Highly stereoselective syn-ring opening of enantiopure epoxides with nitric oxide

Article abstract of DOI:10.1016/j.tetlet.2006.12.095

Reaction of enantiopure epoxides (1) with NO occurred highly stereoselectively, affording syn-ring opened products, nitrates (2). The configuration of 2 was confirmed to be retained by determining the configuration of reduced products 1,2-glycols (4) from 2. A possible mechanism is suggested to trace out the syn-ring opening pathway.

Full text of DOI:10.1016/j.tetlet.2006.12.095

Tetrahedron Letters 48 (2007) 1653–1656
Highly stereoselective syn-ring opening of
enantiopure epoxides with nitric oxide
Wentao Wu, Qiang Liu, Yinglin Shen, Rui Li and Longmin Wu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 4 November 2006; revised 13 December 2006; accepted 18 December 2006
Available online 20 December 2006
Abstract—Reaction of enantiopure epoxides (1) with NO occurred highly stereoselectively, affording syn-ring opened products,
nitrates (2). The configuration of 2 was confirmed to be retained by determining the configuration of reduced products 1,2-glycols
(4) from 2. A possible mechanism is suggested to trace out the syn-ring opening pathway.
ꢀ 2006 Published by Elsevier Ltd.
Nitric oxide (NO) has been explored to be capable of
reacting with various organic compounds such as
olefines,1 amines,2 amides,3 oximes,4 enamines,5 arylhydra-
zines,6 and arylhydrazones.7 Our recent studies have
given some insight into the distinct ring opening setereo-
selectivities of epoxides and aziridines upon reaction
with NO.8,9 NO led to the syn-selective ring opening
of 2,3-epoxy phenyl ketones, giving syn-a-hydroxy
nitrates,8 whereas epoxides bearing a secondary carbon
atom at C-210 and aziridines9 underwent anti-selective
ring opening to afford anti-a-hydroxy and anti-a-N-tosyl
nitrates, respectively. These results clearly indicate that
the syn or anti-selective ring opening fashion of epoxides
is strongly dependent on C2-substituent. It was still
found that epoxides were converted into b-hydroxy
nitrates with cerium ammonium nitrate (CAN) in good
yields in an anti-ring opening manner.11,12 Hence, to
obtain a clear insight into the ring opening reaction of
epoxides with NO is of significance. We have further
investigated the reaction of NO with various enantio-
pure epoxides (1).13,14 The resulting nitrates with reten-
tion of configuration are obtained. To our best
knowledge, there has still no report pertinent to the
reactions of NO with asymmetric organic molecules.
applied to organic syntheses15 and used as effective pro-
tecting groups for hydroxy groups.11 In general, organic
nitrates have been readily prepared from the esterifica-
tion of corresponding alcohols or substitution of reac-
tive alkyl halides by AgNO3.16 Yet, b-hydroxy nitrates
were obtained in unsatisfactory yields by the reaction
of nitrating agents with epoxides.17
The results are collected in Table 1. It is particularly
noteworthy that the reaction proceeded with the
Table 1. Ring opening of enantiopure epoxides by NO
Entry
1
Epoxide
Nitrate ester
Time
(day)
Yielda
(%)
O2NO
Ph
Ph
O Ph
5
5
5
79.8b
72.3c
60.2d
Ph
Ph
OH
1a
2a
O2NO
Ph
Ph
O
O
Ph
2
3
Furthermore, organic nitrates belong to the oldest class
of NO donors applied to clinical purposes and have long
been used to relive angina pectoris. All the major biolog-
ical effects of organic nitrates have been referred to the
formation of NO. Otherwise, nitrates have been widely
Ph
Ph
1b
3b
Ph
O2NO
Ph
O
HO
2c
1c
*
(continued on next page)
Corresponding author. E-mail: wuwt03@lzu.cn
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.12.095

