Asymmetric syntheses of 6-deoxyfagomin, d-deoxyrhamnojirimycin, and d-rhamnono-1,5-lactam

Article abstract of DOI:10.1016/j.tet.2009.09.083

N-Allyl protected 3-O-benzyloxglutarimide 11 was synthesized as a useful variant of the chiral building block 10. This modification allowed a high-yielding deprotection of the allyl group from the lactam intermediate 14. Starting from this building block,

Full text of DOI:10.1016/j.tet.2009.09.083

Tetrahedron 65 (2009) 9765–9771
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric syntheses of 6-deoxyfagomin,
and -rhamnono-1,5-lactam
D
-deoxyrhamnojirimycin,
D
,b,
Rui Fu a, Yu Du a, Zhao-Ying Li a, Wei-Xuan Xu a, Pei-Qiang Huang a
*
a Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, PR China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, 354 Fenglin Lu, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Allyl protected 3-O-benzyloxglutarimide 11 was synthesized as a useful variant of the chiral building
block 10. This modification allowed a high-yielding deprotection of the allyl group from the lactam in-
termediate 14. Starting from this building block, the asymmetric syntheses of aza-sugars 6-deoxy-
Received 29 July 2009
Received in revised form
13 September 2009
Accepted 18 September 2009
Available online 22 September 2009
fagomine (2),
D-rhamnono-1,5-lactam (6), as well as
D-deoxyrhamnojirimycin (5) have been achieved in
high regio- and/or diastereo-controlled manner.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aza-sugars
Asymmetric synthesis
Building block
Samarium diiodide
1. Introduction
pynaertii.6
naringinase.7 In addition,
and its enantiomer D
-deoxyrhamnojirimycin (LRJ),8b,c and
a
-Homo-
L
-rhamnojirimycin 4 is an effective inhibitor of
-deoxyrhamnojirimycin (DRJ) (5),8a,b
-rham-
D
Aza-sugars (also known as iminosugars) are polyhydroxylated
alkaloids with either five- or six-membered, mono- or bi-cyclic
structures.1 Being ‘nitrogen-in-the-ring’ analogs of pyranoses and
furanoses, many aza-sugars were found to be potent inhibitors of
carbohydrate-processing enzymes involved in important biological
systems. Consequently, they are promising for the treatment of
metabolite disorder-associated diseases such as diabetes, cancer,
AIDS, and viral infections.1 Indeed, Miglitol2 and Zavesca3 (Miglu-
stat) have been launched on market as drugs for the treatment of
Type II diabetes and Gaucher’s disease, respectively.
L
nono-1,5-lactam8b (6) have also been synthesized for biological
test. The synthesis of aza-sugars, their stereoisomers, and analogs
have attracted considerable attention, and a number of methods
have been developed.1
OH
OH
OH
OH
OH
OH
HO
OH
N
H
CH3
N
H
N
H
CH3
Fagomine4,5 (1) and 6-deoxyfagomine4 (2) (Fig. 1) are two poly-
hydroxylated piperidine alkaloids isolated from Lycium chinense
(Solanaceae) roots. Before that, the occurrence of fagomine5 and its
stereoisomers in the leaves of Xanthocercis zuinbesiaca (Legumi-
nosae) has already been reported.5a Fagomine and 3-epi-fagomine
fagomine (1)
6-deoxy-fagomine (2) 1,6-dideoxynojirimycin (3)
OH
OH
OH
HO
OH
HO
OH
HO
O
OH
HOH2C
N
H
CH3
N
H
CH3
N
H
CH3
were shown to have activities against mammalian
a-glucosidase
and
b
-galactosidase,5a and have a potent antihyperglycaemic effect
-rhamnono-
D1,5-lactam
α-homo-
L
-
D nojirimycin
-deoxyrham-
in streptozocin-induced diabetic mice and a potentiation of glu-
cose-induced insulin secretion.5b 1,6-Dideoxynojirimycin (3) was
isolated as a new sugar-mimic alkaloid from the Pods of Angylocalyx
rhamnojirimycin
(6)
(4)
(5)
Figure 1.
In continuation of our study on the development of protected
3-hydroxyglutarimide-based synthetic methodology,9 we wish to
report N-allyl protected 3-O-benzyloxyglutarimide 11 as
* Corresponding author. Fax: þ86 592 2186400.
E-mail address: pqhuang@xmu.edu.cn (P.-Q. Huang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.083

9766
R. Fu et al. / Tetrahedron 65 (2009) 9765–9771
a beneficial variant of the building block 10, and its application to
the enantioselective syntheses of 6-deoxyfagomine (2), -rham-
nono-1,5-lactam (6), and -deoxyrhamnojirimycin (5).
15, by the reaction with (Boc)2O [DMAP (cat.), TEA, CH2Cl2]. Suc-
cessive treatment of 15 with LDA (THF, ꢀ78 ꢁC) and PhSeBr produced
D
D
an a
-phenylselenide derivative,14 which, without purification, was
subjected to oxidationwith H2O2 inwet CH2Cl2 at rt to give directly 7
in 74% overall yield from compound 15 (Scheme 3). For the in-
troduction of the hydroxyl group at C-4, an epoxidation–regiose-
lective SmI2 reduction15 procedure was envisioned. Thus, in the
presence of tetrabutyl ammonium fluoride, and potassium carbon-
2. Results and discussion
The retrosynthetic analysis of 6-deoxyfagomine (2) is outlined
in Scheme 1, which featured the introduction of the hydroxyl group
ate, a,b-unsaturated mixed imide 7 was treated with tert-butyl hy-
at C-4 via the a,b-unsaturated mixed imide 7. The latter was envi-
droperoxide (TBHP) in DMF15a,16 to furnish epoxide 16 as a single
diastereomer in 92% yield. The stereochemistry of the product was
assumed to be trans with respect to OBn group on the basis of the
steric effect of the benzyloxyl group in the epoxidation,17 that was
confirmed after its transformation into the natural product 2. Re-
ductive ring-opening of the epoxide 16 with samarium diiodide15
yielded regioselectively the 4-hydroxy-2-piperidinone derivative 17
in high yield. Compound 17 was subjected successively to N-depro-
tection with TFA, lactam reduction with borane dimethyl sulfide
complex, and O-debenzylation under catalytic hydrogenolytic con-
ditions to give 6-deoxyfagomine (2) in high overall yield. The phys-
sioned to be prepared from lactam 9,10 which is available from the
known building block 10. In practicing this plan, it was observed
that the ceric ammonium nitrate (CAN)-mediated oxidative cleav-
age of the p-methoxybenzyl group (PMB) in lactam 9 produced
lactam 8 in only 60% yield. We decided to develop the N-allyl
protected11 glutarimide derivative 11 as an improved building block
for our general synthetic program.9
OBn
CH3
OH
OBn
CH3
OH
O
N
O
N
Boc
7
N
H
CH3
t-
H
8
20
20
ical {[
a
]
ꢀ10.8 (c 0.4, H2O); lit.4
[a]
ꢀ11.1 (c 0.1, H2O)} and
D
D
spectroscopic data of our synthetic compound were in agreement
with those reported for the natural product.4
6-deoxyfagomine (2)
OBn
OBn
OBn
O
OBn
CH3
LDA, THF;
PhSeBr
O
N
CH3
O
N
PMB
10
O
O
N
(Boc)2O, DMAP
PMB
9
8
O
N
t- Boc
−78 °C, 7 h;
30% H2O2, 3 h
74% (from 15)
TEA, CH2Cl2
92%
11
(2R,3S)-15
Scheme 1.
