Asymmetric synthesis of fagomine

Article abstract of DOI:10.1016/j.tetasy.2007.03.022

We report an asymmetric synthesis of the alkaloid fagomine, which is an inhibitor of mammalian α-glucosidase and β-galactosidase, by means of Sharpless asymmetric dihydroxylation and Pd(II)-catalyzed cyclization, starting from 3-(t-butoxylcarbonylamino)propanol.

Full text of DOI:10.1016/j.tetasy.2007.03.022

Tetrahedron: Asymmetry 18 (2007) 852–856
Asymmetric synthesis of fagomine
Hajime Yokoyama, Hiromi Ejiri, Masahiro Miyazawa, Seiji Yamaguchi and Yoshiro Hirai*
University of Toyama, Department of Chemistry, Gofuku3190, Toyama 930-8555, Japan
Received 21 February 2007; revised 20 March 2007; accepted 22 March 2007
Available online 25 April 2007
Dedicated to the memory of Professor Yoshihiko Ito
Abstract—We report an asymmetric synthesis of the alkaloid fagomine, which is an inhibitor of mammalian a-glucosidase and b-galac-
tosidase, by means of Sharpless asymmetric dihydroxylation and Pd(II)-catalyzed cyclization, starting from 3-(t-butoxyl-
carbonylamino)propanol.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Aza sugars, such as 1-deoxynojirimycin (DNJ; see Fig. 1),
are potential drug candidates for the treatment of diabetes,
cancer, AIDS, and viral infections, because of their glyco-
sidase-inhibitory activity. Among them, fagomine 1 is a
piperidine alkaloid isolated from buckwheat seeds (Fago-
pyrum esculentum) (Polygonaceae) and, more recently,
from Xanthocericis zambesiaca, which is found in dry
forests in southern Africa.1–3 Fagomine has inhibitory
activity towards mammalian a-glucosidase and b-
galactosidase.2
The substrate 7 for the Pd(II)-catalyzed cyclization was
prepared from 3-(t-butoxylcarbonylamino)propanol 3 as
shown in Scheme 1. The Swern oxidation of 3 and subse-
quent Horner–Wittig reaction gave the a,b-unsaturated
ester, which was subjected to DIBAL–H reduction to af-
ford allyl alcohol 4 in 83% yield over three steps. The alco-
hol group of 4 was protected with TBSCl to give 5.
Sharpless asymmetric dihydroxylation of 5 with AD-mix-
b and CH3SO2NH2 in t-BuOH and water at 0 ꢁC afforded
the diol. The hydroxyl moieties were protected with benzyl
BocN
H
OH
Herein, we report an asymmetric synthesis of fagomine via
Sharpless asymmetric dihydroxylation4 and Pd(II)-cata-
lyzed cyclization, which is a useful tool in the synthesis of
alkaloids.5
a-c
BocHN
OH
4
3
BocN
OTBS
d
e-g
H
5
OBn
OBn
OBn
OH
OBn
OH
h-j
HO
OH
OH
NH
NH OH
OH
OH
Boc
N
H
Boc
N
H
OH
7
6
Scheme 1. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2;
(b) (EtO)2P(O)CH2CO2Et, NaH, THF, ꢀ78 ꢁC; (c) DIBAL, THF,
ꢀ78 ꢁC, three steps 83%; (d) TBSCl, imidazole, DMF, 89%; (e) AD-
mix-b, CH3SO2NH2, t-BuOH/H2O; (f) BnBr, NaH, Bu4NI, THF; (g) p-
TsOH, MeOH, three steps 29%; (h) IBX, THF/DMSO; (i) (EtO)2-
P(O)CH2CO2Et, NaH, THF; (j) DIBAL–H, THF, ꢀ78 ꢁC, three steps
40%.
Fagomine 1
DNJ 2
Figure 1.
*
Corresponding author. E-mail addresses: hyokoyam@sci.u-toyama.
ac.jp; hirai@sci.u-toyama.ac.jp
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.022

H. Yokoyama et al. / Tetrahedron: Asymmetry 18 (2007) 852–856
853
extended to the synthesis of various piperidine alkaloids
with potential biomedical applications.
