Efficient and stereodivergent synthesis of deoxyimino sugars

Article abstract of DOI:10.1016/j.carres.2005.08.014

Both cis- and trans-2-substituted-1,2,3,6-tetrahydro-pyridin-3-ols have been prepared via an aldol condensation-ring-closing metathesis sequence. A stereodivergent synthesis of optionally functionalized deoxyimino sugars was achieved via asymmetric dihydroxylation or epoxidation/nucleophilic substitution of these tetrahydropyridines.

Full text of DOI:10.1016/j.carres.2005.08.014

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2457–2468
Efficient and stereodivergent synthesis of deoxyimino sugars
Bor-Cherng Hong,a,* Zhong-Yi Chen,a Arumugam Nagarajan,a Rudresha Kottani,a
Vishal Chavan,a Wei-Hung Chen,a Yea-Fen Jiang,a Shuo-Cang Zhang,a
Ju-Hsiou Liaoa and Sepehr Sarsharb
aDepartment of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, ROC
bAuspex Pharmaceuticals, Inc., 1261 Liberty Way, Suite C, Vista, CA 92081-8356, USA
Received 6 May 2005; accepted 25 August 2005
Available online 5 October 2005
Abstract—Both cis- and trans-2-substituted-1,2,3,6-tetrahydro-pyridin-3-ols have been prepared via an aldol condensation–ring-
closing metathesis sequence. A stereodivergent synthesis of optionally functionalized deoxyimino sugars was achieved via asymmet-
ric dihydroxylation or epoxidation/nucleophilic substitution of these tetrahydropyridines.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Imino sugar; Metathesis; Asymmetric dihydroxylation; Stereodivergent
1. Introduction
metathesis sequence6 to the synthesis of deoxyimino
sugars.
Deoxyimino sugarsꢀ are common structural subunits of
a wide variety of naturally occurring alkaloids including
the piperidine alkaloids.1 It has been demonstrated that
polyhydroxylated piperidine alkaloids can mimic enzy-
matic substrates,2 and can act as transition-state analogs
for various enzymes that bind and process glycopro-
teins.3 These compounds are known to possess a broad
range of pharmacological properties,4 and as such, syn-
thetic and medicinal chemists have often incorporated
these structural motifs into the design of novel biologi-
cally active compounds. It is therefore desirable to de-
vise stereodivergent and expedient synthetic strategies
that provide access to novel derivatives of these deoxyi-
mino sugars.5 This manuscript describes the extension of
our previously reported aldol condensation–ring-closing
2. Results and discussion
cis- and trans-2-Substituted-1,2,3,6-tetrahydro-pyridin-
3-ols were prepared via an aldol condensation–ring-
closing metathesis (RCM) sequence (Scheme 1). In our
hands, acetonides 7 and 8 were ideal intermediates that
could be rapidly functionalized to various deoxyimino
sugars. These compounds were prepared in ca. 45%
overall yield (1:1 ratio) from ester 17 (aldol condensation
with acrolein, LAH reduction, acetonide formation, and
RCM, Scheme 1). The structure of 7 was assigned
unambiguously by its single-crystal X-ray analysis
(Fig. 1). In addition, reaction of ester 3 with Grubbsꢁ
catalyst afforded the diastereomeric tetrahydropyridines
9 and 10 in 84% yield. The tosyl group of 7 was removed
by Red-Al [sodium bis(2-methoxyethoxy)aluminum
hydride] to give amine 11 in 84% yield.
*
Corresponding author. Tel.: +886 52428174; fax: +886 52721040;
e-mail: chebch@ccu.edu.tw
Dihydroxylation of trans-acetonide 7 (OsO4, NMO)
afforded diols 12 and 13 in 77% and 12% yield, respec-
tively. Dihydroxylation of cis-acetonide 8 gave exclu-
sively diol 14 in 83% yield (Scheme 2). Asymmetric
ꢀ Imino sugars are sometimes referred to as ꢂazasugarsꢁ, a term that
does not conform to IUPAC rules of nomenclature. See
www.chem.qmw.ac.uk/iupac/2carb/, Rule 2-Carb-34.1.
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.08.014

2458
B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
Ts
N
Ts
N
Ts
N
R
N
b
c
CO2Et
OH
CO2Et
OH
CO2Et
OH
CO2Et
+
1 R = H
a
2 R = Ts
10
9
3
d
Ts
N
Ts
N
Ts
N
O
e
OH
OH
O
+
Me
Me
Me
O
O
Me
6
4
5
f
87%
f
90%
Ts
N
Ts
N
H
N
g
O
O
O
O
Me
Me
Me
O
O
Me
Me
Me
7
8
11
Scheme 1. Preparation of acetonides 7 and 8. Reagents and conditions: (a) TsCl, Et3N, DMAP, CH2CI2; 89%. (b) (1) LDA, THF; (2) Acrolein,
THF; 87%. (c) Ru(IV), CH2Cl2; 84%. (d) LiAlH4, THF, 87%. (e) (CH3)2C(OMe)2, p-TsOH, C6H6; 55% (for 5), 36% (for 6). (f) Ru(IV), CH2Cl2.
(g) Red-AI, THF; 84%.
uously assigned by the single-crystal X-ray analysis of its
diacetonide derivative (+)-19, prepared from (+)-13
with (CH3)2C(OMe)2 and p-TsOH; 88% yield (Fig. 2).
Isofagomine and siastatin B are potent and structur-
ally complex inhibitors of the liver glycogen phosphory-
lase (GP)13 and b-glucuronidase14 enzymes, which are
two important biological targets for the treatment of
type-2 diabetes. Surprisingly, very little is known of
the structure–activity relationships of these inhibitors.15
One of the goals of this project was to devise an efficient
synthesis of the epoxides of 7, which could then serve as
key intermediates in the preparation of novel analogs of
Figure 1. ORTEP view of the single-crystal X-ray diffraction structure
of trans-2,2-dimethyl-5-(toluene-4-sulfonyl)-4a,5,6,8a-tetrahydro-4H-
[1,3]dioxino[5,4-b]pyridine (7) with atomic numbering. Thermal ellip-
rane or MCPBA would lead to the two isomeric
soids are drawn at the 30% probability level.
isofagomine and siastatin B. After much experimenta-
tion, we found that the reaction of 7 with either dioxi-
epoxides 21 and 22. Nucleophilic ring opening of the
epoxides 21 and 22, with KCN, Bu4NI, and Ti(O-i-
Pr)4 in DMSO, gave 23 and 28, respectively. Reduction
dihydroxylation of trans-acetonide 7 with the Hsung–
Vedejs AD-mix b8 gave (+)-13 and (ꢀ)-12 in 42% and
35% yield (Scheme 3). The tosyl groups and acetonides
were subsequently removed by Red-Al and HCl–MeOH
to give 1,5-dideoxy-1,5-imino-D-allitol (+)-179 and 1,5-
dideoxy-1,5-imino-D-mannitol (+)-18.10
Similarly, reaction of trans-acetonide 7 with the
Hsung–Vedejs AD-mix a afforded acetonides (ꢀ)-13
and (+)-12 (50% and 40% yield, respectively). The tosyl
groups and acetonide groups were subsequently re-
moved with Red-Al and HCl–MeOH to give (ꢀ)-1811
and (ꢀ)-17.12 The structure of diol (+)-13 was unambig-
of nitrile 23 with various reducing agents (e.g., LiAlH4,
DIBAL-H, NaBH4, etc.) afforded complex mixtures.
The use of BH3ÆMe2S in THF at reflux afforded the pri-
mary amine and concomitantly reduced the acetonide to
isopropyl ethers 24 and 25, which were deprotected with
BBr3 in CH2Cl2 at 0 ꢁC to afford aminotriol 26. Subse-
quent Birch reduction of the tosyl protecting group of
26 afforded 5-aminomethyl-2-hydroxymethylpiperidine-
3,4-diol (27). Compound 32 was prepared in a similar
way from nitrile 28 (Scheme 4).