O
SmI2, THF
The building block 11 was synthesized from (S)-glutamic acid
and allylamine by the method established previously,10,12 namely,
diazodation, lactone-amide formation, ring expansion, and
O-benzylation (Scheme 2). Methyl magnesium iodide addition,
followed by boron trifluoride etherate-mediated reductive dehy-
droxylation with triethylsilane produced lactam 14 in excellent
regio- and diastereo-selectivities. The stereochemistry of the major
diastereomer 14 was tentatively assigned as trans on the basis of
the observed vicinal coupling constant (J5,6¼1.4 Hz; cf. N-PMB
protected analog: J5,6¼1.5 Hz for trans-diastereomer,10a and
J5,6¼4.6 Hz for cis-diastereomer10c), that was confirmed after final
conversion of 14 into the natural product 6-deoxyfagomine (2).
Cleavage of the lactam N-allyl group was achieved by heating 14
with rhodium trichloride hydrate, in refluxing ethanol,13 which
afforded lactam 8 in 88% yield.
OBn
OBn
CH3
t-BuOOH, K2CO3
(n-Bu)4NF, DMF
CH3OH
−78 °C
30 min
80%
O
N
t-Boc
7
CH3
O
N
92%
t-Boc
16
OH
OH
TFA
OBn
CH3
OBn
CH3
BH2 SMe2
CH2Cl2
0 °C, 1 h
87%
THF, rt, 4 h
82%
O
N
H
O
N
Boc
17
t-
18
OH
OH
OBn
CH3
OH
CH3
Pd/C, H2, EtOH
HCl, rt, 6 h
91%
N
H
19
N
H
6-deoxyfagomine (2)
1. ref. 12
2. SOCl2
H
t-BuOK, THF
Scheme 3.
(S)-Glu
O
CONH
O
(S)-12
−78 to −58 °C
3. allylNH2
93%
To further explore the possibility to use mixed imide 7 for the
synthesis of other aza-sugars such as 4, 5, and 6, the dihydroxylation
of 7 was investigated. In the presence of 1.5 molar equiv of citric acid,
63% for 3 steps
OH
1. CH3MgI, CH2Cl2
−20 °C, 4 h, 97%
OBn
Ag2O, BnBr
treatment of a,b-unsaturated lactam 7 with the co-oxidant system
OsO4 (cat.)–NMO in a mixed solvent system18 (t-BuOH/H2O,1:1) at rt
for 18 h produced the dihydroxylated product 20 as a single
diastereomer in 76% yield (Scheme 4). Stirring compound 20 with
CF3CO2H in CH2Cl2 cleaved the Boc group to give lactam 21 in 90%
yield. Hydrogenolysis of lactam 21 in the presence of 10%Pd(OH)2/C
O
N
O
O
N
O
Et2O, 2 d
95%
2. Et3SiH, F3B OEt2
CH2Cl2, −78 °C to rt
91%
13
11
OBn
CH3
OBn
CH3
RhCl3 xH2O
led to the target molecule
D-rhamnono-1,5-lactam (6) in 92% yield.
EtOH, refl., 13 h
88%
O
N
O
N
The physical and spectroscopic data of the synthetic compound
H
20
were in agreement with those of natural product {[
a
]
D
ꢀ15.6 (c 0.4,
8
20
H2O) {lit.8b
[
a]
ꢀ16.6 (c 0.27, H2O)}.
14
D
Scheme 2.
On the other hand, reduction of lactam 21 with BH3$SMe2 in
THF at rt for 4 h gave piperidine 22 in 97% yield (Scheme 5). Sub-
jection of 22 to catalytic hydrogenolytic conditions (H2, 10%Pd/C)
To introduce the carbon–carbon double bond, lactam 8 was
converted into its activated form, namely, the mixed imide (2R,3S)-
led to D-deoxyrhamnojirimycin (5) in 70% yield. The physical and

R. Fu et al. / Tetrahedron 65 (2009) 9765–9771
9767
OH
Perkin–Elmer 341 automatic polarimeter. Flash column chromato-
graphy was carried out with silica gel (300–400 mesh). THF was
distilled over sodium benzophenone ketyl under N2.
OBn
CH3
OsO4, NMO
citric acid
HO
O
OBn
CH3
O
N
t-Boc
t-BuOH/H2O
N
t-Boc
20
76%
4.2. (S)-N-Allyl-5-oxo-tetrahydro-2-furancarboxamide (12)
7
(5S,6R)-
OH
A mixture of
g-lactone-carboxylic acid (1.076 g, 8.28 mmol),
HO
OBn
CH3
10%Pd(OH)2/C
prepared from
L
-glutamic acid according to the known procedure,12
CF3COOH
and thionyl chloride (2.42 mL, 33.11 mmol) was refluxed for 5 h and
then stirred at room temperature overnight. The excess thionyl
chloride was removed under reduced pressure and the residue was
dissolved in dry CH2Cl2 (17 mL). At ꢀ20 ꢁC and under nitrogen at-
mosphere, triethylamine (1.73 mL, 12.42 mmol) and allylamine
(0.93 mL, 12.42 mmol) in CH2Cl2 (2 mL) were added successively.
After being stirred at 0 ꢁC for 3 h, water (10 mL) was added, and the
aqueous phase was extracted with CH2Cl2 (2ꢂ5 mL). The combined
organic layers were washed with brine (4 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The crude was flash chromatographed (eluent: ethyl acetate/pe-
troleum ether¼3:2) to give compound 12 (880 mg, yield, 63% from
H2, EtOH
92%
CH2Cl2
90%
Ο
N
H
21
OH
HO
OH
CH3
Ο
N
H
6
D
-rhamnono-1,5-lactam ( )
Scheme 4.
L
-glutamic acid) as white crystals. Rf 0.30 (ethyl acetate/petroleum
20
ether¼3:2); mp 50–51 ꢁC (EtOAc/PE); [
a]
ꢀ30.2 (c 1.0, CHCl3); IR
D
OH
OH
(film) nmax: 3307, 3084, 2929, 1786, 1668, 1539, 1420, 1272, 1247,
HO
OBn
HO
O
OBn
CH3
1178, 1147, 1057 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 2.33–2.24 (m,
BH2 SMe2
1H, CHCH2), 2.50 (dd, J¼8.1, 7.6 Hz, 2H, COCH2), 2.62–2.49 (m, 1H,
CHCH2), 3.91–3.76 (m, 2H, NHCH2), 4.82 (dd, J¼7.9, 6.9 Hz,1H, OCH),
5.08 (ddt, J¼10.3, 2.8,1.3 Hz,1H, ]CH2), 5.12 (ddt, J¼17.2, 2.8,1.3 Hz,
1H, ]CH2), 5.75 (ddt, J¼17.2, 10.3, 5.7 Hz, 1H, CH]), 6.77 (br s, 1H,
THF, rt
97%
N
H
CH3
N
H
22
21
OH
HO
OH
NH); 13C NMR (100 MHz, CDCl3)
d 25.6, 27.4, 41.3, 77.3, 116.6, 133.2,
H2, 10%Pd/C
169.1, 175.8; MS (ESI, m/z): 192 (MþNaþ, 100%). Anal. Calcd for
EtOH, 6N HCl
70%
N
H
CH3
C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found: C, 56.47; H, 6.50; N, 8.47.