OBn
OBn
OBn
OBn
a
b
NH
N
4. Experimental
Boc
Boc
8
OH
4.1. 3-[N-(tert-Butoxycarbonyl)amino]-propan-1-ol 3
7
OBn
OH
To a solution of 3-amino-propan-1-ol (1.0 g, 13.30 mmol)
in CH2Cl2 (26.6 mL) was added di-tert-butyl dicarbonate
(4.58 mL, 19.95 mmol) at room temperature under an ar-
gon atmosphere. Triethylamine (2.78 mL, 19.95 mmol)
was added to the mixture at room temperature and the
mixture was then stirred at the same temperature for
21 h. The reaction mixture was quenched with 10% aque-
ous HCl and the resulting mixture was extracted with ethyl
acetate (20 mL · 3). The combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (eluent;
Hex:AcOEt = 4:1) to afford 3-[N-(tert-butoxycarbonyl)-
amino]-propan-1-ol (2.08 g, 89%) as colorless oil. 1H
NMR (400 MHz, CDCl3) d 3.66 (t, J = 5.9 Hz, 2H), 3.28
(t, J = 6.1 Hz, 2H), 1.65 (tt, J = 5.9, 6.1 Hz, 2H), 1.44
(s, 9H), IR (neat) 3729–3093, 2978, 2936, 2879, 1690,
OBn
OH
OH
c,d
OH
Fagomine 1
N
N
H
Boc
9
Scheme 2. Reagents and conditions: (a) PdCl2(MeCN)2, THF, rt, 90%;
(b) O3, CH2Cl2/MeOH (1:4), ꢀ78 ꢁC; NaBH4, ꢀ78 ꢁC, 80%; (c) HCl aq,
MeOH, 70 ꢁC, 64%; (d) H2, Pd–C, AcOH, 87%.
BnO
BnO
N
N
OBn
Pd
OBn
Pd
Boc
Boc
>
H
O
1526, 1172, 1046 cmꢀ1
.
O
A
B
H
4.2. 3-[N-(tert-Butoxycarbonyl)amino]-propanal
Figure 2.
To a stirred solution of dimethylsulfoxide (3.15 mL,
42.0 mmol) in CH2Cl2 (140 mL) under an argon atmo-
sphere was added oxalyl chloride (1.94 mL, 21.0 mmol) at
ꢀ78 ꢁC. The resultant mixture was stirred for 15 min and
a solution of 3-[N-(tert-butoxycarbonyl)amino]-propan-1-
ol (2.60 g, 14.0 mmol) in CH2Cl2 was added dropwise.
After stirring for 1 h at ꢀ78 ꢁC, triethylamine (9.67 mL,
70.0 mmol) was added, and the resulting mixture was
allowed to warm into room temperature. After 30 min,
the reaction mixture was quenched with 10% aqueous
HCl and the resulting mixture extracted with ethyl acetate
(20 mL · 3). The combined organic layers were washed with
saturated aqueous NaHCO3 and brine, dried over MgSO4.
Concentration afforded the crude aldehyde (2.50 g), which
was used in the next step without further purification.
groups and the TBS protecting group was removed under
acidic conditions (p-TsOH, MeOH) to give alcohol 66 in
29% yield and 74% ee from 5. The IBX oxidation7 of 6
and subsequent Horner–Wittig reaction gave the a,b-
unsaturated ester, which was subjected to DIBAL–H
reduction to afford allyl alcohol 7 in 40% overall yield.
The next task was the Pd(II)-catalyzed cyclization (Scheme
2). Allyl alcohol 7 was treated with PdCl2(MeCN)2 in THF
at room temperature to give cyclic compound 8 in 90% yield.
A possible reaction mechanism is shown in Figure 2. The p-
allyl–oxy palladium complex is produced by the coordina-
tion of the Pd catalyst with allyl alcohol and the amine.
The stereoselective formation of 8 can be explained by
assuming transition state A. Transition state B is disadvan-
tageous, because of the non-bonding interaction between
the carbamate moiety and p-allyl–oxy palladium complex
(Fig. 2).