In summary, an efficient and stereodivergent synthesis
of deoxyimino sugars has been achieved via an aldol–

B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
2459
Ts
N
Ts
N
Ts
N
O
O
O
a
Me
Me
+
H
N
Me
Me
HO
O
HO
O
Me
Me
O
O
OH
OH
Me
Me
Me
HO
O
7
12
13
OH
15
b
Ts
N
Ts
N
O
O
a
Me
HO
O
O
Me
Me
OH
8
14
Scheme 2. Dihydroxylation of acetonides 7 and 8. Reagents and conditions: (a) OsO4, NMO/THF–t-BuOH–H2O = 1:3:0.5; 77% (for 12), 12% (for
13); 83% (for 14). (b) Red-Al, THF, reflux; 83%.
(CH3)2C(OMe)2, TsOH; 88%
Ts
N
H
N
Ts
N
H
N
HCl
O
O
OH
OH
MeOH
Red-Al
O
Me
Me
Me
Me
Me
Me
HO
O
O
HO
83%
O
reflux, 10 h
48%
HO
O
O
OH
OH
Me
OH
Me
(+)-19
Ts
N
(+)-17
(+)-16
Hsung−Vedejs
AD-mix-β
42% (+)-13
O
Me
Me
+
O
28h
H
Ts
N
H
N
Ts
N
N
7
O
HCl
OH
OH
Me
OH
OH
Red-Al
MeOH
O
Me
HO
O
HO
Me
HO
reflux, 8 h
52%
90%
HO
O
OH
OH
OH
Me
OH
97%
(-)-15
(+)-18
(+)-20
HCl
(-)-12
35%
MeOH
HCl
MeOH
Ts
N
Ts
N
H
N
H
N
97%
HCl
OH
OH
OH
OH
O
O
Red-Al
MeOH
Me
Me
Me
HO
HO
HO
O
HO
O
reflux, 20 h
37%
89%
HO
(-)-20
Me
OH
OH
OH
(-)-18
(+)-15
(+)-12
40%
Ts
N
Hsung−Vedejs
AD-mix-α
+
O
Me
Me
O
36 h
Ts
N
H
N
H
N
HCl
O
OH
OH
7
MeOH
O
Me
Me
Red-Al
Me
Me
HO
O
HO
HO
O
78%
reflux, 20 h
48%
OH
OH
(-)-17
OH
(-)-16
(-)-13
50%
Hsung−Vedejs AD-mix-α :
alkene:K3Fe(CN)6:K2CO3:MeSO2NH2:(DHQ)2PHAL:OsO4
1:3 :3:2:0.1:0.05
Hsung−Vedejs AD-mix-β :
alkene:K3Fe(CN)6:K2CO3:MeSO2NH2:(DHQP)2PHAL:OsO4 = 1:3
:3 :2:0.1:0.05
=
Scheme 3. Asymmetric dihydroxylation of acetonide 7.
RCM sequence. This protocol provides
approach to polyfunctionalized imino sugars. Further
a
rapid
synthetic applications of this methodology are under
active investigation in our laboratories.

2460
B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
graphy. The HPLC instrument was equipped with ultra-
violet and refractive index detectors. The sample was
analyzed and/or separated on a Spherisorb-Si column
˚
(25 cm · 10 mm, particle size 8 lm, pore size 60 A) or
a l-Porasil column (25 cm · 1.0 cm) using a flow rate
of 5 mL/min and ultraviolet and refractive index detec-
tors (EtOAc and hexane eluants). The flow rate of the
indicated elution solvent was maintained at 5 or 1 mL/
min, and the retention time of a compound is recorded
accordingly. Melting points are uncorrected. Most com-
pounds were characterized by full spectroscopic (1H,
13C, DEPT, HMQC, COSY, NOESY, LRMS, and
Figure 2. ORTEP view of the single-crystal X-ray diffraction structure
of 1,5-deoxy-1,5-imino-2,3:4,6-di-O-isopropylidene-D-allitol [(+)-19]
with atomic numbering. Thermal ellipsoids are drawing on the 30%
probability level.
1
HRMS) data. H NMR, COSY, and NOESY spectra
were obtained in CDCl3 unless otherwise noted at
400 MHz (Bruker DPX-400) or 500 MHz (Varian Unity
INOVA-500). 13C NMRspectra, HMBC, HMQC, and
DEPT experiments were obtained at 100 or 125 MHz.
Mass spectra were recorded on a Finnigan/Thermo
Quest MAT 95XL, or on a VG 70-250S GC–MS or
Micromass TRIO-2000 GC–MS spectrometer in the
electron impact mode. X-ray crystallographic analyses
were performed on a Bruker AXS SMART APEX
CCD X-ray diffractometer with graphite-monochro-
mated Mo Ka radiation. Alpha values were recorded
on a JASCO DIP-1000 digital polarimeter with a Na–
Hg lamp and a Na 589-nm filter.
3. Experimental
3.1. General
All solvents were of reagent grade. All chemicals were
purchased from Aldrich Chemical Co. Reactions were
normally carried out under argon atmosphere in
flame-dried glassware. E. Merck Silica Gel 60 (particle
size 0.04–0.063 mm) was employed for flash chromato-
Ts
N
O
Me
O
Me
7
e
a or b
Ts
N
Ts
N
Me
Me
Ts OH
N
Ts
N
Ts
N
H
N
OH
OH
OH
OH
O
OH
Me
Me
O
O
f
Me
Me
Me
d
c
O
NC
O
+
+
O
NH3 OH
Cl
NH3 OH
O
Me
NH3 OH
Cl
NH3 OH
Cl
OH
Cl
21
23
26
24
25
27
32 %
15 %
46 %
+
Ts
N
Me
Me
Ts OH
N
Ts
N
H
N
Ts
N
OH
OH
Ts
N
O
OH
Me
Me
OH
OH
f
O
c
O
O
+
d
+
Me
Me
Me
NH3 OH
Cl
NH3 OH
Cl
NH3 OH
Cl
NH3 OH
Cl
O
NC
O
O
Me
OH
32
31
29
48 %
30
trace
22
28
43 %
e
Scheme 4. Epoxidation and nucleophilic reactions of 7. Reagents and conditions: (a) (1) 1.4 · 104 M Na2EDTA (aq), CF3COCH3, CH3CN, 0 ꢁC; (2)
NaHCO3, Oxone, 0 ꢁC; 45% (for 21), 37% (for 22). (b) MCPBA, CH2Cl2; 43% (for 21), 36% (for 22). (c) KCN, Bu4NI, Ti(O-i-Pr)4, DMSO, rt; 86%
(for 23), 82% (for 28). (d) (1) BH3ÆSMe2, THF, reflux, 2 h; (2) 6 M HCl in MeOH. (e) (1) BBr3, CH2Cl2, 0 ꢁC, 1.5 h; (2) H2O; 80% (for 26), 78% (for
31). (f) Na/NH3, THF, ꢀ78 ꢁC; 83% (for 27), 87% (for 32).

