Total synthesis of d-fagomine and 6-deoxyfagomine

Article abstract of DOI:10.1016/j.tet.2013.03.046

Total synthesis of d-fagomine and 6-deoxyfagomine from readily available d-lyxose is described. The key steps included regioselective and diastereoselective amination, hydroboration-oxidation, and Appel reaction. The reaction of 3,4-anti-tribenzyl ether with chlorosulfonyl isocyanate in toluene at 0 °C afforded 3,4-anti-amino alcohol, an essential compound for the preparation of d-fagomine and 6-deoxyfagomine, with a high diastereoselectivity (dr=26:1) in 74% yield. The origin of diastereoselectivity can be explained by the neighboring group effect, which leads to retention of the stereochemistry.

Full text of DOI:10.1016/j.tet.2013.03.046

Tetrahedron 69 (2013) 3901e3906
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of
D-fagomine and 6-deoxyfagomine
*
Im Sook Min, Seung In Kim, Seungmin Hong, In Su Kim, Young Hoon Jung
School of Pharmacy, Sungkyunkwan University, 300 Chonchondong, Jangangu, Suwon, Kyunggido 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of
D-fagomine and 6-deoxyfagomine from readily available D-lyxose is described. The key
Received 25 January 2013
Received in revised form 6 March 2013
Accepted 9 March 2013
steps included regioselective and diastereoselective amination, hydroborationeoxidation, and Appel
reaction. The reaction of 3,4-anti-tribenzyl ether with chlorosulfonyl isocyanate in toluene at 0 ꢀC
afforded 3,4-anti-amino alcohol, an essential compound for the preparation of
D-fagomine and
Available online 15 March 2013
6-deoxyfagomine, with a high diastereoselectivity (dr¼26:1) in 74% yield. The origin of diaster-
eoselectivity can be explained by the neighboring group effect, which leads to retention of the
stereochemistry.
Keywords:
Fagomine
Deoxyfagomine
Chlorosulfonyl isocyanate
Amination
Ó 2013 Elsevier Ltd. All rights reserved.
Total synthesis
1. Introduction
Discovery of polyhydroxylated piperidines (azasugars) is one of
the most notable achievements in the field of natural products.
They bind specifically to the active sites of glycosidases by mim-
icking the corresponding natural sugars. Since glycosidases are in-
volved in numerous biological processes, polyhydroxylated
piperidines have remarkable therapeutic potential for the treat-
ment of a wide range of diseases including viral infections, cancer,
AIDS, and diabetes.1 For this reason, a variety of natural and non-
natural polyhydroxylated piperidines have been prepared and
evaluated for their clinical applications.2 Indeed, miglitol (GlysetÔ)
and N-butyldeoxynojirimycin (ZavescaÔ) are currently used as
drugs for the treatment of type II diabetes and Gaucher’s disease,
respectively.3
Fig. 1. Structures of fagomine family.
glucose-induced insulin secretion.9 In addition, non-naturally oc-
1,2-Dideoxy azasugars are a representative example of naturally
occurring polyhydroxylated piperidines and represent an important
curring 4-epi-fagomine (4) was found to be a potent lysosomal a-
galactosidase A inhibitor in Fabry lymphoblasts.10
class of glycosidase inhibitors (Fig. 1).4
-Fagomine (1), a member of
D
To date, a number of synthetic methods for the preparation of 1
and 5 have been reported.11e13 A majority of synthetic approaches
have involved asymmetric synthesis for the construction of ster-
eogenic centers,11 chemical and enzymatic resolution,12 and syn-
thetic strategy from a readily available chiral pool.13 In a recent
example for asymmetric synthesis, Ham reported a total synthesis
of 1 via palladium-catalyzed stereoselective intramolecular oxazine
formation followed by catalytic hydrogenation of oxazine inter-
mediate.11a Wong described a one-pot chemoenzymatic aldol re-
action for the synthesis of a variety of iminocyclitols including 1
and 5 from readily available non-phosphorylated donor sub-
strates.12d Takahata demonstrated the total synthesis of fagomine
this family, was first isolated from Japanese buckwheat seeds of
Fagopyrum esculentum Moench in 1974,5 and was found in the seeds
of Castanospermum australe (Leguminosae).6 Later,
D
-fagomine (1)
and 6-deoxyfagomine (5) were also isolated from the roots
of Lycium chinense (Solanaceae).7
-Fagomine (1) was found to be a
D
potent inhibitor against mammalian a-glucosidase and b-galacto-
sidase,8 and was also reported to display a strong antihyperglycemic
activity in streptozocin-induced diabetic mice and in potentiation of
* Corresponding author. Tel.: þ82 31 290 7711; fax: þ82 31 292 8800; e-mail
address: yhjung@skku.edu (Y.H. Jung).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.046

3902
I.S. Min et al. / Tetrahedron 69 (2013) 3901e3906
and its congeners 1e4, starting from Garner aldehyde derived from
-serine, via ring-closing metathesis and dihydroxylation as the key
steps.13d
as BH3eTHF, 9-BBN, and catecholborane, were conducted for the
chemoselective oxidation of terminal olefin of 8, but with limited/
no success.
D
As part of an ongoing research program aimed at developing
In view of these unsuccessful results, we exchanged our synthetic
plan to prepare the piperidine framework, as shown in Scheme 2. To
our delight, a terminal olefin of the diene 7 under standard hydro-
boration and oxidation conditions (9-BBN, NaOH/H2O2) was con-
verted into the primary alcohol 10, which was subjected to the Appel
reaction (PPh3, CBr4, and Et3N) to furnish compound 11 in 85% yield.