1654
W. Wu et al. / Tetrahedron Letters 48 (2007) 1653–1656
Table 1 (continued)
a few by-products. For instance, in the case of 1a, the
Entry Epoxide
Nitrate ester
Time Yielda
(day) (%)
reaction afforded 2,2-diphenylacetaldehyde. Otherwise,
1b was converted into 3b, a ketone. In the case of 1c,
a small amount of 4c, an 1,2-glycol, was obtained.
O
O2NO
4
3
74.0
Ph
We started with an enantiopure 1 (Table 1). There were
several possible outcomes: retention or inversion of ste-
reochemistry. In order for the absolute configuration of
2 to be specified, 2 was reduced to the corresponding
1,2-glycols (4)11,19 with high ee and dr values (Table 2)
using various reductants such as NH2NH2, NaBH4,
LiAlH4, or (NH4)2S.20 The optical rotation of 4 was
measured and their stereochemistry was determined to
be retained by comparing the measured values with
those reported. It is only possible to infer that epoxides
were opened in syn fashion by NO. Ammonium sulfide
showed to be more favorable for the reduction of
nitrates to glycols. It gave the reducing products in
quantitative yields and with high ee values (Table 2,
entry 4). It is noticed that 3b was not reduced by the
above reductants and 2c was unstable and directly
converted into 4c by standing overnight.
Ph
OH
2d
1d
O2NO
Ph
CH2OTBS
OH
O
CH2OTBS
5
6
7
5
5
5
87.8
36.6
84.1
Ph
Ph
Ph
1e
CH2Cl
2e
O2NO
Ph
CH2Cl
OH
O
1f
CH2OMe
2f
O2NO
Ph
CH2OMe
OH
O
1g
2g
O
O
O
O
O
O2NO
Ph
8
3
80.8
Ph
OH
A proposed mechanism is depicted in Scheme 1. It ap-
pears that a trace of O2 retained in reaction system plays
a key role in the initiation of reactions under consider-
ation. NO is readily oxidized to NO2 and then converted
into N2O3. Displacement of the good leaving group
nitrite (–ONO) from N2O3 by the Lewis basic oxygen
of epoxide leads to form 5. Resonance forms 5, 50, and
500 (Scheme 1) will contribute unequally to the real struc-
ture of carbocation intermediate generated from the
reaction of 1 with N2O3. Among them, 5 is considered
to be the most stable and dominant resonance form. It
is also rationalized by the formation of major products
(Table 1) produced by following the mechanism illus-
trated in Scheme 1 starting with 5. Addition of 2 equiv
of NO to the O-nitroso group of 5 gives 6, which rear-
ranges to 7.1c Compound 7 in turn undergoes intra-
2h
1h
a Isolated yield after silica gel chromatography.
b Along with 20.0% of 2,2-diphenylacetaldehyde.
c Along with 7.2% of 2-hydroxy-1,2,2-triphenylethanone.
d Along with 12.0% of (1R,2R)-1-phenylcyclohexane-1,2-diol.
retention of configuration at the benzyl position. By
comparison, configuration inversions were observed in
other epoxide opening reactions.10–12,18 Except for 1b,
the reaction exclusively afforded erythro-b-hydroxy ni-
trates (2) in moderate yields (Table 1). Table 1 demon-
strates that reactions provided poor yields when the b-
site beared an electron-withdrawing group, such as 1f.
In particular, diaryl or triaryl substituted epoxides gave
Table 2. Reduction of nitrates 2
O2NO
R1
Ph
R2
HO
R1
R2
[H]
H
H
OH
OH
Ph
4
2
Entry
1,2-Glycol
Reductant
Reaction time (h)
Yielda (%)
Configuration (glycol/epoxide)
eeb (%)
drc (%)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4c
4d
4e
4f
NH2NH2
NaBH4
LiAlH4
(NH4)2S
rt
(NH4)2S
(NH4)2S
(NH4)2S
(NH4)2S
(NH4)2S
120
24
4
74.8
0
(R,R)d/(R,R)d
—/(R,R)d
—
—
—
—
85.4
>99
95.0
98.5
67.3
>99
92.3
91.0
(R,R)d/(R,R)d
(R,R)d/(R,R)d
(R,R)d/(R,R)d
(R,R)d/(R,R)d
(R,R)d/(R,R)d
(2S,3R)e/(2S,3R)d
(R,R)e/(R,R)
95.4
>99
>99
90.7
95.7
87.9
93.6
93.9
86:1
>99:1
>99:1
12:1
12:1
37:1
13.4:1
60:1
2
24
0.5
2
0.7
1.5
2
4g
4h
10
(2S,3R)e/(2S,3R)d
a Isolated yield after silica gel chromatography.
b Values for ee were determined by chiral HPLC.
c Values for dr were determined by chiral HPLC.
d The absolute configurations were determined by comparing the measured optical rotations with those reported.
e The absolute configuration were tentatively assumed by analogy syn-ring opening reaction mode.