B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
2461
3.2. Single-crystal X-ray structural analyses
14.4 g, 73%). Lit. 88–89 ꢁC, 30 mmHg,16 90 ꢁC,
25 mmHg,17 67 ꢁC, 20 mmHg, 75–78 ꢁC,18 15 mmHg,19
77–80 ꢁC, 15 mmHg,20 47 ꢁC, 3 mmHg.21 1H NMR
(CDCl3, 400 MHz): d 5.85–5.75 (m, 1H), 5.16–5.03 (m,
2H), 4.12 (q, J 7.2 Hz, 2H), 3.33 (s, 2H), 3.21–3.19 (m,
2H), 1.77 (br s, 1H), 1.21 (t, J 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d 173.02 (C), 136.68 (CH), 117.15
(CH2), 61.31 (CH2), 52.41 (CH2), 50.57 (CH2), 14.81
(CH3). HREIMS: Calcd for C7H13NO2 (M+): m/z
143.0946. Found: m/z 143.0946.
The crystal data and a summary of experimental details
for 7 and 19 are given in Table 1. Data collections were
performed on a Bruker AXS SMART APEX CCD X-
ray diffractometer, with graphite-monochromated Mo
˚
Ka radiation (k = 0.71073 A) in the /–x scan mode.
The structures were solved by
a direct method
(SHELXL-97), and were refined with full-matrix least-
squares on F2. All the non-hydrogen atoms were refined
with anisotropic thermal parameters. All the hydrogen
atoms, calculated at idealized positions, were included
in structure factor calculations but were not refined.
The Flack parameter of 19 was in accordance with the
expected absolute structure.
3.4. Ethyl allyl(toluene-4-sulfonyl)aminoacetate (2)
To a solution of 1 (140 mg, 1.0 mmol) and DMAP
(61 mg, 0.5 mmol) in 9:1 CH2Cl2–Et3N (10 mL) was
added 4-toluenesulfonyl chloride (228 mg, 1.2 mmol).
The resulting solution was stirred at ambient tempera-
ture for 3 h. The solution was diluted with CH2Cl2
(40 mL), washed with H2O (20 mL · 2), dried over
Na2SO4, and concentrated in vacuo. The crude residue
was purified by flash column chromatography with 4:1
EtOAc–hexane (Rf 0.45 in 4:1 EtOAc–hexane) to give
3.3. Ethyl allylaminoacetate (1)
Under an atmosphere of argon, allylamine (15.2 g,
0.27 mmol) was placed in a flask containing Et2O
(20 mL), and the resulting solution was cooled to 0 ꢁC.
Ethyl bromoacetate (23.4 g, 0.14 mmol) was added over
30 min. The solution was allowed to warm to 25 ꢁC and
was stirred at that temperature for 22 h. The mixture
was filtered, and the supernatant was concentrated in
vacuo. The residue was distilled under reduced pressure
to give 1 as a colorless liquid (40–42 ꢁC, 2 mmHg,
1
2 as a colorless liquid (264 mg, 89% yield). H NMR
(CDCl3, 400 MHz): d 7.67 (d, J 8.0 Hz, 2H), 7.23 (d, J
8.0 Hz, 2H), 5.58–5.64 (m, 1H), 5.13 (s, 1H), 5.10 (d, J
7.5 Hz, 1H), 4.01 (q, J 7.5 Hz, 2H), 3.94 (s, 2H), 3.83
(d, J 6.5 Hz, 2H), 2.35 (s, 3H), 1.13 (t, J 7.5 Hz, 3H);
Table 1. Crystal data and structure refinement for 7 and 19
7
19
Molecular formula
C
323.4
298
Orthorhombic
Pbca
16H21NO4S
C19H27NO6S
397.48
298
Monoclinic
Cc
Molecular weight (g molꢀ1
Temperature (K)
Crystal system
)
Space group
˚
a (A)
20.924(2)
7.9873(10)
23.365(3)
90.0
3904.9(8)
8
1.100
0.180
1376
15.742(3)
10.8070(19)
11.583(2)
97.583(3)
1953.2(6)
4
1.352
0.201
848
˚
b (A)
˚
c (A)
b (ꢁ)
3
˚
V (A )
Z (molecules per cell)
Dcalcd (g cmꢀ3
)
Absorption coefficient (mmꢀ1
F(000)
)
Crystal size (mm)
h Range for data collection (ꢁ)
Index ranges
0.23 · 0.16 · 0.12
1.74–28.29
ꢀ27 5 h 5 25
ꢀ10 5 k 5 9
ꢀ31 5 l 5 25
22,970
0.53 · 0.42 · 0.35
2.29–23.32
ꢀ17 5 h 5 15
ꢀ11 5 k 5 12
ꢀ12 5 l 5 12
4083
Reflections collected
Independent reflections
Reflections with [I P 2r(I)]
Function minimizeda
Data/restraints/parameters
Goodness-of-fit on F2
4759
3106
0.1321, 0.0000
4759/0/202
1.070
2340
2277
0.0532, 0.1807
2340/2/250
1.046
Final R/wR indices [I P 2r(I)]
R/wR Indices (all data)
Largest difference peak and hole (e A
0.0658/0.1982
0.0936/0.2154
0.488/ꢀ0.189
0.0308/0.0773
0.0317/0.0780
0.158/ꢀ0.221
ꢀ3
˚
)
a P
2
wðF 20 ꢀ F c2Þ , w ¼ 1=½r2ðF 02Þ þ x2 þ yPꢁ, where P ¼ ðF 02 þ 2F 2c Þ=3.

2462
B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
13C NMR(CDCl , 125 MHz): d 168.73 (C), 143.35 (C),
(CH2), 117.84 (CH2), 117.42* (CH2), 116.73 (CH2),
73.71 (CH), 71.43* (CH), 64.10* (CH), 63.10 (CH),
61.32 (CH2), 60.72* (CH2), 48.60 (CH2), 48.33* (CH2),
21.38 (CH3 and *CH3); HREIMS: Calcd for
C15H21NO4S (M+): m/z 311.1191. Found: m/z 311.1193.
3
136.73 (C), 132.15 (CH), 129.44 (two CH), 127.24 (two
CH), 119.69 (CH2), 61.08 (CH2), 50.60 (CH2), 46.85
(CH2), 21.40 (CH3), 13.90 (CH3); HREIMS: Calcd for
C14H19NO4S (M+): m/z 297.1035. Found: m/z 297.1034.
3.5. Ethyl 2-[Allyl(toluene-4-sulfonyl)amino]-3-hydroxy-
pent-4-enoate (3)
3.7. trans- and cis-N-Allyl-N-(2,2-dimethyl-4-vinyl-
[1,3]dioxan-5-yl)-4-methylbenzenesulfonamide (5) and (6)
Under an atmosphere of argon, lithium diisopropyla-
mide (2.0 M solution in THF–n-heptane, 0.22 mL,
0.44 mmol) was added to dry THF (20 mL) at ꢀ78 ꢁC.