Next, the diastereoselective amination reaction of 11 using
chlorosulfonyl isocyanate was examined under various reaction
conditions, and the selected results are summarized in Table 1. As
shown in entry 1, the reaction in methylene chloride at 0 ꢀC gave
the desired product 12 with 17:1 of a diastereomeric ratio. After
screening of solvents under otherwise identical conditions, toluene
was found to be most effective solvent in this reaction, affording
exclusively the compound 12 in 74% yield with an excellent dia-
stereoselectivity of 26:1 (Table 1, entry 5). The diastereoselectivity
of compound 12 can be explained by the neighboring group effect,
whereby the orientation of the NHCbz group retains its original
configuration through double inversion of configuration.15b
Treatment of 12 with potassium tert-butoxide afforded the pi-
peridine 13. Ozonolysis of 13 and subsequent reduction using
asymmetric total synthesis of biologically active compounds,14 we
recently described a facile strategy for the preparation of (ꢁ)-len-
tiginosine and its analogues via diastereoselective amination of
chiral allylic ethers using chlorosulfonyl isocyanate (CSI).15 In con-
nection with previous works, we herein describe an asymmetric
total synthesis of
from commercially available
D
-fagomine (1) and 6-deoxyfagomine (5) starting
-lyxose via highly stereoselective
D
amination of chiral allylic ether using chlorosulfonyl isocyanate as
the key step.
2. Results and discussion
Our initial investigations focused on the efficient construction
of aminoalcohol 9, which can provide piperidine core by
Appel reaction of primary alcohol followed by intramolecular cy-
clization under basic condition, based on the reported literature
(Scheme 1).14g The synthesis of 9 began with the alcohol 6 prepared
from commercially available -lyxose. Swern oxidation of 6 and
D
subsequent Wittig reaction furnished the dienic compound 7.
Treatment of 7 with CSI in toluene at 0 ꢀC followed by desulfony-
lation using a saturated sodium sulfite solution afforded the cin-
namylic amine 8 in 74% yield with a high diastereoselectivity (anti/
syn¼24:1). A range of hydroboration and oxidation conditions, such
NaBH4 gave the alcohol 14, which was hydrogenated to provide
D
-
fagomine (1) in 95% yield. The spectroscopic data (1H NMR and 13
C
NMR) and specific rotation of the compound 1 were in full agree-
ment with the reported literature values.11a
Scheme 1.
Scheme 2.

I.S. Min et al. / Tetrahedron 69 (2013) 3901e3906
3903
Table 1
synthetic strategy can be applied to the preparation of a broad range
of biologically active compounds containing polyhydroxylated al-
kaloids or other natural products containing a nitrogen atom in the
ring.
Selected optimization for the diastereoselective amination of 11a
Entry
Solvent
Time (h)
Yieldb (%)
anti/sync
1
2
3
4
5
CH2Cl2
Et2O
CCl4
n-Hexanes
Toluene
12
12
19
24
24
50
60
58
65
74
17:1
15:1
19:1
16:1
26:1
4. Experimental
4.1. General method
a
Reaction conditions: (i) 11 (1 equiv), chlorosulfonyl isocyanate (4.5 equiv),
Na2CO3 (6.8 equiv), solvent (0.2 M), 0 ꢀC; (ii) s-Na2SO3, rt, 24 h.
Commercially available reagents were used without additional
purification, unless otherwise stated. All reactions were per-
formed under an inert atmosphere of nitrogen or argon. Nuclear
magnetic resonance spectra (1H and 13C NMR) were recorded on
Varian Unit 500 and 300 MHz spectrometers for CDCl3 solutions
and chemical shifts are reported as parts per million (ppm)
relative to, respectively, residual CHCl3 dH (7.26 ppm) and CDCl3
dC (77.0 ppm) as internal standards. Resonance patterns are re-
ported with the notations s (singlet), d (doublet), t (triplet), q
(quartet), and m (multiplet). In addition, the notation br is used
to indicate a broad signal. Coupling constants (J) are reported in
hertz (Hz). IR spectra were recorded on Bruker Infrared spectro-
photometer and are reported as cmꢁ1. Optical rotations were
measured with a Jasco P1020 polarimeter. Thin layer chroma-
tography was carried out using plates coated with Kieselgel
60F254 (Merck). For flash column chromatography, E. Merck
Kieselgel 60 (230e400 mesh) was used. LC/mass spectra (LC/
MS) were recorded on a Waters 2767 LCMS system. High-
resolution mass spectra (HRMS) were recorded on a JEOL JMS-
600 spectrometer.
b
Isolated yield by flash column chromatography.
c
Diastereomeric ratio was determined by 1H NMR analysis of a crude reaction
mixture.
Based on the above results, we focused on the synthesis of 6-
deoxyfagomine (5) from the piperidine 14 via a three-step syn-
thesis, as illustrated in Scheme 3. To obtain compound 16, we ini-
tially attempted conversion of the alcohol moiety of 14 into OTs and
OMs groups, which can be easily removed by the use of potent
reducing reagents such as LiAlH4 and LiEt3BH.16 However, these
attempts were unsuccessful and led to the decomposition of the
starting material (Table 2).