D
-deoxyrhamnojirimycin (5)
4.3. (S)-1-Allyl-3-hydroxy-2,6-piperidinedione (13)
Scheme 5.
To a THF solution (10 mL) of compound 12 (500 mg, 2.96 mmol),
was added a cooled suspension of potassium tert-butoxide (166 mg,
1.48 mmol) in anhydrous THF (5 mL) at ꢀ78 ꢁC and under nitrogen
atmosphere. After 10 min of stirring at ꢀ78 ꢁC, the temperature
was allowed to arise to ꢀ65 ꢁC over 25 min, and then the solution
was stirred at ꢀ60 ꢁC to ꢀ58 ꢁC for 30 min. The reaction was
quenched with saturated aqueous NH4Cl (2.5 mL) at ꢀ65 ꢁC. The
residue was extracted with ethyl acetate (2ꢂ5 mL). The extracts
were washed with brine (3 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was flash chromatographed (eluent: ethyl acetate/petroleum
ether¼1:1) to give compound 13 (465 mg, yield, 93%) as white
spectroscopic data of synthetic
D
-deoxyrhamnojirimycin (5) were
20
in agreement with those reported {[
a
]
ꢀ55.2 (c 0.4, H2O); lit.19
D
20
[
a]
ꢀ52.7 (c 0.42, H2O)}.
D
3. Conclusion
To summarize, the N-allyl protected 3-O-benzyloxglutarimide
11 is an effective variant of the building block 10. Starting from this
building block, the enantioselective syntheses of the naturally oc-
curring aza-sugars 6-deoxyfagomin (2),
D-rhamnono-1,5-lactam
(6), and -deoxyrhamnojirimycin (5) were achieved. Through this
D
work we were able to demonstrate that the hydroxylation at C-4 of
the building block 11 can be achieved in high regio- and diastereo-
controlled manner. Application of this versatile building block to
the asymmetric synthesis of more complex alkaloids is currently in
progress, and will be reported in due course.
crystals. Rf 0.35 (ethyl acetate/petroleum ether¼1:1); mp 36–37 ꢁC
20
(PE/EtOAc); [
a
]
ꢀ97.1 (c 1.0, CHCl3); IR (film) nmax: 3436, 1731,
D
1677, 1418, 1375, 1334, 1236, 1176, 1131 cmꢀ1
;
1H NMR (400 MHz,
1.92 (dddd, J¼13.5, 13.0, 12.7, 4.8 Hz, 1H, CHCH2), 2.35
CDCl3)
d
(dddd, J¼13.0, 5.5, 5.4, 2.7 Hz, 1H, CHCH2), 2.66 (ddd, J¼18.0, 13.5,
5.4 Hz, 1H, COCH2), 2.91 (ddd, J¼18.0, 4.8, 2.7 Hz, 1H, COCH2), 3.61
(d, J¼1.0 Hz, 1H, OH), 4.22 (ddd, J¼12.7, 5.5, 1.0 Hz, 1H, CHOH), 4.27
(ddt, J¼14.6, 5.9, 1.3 Hz, 1H, NCH2), 4.34 (ddt, J¼14.6, 5.9, 1.3 Hz, 1H,
NCH2), 5.16 (ddt, J¼10.2, 2.6,1.3 Hz,1H, ]CH2), 5.18 (ddt, J¼17.3, 2.6,
1.3 Hz, 1H, ]CH2), 5.78 (ddt, J¼17.3, 10.2, 5.9 Hz, 1H, ]CH); 13C
4. Experimental
4.1. General
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and were uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer using
film KBr pellet techniques. 1H NMR spectra were recorded in CDCl3
on a Bruker AV 400 spectrometer with tetramethylsilane as an in-
NMR (100 MHz, CDCl3) d 25.3, 30.8, 42.4, 68.3, 118.0, 131.4, 170.8,
174.8; MS (ESI, m/z): 192 (MþNaþ, 100%). Anal. Calcd for C8H11NO3:
C, 56.80; H, 6.55; N, 8.28. Found: C, 56.63; H, 6.41; N, 8.50.
4.4. (S)-1-Allyl-3-benzyloxy-2,6-piperidinedione (11)
ternal standard. Chemical shifts are expressed in
d (ppm) units
downfield from TMS. Mass spectra were recorded by a Bruker
Dalton ESquire 3000 plus liquid chromatography–mass spectrum
(direct injection). HRMS spectra were recorded on a Shimadzu
LCMS-IT-TOF apparatus. Optical rotations were measured with
To a mixture of compound 13 (390 mg, 2.31 mmol) and silver
oxide (1.61 g, 6.92 mmol) in dry ether (13.8 mL) was added benzyl
bromide (0.83 mL, 6.92 mmol). The mixture was stirred at room
temperature for 2 days in dark. After filtration through silica gel, the

9768
R. Fu et al. / Tetrahedron 65 (2009) 9765–9771
solvent was removed under reduced pressure. Flash chromato-
graphic purification of the residue on silica gel (eluent: ethyl ace-
tate/petroleum ether¼1:8) provided compound 11 (566 mg, yield,
CH3), 1.88 (dddd, J¼13.9, 8.0, 7.0, 6.6 Hz, 1H, CH2CH), 2.08 (dddd,
J¼13.9, 7.0, 6.6, 3.0 Hz, 1H, CH2CH), 2.31 (ddd, J¼17.7, 7.0, 7.0 Hz, 1H,
COCH2), 2.54 (ddd, J¼17.7, 6.6, 6.6 Hz, 1H, COCH2), 3.37 (ddd, J¼8.0,
3.0, 1.4 Hz, 1H, BnOCH), 3.54 (qd, J¼6.5, 1.4 Hz, 1H, CHCH3), 4.51 (d,
J¼11.7 Hz, 1H, OCH2), 4.64 (d, J¼11.7 Hz, 1H, OCH2), 5.66 (br s, 1H,
95%) as a colorless oil. Rf 0.30 (ethyl acetate: petroleum ether¼1:8);
20
[
a]
ꢀ72.2 (c 1.0, CHCl3); IR (film) nmax: 3088, 3063, 3031, 2942,
D
2875, 1732, 1682, 1455, 1417, 1357, 1334, 1239, 1167, 1129, 1069,
NH), 7.20–7.40 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3)
d 20.7, 23.3,
1019 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
2.17–2.03 (m, 2H, CHCH2),
28.1, 52.5, 70.8, 76.3, 127.6, 127.8, 128.5, 137.9, 171.7; MS (ESI, m/z):
220 (MþHþ, 100%). Anal. calcd for C13H17NO2: C, 71.21; H, 7.81; N,
6.39. Found: C, 71.01; H, 7.44; N, 6.26.
2.60 (ddd, J¼17.7, 12.4, 6.1 Hz, 1H, COCH2), 2.94 (ddd, J¼17.7, 7.7,
6.4 Hz, 1H, COCH2), 4.09 (dd, J¼6.0, 5.1 Hz, 1H, BnOCH), 4.37 (dt,
J¼5.7, 1.4 Hz, 2H, NCH2), 4.68 (d, J¼11.8 Hz, 1H, CH2Ph), 4.88 (d,
J¼11.8 Hz, 1H, CH2Ph), 5.15 (ddt, J¼10.2, 2.6, 1.4 Hz, 1H, ]CH2), 5.18
(ddt, J¼17.2, 2.6,1.4 Hz,1H, ]CH2), 5.82 (ddt, J¼17.2,10.2, 5.7 Hz,1H,
4.7. tert-Butyl (2R,3S)-3-(Benzyloxy)-2-methyl-6-
oxopiperidine-1-carboxylate (15)
CH]CH2), 7.39–7.27 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3)
d 24.1,
28.9, 41.6, 72.4, 73.6, 117.3, 127.9, 128.0, 128.4, 131.8, 137.1, 171.0,
171.3; MS (ESI, m/z): 282 (MþNaþ,100%); Anal. Calcd for C15H17NO3:
C, 69.48; H, 6.61; N, 5.40. Found: C, 69.61; H, 6.65; N, 5.27.