After stirring for 5 min, a solution of 2 (100 mg,
0.34 mmol) in THF (4 mL) was added, and the solution
was stirred at ꢀ78 ꢁC for 10 min. Acrolein (0.03 mL,
0.36 mmol) was added into the reaction mixture. The
reaction was completed in ꢂ15 min and was quenched
with EtOH (2 mL) and allowed to warm to room tem-
perature. The solution was diluted with EtOAc
(30 mL), washed with H2O (20 mL · 2), dried over
Na2SO4, and concentrated in vacuo. The crude residue
was purified by flash column chromatography with 4:1
EtOAc–hexane (Rf 0.32 in 3:7 EtOAc–hexane) to give
To a solution of 4 (310 mg, 1.00 mmol) in dry benzene
(20 mL) was added 2,2-dimethoxypropane (0.37 mL,
3.00 mmol). The resulting solution was stirred for
5 min at ambient temperature, p-TsOH (38 mg,
0.20 mmol) was added, and stirring was maintained at
ambient temperature and for ꢂ1.5 h. The reaction was
quenched with aq NaHCO3 (15 mL), diluted with
EtOAc (50 mL), washed with brine (50 mL), dried over
Na2SO4, and concentrated in vacuo. The crude residue
was purified by flash column chromatography with
5:95 EtOAc–hexane (5: Rf 0.56 in 1:4 EtOAc–hexane;
6: Rf 0.54 in 1:4 EtOAc–hexane) to give 5 (193 mg,
55% yield) as a colorless oil and 6 (126 mg, 36% yield)
1
as a colorless oil. For 5: H NMR(CDCl , 400 MHz):
3
3 as a colorless liquid (105 mg, 87% as two isomers in
d 7.62–7.75 (m, 2H), 7.21–7.27 (m, 2H), 5.70–5.82 (m,
1H), 5.59–5.68 (m, 1H), 5.10–5.32 (m, 4H), 4.40–4.50
(m, 1H), 3.75–3.86 (m, 3H), 3.56–3.68 (m, 2H), 2.39
1
a 4:3 ratio). H NMR(CDCl , 400 MHz): d 7.69–7.64
3
(m, 2H), 7.24–7.18 (m, 2H), 5.95–5.72 (m, 2H), 5.35–
5.02 (m, 4H), 4.57–4.35 (m, 2H), 4.07–3.76 (m, 4H),
(s, 3H), 1.41 (s, 3H), 1.33 (s, 3H); 13C NMR(CDCl ,
3
2.35 (s, 3H), 1.03 (t, J 7.2 Hz, 3H); 13C NMR(CDCl ,
100 MHz): d 143.52 (C), 137.61 (C), 135.39 (CH),
135.07 (CH), 129.68 (CH), 129.43 (CH), 127.34
(CH), 127.23 (CH), 118.53 (CH2), 118.01 (CH2), 99.18
(C), 70.63 (CH), 61.38 (CH2), 57.66 (CH), 49.02
(CH2), 27.42 (CH3), 21.46 (CH3), 20.66 (CH3); HRE-
IMS: Calcd for C18H26NO4S (M++1): m/z 352.1583.
3
100 MHz, for the major isomer): d 170.17 (C), 143.51
(C), 137.13 (C), 136.25 (CH), 134.30 (CH), 129.38 (two
CH), 129.36 (two CH), 118.52 (CH2), 117.99 (CH2),
71.83 (CH), 63.26 (CH), 61.50 (CH2), 49.81 (CH2),
21.47 (CH3), 13.74 (CH3); HREIMS: Calcd for
C17H23NO5S (M+): m/z 353.1297. Found: m/z 353.1297.
Found: m/z 352.1586.
1
For 6: H NMR(CDCl , 400 MHz): d 7.66–7.68 (m,
3
3.6. N-Allyl-N-(2-hydroxy-1-hydroxymethyl-but-3-enyl)-
4-methylbenzenesulfonamide (4)
2H), 7.24–7.30 (m, 2H), 5.94–6.03 (m, 1H), 5.62–5.71
(m, 1H), 5.20–5.31 (m, 2H), 5.06–5.12 (m, 2H), 4.56–
4.59 (m, 1H), 4.29–4.31 (m, 2H), 4.08 (dd, J 12.8,
4.2 Hz, 1H), 3.79–3.82 (m, 1H), 3.66 (dd, J 12.8,
2.1 Hz, 1H), 2.41 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H);
13C NMR(CDCl 3, 100 MHz): d 143.56 (C), 138.62
(C), 136.39 (CH), 134.77 (CH), 129.87 (two CH),
127.75 (two CH), 117.13 (CH2), 117.04 (CH2), 99.60
(C), 72.28 (CH), 63.72 (CH2), 52.87 (CH), 49.77
(CH2), 29.13 (CH3), 21.86 (CH3), 19.44 (CH3); HRE-
IMS: Calcd for C18H26NO4S (M++1): m/z 352.1583.
Found: m/z 352.1581.
To a solution of 3 (200 mg, 0.56 mmol) in THF (15 mL)
was added LiAlH4 (64 mg, 1.68 mmol). The resulting
mixture was stirred at ambient temperature for 15 min
and then quenched with H2O (10 mL). The solution
was diluted with EtOAc (50 mL · 2), washed with brine
(50 mL), dried over Na2SO4, and concentrated in vacuo.
The crude residue was purified by flash column chroma-
tography with 7:3 EtOAc–hexane (Rf 0.28 in 1:1
EtOAc–hexane) to give 4 as a colorless liquid (152 mg,
1
87% yield). H NMR(CDCl , 400 MHz): d 7.69–7.75
3
(m, 2H), 7.26–7.31 (m, 2H), 5.72–5.86 (m, 2H), 5.05–
5.30 (m, 5H), 4.24–4.32 (m, 1H), 3.92–3.98 (m, 2H),
3.71–3.83 (m, 3H), 3.08 (br s, 1H), 2.40 (s, 3H); 13C
3.8. trans-2,2-Dimethyl-5-(toluene-4-sulfonyl)-4a,5,6,8a-
tetrahydro-4H-[1,3]dioxino[5,4-b]pyridine (7)
NMR(CDCl , 100 MHz, 2:1 isomeric forms, * denotes
To a solution of 5 (90 mg, 0.26 mmol) in CH2Cl2
(10 mL) was added bis(tricyclohexylphosphine)benzyli-
dine ruthenium(IV) chloride (Grubbꢁs catalyst) (10 mg,
0.01 mmol), and the resulting mixture was stirred at
ambient temperature for 24 h. The solution was concen-
3
minor isomer): d 143.47* (C), 143.44 (C), 137.98 (CH),
137.55* (CH), 137.38 (C), 137.36* (C), 135.43 (CH),
135.39* (CH), 129.56 (two CH), 129.48* (two
CH), 127.44 (two CH), 127.26* (two CH), 117.96*

B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
2463
1
trated in vacuo, and the crude residue was purified by
flash column chromatography with 1:1 EtOAc–hexane
(Rf 0.40 in 15:85 EtOAc–hexane) to give the product
For 10: Rt (1:4 EtOAc–hexane) 11.5 min; H NMR
(CDCl3, 400 MHz): d 7.63–7.70 (m, 2H), 7.23–7.28 (m,
2H), 5.73–5.76 (m, 1H), 5.61–5.66 (m, 1H), 4.92 (d, J
6.1 Hz, 1H), 4.44–4.46 (m, 1H), 3.92–4.04 (m, 2H),
3.80–3.88 (m, 1H), 3.60–3.66 (m, 1H), 2.39 (s, 3H),
1
as a white solid (73 mg, 87% yield); mp 68–70 ꢁC; H
NMR(CDCl , 400 MHz): d 7.62–7.66 (m, 2H), 7.30–
3
7.32 (m, 2H), 5.59–5.68 (m, 2H), 4.31–4.38 (m, 3H),
4.11–4.17 (m, 1H), 3.42–3.48 (m, 1H), 2.65–2.69 (m,
1H), 2.41 (s, 3H), 1.47 (s, 3H), 1.35 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 143.98 (C), 134.65 (C), 129.94
(two CH), 127.67 (CH), 127.43 (two CH), 123.79
(CH), 98.95 (C), 68.69 (CH), 63.19 (CH2), 55.78 (CH),
48.00 (CH2), 29.27 (CH3), 21.49 (CH3), 18.81 (CH3);
HREIMS: Calcd for C16H21NO4S (M+): m/z 323.1191.
Found: m/z 323.1191.
1.00 (t, J 7.1 Hz, 3H) ; 13C NMR(CDCl , 100 MHz):
3
d 170.04 (C), 143.65 (C), 136.05 (C), 129.61 (CH),
129.54 (two CH), 127.23 (two CH), 123.28 (CH), 66.27
(CH), 61.51 (CH2), 55.96 (CH), 42.33 (CH2), 21.44
(CH3), 13.71 (CH3); HREIMS: Calcd for C15H19NO5S
(M+): m/z 325.0984. Found: m/z 325.0959.