4.3. Ethyl-5-[N-(tert-butoxycarbonyl)amino]-2-pentenoate
To a suspension of NaH (784 mg, 19.6 mmol) in THF
(135 mL) was added diethyl triethyl phosphonoacetate
(4.16 mL, 21.0 mmol) at 0 ꢁC under an argon atmosphere
and the mixture was stirred at the same temperature for
10 min. A solution of 3-[N-(tert-butoxycarbonyl)amino]-
propanal (2.50 g) in THF (5 mL) was added to the Wittig
mixture at ꢀ50 ꢁC and the reaction mixture was warmed
to room temperature for 1 h. The reaction mixture was
quenched with saturated aqueous NH4Cl and the resulting
mixture was extracted with hexane (20 mL · 3). The com-
bined organic layers were washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (eluent; Hex:
AcOEt = 9:1) to afford ethyl-5-[N-(tert-butoxycarbonyl)-
amino]-2-pentenoate (2.86 g, two steps 84%) as a yellow
Next, we examined the transformation of 8 into fagomine 1.
Ozonolysis of 8 followed by reductive work-up with NaBH4
provided the alcohol 9. Deprotection of the Boc group of 9
under acidic conditions and removal of the benzyl groups
by hydrogenation provided fagomine 1. The spectral data
of (+)-1 were in agreement with reported data.3d
3. Conclusion
In conclusion, we have achieved an asymmetric synthesis of
fagomine, using an approach that should be easily

854
H. Yokoyama et al. / Tetrahedron: Asymmetry 18 (2007) 852–856
oil. 1H NMR (400 MHz, CDCl3) d 6.89 (dt, J = 1.5,
15.6 Hz, 1H), 5.87 (dt, J = 7.1, 15.6 Hz, 1H), 4.20 (q,
J = 7.1 Hz, 2H), 3.23–3.26 (m, 2H), 2.43–2.37 (m, 2H),
1.44 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), IR (neat) 3367,
dried over MgSO4 and concentrated in vacuo. The
crude diol was used without further purification for the
next step.
1716 cmꢀ1
.
4.7. (2R,3R)-5-[N-(tert-butoxycarbonyl)amino]-2,3-dibenz-
yloxy-(tert-butyl-dimethyl-silyloxy)-pentane
4.4. 5-[N-(tert-Butoxycarbonyl)amino]-2-penten-1-ol 4
To a suspension of NaH (309 mg, 7.71 mmol) in THF
(12.8 mL) was added (2R,3R)-5-[N-(tert-butoxycarb-
onyl)amino]-(tert-butyl-dimethyl-silyloxy)-pentan-2,3-diol
(900 mg, 2.57 mmol) at 0 ꢁC under an argon atmosphere
and the reaction mixture was stirred for 1.5 h at the same
temperature. Benzyl bromide (0.67 mL, 5.65 mmol) and
tetrabutylammonium iodide (9.4 mg, 0.02 mmol) were
added to the mixture at 0 ꢁC. The resulting mixture was
stirred at room temperature for 4 h and then quenched
with ice water. The resulting mixture was extracted with
ethyl acetate (5 mL · 3). The combined organic layers were
washed with brine, dried over MgSO4 and concentrated in
vacuo. The crude dibenzylether was used without further
purification for the next step.
To a solution of ethyl-5-[N-(tert-butoxycarbonyl)amino]-2-
pentenoate (2.37 g, 9.7 mmol) in THF (97 mL) was added
diisobutylaluminum hydride (0.93 M n-hexane solution)
(31.4 mL, 29.1 mmol) at ꢀ78 ꢁC under an argon atmo-
sphere. The mixture was stirred for 2 h at the same temper-
ature. The reaction mixture was quenched with saturated
aqueous NH4Cl and the resulting mixture extracted with
ethyl acetate (20 mL · 3). The combined organic layers
were washed with brine, dried over MgSO4 and concen-
trated in vacuo. The residue was purified by silica
gel column chromatography (eluent; Hex:AcOEt = 8:2)
to afford 5-[N-(tert-butoxycarbonyl)amino]-2-penten-1-ol
1
(1.93 g, 99%) as a yellow oil. H NMR (600 MHz, CDCl3)
d 5.69 (tq, J = 5.4, 6.6 Hz, 2H), 4.11 (d, J = 5.4 Hz, 2H),
3.18 (t, J = 6.6 Hz, 2H), 2.24 (dt, J = 6.6 Hz, 2H), 1.44
(s, 9H), IR (neat) 3278–3100, 2978, 2933, 1694 cmꢀ1
.