4.2. ((3R,4S,5R)-1-Phenylhepta-1,6-diene-3,4,5-triyl)tris(oxy)
tris(methylene)tribenzene (7)
To a stirred solution of oxalic chloride (15.1 mL, 30.18 mmol,
2.0 M in CH2Cl2) in anhydrous CH2Cl2 (91 mL) was carefully added
DMSO (4.3 mL, 60.35 mmol) at ꢁ78 ꢀC and stirred for 1 h at same
temperature. The alcohol 6 (9.95 g, 20.12 mmol) and Et3N (14.0 mL,
23.86 mmol) were added to the reaction mixture, which was
stirred for 1 h at ꢁ78 ꢀC and then stirred for 0.5 h at ꢁ40 ꢀC. The
resulting mixture was carefully quenched with H2O and the
aqueous layer was extracted with CH2Cl2 (100 mL). The organic
layer was washed with H2O and brine, dried over MgSO4, and
concentrated in vacuo. The residual oil (about 9.9 g) was subjected
to the next step without purification. To a stirred solution of
MePPh3Br (10.77 g, 30.15 mmol) in THF (61.1 mL) was added
NaHMDS (30.2 mL, 1.0 M in THF) at 0 ꢀC under N2. The reaction
mixture was stirred for 1 h at 0 ꢀC. The crude aldehyde was sus-
pended in THF (40 mL), and then was slowly added to the reaction
mixture at 0 ꢀC. The reaction mixture was stirred for 10 min at 0 ꢀC.
The reaction mixture was quenched with H2O and the aqueous
layer was extracted with EtOAc (100 mL). The organic layer was
washed with H2O and brine, dried over MgSO4, and concentrated
in vacuo. The residue was purified by flash column chromatogra-
Scheme 3.
Table 2
Selected optimization for the reduction of 15ae15c
Entry
Substrate
Reaction conditions
Yielda (%)
1
2
4
3
15a
15b
15b
15c
LiAlH4 (3 equiv), THF (0.3 M), 70 ꢀC, 8 h
LiAlH4 (3 equiv), THF (0.3 M), 70 ꢀC, 8 h
LiEt3BH (3 equiv), THF (0.3 M), 100 ꢀC, 14 h
n-Bu3SnH (2 equiv), AIBN (0.2 equiv),
toluene (0.1 M), reflux, 12 h
0
0
0
81
a
Isolated yield by flash column chromatography.
Consequently, our strategy was changed to conversion of pri-
mary alcohol to halogen group followed by dehalogenation using
radical reaction. Thus, the alcohol 14 was subjected to Appel con-
ditions to afford compound 15c, which was readily hydrogenated
using n-Bu3SnH and AIBN to give compound 16 in 81% yield.17 Fi-
nally, benzyl and Cbz protection groups were removed via Pd-
catalyzed hydrogenation to afford 6-deoxyfagomine (5). The spec-
troscopic data and the specific rotation of 5 were found to be in full
agreement with the reported literature value.13a
phy (n-hexanes/EtOAc¼20:1) to afford 7.59
g
(77%, cis/
trans¼3.2:1) of 7 as a colorless syrup. Rf¼0.29 (n-hexanes/
EtOAc¼20:1); cis-isomer: 1H NMR (500 MHz, CDCl3)
d 3.57e3.61
(m, 1H), 3.90 (d, J¼11.0 Hz, 1H), 4.07e4.15 (m, 1H), 4.24 (d,
J¼11.0 Hz, 1H), 4.41 (d, J¼11.0 Hz, 1H), 4.61 (d, J¼11.0 Hz, 1H), 4.70
(d, J¼11.0 Hz, 1H), 4.81 (d, J¼11.0 Hz, 1H), 4.83e4.86 (m, 1H),
5.22e5.37 (m, 2H), 5.78 (dd, J¼11.5, 10.0 Hz, 1H), 5.85e5.98 (m,
1H), 6.92 (d, J¼11.5 Hz, 1H), 7.10e7.50 (m, 20H); trans-isomer: 1H
3. Conclusions
NMR (500 MHz, CDCl3)
d 3.64e3.68 (m, 1H), 4.07e4.13 (m, 2H),
In conclusion, we have described a concise total synthesis of
-fagomine and 6-deoxyfagomine starting from readily available
-lyxose via a stereoselective amination reaction into chiral allylic
4.26 (d, J¼11.0 Hz, 1H), 4.45e4.48 (m, 1H), 4.63 (d, J¼11.0 Hz, 1H),
4.68 (d, J¼11.0 Hz, 1H), 4.71 (d, J¼11.0 Hz, 1H), 4.76 (d, J¼11.0 Hz,
1H), 5.22e5.37 (m, 2H), 5.76 (dd, J¼16.0, 7.5 Hz, 1H), 5.86e5.97 (m,
1H), 6.69 (d, J¼16.0 Hz, 1H), 7.10e7.50 (m, 20H); 13C NMR
D
D
ethers using chlorosulfonyl isocyanate. It is believed that this

3904
I.S. Min et al. / Tetrahedron 69 (2013) 3901e3906
(125 MHz, CDCl3)
d
70.2, 70.5, 70.9, 73.6, 75.3, 75.5, 80.3, 80.4, 81.0,
4.5. Benzyl (3R,4R,5R)-4,5-bis(benzyloxy)-7-bromo-1-
83.7, 84.3, 118.3, 118.8, 126.9, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8,
127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8,
128.9, 129.4, 130.0, 130.5, 134.5, 134.9, 136.3, 136.5, 136.9, 137.0,
138.5, 138.6, 138.7, 138.8, 138.9; HRMS (FAB) calcd for C34H34O3
[MþH]þ 490.2508, found 490.2514.
phenylhept-1-en-3-ylcarbamate (12)
To a stirred solution of 11 (5.79 g, 10.13 mmol) in anhydrous
toluene (50.7 mL) were added Na2CO3 (7.25 g, 68.40 mmol) and
chlorosulfonyl isocyanate (3.97 mL, 45.60 mmol) at 0 ꢀC under N2.
