A facile synthesis of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol

Article abstract of DOI:10.1016/j.carres.2010.11.012

A facile and short synthesis of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2- en-1-ol (1) has been achieved in high yield starting from 4,5-epoxycyclohex-1- ene by using a catalytic asymmetric allylic oxidation reaction.

Full text of DOI:10.1016/j.carres.2010.11.012

Carbohydrate Research 346 (2011) 340–342
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Note
A facile synthesis of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol
⇑
Takanori Tanaka, Qitao Tan, Kazunari Iwanaga, Masahiko Hayashi
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and short synthesis of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol (1) has been achieved
in high yield starting from 4,5-epoxycyclohex-1-ene by using a catalytic asymmetric allylic oxidation
reaction.
Received 14 September 2010
Accepted 11 November 2010
Available online 19 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
This paper is dedicated to the memory of the
late Professor Mugio Nishizawa
Keywords:
Aminocyclitol
Asymmetric allylic oxidation
D-Glucose
Aminocyclitols and their analogs such as (1S,5R,6S)-5-azido-
1. Experimental
1.1. General
6-benzyloxycyclohex-2-en-1-ol (1) have been recognized for
their importance as glycosidase inhibitors.1–4 Recently, Pelyvás,
Sztaricskai and co-workers reported the synthesis of 1 and struc-
turally related compounds starting from
D
-glucose.5 Here, we
All reactions were performed under an argon atmosphere using
Schlenk tube techniques and freshly distilled solvents. All melting
points were measured on a Yanaco MP-500D apparatus and are
uncorrected. 1H and 13C NMR spectra (400 and 100.6 MHz, respec-
tively) were recorded on a JEOL JNM-LA 400 using Me4Si as the
internal standard (0 ppm). The following abbreviations are used:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Ele-
mental analyses were performed with a Yanaco CHN Corder MT-
5. Mass spectra were measured on a Thermo Quest LCQ DECA plus.
Optical rotations were measured on a HORIBA SEPA-300 polarim-
eter for solutions in a 1-dm cell. Preparative column chromatogra-
phy was carried out on Fuji Silysia BW-820MH or YMC GEL silica
gel (6 nm I-40–63 lm). Thin-layer chromatography (TLC) was car-
ried out on E. Merck 25 TLC aluminum sheets coated with Silica Gel
60 F254. Chiral HPLC was performed on a HITACHI L-2000 series
instrument equipped with an L-2455 diode array detector.
report the facile synthesis of 1 based on a catalytic asymmetric
allylic oxidation reaction.
We recently reported the efficient synthesis of enantiopure
(1S,5S,6R)-5,6-epoxycyclohex-2-en-1-ol (2) based on the enantio-
selective allylic oxidation of 4,5-epoxycyclohex-1-ene as shown
in Scheme 1.6
The hydroxy group of enantiomerically pure 2 was protected by
a MOM group (94%), followed by the ring opening with NaN3/
NH4Cl that proceeded regioselectively to afford the MOM-
protected azido alcohol 4 (80%) (Scheme 2). The remaining hydro-
xyl group was then benzylated to give 5 (91%). Finally, the MOM
group was deprotected by CF3CO2H to give the desired
*
(1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol (1) (94%) (½a D22
ꢀ
110.5 (c 1.0, CHCl3)). Pelyvás, Sztaricskai and co-workers synthe-
sized 1 in 13 steps from
fore, compared with the reported method starting from
D
-glucose ([
a
]
D 106.2 (c 1.0, CHCl3)). There-
D
-glucose,5
1.2. (1S,5S,6R)-5,6-Epoxycyclohex-2-en-1-ol (2)
the present method is clearly superior from the viewpoint of a
shorter number of steps, total yield and operational simplicity (4
steps in 64% yield from 2).
To a solution of the p-nitrobenzoate of 5,6-epoxycyclohex-2-en-
1-ol (2.09 g, 8.0 mmol) in MeOH (20 mL) was added a 0.5 M
NaOMe solution (0.8 mL, 0.4 mmol). After 2 h stirring at rt, TLC
showed the disappearance of starting material, and AcOH (24 mL,
0.4 mmol) was added to quench the reaction. MeOH was removed
by rotary evaporator and the residue was purified by chromatogra-
phy (4:1–2:1 hexane–EtOAc) to give compound 26 as a colorless
⇑
Corresponding author.
E-mail address: mhayashi@kobe-u.ac.jp (M. Hayashi).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.11.012