4.8. (2R,3R)-5-[N-(tert-Butoxycarbonyl)amino]-2,3-dibenz-
yloxypentan-1-ol 6
4.5. 5-[N-(tert-Butoxycarbonyl)amino]-(tert-butyl-dimethyl-
silyloxy)-2-pentene 5
To
a solution of (2R,3R)-5-[N-(tert-butoxycarbonyl)-
amino]-2,3-dibenzyloxy-(tert-butyl-dimethyl-silyloxy)-pen-
tane (804 mg) in MeOH (15 mL) was added p-TsOH (26 mg,
0.01 mmol) at 0 ꢁC under an argon atmosphere and the
reaction mixture was stirred for 3 h at room temperature.
The mixture was quenched with saturated aqueous NaH-
CO3 and the resulting mixture extracted with ethyl acetate
(5 mL · 3). The combined organic layers were washed with
brine, dried over MgSO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(eluent; Hex:AcOEt = 8:2) to afford (2R,3R)-5-[N-(tert-
To a solution of 5-[N-(tert-butoxycarbonyl)amino]-2-pen-
ten-1-ol (1.93 g, 9.70 mmol) in DMF (5.0 mL) was added
imidazole (792 mg, 11.6 mmol) and TBSCl (1.60 g,
10.7 mmol) at 0 ꢁC under an argon atmosphere. The reac-
tion mixture was stirred for 3 h at the room temperature.
The mixture was quenched with 10% aqueous HCl and
the resulting mixture extracted with diethyl ether
(5 mL · 3). The combined organic layers were washed with
saturated aqueous NaHCO3 and brine, dried over
MgSO4 and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (eluent; Hex:
AcOEt = 33:1) to afford 5-[N-(tert-butoxycarbonyl)amino]-
(tert-butyl-dimethyl-silyloxy)-2-pentene (2.73 g, 89%) as a
colorless oil. 1H NMR (600 MHz, CDCl3) d 5.59–5.55
(m, 2H), 4.07 (d, J = 4.8 Hz, 2H), 3.13–3.08 (br s, 2H),
2.16 (dt, J = 6.2 Hz, 2H), 1.48 (s, 9H), 0.84 (s, 9H), 0.00
(s, 6H), IR (neat) 3356, 2957, 2897, 2857, 1698, 1253,
butoxycarbonyl)amino]-2,3-dibenzyloxypentan-1-ol (368 mg,
24
two steps 29%, 74% ee) as colorless oil. ½aꢁD ¼ þ16:8 (c
1
0.25, CHCl3), H NMR (600 MHz, CDCl3) d 7.35–7.27
(m, 10 H), 4.62–4.59 (m, 3H), 4.50 (d, J = 11.6 Hz, 1H),
3.77 (dd, J = 3.3, 13.7 Hz, 1H), 3.66–3.61 (m, 3H), 3.15–
3.10 (br, 2H), 1.82 (ddt, J = 3.3, 6.6, 18.1 Hz, 1H), 1.60
(ddt, J = 6.0, 6.6, 18.1 Hz, 1H), 1.40 (s, 9H), IR (neat)
3699–3137, 2976, 2931, 2877, 1694, 1170, 1092, 1059 cmꢀ1
.
837, 777 cmꢀ1
.
4.6. (2R,3R)-5-[N-(tert-Butoxycarbonyl)amino]-(tert-butyl-
dimethyl-silyloxy)-2-penten-2,3-diol
4.9. (2R,3R)-5-[N-(tert-Butoxycarbonyl)amino]-2,3-
dibenzyloxypentanal
To a solution of AD-mix-b (6.65 g) in t-BuOH (18.0 mL)
and water (18.0 mL) was added methanesulfonamide
(451 mg, 4.75 mmol) at room temperature and reac-
tion mixture was stirred at 0 ꢁC. 5-[N-(tert-Butoxy-
carbonyl)amino]-(tert-butyl-dimethyl-silyloxy)-2-pentene
(1.5 g, 4.75 mmol) was added to the mixture at 0 ꢁC. The
resulting mixture was stirred at the same temperature for
20 h, then quenched with sodium sulfite (7.13 g). After
being stirred for 1 h at room temperature, the resulting
mixture was extracted with ethyl acetate and the aqueous
layer was extracted with AcOEt (5 mL · 3). The combined
organic layers were washed with 2 M KOH (5 mL · 1),
To a solution of (2R,3R)-5-[N-(tert-butoxycarbonyl)-
amino]-2,3-dibenzyloxypentan-1-ol (237 mg, 0.57 mmol)
in THF–DMSO (4.5 mL:4.5 mL) was added 1-hydroxy-
1,2-benziodoxol-3(1H)-one-1-oxide (319 mg, 1.14 mmol)
at 0 ꢁC under an argon atmosphere and the reaction mix-
ture stirred for 4 h at room temperature. The mixture
was quenched with ice and the resulting mixture extracted
with ethyl acetate (5 mL · 3). The organic layers were
washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4. Concentration afforded the crude aldehyde
(187 mg), which was used in the next step without further
purification.