3.11. 2,2-Dimethyl-4a,5,6,8a-tetrahydro-4H-[1,3]diox-
ino[5,4-b]pyridine (11)
3.9. cis-2,2-Dimethyl-5-(toluene-4-sulfonyl)-4a,5,6,8a-tetra-
hydro-4H-[1,3]dioxino[5,4-b]pyridine (8)
To a solution of 7 (100 mg, 0.31 mmol) in THF (5 mL)
was added Red-Al (sodium bis(2-methoxyethoxy)alumi-
num hydride, 70% in toluene, 1.1 mL, 3.72 mmol). The
resulting solution was heated at reflux for 8 h. The reac-
tion was cooled to 0 ꢁC and quenched by slow addition
of 15% NaOH (5 mL), diluted with EtOAc (50 mL · 2),
washed with brine (50 mL), dried over Na2SO4, and
concentrated in vacuo. The crude residue was purified
by flash column chromatography with pure 99:1
EtOAc–Et3N (Rf 0.15 in EtOAc) to give 11 as a colorless
liquid (44 mg, 84%). 1H NMR(acetone- d6, 400 MHz): d
5.80–5.58 (m, 2H), 4.18–4.10 (m, 1H), 3.71–3.78 (m,
1H), 3.65 (dd, J 10.8, 13.5 Hz, 1H), 3.45–3.32 (m, 1H),
3.30–3.18 (m, 1H), 2.75–2.47 (m, 2H), 1.47 (s, 3H),
1.32 (s, 3H); 13C NMR(acetone- d6, 100 MHz): d
129.04 (CH), 128.57 (CH), 99.60 (C), 70.41 (CH),
64.84 (CH2), 55.33 (CH), 46.06 (CH2), 29.98 (CH3),
19.45 (CH3); HREIMS: Calcd for C9H15NO2 (M+): m/
z 169.1103. Found: m/z 169.1107.
Prepared from 6 according to procedure 3.8. Colorless
oil: 90% yield, Rf 0.38 in 15:85 EtOAc–hexane. 1H
NMR(CDCl , 400 MHz): d 7.70–7.73 (m, 2H), 7.28–
3
7.31 (m, 2H), 5.85–5.89 (m, 1H), 5.73–5.77 (m, 1H),
4.26–4.36 (m, 2H), 4.03–4.09 (m, 1H), 3.85 (t, J
10.2 Hz, 1H), 3.55–3.68 (m, 2H), 2.42 (s, 3H), 1.41 (s,
3H), 1.34 (s, 3H); 13C NMR(CDCl 3, 100 MHz): d
143.71 (C), 136.91 (C), 129.86 (two CH), 127.65 (CH),
126.93 (two CH), 123.01 (CH), 98.40 (C), 65.77
(CH), 57.27 (CH2), 46.73 (CH), 40.80 (CH2), 29.63
(CH3), 23.55 (CH3), 21.45 (CH3); HREIMS: Calcd
for C16H21NO4S (M+): m/z 323.1191. Found: m/z
323.1191.
3.10. Ethyl trans- and cis-3-hydroxy-1-(toluene-4-sulfon-
yl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9) and (10)
To a solution of 3 (90 mg, 0.25 mmol) in CH2Cl2
(10 mL) was added bis(tricyclohexylphosphine)benzyli-
dine ruthenium(IV) chloride (Grubbꢁs catalyst) (10 mg,
0.01 mmol), and the resulting mixture was stirred at
ambient temperature for 24 h. The solution was concen-
trated in vacuo, and the crude residue was purified by
flash column chromatography with 1:1 EtOAc–hexane
(Rf 0.49 in 1:1 EtOAc–hexane) to give the product as a
colorless liquid (68 mg, 84% yield as two isomers in a
2:1 ratio). The diastereomers were separated by HPLC.
For 9: Rt (1:4 EtOAc–hexane) 13.4 min; 1H NMR
(CDCl3, 400 MHz): d 7.65–7.70 (m, 2H), 7.23–7.25 (m,
2H), 5.81–5.91 (m, 2H), 4.82 (d, J 2.0 Hz, 1H), 4.46–
4.47 (m, 1H), 4.03–4.08 (m, 1H), 3.90–3.98 (m, 1H),
3.78–3.86 (m, 2H), 2.52 (br s, 1H), 2.35 (s, 3H), 1.02
(t, J 7.1 Hz, 3H); 13C NMR(CDCl 3, 100 MHz): d
168.08 (C), 143.49 (C), 135.73 (C), 129.36 (two CH),
127.70 (CH), 127.33 (two CH), 124.51 (CH), 64.47
(CH), 61.20 (CH2), 60.67 (CH), 42.31 (CH2), 21.35
(CH3), 13.68 (CH3); HREIMS: Calcd for C15H19NO5S
(M+): m/z 325.0984. Found: m/z 325.0961.
3.12. 2,2-Dimethyl-5-(toluene-4-sulfonyl)-hexahydro-
[1,3]dioxino[5,4-b]pyridine-7,8-diol (12) and (13)
To a solution of 7 (40 mg, 0.12 mmol) in THF–t-BuOH–
H2O (1:3:0.5 mL) was added N-methylmorpholine N-
oxide (NMO, 17 mg, 0.14 mmol), and the solution was
stirred for 5 min at ambient temperature. OsO4
(0.1 mL, 2.5 wt % in t-BuOH) was added, and stirring
was maintained at ambient temperature for ca. 18 h.
The reaction was quenched by the addition of sodium-
hydrosulfite (0.2 g), Florisil (2.0 g), and H2O (5 mL).
The mixture was stirred for 30 min, washed with acetone
(100 mL), filtered through filter paper, and extracted
with EtOAc (50 mL · 2). The combined organic layers
were washed with brine (30 mL), dried over Na2SO4,
and concentrated in vacuo. The residue was purified
by flash column chromatography with 4:1 EtOAc–hex-
ane (12: Rf 0.21; 13: Rf 0.30 in 4:1 EtOAc–n-hexane)
to give 12 (33 mg; 77% yield) as a white solid and 13
(5 mg; 12% yield) as a white solid. For 12: mp 198–
200 ꢁC; 1H NMR(CDCl 3, 400 MHz): d 7.61 (d, J

2464
B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
8.2 Hz, 2H), 7.32 (d, J 8.1 Hz, 2H), 4.29 (dd, J 12.0,
4.8 Hz, 1H), 4.21 (dd, J 10.3, 1.5 Hz, 1H), 4.15–3.95
(m, 3H), 3.39 (dd, J 9.3, 3.2 Hz, 1H), 2.82 (br s, 3H),
2.56 (d, J 12.5 Hz, 1H), 2.40 (s, 3H), 1.46 (s, 3H), 1.34
(s, 3H); 13C NMR(CDCl 3, 100 MHz): d 144.17 (C),
133.80 (C), 130.04 (two of CH), 127.41 (two of CH),
99.18 (C), 72.28 (CH), 71.32 (CH), 66.50 (CH), 62.36
(CH2), 56.03 (CH), 52.39 (CH2), 29.15 (CH3), 21.49
(CH3), 18.95 (CH3); MS (m/z, relative intensity): 357
(M+, 5), 342 (11), 300 (5), 285 (10), 269 (58), 226 (82),
225 (59), 197 (28), 155 (59), 154 (68), 91 (100); HRE-
IMS: Calcd for C16H23NO6S (M+): m/z 357.1246.
Found: m/z 357.1226.
quinone 1,4-phthalazinediyl diether (15 mg, 0.02 mmol).
The solution was stirred for 10 min at 0 ꢁC, OsO4 (20 L,
2.5 wt % in t-BuOH) was added, and stirring was main-
tained for 1 h. The solution was slowly warmed to ambi-
ent temperature, and stirring was maintained for 36 h.
Sodium sulfite (100 mg) was added, the mixture was stir-
red for 30 min and then extracted with EtOAc
(50 mL · 2). The combined organic layers were washed
with brine (50 mL), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by flash col-
umn chromatography with EtOAc [for (ꢀ)-13: Rf 0.87.