The reaction mixture was stirred for 24 h at 0 ꢀC and quenched with
H2O (15 mL). The aqueous layer was extracted with EtOAc
(30 mLꢂ2). The organic layer was added to a saturated solution of
Na2SO3 (100 mL), and the reaction mixture was stirred for 24 h at
room temperature. The organic layer was washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography (n-hexanes/
EtOAc¼13:1) to afford 4.61 g (74%, cis/trans¼4.3:1, anti/syn¼26:1)
of 12 as a pale yellow syrup. Rf¼0.11 (n-hexanes/EtOAc¼13:1); IR
(neat) 3417, 3062, 3030, 1710, 1498, 1454, 1217, 1070 cmꢁ1; cis-
4.3. (3R,4S,5R)-3,4,5-Tris(benzyloxy)-7-phenylhept-6-
en-1-ol (10)
To a stirred solution of the diene 7 (7.59 g, 15.47 mmol) in an-
hydrous THF (8.0 mL) was added 9-BBN (62.1 mL, 0.5 M in THF) at
room temperature. After stirring for 24 h at 40 ꢀC, the reaction
mixture was added to 3 N NaOH (22 mL) and 35% H2O2 (22 mL) at
0 ꢀC. The reaction mixture was stirred for 8 h at 55 ꢀC and quenched
with H2O. The aqueous layer was extracted with EtOAc (200 mL).
The organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc¼3:1) to afford
6.06 g (77%, cis/trans¼3.6:1) of 10 as a colorless syrup. Rf¼0.26 (n-
isomer: 1H NMR (300 MHz, CDCl3)
d 1.77e1.96 (m, 2H), 2.91e3.02
(m, 1H), 3.18e3.21 (m, 1H), 3.42 (t, J¼4.8 Hz, 1H), 3.76 (dd, J¼5.7,
4.8 Hz, 1H), 4.41e4.74 (m, 4H), 4.97e5.18 (m, 3H), 5.54 (t, J¼9.9 Hz,
1H), 5.56e5.61 (br, 1H), 6.60 (d, J¼9.9 Hz, 1H), 7.13e7.32 (m, 20H);
hexanes/EtOAc¼3:1); IR (neat) 3445, 3061, 1716, 1495, 1453 cmꢁ1
;
trans-isomer: 1H NMR (300 MHz, CDCl3)
d 2.12e2.20 (m, 2H),
cis-isomer: 1H NMR (300 MHz, CDCl3)
d
1.55e1.86 (m, 3H),
3.13e3.18 (m, 1H), 3.22e3.38 (m, 1H), 3.57 (t, J¼4.8 Hz, 1H),
3.85e3.89 (m, 1H), 4.44e4.75 (m, 5H), 4.99e5.20 (m, 2H),
5.62e5.65 (br, 1H), 6.05 (dd, J¼15.6, 7.2 Hz, 1H), 6.51 (d, J¼15.6 Hz,
3.45e3.56 (m, 2H), 3.59e3.68 (m, 1H), 3.79e3.92 (m, 1H), 4.04 (d,
J¼11.4 Hz, 1H), 4.46 (s, 2H), 4.51 (d, J¼11.4 Hz, 1H), 4.62 (d,
J¼11.4 Hz, 1H), 4.71e4.80 (m, 1H), 4.83 (d, J¼11.4 Hz, 1H), 5.85 (dd,
J¼12.0, 9.9 Hz, 1H), 6.91 (d, J¼12.0 Hz, 1H), 7.09e7.43 (m, 20H);
1H), 7.14e7.30 (m, 20H); 13C NMR (125 MHz, CDCl3)
d 29.8, 29.9,
30.7, 33.4, 33.5, 33.7, 49.3, 53.8, 66.7, 73.1, 74.3, 74.7, 79.4, 125.9,
126.7, 126.8, 127.7, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6,
128.7, 128.8, 128.9, 130.9, 132.9, 136.5, 136.8, 136.9, 137.8, 137.9,
156.0; HRMS (CI) calcd for C34H37O4 [MþH]þ 614.1906, found
614.1929.
trans-isomer: 1H NMR (300 MHz, CDCl3)
d 1.58e1.83 (m, 3H),
3.44e3.52 (m, 2H), 3.60e3.64 (m,1H), 3.80e3.93 (m,1H), 4.17e4.20
(m, 1H), 4.38 (d, J¼11.4 Hz, 1H), 4.42e4.58 (m, 3H), 4.69 (d,
J¼11.4 Hz, 1H), 4.78 (d, J¼11.4 Hz, 1H), 6.35 (dd, J¼16.5, 7.5 Hz, 1H),
6.64 (d, J¼16.5 Hz, 1H), 7.12e7.40 (m, 20H); 13C NMR (125 MHz,
CDCl3)
d
34.1, 34.3, 60.6, 60.7, 70.0, 70.3, 73.4, 73.5, 73.8, 74.7, 75.0,
4.6. (2R,3R,4R)-Benzyl 3,4-bis(benzyloxy)-2-styrylpiperidine-
77.5, 78.3, 80.7, 82.6, 83.3, 126.9, 127.2, 127.5, 127.7, 127.8, 127.9,
128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9,
129.3, 130.4, 134.8, 135.0, 136.8, 138.4, 138.5, 138.6; HRMS (CI) calcd
for C34H37O4 [MþH]þ 509.2692, found 509.2686.