T. Tanaka et al. / Carbohydrate Research 346 (2011) 340–342
341
O
O
OH
2.5 mol % Cu(CH3CN)4PF6
3 mol % chiral ligand
R
PhCO3-t-Bu
O
+
O
O
acetone
R = H; 84% ee
R = NO2; >99% ee
>99% ee
2
ligand:
Me
after recrystallization
N
H
N
Me
Scheme 1.
the MeOH was removed by an evaporator. The aqueous solution
was extracted with EtOAc (50 mL ꢁ 3). The combined organic layer
was washed with brine (20 mL ꢁ 3) and dried (Na2SO4). After evap-
oration of the solvent, the residue was purified by chromatography
(5:1 hexane–EtOAc) to give compound 4 as a colorless liquid
OH
OMOM
OMOM
NaN3
HO
N3
MOMCl
NH4Cl
O
O
MeOH
80%
CH2Cl2
94%
(1.04 g, 82%). Rf 0.26 (3:1 hexane–EtOAc); ½a D18
ꢀ
+165 (c 0.5, CHCl3);
>99% ee
3
4
1H NMR (400 MHz, CDCl3): d 5.71–5.66 (m, 1H), 5.60–5.55 (m, 1H),
4.79 (s, 2H), 4.4 (br s, 1H), 4.0 (br s, 1H), 3.66–3.57 (m, 2H), 3.47 (s,
3H), 2.50–2.43 (m, 1H), 2.13–2.06 (m, 1H); 13C NMR (100.6 MHz,
CDCl3): d 127.2, 125.9, 97.6, 83.3, 75.6, 60.6, 55.8, 30.7; ESIMS:
m/z 222.3 (M+Na)+. Anal. Calcd for C8H13N3O3: C, 48.23; H, 6.58;
N, 21.09. Found: C, 48.55; H, 6.61; N, 20.95.
2
OMOM
OH
BnBr
NaH
BnO
N3
BnO
N3
CF3CO2H
DMF
91%
CH2Cl2
94%
5
1
1.5. (1S,5R,6S)-5-Azido-6-benzyloxy-1-methoxymethoxycy-
clohex-2-ene (5)
Scheme 2.
liquid (0.89 g, 99%). Rf 0.18 (1:1 hexane–EtOAc); ½a D20
ꢀ
+119 (c 0.5,
To a suspension of NaH (60% dispersion in oil, 40 mg, 1.0 mmol)
in DMF (1 mL) was added 4 (100 mg, 0.5 mmol) in DMF (0.5 mL).
The mixture was stirred for 30 min. Then, BnBr (120 lL, 1.0 mmol)
CHCl3); 99% ee (determined by GC: b-DEX-225 (SupelcoÒ), oven
temp.150 °C,tR ofmajorisomer = 7.17 min(1S,5S,6R), tR ofminoriso-
mer = 8.57 min (1R, 5R, 6S)); 1H NMR (400 MHz, CDCl3): d 5.71–5.67
(m, 1 H), 5.62–5.58 (m, 1H), 4.5 (br s, 1H), 3.3 (br s, 1H), 3.3 (br s, 1H),
2.59–2.50 (m, 2H), 2.0 (br s, 1H); 13C NMR (100.6 MHz, CDCl3): d
124.7, 124.6, 62.8, 53.6, 50.2, 25.0; ESIMS: m/z 113.0 (M+H)+.
was added. The mixture was stirred for 3 h and brine (10 mL) was
added to quench the reaction. The aqueous solution was extracted
with EtOAc (50 mL ꢁ 3). The combined organic layer was washed
with brine (20 mL) and dried (Na2SO4). After evaporation of the
solvent, the residue was purified by chromatography (20:1 hex-
ane–EtOAc) to give compound 5 (130 mg, 90%). Rf 0.55 (2:1 hex-
1.3. (1S,5S,6S)-1-Methoxymethoxy-5,6-epoxycyclohex-2-ene (3)
ane–EtOAc); ½a 2D1
ꢀ
+78.4 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 7.41 (d, J = 7.0 Hz, 2H), 7.36 (t, J = 7.0 Hz, 2H), 7.31 (d, J = 7.0 Hz,
1H), 4.89 (d, J = 10.8 Hz, 1H), 4.82 (d, J = 10.8 Hz, 1H), 4.80 (d,
J = 7.0 Hz, 1H), 4.71 (d, J = 7.0 Hz, 1H), 4.24–4.27 (m, 1H), 3.68
(ddd, J = 6.0, 10.4, 10.4 Hz, 1H), 3.54 (dd, J = 7.2, 10.4 Hz, 1H),
3.38 (s, 3H), 2.43–2.50 (m, 1H), 2.05–2.13 (m, 1H); 13C NMR (CDCl3,
100.6 MHz): d 138.1, 128.4, 128.2, 128.0, 127.8, 125.2, 96.9, 83.3,