To a cooled (0 ꢁC) solution of compound 8 (158 mg, 0.72 mmol)
and DMAP (cat.) in CH2Cl2 (2.5 mL) was added Et3N (0.30 mL,
2.2 mmol) under nitrogen atmosphere. After stirred for 10 min at
the same temperature, Boc2O (0.33 mL, 1.5 mmol) was added
dropwise. The mixture was allowed to warm to room temperature
over 15 min and stirred overnight. The resultant mixture was
quenched with saturated aqueous NH4Cl (0.5 mL), diluted with
CH2Cl2 (2 mL) and brine (1 mL). The organic layer was separated
and the aqueous phase was extracted with CH2Cl2 (3 mLꢂ3). The
combined organic layers were dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (EtOAc/PE) to give com-
4.5. (5S,6R)-1-Allyl-5-(benzyloxy)-6-methylpiperidin-2-one (14)
To
a
cooled (ꢀ20 ꢁC) solution of compound 11 (385 mg,
1.54 mmol) in CH2Cl2 (15 mL) was added dropwise a solution of
MeMgI in Et2O (2 M, 2.3 mL, 4.6 mmol). The mixture was stirred for
4 h at ꢀ20 ꢁC. The reaction was quenched with saturated aqueous
NH4Cl (5 mL). After extraction with ethyl acetate (2ꢂ10 mL), the
combined organic layers were washed with brine (4 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
(eluent: ethyl acetate/petroleum ether¼2:1) to yield the N,O-acetal
as a diastereomeric mixture (390 mg, yield, 97%), which is used in
the next step without further separation. To a cooled (ꢀ78 ꢁC) so-
lution of the diastereomeric mixture of N,O-acetal (210 mg,
0.76 mmol) in CH2Cl2 (6 mL) were added dropwise Et3SiH (1.2 mL,
7.6 mmol) and BF3$OEt2 (0.3 mL, 2.3 mmol) successively. The mix-
ture was stirred at ꢀ78 ꢁC for 4 h, then allowed to warm up slowly,
and stirred at room temperature overnight. To the resultant mixture
was added a half saturated aqueous NaHCO3 (6 mL). The aqueous
layer was separated and extracted with CH2Cl2 (2ꢂ10 mL). The
combined organic layers were washed with brine (4 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
pound 15 (210 mg, yield: 92%) as a white solid. Mp 43–45 ꢁC (PE/
20
CH2Cl2); [
a
]
D
ꢀ6.3 (c 0.98, CHCl3); IR (film) nmax: 2934, 2836, 1673,
1621, 1462, 1095 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.22 (d,
J¼6.7 Hz, 3H, CH3), 1.52 (s, 9H, t-Bu-H), 2.02–1.99 (m, 2H,
BnOCHCH2), 2.42 (dd, J¼17.6, 4.8, 4.8 Hz, 1H, COCH2), 2.73 (ddd,
J¼17.6, 8.8, 8.7 Hz,1H, COCH2), 3.59–3.61 (m,1H, BnOCH), 4.51–4.46
(m, 1H, CH3CH), 4.57 (s, 2H, OCH2Ph), 7.36–7.26 (m, 5H, ArH); 13C
NMR (100 MHz, CDCl3) d 21.7, 28.0, 29.8, 54.7, 70.1, 74.3, 82.8, 127.5,
127.8, 128.5, 137.5, 152.3, 170.9; MS (ESI, m/z): 320 (MþHþ, 100%);
Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.61;
H, 8.24; N, 4.41.
4.8. tert-Butyl (5S,6R)-5-(benzyloxy)-6-methyl-2-oxo-5,6-
dihydropyridine-1(2H)-carboxylate (7)
(eluent: ethyl acetate/petroleum ether¼4:3) to yield compound 14
To a solution of 15 (200 mg, 0.63 mmol) in THF (1.5 mL) was
added slowly a solution of freshly prepared 2 mL of a THF solution
of LDA (0.45 M, 0.90 mmol) at ꢀ78 ꢁC, and the mixture was stirred
at this temperature for 1.5 h. To the resultant mixture was added
slowly a solution of PhSeBr (190 mg, 0.82 mmol) in THF (1.5 mL),
and the solution was stirred at ꢀ78 ꢁC for 7 h. The reaction mixture
was poured into 20 mL of saturated aqueous NaHCO3 and extracted
with EtOAc (10 mLꢂ3). The combined organic layers were washed
successively with water (5 mLꢂ2) and brine (5 mLꢂ2), dried over
Na2SO4, filtered, and concentrated in vacuum. To the residue was
added successively CH2Cl2 (5 mL), water (0.1 mL), and a solution of
30% aqueous H2O2 (0.05 mmol). After being stirred for 1 h, the
mixture was treated with another portion of 30% aqueous H2O2
(0.05 mmol) and stirred for 2 h. The reaction was quenched with
water. The organic phase was separated, and the aqueous layer was
extracted with CH2Cl2 (5 mLꢂ3). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated in
20
(180 mg, yield, 91%) as a colorless oil. [
a
]
þ77.3 (c 1.3, CHCl3); IR
D
(film) nmax: 3428, 2973, 2941, 2872, 1634, 1472, 1454, 1413, 1358,
1273, 1094, 1073 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.17 (d,
J¼6.7 Hz, CH3), 2.08–1.95 (m, 2H, CH2CH), 2.35 (ddd, J¼18.1, 5.6,
3.5 Hz, 1H, COCH2), 2.63 (ddd, J¼18.1, 10.2, 8.2 Hz, 1H, COCH2), 3.49
(ddt, J¼15.6, 6.6, 1.5 Hz, 1H, NCH2), 3.56 (ddd, J¼3.1, 2.9, 2.4 Hz, 1H,
BnOCH), 3.65 (qd, J¼6.7, 2.4 Hz, 1H, CHCH3), 4.54 (ddt, J¼15.6, 4.5,
1.5 Hz, 1H, NCH2), 4.54 (d, J¼11.8 Hz, 1H, CH2Ph), 4.58 (d, J¼11.8 Hz,
1H, CH2Ph), 5.14 (ddt, J¼10.3, 3.0, 1.5 Hz, 1H, C]CH2), 5.23 (ddt,
J¼17.1, 3.0, 1.5 Hz, 1H, C]CH2), 5.77 (dddd, J¼17.1, 10.3, 6.6, 4.5 Hz,
1H, CH]), 7.36–7.24 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3)
d 18.7,
21.2, 27.1, 47.2, 55.1, 70.0, 75.1, 116.7, 127.3, 127.6, 128.3, 133.3, 138.1,
169.1; MS (ESI, m/z): 282 (MþNaþ,100%); Anal. Calcd for C16H21NO2:
C, 74.10; H, 8.16; N, 5.40. Found: C, 73.92; H, 8.42; N, 5.43.