1-carboxylate (13)
To a stirred solution of 12 (3.98 g, 6.48 mmol) in anhydrous THF
(32.4 mL) was slowly added potassium tert-butoxide (1.67 g,
14.90 mmol) at 0 ꢀC under N2. The reaction mixture was stirred for
3 h at 0 ꢀC and quenched with aqueous solution of saturated NH4Cl
(15 mL). The aqueous layer was extracted with EtOAc (30 mL). The
organic layer was washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (n-hexanes/acetone¼15:1) to afford 2.63 g
(76%) of 13 as a colorless syrup. Rf¼0.10 (n-hexanes/acetone¼15:1);
IR (neat) 3030, 1698, 1496, 1454, 1426, 1092, 1029 cmꢁ1; cis-isomer:
4.4. ((3R,4S,5R)-7-Bromo-1-phenylhept-1-ene-3,4,5-triyl)
tris(oxy)tris(methylene)tribenzene (11)
To a stirred solution of the alcohol 10 (6.06 g, 11.91 mmol) in
anhydrous CH2Cl2 (24.4 mL) were added PPh3 (9.37 g, 35.73 mmol),
CBr4 (5.93 g, 17.87 mmol), and Et3N (12.2 mL) at 0 ꢀC under N2. The
reaction mixture was stirred for 2 h at 0 ꢀC and quenched with H2O
(15 mL). The aqueous layer was extracted with CH2Cl2 (30 mLꢂ2).
The organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc¼30:1) to afford
5.79 g (85%, cis/trans¼3.3:1) of 11 as a colorless syrup. Rf¼0.22 (n-
hexanes/EtOAc¼30:1); IR (neat) 3062, 3029, 1723, 1495, 1453, 1090,
1H NMR (300 MHz, CDCl3)
d
1.71 (br d, J¼11.4 Hz, 1H), 1.94e2.12 (m,
1H), 3.40 (dt, J¼13.2, 2.7 Hz, 1H), 3.51 (br s, 1H), 3.66e3.68 (m, 1H),
4.01 (d, J¼12.0 Hz, 1H), 4.08 (d, J¼12.0 Hz, 1H), 4.47 (d, J¼12.0 Hz,
1H), 4.54 (d, J¼12.0 Hz, 1H), 4.74 (d, J¼12.0 Hz, 1H), 5.11 (s, 2H), 5.61
(br d, J¼11.7 Hz, 1H), 6.12 (dd, J¼9.3, 8.7 Hz, 1H), 6.50 (d, J¼9.3 Hz,
1H), 7.02e7.37 (m, 20H); trans-isomer: 1H NMR (300 MHz, CDCl3)
1068 cmꢁ1; cis-isomer: 1H NMR (300 MHz, CDCl3)
d
2.01e2.23 (m,
d 1.96e2.11 (m, 2H), 3.25e3.74 (m, 2H), 3.96e4.06 (m, 1H),
2H), 3.28 (t, J¼6.6 Hz, 2H), 3.59e3.61 (m, 1H), 3.82e3.90 (m, 1H),
3.93 (d, J¼11.4 Hz, 1H), 4.42 (s, 2H), 4.47 (d, J¼11.4 Hz, 1H), 4.71 (d,
J¼11.4 Hz, 1H), 4.78e4.81 (m, 1H), 4.84 (d, J¼11.4 Hz, 1H), 5.84 (dd,
J¼12.0, 9.9 Hz, 1H), 6.94 (d, J¼12.0 Hz, 1H), 7.09e7.47 (m, 20H);
4.18e4.57 (m, 2H), 4.64 (d, J¼12.0 Hz, 1H), 4.77 (d, J¼12.0 Hz, 1H),
5.22e5.28 (m, 2H), 5.46e5.62 (m, 1H), 6.22 (dd, J¼15.6, 8.8 Hz, 1H),
6.42 (d, J¼15.6 Hz, 1H), 6.92e7.36 (m, 20H); 13C NMR (125 MHz,
CDCl3) d 25.7, 34.9, 51.3, 67.4, 71.0, 71.1, 73.7, 75.0, 126.7, 127.3, 127.6,
trans-isomer: 1H NMR (300 MHz, CDCl3)
d
1.87e1.98 (m, 2H), 3.67
127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.5, 128.6, 130.1, 137.0, 137.1,
138.2,138.5,156.2; HRMS (CI) calcd for C35H35O4 [MþH]þ 534.2644,
found 534.2639.