H. Yokoyama et al. / Tetrahedron: Asymmetry 18 (2007) 852–856
855
4.10. (4R,5R)-Ethyl-7-[N-(tert-butoxycarbonyl)amino]-4,5-
dibenzyloxy-2-heptenate
argon atmosphere and the mixture was stirred at room
temperature for 3 h. The reaction mixture was diluted with
diethyl ether and filtered through a silica gel pad and fol-
lowed by Florisil sequentially with diethyl ether and the
eluent was concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (eluent; Hex:
AcOEt = 93:7) to afford (2R,3R,4R)-N-tert-butoxycar-
bonyl-3,4-dibenzyloxy-2-vinylpiperidine (112 mg, 90%) as
a colorless oil. ½aꢁD ¼ ꢀ18:6 (c 0.85, CHCl3), H NMR
(400 MHz, CDCl3) d 7.34–7.26 (m, 10H), 6.07–5.99 (m,
J = 1.7 Hz, 1H), 5.12–5.11 (m, J = 1.7 Hz, 1H), 5.09–5.08
(br, 1H), 4.69 (d, J = 11.9 Hz, 1H), 4.50–4.47 (m,
J = 11.9 Hz, 3H), 3.88–3.85 (br d, J = 12.9 Hz, 1H), 3.70
(dt, J = 2.7, 3.2 Hz, 1H), 3.58 (br, 1H), 3.21 (dt, J = 2.7,
13.2 Hz, 1H), 1.98 (ddt, J = 3.7, 2.7, 13.2 Hz, 1H), 1.66
(dd, J = 2.7, 13.2 Hz, 1H), 1.44 (s, 9H), IR (neat) 3065,
3030, 2975, 2930, 2882, 1692 cmꢀ1; EI-Mass (m/z) 423.
To a suspension of NaH (32 mg, 0.79 mmol) in THF
(6 mL) was added diethyl triethyl phosphonoacetate
(0.17 mL, 0.86 mmol) at 0 ꢁC under an argon atmosphere
and the mixture was stirred at the same temperature for
10 min. A solution of (2R,3R)-5-[N-(tert-butoxycarbonyl)-
amino]-2,3-dibenzyloxypentanal (187 mg, 0.57 mmol) was
added to the Wittig mixture at the same temperature and
the reaction mixture was refluxed for 30 min. The reaction
mixture was quenched with saturated aqueous NH4Cl and
the resulting mixture extracted with ethyl acetate
(5 mL · 3). The combined organic layers were washed with
brine, dried over MgSO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(eluent; Hex:AcOEt = 6:1) to afford (4R,5R)-ethyl-7-[N-
24
1
(tert-butoxycarbonyl)amino]-4,5-dibenzyloxy-2-heptenate
24
(173 mg, 63%) as a yellow oil. ½aꢁD ¼ þ7:9 (c 1.00, CHCl3),
4.13. (2R,3R,4R)-(N-tert-Butoxycarbonyl-3,4-dibenzyloxy-
2-piperidinyl)-methanol 9
1H NMR (400 MHz, CDCl3) d 7.37–7.28 (m, 10H), 6.93
(dd, J = 5.9, 15.9 Hz, 1H), 6.07 (dd, J = 1.5, 15.9 Hz,
1H), 4.66 (dd, J = 11.4, 12.0 Hz, 2H), 4.50 (d,
J = 11.4 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.20 (q,
J = 7.1 Hz, 2H), 4.14 (dt, J = 1.5, 5.4 Hz, 1H), 3.58 (ddd,
J = 1.5, 3.2, 5.4 Hz, 1H), 3.19–3.11(m, 2H), 1.78–1.70 (m,
1H), 1.41 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H), IR (neat)
O3 gas was bubbled into a solution of (2R,3R,4R)-
N-tert-butoxycarbonyl-3,4-dibenzyloxy-2-vinylpiperidine
(10 mg, 0.02 mmol) in CH2Cl2–MeOH (4:1, 1.3 mL) at
ꢀ78 ꢁC until the solution turned to blue. Then an argon
gas bubbled through the solution until its color became
clear. To the reaction mixture was added NaBH4 (9.1 mg,
0.24 mmol) at ꢀ78 ꢁC. The mixture was warmed slowly
to the room temperature, and stirred for 2 h. The reaction
mixture was quenched with saturated aqueous NaHCO3.
