-2-ol 7e
Yellow oil, 64% yield, mp 73–77 °C. ½a D20
¼ þ14:4 (c 1.0, CHCl3),
ꢁ
63% ee. 1H NMR (CDCl3, 400 MHz): d 1.51 (s, 3H, CH3), 1.80 (t,
J = 13.6 Hz, 1H), 2.14 (dd, J = 4.0 and 13.6 Hz, 1H), 2.18 (br s, 1H,
OH), 3.87 (dt, J = 4.0 and 12.4 Hz, 1H), 4.10 (dd, J = 4.4 and
12.8 Hz, 1H), 4.37 (t, J = 10.8 Hz, 1H), 4.82 (dt, J = 4.8 and 10.8 Hz,
1H), 6.93–7.02 (m, 3H arom), 7.28–7.32 (m, 1H arom). 13C NMR
(CDCl3, 100.6 MHz): d 29.3, 40.7, 40.9, 61.9, 86.2, 95.4, 114.2 (d,
J = 21.8 Hz), 114.8 (d, J = 21.0 Hz), 123.0 (d, J = 2.8 Hz), 130.5 (d,
J = 8.2 Hz), 141.4 (d, J = 7.1 Hz), 163.0 (d, J = 247.1 Hz). HRMS
4.1.10. (2R,4S,5R)-2-Methyl-5-nitro-4-(thiophen-2-yl)-
tetrahydro-2H-pyran-2-ol 7j
White solid, 68% yield, mp 88–89 °C. ½a D20
¼ þ23:2 (c 1.0,
ꢁ
(ESI) m/z calcd for
C
12H14FNO4, [M+Na]+: 278.0799, found
CHCl3), 50% ee. 1H NMR (CDCl3, 400 MHz): d 1.52 (s, 3H, CH3),
1.87 (t, J = 13.6 Hz, 1H), 2.19 (br s, 1H, OH), 2.29 (dd, J = 4.0 and
13.6 Hz, 1H), 4.07 (dd, J = 4.8 and 10.8 Hz, 1H), 4.19 (dt, J = 4.4 Hz
and 12.8 Hz, 1H), 4.36 (t, J = 10.8 Hz, 1H), 4.73 (dt, J = 4.8 and
10.8 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H arom), 6.93 (t, J = 3.6, 4.8 Hz,
1H arom), 7.20 (d, J = 5.2 Hz, 1H arom). 13C NMR (CDCl3,
100.6 MHz): d 29.3, 36.4, 41.7, 62.0, 87.9, 95.5, 124.5, 125.3,
127.0, 142.1. HRMS (ESI) m/z calcd for C10H13NO4S, [M+Na]+:
266.0457, found 266.0459. HPLC analysis (Chiralpak AD-H column,
Hexane/2-propanol = 80:20, flow rate = 1.0 mL/min, wavelength =
225 nm): Rt = 6.75 (major) and 21.18 min (minor).
278.0797. HPLC analysis (Chiralpak AD-H column, Hexane/2-
propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 225 nm):
Rt = 9.78 (major) and 19.95 min (minor).
4.1.6. (2R,4R,5R)-2-Methyl-5-nitro-4-(2-nitrophenyl)-
tetrahydro-2H-pyran-2-ol 7f
Yellow oil. 82% yield, ½a D20
ꢁ
¼ ꢀ156:8 (c 1.0, CHCl3), 74% ee. 1H
NMR (CDCl3, 400 MHz): d 1.52 (s, 3H, CH3), 1.77 (t, J = 13.6 Hz,
1H), 2.34 (br s, 1H, OH), 2.40 (dd, 4.0 and 13.6 Hz, 1H), 4.15 (dd,
J = 4.8 and 10.4 Hz, 1H), 4.34 (t, J = 10.4 Hz, 1H), 4.53 (dt, J = 4.0
and 12.4 Hz, 1H), 5.01 (dt, J = 4.4 and 10.8 Hz, 1H), 7.41 (t,
J = 7.6 Hz, 1H arom), 7.46 (d, J = 7.6 Hz, 1H arom), 7.60 (t,
J = 7.6 Hz, 1H arom), 7.82 (d, J = 8.0 Hz, 1H arom),. 13C NMR (CDCl3,
100.6 MHz): d 29.0, 35.7, 41.1, 62.0, 94.5, 95.4, 125.0, 127.4, 128.4,
133.1, 133.5, 150.3. HRMS (ESI) m/z calcd for C12H14N2O6, [M+Na]+:
305.0744, found 305.0746. HPLC analysis (Chiralpak AD-H column,
Hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
225 nm): Rt = 25.59 (minor) and 31.56 min (major).
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Nos. 20772058, 20972070), the National Basic research
Program of China (973 program 2010CB833301) and the Key
laboratory of Elemento-Organic Chemistry for generous financial
support for our programs.
4.1.7. (2R,4R,5R)-4-(2-Methoxyphenyl)-2-methyl-5-nitro-
tetrahydro-2H-pyran-2-ol 7g
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Yellow oil, 33% yield, ½a D20
ꢁ
¼ þ6:0 (c 1.0, CHCl3), 52% ee. 1H NMR
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