(t, J¼6.6 Hz, 2H), 3.72 (t, J¼4.8 Hz,1H), 3.85e3.99 (m, 3H), 4.17e4.22
(m, 1H), 4.42 (d, J¼11.4 Hz, 1H), 4.47 (d, J¼11.4 Hz, 1H), 4.78 (d,
J¼11.4 Hz, 1H), 4.83 (d, J¼11.4 Hz, 1H), 6.34 (dd, J¼16.2, 8.4 Hz, 1H),
6.66 (d, J¼16.2 Hz, 1H), 7.10e7.44 (m, 20H); 13C NMR (125 MHz,
4.7. (2R,3R,4R)-Benzyl 3,4-bis(benzyloxy)-2-(hydroxymethyl)
piperidine-1-carboxylate (14)
CDCl3)
d
30.9, 35.0, 69.9, 70.3, 73.6, 73.7, 73.8, 74.6, 74.8, 77.1, 80.6,
81.8, 82.8, 126.6, 126.9, 127.1, 127.3, 127.5, 127.7, 127.8, 127.9, 128.0,
128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 129.0,
129.3, 129.5, 130.4, 134.8, 135.2, 136.7, 136.8, 138.3, 138.4, 138.6,
138.7; HRMS (EI) calcd for C34H35BrO3 [M]þ 570.1770, found
570.1771.
A stirred solution of 13 (2.63 g, 4.93 mmol) in anhydrous CH2Cl2
(19.3 mL) and MeOH (19.3 mL) was allowed to react with ozone
(40 mL/min) for 3 h at ꢁ78 ꢀC. After removal of an excess ozone by
flushing argon, NaBH4 (1.70 g, 44.97 mmol) was slowly added at

I.S. Min et al. / Tetrahedron 69 (2013) 3901e3906
3905
ꢁ78 ꢀC and the reaction mixture was stirred for 2 h at 0 ꢀC. The
resulting mixture was quenched with aqueous solution of saturated
NH4Cl (20 mL) and extracted with CH2Cl2 (35 mLꢂ2). The organic
layer was washed with H2O and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
extracted with CH2Cl2 (5 mLꢂ2). The organic layer was washed
with saturated NaHCO3 and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (n-hexanes/EtOAc¼2:1) to afford 0.221 g (95%) of 15b
as colorless syrup. Rf¼0.32 (n-hexanes/EtOAc¼2:1); 1H NMR
chromatography (n-hexanes/EtOAc¼3:1) to afford 1.80 g (79%) of
(300 MHz, CDCl3)
d
1.73 (br d, J¼13.5 Hz, 1H), 1.97e2.05 (br m, 1H),
29
14 as a colorless syrup. Rf¼0.22 (n-hexanes/EtOAc¼3:1); [
a
]
2.78 (br s, 3H), 3.10e3.30 (m, 1H), 3.56 (s, 1H), 3.74 (d, J¼2.7 Hz, 1H),
4.08e4.17 (m, 1H), 4.34e4.36 (m, 1H), 4.43e4.76 (m, 5H), 4.86 (br s,
1H), 5.11e5.19 (m, 2H), 7.26e7.51 (m, 15H); 13C NMR (75 MHz,
D
ꢁ53.3 (c 1.2, CHCl3); IR (neat) 3445, 3031, 3029, 1696, 1454, 1430,
1093, 1069 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.69 (br d, J¼13.5 Hz,
1H), 1.94e2.04 (m, 1H), 3.32 (br d, J¼12.6 Hz, 1H), 3.68 (s, 1H), 3.72
(br d, J¼3.3 Hz, 1H), 3.79 (br s, 1H), 3.91 (dd, J¼11.4, 6.9 Hz, 2H),
4.43e4.67 (m, 5H), 5.14 (s, 2H), 7.25e7.42 (m, 15H); 13C NMR
CDCl3) d 24.6, 31.8, 34.7, 37.6, 66.6, 67.6, 71.5, 71.6, 72.3, 73.3, 127.9,
128.0, 128.1, 128.2, 128.3, 128.7, 128.8, 128.9, 129.1, 129.8, 129.9,
136.9, 137.9, 138.0, 156.2; LC/MS (ESI) m/z 540.01 [MþH]þ.
(125 MHz, CDCl3) d 25.0, 35.8, 56.0, 61.9, 67.5, 71.6, 73.8,127.8,127.9,
128.0, 128.2, 128.6, 128.7, 128.8, 129.9, 137.0, 138.0, 138.2, 158.9;
4.11. (2S,3R,4R)-Benzyl 3,4-bis(benzyloxy)-2-(chloromethyl)
piperidine-1-carboxylate (15c)
HRMS (CI) calcd for C28H31NO5 [MþH]þ 462.2280, found 462.2274.
4.8. (2R,3R,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (
omine, 1)
D
-fag-
To a stirred solution of the alcohol 14 (1.0 g, 2.17 mmol) in an-
hydrous CCl4 (10.8 mL) were added PPh3 (1.21 g, 4.60 mmol) and
pyridine (4.34 mL) at room temperature under N2. The reaction
mixture was stirred for 3 h at 75 ꢀC and quenched with H2O
(10 mL). The aqueous layer was extracted with CH2Cl2 (15 mLꢂ2).
The organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc¼8:1) to afford
To a stirred solution of 14 (0.80 g, 1.73 mmol) in EtOH (86.5 mL)
were added aqueous solution of 6 N HCl (15.3 mL) and 10% Pd/C
(0.40 g, 0.40 mmol). The reaction mixture was shaken on a Parr
apparatus under hydrogen (60
j) for 12 h. The resulting mixture
was filtered through a Celite pad and concentrated in vacuo. The
residue was purified by ion-exchange resin DOWEX-50Wꢂ8 (Hþ
form) using aqueous 0.5 M NH4OH as eluent to afford 0.24 g (95%)
0.56 g (54%) of 15c as colorless syrup. Rf¼0.20 (n-hexanes/
29
EtOAc¼8:1); [
a]
ꢁ47.0 (c 2.0, CHCl3); IR (neat) 3031, 1701, 1454,
D
of
D
-fagomine (1) as a white solid. Rf¼0.36 (CH2Cl2/MeOH/EtOH/
1424, 1213, 1092, 1069 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.67 (br d,
30%NH4Cl¼5:2:2:1); mp 184e185 ꢀC; [
a
]
D
29 þ14.9 (c 0.5, CH3OH); 1H
J¼13.8 Hz, 1H), 1.95 (br m, 1H), 3.09e3.17 (br, 1H), 3.71e3.90 (m,
4H), 4.02 (br s, 1H), 4.41 (d, J¼11.7 Hz, 1H), 4.49 (d, J¼11.7 Hz, 2H),
4.65 (br s, 2H), 5.15 (s, 2H), 7.24e7.34 (m 15H); 13C NMR (75 MHz,
NMR (300 MHz, D2O)
d
1.41 (ddt, J¼12.9, 11.4, 4.2 Hz, 1H), 1.98 (ddd,
J¼12.9, 4.8, 2.1 Hz, 1H), 2.51 (ddd, J¼13.5, 6.9, 3.3 Hz, 1H), 2.62 (dd,
J¼12.9, 2.4 Hz, 1H), 3.00 (ddd, J¼12.9, 4.5, 2.1 Hz, 1H), 3.16 (t,
J¼9.3 Hz, 1H), 3.53 (ddd, J¼14.1, 8.7, 4.8 Hz, 1H), 3.86 (dd, J¼11.7,
6.6 Hz,1H), 3.83 (dd, J¼11.1, 2.7 Hz,1H); 13C NMR (125 MHz, CD3OD)
CDCl3)
d 25.0, 29.9, 34.8, 42.2, 67.6, 67.8, 71.5, 71.6, 72.1, 73.9, 127.7,
127.9, 128.0, 128.2, 128.6, 128.7, 128.8, 128.9, 129.7, 137.0, 138.1,
138.2, 156.2; HRMS (EI) calcd for C28H30ClNO4 [M]þ 479.1863, found
479.1856.
d
34.8, 44.7, 63.3, 63.4, 75.1, 75.3; HRMS (CI) calcd for C6H13NO3
[MþH]þ 148.0974, found 148.0976.
4.12. (2R,3R,4R)-Benzyl 3,4-bis(benzyloxy)-2-
4.9. (2R,3R,4R)-2-Benzenesulfonyloxymethyl-3,4-bis-benzy-
methylpiperidine-1-carboxylate (16)
loxy-piperidine-1-carboxylic acid benzyl ester (15a)
To a stirred solution of 15c (0.56 g, 1.17 mmol) in anhydrous
toluene (11.7 mL) were added AIBN (0.04 g, 0.23 mmol) and n-
Bu3SnH (0.63 mL, 2.34 mmol) at room temperature under N2. The
reaction mixture was refluxed for 12 h and quenched with H2O
(10 mL). The aqueous layer was extracted with CH2Cl2 (15 mLꢂ2).
The organic layer was washed with 10% KF and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc¼8:1) to afford
To a stirred solution of the alcohol 14 (0.2 g, 0.433 mmol) in
anhydrous CH2Cl2 (0.7 mL) were added Et3N (0.18 mL, 1.299 mmol)
and p-toluenesulfonyl chloride (0.12 g, 0.650 mmol) at 0 ꢀC under
N2. The reaction mixture was stirred for 24 h at room temperature
and quenched with H2O (3 mL). The aqueous layer was extracted
with CH2Cl2 (5 mLꢂ2). The organic layer was washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography (n-hexanes/
EtOAc¼2:1) to afford 0.176 g (66%) of 15a as colorless syrup. Rf¼0.42
0.44
EtOAc¼8:1); [
1426, 1212, 1072 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.30 (d,
g
(81%) of 16 as colorless syrup. Rf¼0.40 (n-hexanes/
29
a
]
ꢁ54.2 (c 1.2, CHCl3); IR (neat) 3031, 1697, 1454,
D
(n-hexanes/EtOAc¼2:1); 1H NMR (300 MHz, CDCl3)
d
1.60e1.72 (m,
1H), 1.88e1.97 (m, 1H), 2.39 (s, 3H), 2.81 (br s, 1H), 3.49 (br s, 1H),
3.65 (d, J¼2.4 Hz, 1H), 3.88 (br s, 1H), 4.09e4.17 (m, 1H), 4.34e4.59
(m, 5H), 4.77 (br s, 1H), 5.12e5.14 (m, 2H), 7.22e7.39 (m, 17H),
J¼7.2 Hz, 3H), 1.69 (dd, J¼13.8, 2.4 Hz, 1H), 1.93e2.04 (m, 1H), 3.20
(dt, J¼13.2, 2.7 Hz,1H), 3.43 (s, 1H), 3.71 (d, J¼3.0 Hz,1H), 3.91 (br d,
J¼11.7 Hz, 1H), 4.41 (dd, J¼12.0, 2.7 Hz, 1H), 4.50 (d, J¼3.9 Hz, 2H),
4.55e4.63 (br m, 2H), 5.13 (s, 2H), 7.25e7.40 (m, 15H); 13C NMR
7.64e7.66 (br m, 2H); 13C NMR (75 MHz, CDCl3)
d 21.9, 67.0, 67.5,
71.4, 71.5, 82.0, 127.7, 128.0, 128.1, 128.2, 128.6, 128.7, 128.9, 130.0,
133.1, 136.9, 137.9, 138.1, 144.9, 156.0; LC/MS (ESI) m/z 616.10
[MþH]þ.