4.6. (5S,6R)-5-(Benzyloxy)-6-methylpiperidin-2-one (8)
vacuum. The residue was purified by column chromatography on
20
RhCl3$xH2O (217 mg, 0.4 mmol) was added to a solution of
compound 14 (2.087 g, 8.09 mmol) in EtOH (16 mL). The suspension
was heated to reflux for 13 h. After cooling to room temperature, the
reaction mixture was concentrated and purified by column
silica gel (EtOAc/PE) to give compound 7 as a colorless oil. [a]
D
þ143.5 (c 1.1, CHCl3); IR (film) nmax: 2969, 1766, 1715, 1400, 1365,
1299, 1248, 1159, 1062 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.22 (d,
J¼6.9 Hz, 3H, CH3), 1.55 (s, 9H, t-Bu), 3.79 (dd, J¼5.8, 1.6 Hz,
1H, BnOCH), 4.57 (d, J¼11.9 Hz, 1H, PhCH2), 4.64 (d, J¼11.9 Hz, 1H,
PhCH2), 4.71 (qt, J¼6.9, 1.6 Hz, 1H, BocNCH), 6.11 (d, J¼9.7 Hz,
1H, COCH]), 6.62 (ddd, J¼9.7, 5.8, 1.6 Hz, 1H, COCH]CH), 7.28–7.41
chromatography on silica gel (eluent: EtOAc/petroleum ether 4:1) to
20
give compound 8 (1.553 g, yield: 88%) as a wax solid. [
a
]
ꢀ49.3
D
(c 0.9, CHCl3); IR (film) nmax: 3206, 3063, 2924, 1668, 1496, 1454,
1410, 1094 cmꢀ1; 1H NMR (400 MHz, CDCl3)
1.22 (d, J¼6.5 Hz, 1H,
d
(m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3)
d 18.6, 28.0, 53.3, 70.8,

R. Fu et al. / Tetrahedron 65 (2009) 9765–9771
9769
71.8, 83.1, 127.8, 128.0, 128.6, 128.9, 137.1, 137.5, 152.3, 162.0; MS
(ESI, m/z): 340.1 (MþNaþ, 100%); HRMS calcd for C18H23NO4Na
[MþNaþ]: 340.1525; found: 340.1533.
þ4.1 (c 0.9, CHCl3); IR (film) nmax: 3381, 3202, 2875,1676,1400,1104,
1027 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.28 (d, J¼6.2 Hz, 1H, CH3),
2.43 (dd, J¼17.3, 9.6 Hz, 1H, COCH2), 2.78 (dd, J¼17.3, 6.0 Hz, 1H,
COCH2), 3.21 (t, J¼8.3 Hz, 1H, BnOCH), 3.26 (s, OH, D2O exchange-
able), 3.30–3.39 (m, 1H, NHCH), 3.92–4.02 (m, 1H, HOCH), 4.75 (d,
J¼11.2 Hz,1H, PhCH2), 4.82 (d, J¼11.2 Hz,1H, PhCH2), 6.68 (s, NH, D2O
exchangeable), 7.28–7.48 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3)
4.9. tert-Butyl (1S,4R,5R,6S)-5-(benzyloxy)-4-methyl-2-oxo-7-
oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (16)
To a solution of compound 7 (80 mg, 0.252 mmol) in DMF
(2.5 mL) under nitrogen atmosphere were added K2CO3 (34.8 mg,
0.252 mmol) and t-BuOOH (5.5 M solution in nonane, 0.10 mL,
0.56 mmol). After stirring at ambient temperature for 30 min,
a 1.0 M THF solution of Bu4NF was added in small portions until the
reaction was completed (as indicated by TLC monitoring). The re-
action was quenched with a saturated ammonium chloride solution
and diluted with Et2O (8 mL) and water (25 mL). The layers were
separated and the water layer extracted with Et2O (10ꢂ3 mL). The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (el-
d 19.5, 37.9, 50.5, 68.7, 74.9, 84.0, 128.0, 128.1, 128.6, 137.6, 170.7; MS
(ESI, m/z): 258.1 (MþNaþ,100%); Anal. Calcd for C13H17NO3: C, 66.36;
H, 7.28; N, 5.95. Found: C, 66.72; H, 7.03; N, 5.74.
4.12. (2R,3R,4R)-3-(Benzyloxy)-2-methylpiperidin-4-ol (19)
To a solution of 18 (47 mg, 0.2 mol) in dry THF (2 mL) BH3$SMe2
(0.076 mL, 0.8 mmol) was added at 0 ꢁC and the mixture was stirred
under nitrogen for 4 h at room temperature. The reaction was
quenched by cautiously adding methanol until gas evolution
stopped. Additional methanol was added and the solvents were
evaporated. The residue was dissolved in methanol and 6 M HCl
was added to the solution, the mixture was refluxed for 5 min to
destroy the borane–amine complex. After cooling, the solution was
evaporated and the pH was adjusted to 11–12 with NH3$H2O. The
solution was evaporated and residue purified by flash column
uent: EtOAc/petroleum ether¼1:5) to give compound 16 (77 mg,
20
92%) as a white solid. Mp 63–64 ꢁC (PE/EtOAc); [
a]
þ35.3 (c 1.2,
D
CHCl3); IR (film) nmax: 2969, 2922, 1766, 1723, 1373, 1287, 1248,
1147 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.31 (d, J¼7.1 Hz, 3H, CH3),
1.52 (s, 9H, t-Bu), 3.57–3.61 (m, 2H, BnOCHCH, BnOCH), 3.97–4.01
(m, 1H, COCH), 4.48–4.54 (m, 1H, BocNCH), 4.56 (d, J¼12.1 Hz, 1H,
chromatograph on silica gel (eluent: CH2Cl2/CH3OH¼10:1) to afford
20
compound 19 (26 mg, 82%) as a wax solid. [
a
]
þ24.6 (c 1.0,
D
PhCH2), 4.72 (d, J¼12.1 Hz, 1H, PhCH2), 7.28–7.43 (m, 5H, Ph-H); 13
C
CH3OH); IR (film) nmax: 3346, 2918, 1595, 1381, 1093, 1027 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
NMR (100 MHz, CDCl3)
d
19.4, 27.9, 51.9, 52.8, 54.7, 71.8, 74.4, 83.6,
d
1.25 (d, J¼6.3 Hz, 3H, CH3), 1.52 (ddt,
127.7, 128.2, 128.6, 137.1, 152.1, 167.5; MS (ESI, m/z): 355.9 (MþNaþ,
100%); Anal. Calcd for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found:
C, 64.91; H, 6.98; N, 4.15.