78.8, 75.3, 60.8, 55.6, 31.3; ESIMS: m/z 312 (M+Na)+.
To a solution of the deprotected compound 2 (0.64 g, 5.7 mmol) in
CH2Cl2 (30 mL) was added diisopropylethylamine (DIPEA, 2.9 mL,
17.3 mmol), followed by the additionofMOMCl(1.3 mL, 17.3 mmol).
The mixture was stirred for 10 h and H2O (30 lL) was added to
quench the reaction. The aqueous layer was extracted with EtOAc
(30 mL ꢁ 3). The combined organic layer was washed with brine
(20 mL) and dried over Na2SO4. After evaporation of the solvent,
the residue was purified by chromatography (5:1 hexane–EtOAc)
to give the MOM-protected compound 3 as a colorless oil (0.88 g,
1.6. Preparation of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-
ene-1-ol (1)
99%). Rf 0.28 (3:1 hexane–EtOAc); ½a D17
ꢀ
+118.3 (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3): d 5.6 (br s, 2H), 4.78 (d, J = 7.2 Hz, 1H), 4.75
(d, J = 7.2 Hz, 1H), 4.4 (br s, 1H), 3.40 (s, 3H), 3.2 (br s, 1H), 3.3 (br s,
1H), 2.63–2.51 (m, 2H); 13C NMR (100.6 MHz, CDCl3): d 125.3,
122.8, 95.9, 68.7, 55.5, 52.4, 50.3, 25.1; ESIMS: m/z 157 (M+H)+. Anal.
Calcd for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.25; H, 7.81.
To a solution of 5 (90 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added
TFA (0.5 mL, 3.0 mmol). The mixture was stirred at 18 °C for 1.5 h,
and the TFA and CH2Cl2 were evaporated. EtOAc (40 mL) was
added to dilute the mixture. The solution was washed with satd
aq NaHCO3 (10 mL ꢁ 2) and the organic layer was dried (Na2SO4).
After evaporation of the solvent, the residue was purified by chro-
matography (10:1 hexane–EtOAc) to give compound 1 (65 mg,
1.4. (1S,5R,6S)-5-Azido-1-methoxymethoxy-cyclohex-2-ene-6-ol
(4)
86%). Rf 0.40 (2:1 hexane–EtOAc); ½a D22
ꢀ
+110.5 (c 1.0, CHCl3) (lit.5
[a]
+106.2 (c 1.16, CHCl3)); 1H NMR (CDCl3, 400 MHz): d 7.41 (d,
D
To a solution of 3 (1.0 g, 6.4 mmol) in MeOH (48 mL) and H2O
(6 mL) were added NH4Cl (0.68 g, 12.8 mmol) and NaN3 (1.25 g,
19.2 mmol). The mixture was heated at 80 °C for 16 h. After cooling
to rt, additional H2O (30 mL) was added to dissolve the solid, and
J = 7.4 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 7.4 Hz, 1H),
5.55–5.65 (m, 2H), 4.97 (d, J = 11.4 Hz, 1H), 4.76 (d, J = 11.4 Hz,
1H), 4.26 (br s, 1H), 3.69 (ddd, J = 5.6, 9.6, 9.6 Hz, 1H), 3.42 (dd,

342
T. Tanaka et al. / Carbohydrate Research 346 (2011) 340–342
J = 7.2, 9.6 Hz, 1H), 2.46–2.53 (m, 1H), 2.04–2.16 (m, 2H); 13C NMR
(CDCl3, 100.6 MHz): d 138.1, 128.8, 128.6, 128.1, 128.0, 124.9, 84.2,
74.8, 72.1, 60.5, 31.2; ESIMS: m/z 268 (M+Na)+.
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Acknowledgments
This work was supported by Grants-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformations of
Carbon Resources’ and No. B17340020 from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
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