For (+)-12: Rf 0.70 in EtOAc] to give 30 mg of (+)-12
(40% yield) as a white solid and 38 mg of (ꢀ)-13 (50%
25
For 13: mp 171–173 ꢁC; 1H NMR(1:1 CDCl
–
yield) as a white solid. For (ꢀ)-13: ½aꢁD ꢀ33.3 (c 0.53,
3
25
CD3OD, 500 MHz): d 7.61 (d, J 8.5 Hz, 2H), 7.37 (d,
J 8.0 Hz, 2H), 4.32 (dd, J 4.5, 12.5 Hz, 1H), 4.14 (t, J
11.0 Hz, 1H), 3.88 (s, 1H), 3.79–3.77 (m, 1H), 2.76–
2.74 (m, 3H), 2.63 (dd, J 11.0, 10.5 Hz, 1H), 2.43 (s,
EtOAc); For (+)-12: ½aꢁD +21.2 (c 0.53, EtOAc).
3.15. 2,2-Dimethyl-5-(toluene-4-sulfonyl)-hexahydro-
[1,3]dioxino[5,4-b]pyridine-7,8-diol (14)
3H), 1.86 (s, 3H), 1.46 (s, 3H); 13C NMR(1:1 CDCl –
3
CD3OD, 125 MHz): d 143.63 (C), 132.36 (C), 129.49
(two CH), 126.81 (two CH), 98.20 (C), 71.61 (CH),
68.37 (CH), 66.04 (CH), 62.36 (CH2), 79.71 (CH),
47.94 (CH2), 29.00 (CH3), 28.02 (CH3), 17.92 (CH3);
HREIMS: Calcd for C16H23NO6S (M+): m/z 357.1246.
Found: m/z 357.1252.
Prepared from 8 according to procedure 3.12. Colorless
oil: 83% yield, Rf 0.40 in 8:2 EtOAc–n-hexane. 1H NMR
(C6D6, 400 MHz): d 7.80 (d, J 8.2 Hz, 2H), 6.92 (d, J
8.2 Hz, 2H), 4.36 (dd, J 12.8, 4.3 Hz, 1H), 4.18 (dd, J
4.3, 4.3 Hz, 1H), 4.12–4.08 (m, 1H), 4.03 (d, J 4.2,
1H), 3.73–3.90 (m, 3H), 3.65–3.55 (m, 1H), 3.47 (dd, J
12.7, 6.4 Hz, 1H), 2.54 (br s, 1H), 1.97 (s, 3H), 1.33 (s,
3H), 1.22 (s, 3H); 13C NMR (C6D6, 100 MHz): d
143.38 (C), 136.81 (C), 129.77 (two CH), 127.92 (two
CH), 99.32 (C), 70.18 (CH), 68.68 (CH), 66.19 (CH),
61.71 (CH2), 49.67 (CH), 46.77 (CH2), 27.78 (CH3),
21.51 (CH3), 21.19 (CH3); HREIMS: Calcd for
C16H23NO6S (M+): m/z 357.1246. Found: m/z 357.1221.
3.13. 2,2-Dimethyl-5-(toluene-4-sulfonyl)-hexahydro-
[1,3]dioxino[5,4-b]pyridine-7,8-diol [(+)-13] and [(ꢀ)-12]
To a solution of 7 (70 mg, 0.22 mmol) in H2O–t-BuOH
(1:1.8 mL) was added potassium ferricyanide (217 mg,
0.66 mmol), potassium carbonate (91 mg, 0.66 mmol),
methanesulfonamide (42 mg, 0.44 mmol), and hydroqui-
nidine 1,4-phthalazinediyl diether (15 mg, 0.02 mmol).
The solution was stirred for 10 min at 0 ꢁC, OsO4
(20 lL, 2.5 wt % in t-BuOH) was added, and stirring
was maintained for 1 h. The solution was slowly warmed
to ambient temperature and stirred for an additional
28 h. Sodium sulfite (100 mg) was added, the reaction
was stirred for 30 min, and then extracted with EtOAc
(50 mL · 2). The combined organic layers were washed
with brine (50 mL), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by flash col-
umn chromatography with EtOAc [(+)-13: Rf 0.79;
(ꢀ)-12: Rf 0.52 in EtOAc] to give 33 mg of (+)-13
(42% yield) as a white solid, and 27 mg of (ꢀ)-12 (35%
3.16. 1,5-Dideoxy-1,5-imino-4,6-O-isopropylidenemann-
itol (15)
To a solution of 12 (30 mg, 0.09 mmol) in THF (5 mL)
was added Red-Al (sodium bis-(2-methoxyethoxy)alu-
minum hydride, 70% in toluene, 0.7 mL, 2.61 mmol).
The resulting mixture was heated to reflux for 8 h. The
reaction mixture was cooled to 0 ꢁC and quenched by
slow addition of 15% NaOH (5 mL), diluted with
EtOAc (50 mL · 2), washed with brine (50 mL), dried
over Na2SO4, and concentrated in vacuo. The crude res-
idue was purified by flash column chromatography with
3:7 MeOH–CH2Cl2 (1% Et3N) [Rf 0.13 in 3:7 MeOH–
25
yield) as a white solid. For (+)-13: ½aꢁD +32.6 (c 0.47,
CH2Cl2 (1% Et3N)] to give 15 as a colorless oil
25
1
EtOAc); For (ꢀ)-12: ½aꢁD ꢀ20.6 (c 0.52, EtOAc).
(15 mg, 83% yield). H NMR(CD OD, 500 MHz): d
3
4.06 (d, J 13.5 Hz, 1H), 3.87–3.90 (m, 1H), 3.76 (dd, J
10.0, 5.5 Hz, 2H), 3.56–3.63 (m, 1H), 3.49 (dd, J 5.0,
4.5 Hz, 1H), 3.25–3.27 (m, 1H), 3.18–3.21 (m, 1H),
2.91 (d, J 10.5 Hz, 1H), 0.89 (s, 6H); 13C NMR
(CD3OD, 125 MHz): d 100.90 (C), 73.36 (CH), 70.61
(CH), 63.16 (CH2), 55.74 (CH), 53.61 (CH), 51.06
(CH2), 29.71 (CH3), 19.48 (CH3); HREIMS: Calcd for
C9H17NO4 (M+): m/z 203.1158. Found: m/z 203.1165.
3.14. 2,2-Dimethyl-5-(toluene-4-sulfonyl)-hexahydro-
[1,3]dioxino[5,4-b]pyridine-7,8-diol [(ꢀ)-13] and [(+)-12]
To a solution of 7 (70 mg, 0.22 mmol) in H2O–t-BuOH
(1:1, 8 mL) was added potassium ferricyanide (217 mg,
0.66 mmol), potassium carbonate (91 mg, 0.66 mmol),
methanesulfonamide (42 mg, 0.44 mmol), and hydro-

B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
2465
3.17. 1,5-Dideoxy-1,5-imino-4,6-O-isopropylidene-L-
mannitol [(ꢀ)-15]
3.23. 1,5-Dideoxy-1,5-imino-L-mannitol [(+)-18]
Prepared from (ꢀ)-15 according to procedure 3.21.
Prepared from (ꢀ)-12 according to procedure 3.16.
Colorless oil: 52% yield, Rf 0.46 in 2:3 MeOH–CH2Cl2;
White solid: 90% yield; mp 183–184 (dec), lit. 184–186
21
(dec); ½aꢁD +27.3 (c 0.15, H2O); 1H NMR(D 2O,
30
½aꢁD ꢀ11.5 (c 0.14, MeOH).