J¼12.6, 11.8, 4.6 Hz, 1H, NHCH2CH2), 1.92 (2H, OH, NH, D2O ex-
changeable), 1.97 (ddt, J¼12.6, 4.8, 2.4 Hz, 1H, NHCH2CH2), 2.59 (m,
1H, NHCH), 2.64 (ddd, J¼12.2, 4.6, 2.4 Hz, 1H, NHCH2), 2.87 (t,
J¼8.8 Hz, 1H, BnOCH), 2.99 (ddd, J¼12.2, 4.6, 2.4 Hz, 1H, NHCH2),
3.56 (ddd, J¼11.8, 8.8, 4.8 Hz, 1H, HOCH), 4.70 (d, J¼11.3 Hz, 1H,
4.10. tert-Butyl (2R,3R,4R)-3-(benzyloxy)-4-hydroxy-2-
methyl-6-oxopiperidine-1-carboxylate (17)
PhCH2), 4.79 (d, J¼11.3 Hz, 1H, PhCH2), 7.20–7.40 (m, 5H, Ph-H); 13
C
NMR (100 MHz, CDCl3) d 19.1, 33.9, 44.0, 55.9, 73.6, 75.2, 88.4, 127.9
Epoxide 16 (91 mg, 0.273 mmol) in a mixed solvent of THF
(0.6 mL) and MeOH (0.3 mL) was added dropwise under argon to
a stirring solution of SmI2 (0.1 M in THF, 6.8 mL, 0.683 mmol) at
ꢀ78 ꢁC. After being stirred about 0.5 h at ꢀ78 ꢁC, a saturated
aqueous solution of K2CO3 was added. The mixture was allowed to
reach room temperature and was extracted with EtOAc. The com-
bined organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent: EtOAc/
(2C), 128.6, 138.4; MS (ESI, m/z): 222.1 (MþHþ, 100%); HRMS calcd
for C13H20NO2 [MþHþ]: 222.1494; found: 222.1499.
4.13. (2R,3R,4R)-2-Methylpiperidine-3,4-diol (2)
0.1 mL of 6 N HCl was added to a mixture of compound 19
(26 mg), 10% Pd/C (78 mg), and EtOH (9.8 mL). The suspension was
stirred under a hydrogen atmosphere for 6 h. The resultant mixture
was filtered through a short pad of Celite. The filter cake was
washed several times with EtOH and then concentrated under re-
duced pressure. The residue was dissolved in water and passed
through a column of ion-exchange resin (Dowex-8ꢂ100, OH form)
and eluted with water. The eluent was concentrated under reduced
pressure to give 6-deoxyfagomine (2) (14 mg, 91%) as a wax solid.
petroleum ether¼1:1) to give compounds 17 (73 mg, 80%) as
20
a colorless oil. [
a
]
D
ꢀ63.6 (c 1.0, CHCl3); IR (film) nmax: 3447, 2976,
2918, 1766, 1727, 1459, 1369, 1291, 1248, 1147 cmꢀ1
(400 MHz, CDCl3)
;
1H NMR
d
1.38 (d, J¼7.0 Hz, 3H, CH3), 1.52 (s, 9H, t-Bu),
2.39 (d, J¼3.4 Hz, OH, D2O exchangeable), 2.51 (dd, J¼16.9, 9.1 Hz,
1H, COCH2), 2.87 (dd, J¼16.9, 5.2 Hz, 1H, COCH2), 3.47 (dd, J¼6.0,
3.1 Hz,1H, BnOCH), 4.05–4.14 (m,1H, HOCH), 4.35 (qd, J¼7.0, 3.1 Hz,
1H, BocNCH), 4.63 (d, J¼11.7 Hz, 1H, PhCH2), 4.72 (d, J¼11.7 Hz, 1H,
20
20
[a
]
ꢀ10.8 (c 0.4, H2O) {lit. [
a
]
20–11.1 (c 0.1, H2O);4
[
a]
D
þ9.6
D
D
(c 0.41, H2O)19}; IR (film) nmax: 3346, 2918 cmꢀ1; 1H NMR (400 MHz,
D2O)
d
1.12 (d, J¼6.4 Hz, 1H, CH3), 1.42 (ddt, J¼12.8, 11.5, 4.5 Hz, 1H,
PhCH2), 7.27–7.42 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3)
d
20.6,
NHCH2CH2), 1.94 (ddt, J¼12.8, 5.0, 2.5 Hz, 1H, NHCH2CH2), 2.44 (m,
1H, NHCH), 2.55 (td, J¼12.8, 2.5 Hz, 1H, NHCH2), 2.89 (ddd, J¼12.8,
4.5, 2.5 Hz, 1H, NHCH2), 2.92 (dd, J¼9.4, 9.0 Hz, 1H, NHCHCHOH),
3.46 (ddd, J¼11.5, 9.0, 5.0 Hz, 1H, NHCH2CH2CHOH); 13C NMR
27.9, 39.7, 54.8, 68.4, 72.4, 82.5, 83.4, 127.8, 128.1, 128.6, 137.5, 152.2,
169.2; MS (ESI, m/z): 358.2 (MþNaþ, 100%); HRMS calcd for
C18H25NO5Na [MþNaþ]: 358.1630; found: 358.1633.
(100 MHz, D2O)
d 19.9, 35.6, 45.2, 58.0, 75.6, 80.8; MS (ESI, m/z):
4.11. (4R,5R,6R)-5-(Benzyloxy)-4-hydroxy-6-methylpiperidin-
2-one (18)
132.1 (MþHþ, 100%); HRMS calcd for C6H14NO2 [MþHþ]: 132.1025;
found: 132.1025.
Trifluoroacetic acid (0.83 mL) was added dropwise to a solution
of compound 17 (72 mg, 0.215 mmol) in CH2Cl2 (7.2 mL) at 0 ꢁC. The
mixture was stirred for 10 min and then warmed to room temper-
ature. After 1 h, the reaction mixture was concentrated under re-
duced pressure. The product was purified by flash column
4.14. tert-Butyl (2R,3R,4R,5S)-3-(benzyloxy)-4,5-dihydroxy-2-
methyl-6-oxopiperidine-1-carboxylate (20)
A solution of OsO4 (0.03 M, 0.8 mL) in water was added to a so-
lution of compound 7 (78 mg, 0.25 mmol) and NMO (86 mg,
0.74 mmol) in t-BuOH (2.5 mL) at room temperature. After stirred
for 20 h, the reaction was quenched by adding an excess of solid
chromatography on silica gel (eluent: EtOAc) to afford compound 18
20
(44 mg, yield: 87%) as a white solid. Mp 125–127 ꢁC (EtOAc); [
a]
D

9770
R. Fu et al. / Tetrahedron 65 (2009) 9765–9771
Na2SO3. The solvents were removed under reduced pressure until
the reaction color began to turn gray. The resultant mixture was
diluted with MeOH and filtered. The solid was washed successively
with CH2Cl2 and MeOH for three times. The residue was purified by
was evaporated and the pH was adjusted to 11–12 with NH3$H2O.
The solution was evaporated and the residue purified by flash
column chromatograph on silica gel (eluent: CH2Cl2/CH3OH¼20:3)
to afford piperidine derivative 22 (59.8 mg, 97%) as a wax solid.