(125 MHz, CDCl3) d 15.7, 25.5, 34.2, 49.3, 67.1, 71.2, 71.3, 74.4, 76.0,
127.5,127.7,127.8,127.9,128.0,128.5,128.6,128.7,137.3,138.5,138.6,
156.1; HRMS (EI) calcd for C28H31NO4 [M]þ 445.2253, found
445.2251.
4.10. (2R,3R,4R)-3,4-Bis-benzyloxy-2-
methanesulfonyloxymethyl-piperidine-1-carboxylic acid
benzyl ester (15b)
4.13. (2R,3R,4R)-2-Methylpiperidine-3,4-diol (6-
deoxyfagomine, 5)
To a stirred solution of the alcohol 14 (0.2 g, 0.433 mmol) in
To a stirred solution of 16 (0.44 g, 0.99 mmol) in EtOH (49.5 mL)
were added aqueous solution of 6 N HCl (8.76 mL) and 10% Pd/C
(0.22 g, 0.22 mmol). The reaction mixture was shaken on a Parr
anhydrous CH2Cl2 (0.7 mL) were added Et3N (0.18 mL, 1.299 mmol)
and methanesulfonyl chloride (67 m
L, 0.866 mmol) at 0 ꢀC under N2.
The reaction mixture was stirred for 12 h at room temperature and
quenched with saturated NaHCO3 (2 mL). The aqueous layer was
apparatus under hydrogen (60
was filtered through a Celite pad and concentrated in vacuo. The
j) for 12 h. The resulting mixture

3906
I.S. Min et al. / Tetrahedron 69 (2013) 3901e3906
residue was purified by ion-exchange resin DOWEX-50Wꢂ8 (Hþ
form) using aqueous 0.5 M NH4OH as eluent to afford 0.12 g (95%) of
6-deoxyfagomine (5) as a waxy solid. Rf¼0.40 (CH2Cl2/MeOH/EtOH/
8. Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Watson, A. A.; Nash, R. J. J. Nat. Prod.
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J. Nat. Prod. 1998, 61, 397.
30%NH4Cl¼5:2:2:1); [
D2O)
a
]
D
29 ꢁ11.5 (c 1.5, CH3OH); 1H NMR (300 MHz,
10. Fan, J.-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5, 112.
11. (a) Kim, J.-Y.; Mu, Y.; Jin, X.; Park, S.-H.; Pham, V.-T.; Song, D.-K.; Lee, K.-Y.; Ham,
W.-H. Tetrahedron 2011, 67, 9426; (b) Kundu, P. K.; Ghosh, S. K. Tetrahedron:
Asymmetry 2011, 22, 1090; (c) Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi,
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d
1.20 (d, J¼6.6 Hz, 3H), 1.44 (ddt, J¼12.6, 12.0, 4.5 Hz, 1H),
2.00e2.05 (m, 1H), 2.54e2.61 (m, 1H), 2.62 (dt, J¼12.6, 2.4 Hz, 1H),
3.01 (t, J¼9.0 Hz, 2H), 3.50e3.58 (m, 1H); 13C NMR (125 MHz, D2O)
852.
12. (a) Babich, L.; van Hemert, L. J. C.; Bury, A.; Hartog, A. F.; Falcicchio, P.; van der
Oost, J.; van Herk, T.; Wever, R.; Rutjes, F. P. J. T. Green Chem. 2011, 13, 2895; (b)
Bartali, L.; Casini, A.; Guarna, A.; Occhiato, E. G.; Scarpi, D. Eur. J. Org. Chem.
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d
17.0, 32.5, 42.7, 55.5, 72.7, 77.8; HRMS (EI) Calcd for C6H13NO2
[M]þ 131.0946, found 131.0945.
Acknowledgements
ꢁ
This work was supported by the National Research Foundation
of Korea (NRF-2011-0029199 and NRF-2012-002506) funded by the
Ministry of Education, Science and Technology.
oue, T.; Sprenger, G. A.; Joglar, J.; Clapes, P. Org. Lett. 2006, 8, 6067; (f) Espelt, L.;
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Parella, T.; Bujons, J.; Solans, C.; Joglar, J.; Delgado, A.; Clapes, P. Chem.dEur. J.
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2003, 9, 4887; (g) Desire, J.; Dransfield, P. J.; Gore, P. M.; Shipman, M. Synlett
2001, 1329.
13. (a) Fu, R.; Du, Y.; Li, Z.-Y.; Xu, W.-X.; Huang, P.-Q. Tetrahedron 2009, 65, 9765; (b)
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H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60,
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.046.
14. For a review, see: (a) Kim, I. S.; Jung, Y. H. Heterocycles 2011, 83, 2489; For
recent examples, see: (b) Dong, G. R.; Hong, S.; Kim, S. I.; Kim, I. S.; Jung, Y. H.
Eur. J. Org. Chem. 2012, 4200; (c) Kim, S. J.; Jeon, T. H.; Min, I. S.; Kim, I. S.;
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Dong, G. R.; Jeong, L. S.; Jung, Y. H. J. Org. Chem. 2011, 76, 10011; (e) Kim, I. S.;
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