500 MHz): d 4.13 (d, J 1.0 Hz, 1H), 3.87 (dd, J 12.5,
3.0 Hz, 1H), 3.80–3.62 (m, 2H), 3.57 (dd, J 9.5, 3.0 Hz,
1H), 3.35–3.26 (m, 3H), 3.18–3.10 (m 1H); 13C NMR
(D2O, 125 MHz): d 75.16 (CH), 68.62 (CH), 68.46
(CH), 63.10 (CH), 60.85 (CH2), 50.26 (CH2); MS (m/z,
relative intensity): 163 (M+, 28), 132 (50), 105 (82), 87
(100); HREIMS: C6H13NO4 (M+): m/z 163.0845.
Found: m/z 163.0814.
3.18. 1,5-Dideoxy-1,5-imino-4,6-O-isopropylidene-D-
mannitol [(+)-15]
Prepared from (+)-12 according to procedure 3.16.
Colorless oil: 37% yield, Rf 0.44 in 2:3 MeOH–CH2Cl2;
28
½aꢁD +10.1 (c 0.08, MeOH).
3.24. 1,5-Dideoxy-1,5-imino-D-mannitol [(ꢀ)-18]
3.19. 1,5-Dideoxy-1,5-imino-4,6-O-isopropylidene-L-all-
itol [(ꢀ)-16]
Prepared from (+)-15 according to procedure 3.21.
21
Yield (89%); ½aꢁD ꢀ28.0 (c 0.13, H2O).
Prepared from (ꢀ)-13 according to procedure 3.16.
Colorless oil: 48% yield, Rf 0.44 in 2:3 MeOH–CH2Cl2;
3.25. 1,5-Deoxy-2,3:4,6-di-O-isopropylidene-1,5-sulfon-
amino-D-allitol [(+)-19]
30
½aꢁD ꢀ12.5 (c 0.15, MeOH).
3.20. 1,5-Dideoxy-1,5-imino-4,6-O-isopropylidene-D-all-
itol [(+)-16]
Prepared from (+)-13 according to procedure 3.7. White
solid: 88% yield; Rf 0.28 in 1:4 EtOAc–hexane; mp 162–
23:3
163 ꢁC; ½aꢁD 27.7 (c 0.6, EtOAc); 1H NMR(acetone- d6,
Prepared from (+)-13 according to procedure 3.16. Col-
400 MHz): d 7.70 (d, J 8.2 Hz, 2H), 7.39 (d, J 8.1 Hz,
2H), 4.42–4.33 (m, 2H), 4.28 (dd, J 8.3, 2.6 Hz, 1H),
4.16 (dd, J 10.3, 2.7 Hz, 1H), 3.96 (dd, J 15.5, 2.3 Hz,
1H), 3.81 (dd, J 11.2, 10.7 Hz, 1H), 3.49 (dd, J 15.6,
1.8 Hz, 1H), 3.42–3.32 (m, 1H), 2.41 (s, 3H), 1.48 (s,
3H), 1.30 (s, 3H), 1.16 (s, 3H), 0.81 (s, 3H); 13C NMR
(acetone-d6, 100 MHz): d 144.08 (C), 138.18 (C),
130.23 (two CH), 128.68 (two CH), 109.16 (C), 99.51
(C), 73.63 (CH), 71.75 (CH), 69.57 (CH), 64.72 (CH2),
47.24 (CH), 44.61 (CH2), 29.34 (CH3), 25.27 (CH3),
23.59 (CH3), 21.31 (CH3), 19.13 (CH3); HREIMS: Calcd
for C19H27NO6S (M+): m/z 397.1559. Found: m/z
397.1565.
31
orless oil: 48% yield, Rf 0.44 in 2:3 MeOH–CH2Cl2; ½aꢁD
+13.2 (c 0.11, MeOH); 1H NMR(CD 3OD, 500 MHz): d
3.89–3.99 (m, 1H), 3.72–3.82 (m, 2H), 3.40–3.50 (m,
2H), 2.95–3.10 (m, 1H), 2.80–2.90 (m, 1H), 2.45–2.60
(m, 1H), 1.51 (s, 3H), 1.48 (s, 3H); 13C NMR(CD OD,
3
125 MHz): d 100.33 (C), 74.01 (CH), 70.85 (CH), 69.71
(CH2), 63.81 (CH), 48.73 (CH), 46.64 (CH2), 29.51
(CH3), 19.44 (CH3); HREIMS: Calcd for C9H17NO4
(M+): m/z 203.1158. Found: m/z 203.1162.
3.21. 1,5-Dideoxy-1,5-imino-D-allitol [(+)-17]
To a solution of (+)-16 (10.8 mg, 0.05 mmol) in MeOH
(10 mL) was added a solution of methanolic HCl (1 mL,
prepared from 0.5 mL concd HCl in 30 mL of MeOH).
The resulting mixture was stirred for 6 h at ambient tem-
perature and concentrated in vacuo to give (+)-17
3.26. 2-Hydroxymethyl-1-(toluene-4-sulfonyl)piperidine-
3,4,5- triol [(+)-20]
Prepared from (ꢀ)-15 according to procedure 3.21.
25
23
(8.8 mg; 83% yield); mp 149–150 ꢁC; ½aꢁD +30.5 (c
Yield (97%); ½aꢁD +22.4 (c 0.25, H2O).
1
0.15, H2O). H NMR(CD OD, 500 MHz): d 4.04 (br
3
s, 2H), 3.80–3.92 (m, 3H), 3.68 (dd, J 10.5, 2.0 Hz,
1H), 3.30 (dd, J 3.0, 1.5 Hz, 1H), 3.21–3.28 (m, 1H),
3.27. 2-Hydroxymethyl-1-(toluene-4-sulfonyl)piperidine-
3,4,5- triol [(ꢀ)-20]
3.02–3.10 (m, 2H); 13C NMR(CD OD, 125 MHz): d
3
71.82 (CH), 67.24 (CH), 66.41 (CH), 59.06 (CH2),
56.60 (CH), 43.38 (CH2); HREIMS: Calcd for
C6H13NO4 (M+): m/z 163.0845. Found: m/z 163.0814.
Prepared from (+)-15 according to procedure 3.21.
23
Yield (97%). ½aꢁD ꢀ20.4 (c 0.30, H2O); 1H NMR
(D2O, 500 MHz): d 7.66 (d, J 8.0 Hz, 2H), 7.27 (d, J
8.0 Hz, 2H), 3.94–3.88 (m, 1H), 3.84–3.81 (m, 1H),
3.80–3.74 (m, 1H), 3.70–3.68 (m, 1H), 3.60–3.50 (m,
2H), 3.45–3.35 (m, 1H), 3.11–3.03 (m, 1H), 2.27 (s,
3.22. 1,5-Dideoxy-1,5-imino-L-allitol [(ꢀ)-17]
Prepared from (ꢀ)-16 according to procedure 3.21.
3H); 13C NMR(D O, 125 MHz): d 145.02 (C), 136.02
2
27
Yield (78%); ½aꢁD ꢀ31.6 (c 0.10, H2O).
(C), 129.87 (two CH), 127.33 (two CH), 69.51 (CH),

2466
B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
69.01 (CH), 63.29 (CH), 60.69 (CH), 58.86 (CH2), 40.39
(CH2), 20.78 (CH3); HREIMS: Calcd for C13H19NO6S
(M+): m/z 317.0933. Found: m/z 317.0936.
with EtOAc (30 mL · 2), washed with water and brine
(30 mL), dried over Na2SO4, and concentrated in vacuo.
The crude residue was purified by flash chromatography
with 1:1 EtOAc–hexane (Rf 0.35 in 1:1 EtOAc–hexane)
to give 23 (22 mg; 86% yield). The same procedure was
applied on 22 (24 mg, 0.07 mmol) to give 28 (Rf 0.30
3.28. 6,6-Dimethyl-3-(toluene-4-sulfonyl)hexahydro-
1,5,7-trioxa-3-aza-cyclopropa[a]naphthalene (22) and (21)
1
in 1:1 EtOAc–hexane; 21 mg, 82% yield). For 23: H
To a solution of 7 (144 mg, 0.45 mmol) in CH3CN
(15 mL) was successively added aqueous Na2EDTA
(4 · 10ꢀ4 M, 13 mL) and CF3COCH3 (1 mL) at 0 ꢁC.