20
chromatography on silica gel (EtOAc/PE) to give compound 20 as
[a
]
þ2.3 (c 1.1, CH3OH); IR (film) nmax: 3323, 2920 cmꢀ1; 1H NMR
D
20
a colorless oil. [
a
]
D
ꢀ33.8 (c 0.8, CHCl3); IR (film) nmax: 3416, 2944,
(400 MHz, CD3OD)
d
1.33 (d, J¼6.5 Hz, 3H, CH3), 2.99 (dq, J¼9.4,
2837, 1666, 1630, 1465, 1361, 1255, 1105 cmꢀ1
CDCl3)
;
1H NMR (500 MHz,
6.5 Hz, 1H, H-6), 3.07 (dd, J¼13.3, 1.0 Hz, 1H, H-2), 3.21 (dd, J¼13.3,
3.3 Hz, 1H, H-2), 3.57 (t, J¼9.4 Hz, 1H, H-5), 3.72 (dd, J¼9.4, 3.0 Hz,
1H, H-4), 4.05–4.11 (m, 1H, H-3), 4.67 (d, J¼11.2 Hz,1H, PhCH2), 4.95
(d, J¼11.2 Hz, 1H, PhCH2), 7.25–7.42 (m, 5H, Ph-H); 13C NMR
d
1.26 (br, 1H, OH), 1.28 (d, J¼7.0 Hz, 3H, CH3), 1.54 (s, 9H,
t-Bu), 1.70–1.65 (br, 1H, OH), 2.94–2.88 (m, 1H, BnOCH), 3.88 (d,
J¼4.9 Hz, 1H, BnOCHCHOH), 4.19 (dq, J¼13.8, 7.0 Hz, 1H, NCH),
4.42–4.41 (m,1H, BocNCOCH), 4.71 (s, 2H, CH2Ph), 7.37–7.27 (m, 5H,
(100 MHz, CD3OD)
d 16.2, 49.9, 56.0, 68.6, 74.9, 76.1, 80.4, 128.8,
ArH); 13C NMR (125 MHz, CDCl3)
d
17.3, 28.0, 55.9, 71.2, 72.2, 77.7,
129.3 (2C), 139.6; MS (ESI, m/z): 238 (MþHþ, 100%). HRMS calcd for
83.5, 127.3 (2C), 128.6, 137.0, 149.7, 171.9; MS (ESI, m/z): 352 (MþHþ,
100%); HRMS calcd for C18H26NO6 [MþHþ]: 352.1760; found:
352.1765. HRMS calcd for C13H17NNaO4 [MþNaþ]: 274.1055; found:
274.1043.
C13H20NO3 [MþHþ]: 238.1443; found: 238.1435.
4.18. (2R,3R,4R,5R)-2-Methylpiperidine-3,4,5-triol (5)
0.2 mL of 6 N HCl was added to a mixture of compound 22
(52.5 mg, 0.22 mmol), 10% Pd/C (45 mg), and EtOH (4 mL).
The suspension was stirred under a hydrogen atmosphere for 15 h.
The resultant mixture was filtered through a short pad of Celite. The
filter cake was washed with EtOH for several times and the filtrate
was concentrated under reduced pressure. The residue was dis-
solved in water and passed through a column of ion-exchange resin
(Dowex-8ꢂ100, OH form) eluting with water. The eluent was
4.15. (3S,4R,5R,6R)-5-(Benzyloxy)-3,4-dihydroxy-6-
methylpiperidin-2-one (21)
Trifluoroacetic acid (1.1 mL) was added dropwise to a solution
of compound 20 (387 mg, 1.1 mmol) in CH2Cl2 (11 mL) at 0 ꢁC.
After stirring at 0 ꢁC for 30 min, the reaction mixture was con-
centrated under reduced pressure. The residue was purified by
flash column chromatograph on silica gel (eluent: CH2Cl2/
concentrated under reduced pressure to give D-deoxyrhamnojir-
CH3OH¼20:1) to afford lactam 21 (250 mg, 90%) as a white solid.
20
imycin (5) (22.8 mg, 70%) as a wax solid. [
a
]
D
ꢀ55.2 (c 0.4, H2O)
20
Mp 131–133 ꢁC (CH2Cl2/CH3OH); [
a
]
D
þ103.2 (c 0.92, CHCl3); IR
20
{lit.19
[a]
ꢀ52.7 (c 0.42, H2O)}; IR (film) nmax: 3354, 2926 cmꢀ1; 1H
D
(film) nmax: 3280, 2884, 1680 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CD3OD)
d
1.19 (d, J¼6.4 Hz, 3H, CH3), 2.38 (dq,
d
1.31 (d, J¼6.1 Hz, 1H, CH3), 3.37–3.47 (m, 3H, OH, D2O ex-
J¼9.4, 6.4 Hz, 1H, H-2), 2.69 (dd, J¼14.0, 1.5 Hz, 1H, H-6), 2.92 (dd,
J¼14.0, 2.7 Hz, 1H, H-6), 3.23 (dd, J¼9.4, 9.4 Hz, 1H, H-3), 3.35 (dd,
J¼9.4, 3.2 Hz, 1H, H-4), 3.84–3.87 (m, 1H, H-5); 13C NMR (100 MHz,
changeable, H-5, H-6), 4.28–4.35 (m, 2H, H-3, H-4), 4.40 (br s, 1H,
OH, D2O exchangeable), 4.55 (d, J¼11.5 Hz, 1H, PhCH2), 4.75 (d,
J¼11.5 Hz, 1H, PhCH2), 6.65 (br s, 1H, CONH, D2O exchangeable),
CD3OD)
d 18.3, 50.6, 57.3, 70.9, 75.8, 76.4; MS (ESI, m/z): 148
7.27–7.42 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3)
d 19.0, 49.4,
(MþHþ, 100%). HRMS calcd for C6H13NNaO3 [MþNaþ]: 170.0793;
68.5, 71.6, 71.9, 82.7, 128.0 (2C), 128.5, 137.3, 172.5; MS (ESI, m/z):
274 (MþNaþ, 100%). HRMS calcd for C13H17NNaO4 [M+Na+]:
274.1055; found: 274.1043.
found: 170.0785.
Acknowledgements
4.16. (3S,4S,5R,6R)-3,4,5-Trihydroxy-6-methylpiperidin-
2-one (6)
The authors are grateful to the NSFC (20832005) and NFFTBS
(No. J0630429) for financial support.
To a suspension of 10% Pd(OH)2/C (14 mg) in EtOH (1 mL) was
added a solution of compound 21 (22 mg, 0.09 mmol) in EtOH
(2 mL). The resultant suspension was stirred under a hydrogen at-
mosphere for 12 h. The resultant mixture was filtered, washed
several times with EtOH, and then concentrated under reduced
References and notes
1. For reviews on aza-sugars, see: (a) Compain, P.; Martin, O. R. Iminosugars:
From Synthesis to Therapeutic Applications; Wiley-VCH: New York, NY, 2007;
(b) Elbein, A. D.; Molyneux, R. J. In Iminosugars as Glycosidase Inhibitors;
Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999; p 216; (c) Watson,
A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry
2001, 56, 265–295; (d) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (e) Wrodnigg, T. M. Mon-
atsh. Chem. 2002, 133, 393–426; (f) El-Ashry, E.-S. H.; El Nemr, A. Carbo-
hydr. Res. 2003, 338, 2265–2290; (g) Afarinkia, K.; Bahar, A. Tetrahedron:
Asymmetry 2005, 7, 1239–1287.
pressure to give
D-rhamnono-1,5-lactam (6) (12.9 mg, 92%) as
20
a white solid. Mp 165–166 ꢁC; {lit.8b 164–166 ꢁC}; [
a
]
ꢀ15.6 (c 0.4,
D
20
H2O) {lit.8b
1665 cmꢀ1
[a
]
ꢀ16.6 (c 0.27, H2O)}; IR (film) nmax: 3299, 2915,
D
;
1H NMR (400 MHz, D2O)
d
1.35 (d, J¼6.6 Hz, 1H, CH3),
3.36 (qd, J¼6.6, 7.7 Hz, 1H, H-6), 3.61 (dd, J¼7.7, 5.7 Hz, 1H, H-5),
4.04 (dd, J¼5.7, 4.2 Hz, 1H, H-4), 4.37 (d, J¼4.2 Hz, 1H, H-3); 13C
2. Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605–611.