The resulting mixture was extracted with ethyl acetate
(3 mL · 3). The combined organic layers were washed with
brine and dried over MgSO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatogra-
phy (eluent; Hex:AcOEt = 4:1) to afford (2R,3R,4R)-(N-
3429, 3375, 2978, 2931, 2871, 1715, 1657 cmꢀ1
.
4.11. (4R,5R)-Ethyl-7-[N-(tert-butoxycarbonyl)amino]-4,5-
dibenzyloxy-2-hepten-1-ol 7
To a solution of (4R,5R)-ethyl-7-[N-(tert-butoxycarbonyl)-
amino]-4,5-dibenzyloxy-2-heptenoate (173 mg, 0.36 mmol)
in THF (3.5 mL) was added diisobutylaluminum hydride
(0.93M n-hexane solution) (1.15 mL, 1.07 mmol) at
ꢀ78 ꢁC under an argon atmosphere. The mixture was
warmed up to room temperature and stirred for 5 h at
the same temperature. The reaction mixture was quenched
with 10% aqueous HCl at 0 ꢁC and the resulting mixture
extracted with ethyl acetate (5 mL · 3). The combined
organic layers were washed with NaHCO3 and brine,
dried over MgSO4 and concentrated in vacuo. The resi-
due was purified by silica gel column chromatography
(eluent; Hex:AcOEt = 8:2) to afford (4R,5R)-ethyl-7-[N-
tert-butoxycarbonyl-3,4-dibenzyloxy-2-piperidinyl)-metha-
25
nol (8.0 mg, 80%) as a colorless oil. ½aꢁD ¼ ꢀ45:6 (c 1.00,
CHCl3), 1H NMR (400 MHz, CDCl3) d 7.35–7.28 (m,
10H), 4.65 (d, J = 11.7 Hz, 1H), 4.60 (d, J = 11.7 Hz,
1H), 4.48 (dd, J = 11.7, 11.9 Hz, 3H), 3.94 (ddd, J = 4.9,
7.3, 11.7 Hz, 1H), 3.90–3.80 (br, 1H), 3.79–3.74 (ddd,
J = 2.2, 7.3, 11.7 Hz, 1H), 3.74–3.70 (br d, J = 3.2 Hz,
1H), 3.29–3.22 (br t, J = 12.4 Hz, 1H), 1.98 (ddt, J = 3.2,
4.9, 12.4 Hz, 1H), 1.71 (dd, J = 2.2, 11.7 Hz, 1H), 1.45 (s,
9H), IR (neat) 3721–3139, 2975, 2930, 2886, 1687, 1423,
(tert-butoxycarbonyl)amino]-4,5-dibenzyloxy-2-hepten-1-ol
24
(101 mg, 64%) as a yellow oil. ½aꢁD ¼ þ14:0 (c 0.27,
1171, 1069 cmꢀ1
.