W. Wu et al. / Tetrahedron Letters 48 (2007) 1653–1656
1655
2 NO + O2
NO2 + NO
2 NO2
N2O3
ONO-
O
O
O
O
O
O
N
N
N
O
N
O
N
+
R1
Ph
R2
R1
Ph
R2
R1
Ph
R2
R1
O
R2
O
+
+
β
α
Ph
5'
5''
5
1
O
N
ONO2
N
N
O
O
N
N
O
O
N
O
N
N
+
O
R1
+
R1
R2
R1
Ph
R2
R2
+
O
O
2 NO
Ph
Ph
8
7
6
.
O
O
+
N
N2
ONO- NO2
Solvent
R2
R2
H
O2NO
R1
O
R1
Ph
H
Ph
.
OH
O
2
9
Scheme 1. Mechanism for the ring opening of epoxides.
molecular nucleophilic substitution to form 9. Such a
front side approach causes the retention of configuration.
The resulting 9 undergoes electron transfer with
–ONO and H-abstraction from solvent molecules to
generate nitrate 2. In species 5, most of the positive
charge will reside at the a-site because the positive
charged carbon will be resonance-stabilized by the phen-
yl group. Therefore, the b-carbon–oxygen bond will be
longer and weaker than the other and will be the major
bond being broken by the addition of a nucleophile.
O
.
O
O
+
N
N
+
O
O
Ph
Ph
Ph
- N2
+ 2NO
Ph
Ph
Ph
.
O
5b
9b
ONO- NO2
+ NO
O2NO
Ph
O2NO
Ph
Ph
Ph
- HNO
H
Ph
Ph
In the case of 1a, the formation of by-product 2,2-diphen-
ylacetaldehyde in a yield of 20% involves a mechanism
in which less stable resonance form 5a0 undergoes a rear-
rangement like the pinacol rearrangement induced by a
nucleophilic attack of ONOꢀ at nitrogen atom to gener-
ate by-product 2,2-diphenylacetaldehyde (Scheme 2).
However, in the case of 1b, a rearrangement from a sta-
ble tertiary carbocation 5b0 may be thermodynamically
unfavorable. Another reason for it may be due to the
spatial factor caused by two phenyl groups at the a-car-
ONO
O
10b
3b
Scheme 3.
bon in the rearrangement of 5b0. Hence, resonance form
5b undergoes a process indicated in Scheme 3 to give
3b.2b,21 Thus, the formation of 2,2-diphenylacetaldehyde
and 3b provides unambiguous evidence for supporting
the mechanism suggested in Scheme 1 involving a cat-
ionic intermediate 5.
These findings of research have allowed the author to
reach a conclusion at the reaction of enantiopure epox-
ides with NO, which leads to a syn-ring opening and to
the production of single erythro-b-hydroxy nitrates with
the retention of configuration. The resulting nitrates will
be easily converted into other vicinal difunctionalized
compounds. Problems remained in this study are that
the reaction occurred within a time span of 3–5 days.
-ONO
O
H
Ph
O
H
H
+
+
N2O3
N
Ph
Ph
Ph
O
5a'
2,2-Diphenylacetaldehyde
Scheme 2.

1656
W. Wu et al. / Tetrahedron Letters 48 (2007) 1653–1656
containing distilled water, 4 M NaOH, CaCl2 in this order.
Acknowledgment
Purified NO was bubbled through the stock solution until
the completion of reaction, as indicated by TLC. The
solution was then concentrated under vacuum and purified
by column chromatography on silica gel to give 228 mg of
2a (80% yield) as white crystallines. Data for 2a: white
Projects 20572040 and 20272022 supported by National
Natural Science Foundation of China.
22
References and notes
crystal, ½aꢁD +39 (c 0.48, EtOH), mp 96–98 ꢁC; Rf = 0.3
[EtOAc/n-hexane, 1:10, v/v, silica gel plate]; IR (KBr)
m
max 3454 (OH), 1632 (NO2), 1277 (NO2), 880 (ON) cmꢀ1
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1H); 13C NMR (75 MHz, CDCl3) d 137.8, 134.3, 129.1,
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64.59; H, 4.64; N, 5.42.
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nitrates with (NH4)2S:19a 53 mg (0.20 mmol) of 2a was
treated with 1 mL of aqueous solution containing a vast
excess of ammonium sulfide (corresponding to 8% free
sulfur) and 2 mL of ethanol. The treatment was accom-
panied by a color change to orange and by the precipi-
tation of sulfur. After completion of the reaction, as
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acetate. The extract was washed with brine, dried over
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22
21
white crystal, ½aꢁD +86 (c 0.9, EtOH) [lit.,22 ½aꢁD +91 (c,
1.1, EtOH)]; mp 136–138 ꢁC; Rf = 0.2 [ethyl acetate/
n-hexane, 1:3, v/v, silica gel plate]; IR (KBr) mmax 3393
14. Representative procedure for the reaction of epoxides with
NO:
A stock solution was prepared by dissolving
1.16 mmol of 1a (216 mg) in 80 mL of anhydrous CH2Cl2.
The stock solution was previously deaerated with argon
for 15 min.22 In the course of degassing, the argon flow
rate was controlled by regulating the flow meter at
0.8 L minꢀ1 and the stock solution was kept at a pressure
of up to +10 mm H2O over local atmospheric pressure at
room temperature. NO was produced by the reaction of
1 M H2SO4 solution with saturated NaNO2 aqueous
solution under an argon atmosphere, in which the sulfuric
acid was added dropwise. NO was carried by argon and
purified by passing it through a series of scrubbing bottles
1
(OH) cmꢀ1; H NMR (300 MHz, CDCl3) d 7.27–7.22 (m,
6H), 7.14–7.11 (m, 4H), 4.71 (d, J = 2.4 Hz, 2H), 2.92 (br,
2H); 13C NMR (75 MHz, CDCl3) d 139.8, 128.1, 127.9,
126.9, 79.1 (CH); MS (EI, 70 eV) m/z (%) 214 (M+, 0.4),
165 (1.3), 152 (0.7), 107 (100.0); ee >99%, dr >99:1 [HPLC,
Chiralcel OJ-H column, hexane/2-propanol, 90:10, v/v,
the flow rate, 0.8 mL/min].
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