NMR (100 MHz, D2O)
d 19.0, 52.1, 69.6, 73.8, 74.4, 174.1; MS (ESI,
3. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683–4696; (b)
Platt, F. M.; Neises, G. R.; Dwek, R. A.; Butters, T. D. J. Biol. Chem. 1994, 269,
8362–8365.
4. Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tomimori, T.; Matsui, K.; Nash, R. J.;
Molyneux, R. J. Eur. J. Biochem. 1997, 248, 296–303.
5. For isolation of fagomine from other sources, see: (a) Kato, A.; Asano, N.;
Kizu, H.; Matsui, K.; Watson, A. A.; Nash, R. J. J. Nat. Prod. 1997, 60, 312–314;
(b) Nojima, H.; Kimura, I.; Chen, F.-J.; Sugihara, Y.; Haruno, M.; Kato, A.;
Asano, N. J. Nat. Prod. 1998, 61, 397–400; (c) Taniguchi, S.; Asano, N.; Tomino,
F.; Miwa, I. Horm. Metab. Res. 1998, 30, 679–683. For selected enantiose-
lective synthesis of fagomine, see: (d) Fleet, G. W. J.; Smith, P. W. Tetrahedron
Lett. 1985, 26, 1469–1472; (e) Fleet, G. W. J.; Witty, D. R. Tetrahedron:
Asymmetry 1990, 1, 119–136; (f) Effenberger, F.; Null, V. Liebigs Ann. Chem.
1992, 1211–1212; (g) Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.;
Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817–819; (h) Yokoyama, H.;
Ejiri, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Tetrahedron: Asymmetry 2007,
18, 852–856.
m/z): 184 (MþNaþ, 100%). HRMS calcd for C6H11NNaO4 [MþNaþ]:
184.0586; found: 184.0574.
4.17. (3R,4R,5R,6R)-5-(Benzyloxy)-6-methylpiperidine-3,4-
diol (22)
To a solution of lactam 21 (65.2 mg, 0.26 mol) in dry THF
(2.6 mL) was added BH3$SMe2 (0.2 mL, 1.04 mmol) at 0 ꢁC. After
stirring under nitrogen and at room temperature for 4 h, the re-
action was quenched by cautiously adding methanol until gas
evolution ceased. Additional methanol was added and the solvents
were evaporated. The residue was dissolved in methanol and 6 N
HCl was added to the solution. The mixture was refluxed for 5 min
to destroy the borane–amine complex. After cooling, the solution
6. Yasuda, K.; Kizu, H.; Yamashita, T.; Kameda, Y.; Kato, A.; Nash, R. J.; Fleet, G. W.
J.; Molyneux, R. J.; Asano, N. J. Nat. Prod. 2002, 65, 198–202.

R. Fu et al. / Tetrahedron 65 (2009) 9765–9771
9771
7. Shilvock, J. P.; Wheatley, J. R.; Davis, B.; Nash, R. J.; Griffiths, R. C.; Jones, M. G.;
Muller, M.; Crook, S.; Watkin, D. J.; Smith, C.; Besra, G. S.; Brennan, P. J.; Fleet, G.
W. J. Tetrahedron Lett. 1996, 37, 8569–8572.
8. (a) Winchester, B. G.; Cenci di Bello, I.; Richardson, A. C.; Nash, R. J.; Fellows, L.
E.; Ramsden, N. G.; Fleet, G. W. J. Biochem. J. 1990, 269, 227–231; (b) Fairbanks,
A. J.; Carpenter, N. C.; Fleet, G. W. J.; Ramsden, N. G.; de Bello, I. C.; Winchester,
B. G.; Al-Dahe, S. S.; Nagahashi, G. Tetrahedron 1992, 48, 3365–3376; (c) Zhou,
P.-Z.; Salleh, H. M.; Chan, P. C. M.; Lajoie, G.; Honek, J. F.; Nambiar, P. T. C.; Ward,
O. P. Carbohydr. Res. 1993, 239, 155–166.
9. For an account, see: (a) Huang, P.-Q. Synlett 2006, 1133–1149; For recent
examples, see: (b) Wei, B.-G.; Chen, J.; Huang, P.-Q. Tetrahedron 2006, 62,
190–198; (c) Huang, P.-Q.; Guo, Z.-Q.; Ruan, Y.-P. Org. Lett. 2006, 8, 1435–
1438; (d) Wei, B.-G.; Chen, J.; Lin, G.-J.; Huang, P.-Q. Xiamen Daxue Xuebao,
Ziran Kexueban 2006, 45, 670–672 (in Chinese).
12. Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.; Huang, P.-Q. Chi-
rality 2005, 17, 595–599.
13. Zacuto, M. J.; Xu, F. J. Org. Chem. 2007, 72, 6298–6300.
14. Clive, D. L. J. Tetrahedron 1978, 34, 1049–1132.
15. (a) Panday, S. K.; Langlois, N. Synth. Commun. 1997, 27, 1373–1384; (b) Molander,
G. A.; Hahn, G. J. Org. Chem. 1986, 51, 2596–2599.
16. (a) Herdeis, C.; Aschenbrenner, A.; Kirfel, A.; Schwabenlander, F. Tetrahedron:
Asymmetry 1997, 8, 2421–2432; (b) Langlois, N.; Rakotondradany, F. Tetrahedron
2000, 56, 2437–2448; (c) Herdeis, C.; Hubmanm, H. P. Tetrahedron: Asymmetry
1994, 5, 119–128; (d) Yadav, V. K.; Kapoor, K. K. Tetrahedron 1995, 51,
8573–8584.
17. (a) Miyashita, K.; Park, M.; Adachi, S.; Seki, S.; Obika, S.; Imanishi, T. Bioorg. Med.
Chem. Lett. 2002, 12, 1075–1077; (b) Ouchi, H.; Mihara, Y.; Takahata, H. J. Org.
Chem. 2005, 70, 5207–5214.
10. (a) Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69, 6001–
6009; (b) Yu, D.-S.; Xu, W.-X.; Liu, L.-X.; Huang, P.-Q. Synlett 2008, 1189–1192;
(c) Liu, L.-X.; Xiao, K.-J.; Huang, P.-Q. Tetrahedron 2009, 65, 3834–3841.
11. Luo, J.-M.; Dai, C.-F.; Lin, S.-Y.; Huang, P.-Q. Chem. Asian J. 2009, 4, 328–335.
18. Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org. Lett. 2004, 6, 4045–4048
and references cited therein.
19. Sujiyama, M.; Hong, Z.-Y.; Liang, P.-H.; Dean, S. M.; Whalen, L. J.; Greenberg, W.
A.; Wong, C.-H. J. Am. Chem. Soc. 2007, 129, 14811–14817.