CHCl3), 1H NMR (400 MHz, CDCl3) d 7.40–7.30 (m,
10H), 5.93 (dt, J = 15.6, 5.1 Hz, 1H), 5.65 (dd, J = 15.6,
7.3 Hz, 1H), 4.72 (d, J = 11.3 Hz, 1H), 4.63 (d, J =
11.8 Hz, 1H), 4.55 (d, J = 11.3 Hz, 1H), 4.42 (d,
J = 11.8 Hz, 1H), 4.19 (br t, J = 5.1 Hz, 2H), 3.97 (t,
J = 6.8 Hz, 1H), 3.58–3.53 (m, 1H), 3.18–3.12 (m, 2H),
1.79–1.76 (m, 2H), 1.41 (s, 9H), IR (neat) 3695–3128,
4.14. (2R,3R,4R)-3,4-Dibenzyloxy-1,5-imino-1,2,5-trideoxy-
D-arabino hexitol
A mixture of (2R,3R,4R)-(N-tert-butoxycarbonyl-3,4-di-
benzyloxy-2-piperidinyl)-methanol (31 mg, 0.07 mmol)
and 10% aqueous HCl (2 mL) in MeOH (2 mL) was stirred
at 70 ꢁC for 5 h. The reaction mixture was alkalified with
2 M NaOH at 0 ꢁC. The resulting mixture was extracted
with CH2Cl2 (3 mL · 3). The combined organic layers were
dried over K2CO3 and concentrated in vacuo. The residue
was purified by silica gel chromatography (eluent; CHCl3:
iPrOH = 73:27) to afford (2R,3R,4R)-3,4-dibenzyloxy-1,5-
2977, 2931, 2869, 1694 cmꢀ1
.
4.12. (2R,3R,4R)-N-tert-Butoxycarbonyl-3,4-dibenzyloxy-2-
vinylpiperidine 8
To a solution of (4R,5R)-ethyl-7-[N-(tert-butoxycarbonyl)-
amino]-4,5-dibenzyloxy-2-hepten-1-ol (130 mg, 0.3 mmol)
in THF (3.0 mL) was added a catalytic amount of
PdCl2 (CH3CN)2 (7.63 mg, 0.03 mmol) at 0 ꢁC under an
imino-1,2,5-trideoxy-D-arabino hexitol (15 mg, 64%) as a
26
colorless oil. ½aꢁD ¼ þ11:6 (c 0.80, CHCl3), 1H NMR
(600 MHz, CDCl3) d 7.37–7.27 (m, 10H), 4.98 (d,

856
H. Yokoyama et al. / Tetrahedron: Asymmetry 18 (2007) 852–856
J = 11.0 Hz, 1H), 4.65 (dd, J = 11.0, 11.6 Hz, 3H), 3.77
(dd, J = 3.3, 11.0 Hz, 1H), 3.65 (dd, J = 5.5, 11.0 Hz,
1H), 3.54 (ddd, J = 2.2, 3.8, 8.8 Hz, 1H), 3.30 (t,
J = 8.8 Hz, 1H), 3.00 (ddd, J = 3.8, 11.5, 12.6 Hz, 1H),
2.62–2.56 (m, 2H), 2.13 (ddt, J = 2.2, 4.4, 12.6 Hz, 1H),
1.45 (ddd, J = 4.4, 11.5, 12.6 Hz, 1H), IR (neat) 3713–
of Education, Culture, Sports, Science and Technology
(MEXT).
References
3128, 2927, 2867, 1454, 1098 cmꢀ1
.
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To a solution of (2R,3R,4R)-3,4-dibenzyloxy-1,5-imino-
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and the solution was stirred with Dowex 50w-X8 (H+
form) ion-exchange for 5 h. The suspension was eluted with
water and then 0.5 M NH4Cl, so gave 1,5-imino-1,2,5-tri-
27
deoxy-D-arabino hexitol (68 mg, 87%). ½aꢁD ¼ þ13:4 (c
0.86, H2O), 1H NMR (600 MHz, D2O) d 3.84 (dd,
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3.53 (ddd, J = 5.1, 9.1, 11.4 Hz, 1H), 3.15 (t, J = 9.6 Hz,
1H), 3.00 (ddd, J = 4.4, 11.7, 12.7 Hz, 1H), 2.60 (dt,
J = 2.6, 5.1, 12.9 Hz, 1H), 2.52 (ddd, J = 2.9, 7.0, 9.9 Hz,
1H), 1.90 (ddt, J = 2.6, 12.5, 4.4 Hz, 1H), 1.39 (ddd,
J = 2.6, 11.7, 12.8 Hz, 1H), IR (neat) 3792–2955, 2951,
1601, 1455, 1069 cmꢀ1, EI-Mass (m/z) 147.
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Acknowledgement
1
6. The enantiomeric ratio was determined by H NMR analysis
This work was supported by a grant-in-Aid for Scientific
Research in priority areas (17035032) from the Ministry
of (S)-(+)-a-methoxyphenyl acetic acid derivatives of 6.
7. Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812.