A mixture of NaHCO3 (0.40 g, 4.8 mmol) and Oxone
(2.0 g) was added to the reaction mixture over 1 h at
0 ꢁC, and the whole mixture was stirred at the same tem-
perature for 30 min. H2O (15 mL) was added to the
reaction mixture, and the solution was extracted with
CH2Cl2 (40 mL · 2). The extracts were washed with
brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatogra-
phy with 1:3 EtOAc–hexane (for 21: Rf 0.64 in 1:1
EtOAc–hexane. For 22: Rf 0.58 in 1:1 EtOAc–hexane)
NMR(CDCl 3, 500 MHz): d 7.61 (d, J 8.5 Hz, 2H),
7.36 (d, J 8.5 Hz, 2H), 4.22–4.36 (m, 4H), 4.02 (dd, J
13.0, 1.0 Hz, 1H), 3.18 (s, 1H), 2.95 (d, J 13.0 Hz, 1H),
2.70–2.80 (m, 1H), 2.44 (s, 3H), 1.51 (s, 3H), 1.37 (s,
3H); 13C NMR(CDCl 3, 125 MHz): d 144.87 (C),
133.19 (C), 130.40 (two CH), 127.21 (two CH), 116.45
(C), 99.53 (C), 66.30 (CH), 65.58 (CH), 62.08 (CH2),
55.36 (CH), 51.47 (CH2), 38.29 (CH), 28.86 (CH3),
21.57 (CH3), 18.89 (CH3); HREIMS: Calcd for
C17H23N2O5S (M++1): m/z 367.1328. Found: m/z
367.1325.
1
For 28: H NMR(CDCl , 500 MHz): d 7.63 (d, J
3
8.0 Hz, 2H), 7.34 (d, J 8.0 Hz, 2H), 4.34 (dd, J 12.5,
4.5 Hz, 1H), 4.22 (t, J 11.0 Hz, 1H), 4.09 (dd, J
9.5, 3.0 Hz, 1H), 4.05–4.06 (m, 1H), 3.98 (dd, J 12.5,
2.5 Hz, 1H), 3.07 (t, J 2.5 Hz, 1H), 3.03 (dd, J
12.0, 3.0 Hz, 1H), 2.86 (td, J 10.0, 4.5 Hz, 1H), 2.43 (s,
to give 21 (45.5 mg; 45% yield) and 22 (37.3 mg; 37%
1
yield). For 21: H NMR(C D6, 500 MHz): d 7.61 (d,
6
J 8.0 Hz, 2H), 6.73 (d, J 8.0 Hz, 2H), 4.37 (d,
J 7.0 Hz, 2H), 4.14 (d, J 15.0 Hz, 1H), 3.78 (d, J
10.0 Hz, 1H), 2.91 (d, J 3.5 Hz, 1H), 2.56 (d, J
14.5 Hz, 1H), 2.50–2.41 (m, 1H), 2.39 (br s, 1H), 1.87
3H), 1.51 (s, 3H), 1.35 (s, 3H); 13C NMR(CDCl
,
3
125 MHz): d 144.50 (C), 133.91 (C), 130.21 (two CH),
127.41 (two CH), 117.34 (C), 99.56 (C), 70.82 (CH),
65.91 (CH), 62.36 (CH2), 51.93 (CH), 44.70
(CH2), 32.07 (CH), 29.00 (CH3), 21.57 (CH3), 19.20
(CH3); HREIMS: Calcd for C17H22N2O5S (M+): m/z
366.1249. Found: m/z 366.1249.
(s, 3H), 1.37 (s, 3H), 1.10 (s, 3H); 13C NMR(C D6,
6
125 MHz): d 143.13 (C), 137.93 (C), 129.66 (two CH),
127.91 (two CH), 99.70 (C), 67.53 (CH), 63.08 (CH2),
55.54 (CH), 54.29 (CH), 49.38 (CH), 47.60 (CH2),
29.36 (CH3), 21.06 (CH3), 18.55 (CH3); HREIMS: Calcd
for C16H22NO5S (M++1): m/z 340.1219. Found: m/z
340.1219.
3.30. 4,5-Dihydroxy-6-isopropoxymethyl-1-(toluene-4-
sulfonyl)-piperidin-3-ylmethylammonium chloride (24), 4-
hydroxy-6-hydroxymethyl-5-isopropoxy-1-(toluene-4-sul-
fonyl)-piperidin-3-ylmethylammonium chloride (25), and
5-aminomethyl-2-hydroxymethyl-1-(toluene-4-sulfonyl)-
piperidine-3,4-diol (26)
For 22: 1H NMR(C 6D6, 500 MHz): d 7.51 (d, J
8.5 Hz, 2H), 6.67 (d, J 8.5 Hz, 2H), 4.50–4.57 (m, 1H),
4.44 (dd, J 11.0, 11.5 Hz, 1H), 3.89 (d, J 9.5 Hz, 1H),
3.66 (dd, J 4.0, 14.5 Hz, 1H), 3.02–3.10 (m, 1H), 3.02
(d, 14.5 Hz, 1H), 2.83 (d, J 4.5 Hz, 1H), 2.58 (dd, J
4.0, 4.0 Hz, 1H), 1.85 (s, 3H), 1.41 (s, 3H), 1.24 (s,
3H); 13C NMR(C D6, 125 MHz): d 143.38 (C), 135.00
To a stirred solution of 23 (20 mg, 0.05 mmol) in dry
THF (10 mL) was added BH3ÆSMe2 (10 drops) at 0 ꢁC.
The reaction mixture was heated to reflux for 2 h, cooled
to ambient temperature and treated with a 6 M solution
of HCl in MeOH for 18 h. The solvent was removed in
vacuo, and the crude residue was purified by flash chro-
matography with 1:4 MeOH–CH2Cl2 (1% NH4OH) to
100% MeOH (1% NH4OH) to give the products. For
24: Colorless solid: yield, 10.3 mg, 46%; Rf 0.24 in
6
(C), 129.88 (two CH), 127.56 (two CH), 99.24 (C),
70.99 (CH), 63.01 (CH2), 52.03 (CH), 51.19 (CH),
50.21 (CH), 46.18 (CH2), 29.35 (CH3), 21.07 (CH3),
18.73 (CH3); HREIMS: Calcd for C16H22NO5S
(M++H): m/z 340.1219. Found: m/z 340.1221.
3.29. 8-Hydroxy-2,2-dimethyl-5-(toluene-4-sulfon-
yl)hexahydro[1,3]dioxino-[5,4-b]pyridine-7-carbonitrile
(28) and (23)
1
1:4 MeOH–CH2Cl2 (1% NH4OH); mp 161–163 ꢁC; H
NMR(CD OD, 500 MHz): d 7.79 (d, J 8.0 Hz, 2H),
3
To a stirred solution of 21 (24 mg, 0.07 mmol) in dry
DMSO (2 mL) was added KCN (44 mg, 0.64 mmol),
followed by Bu4NI (116 mg, 0.32 mmol). After 5 min,
titanium tetraisopropoxide (0.12 mL, 0.38 mmol) was
slowly injected, and the resulting mixture was stirred
at room temperate for 84 h. The solution was diluted
7.35 (d, J 8.0 Hz, 2H), 4.12 (t, J 6.0 Hz, 1H), 4.06 (s,
1H), 3.69–3.75 (m, 2H), 3.46–3.57 (m, 3H), 3.09–3.20
(m, 2H), 2.88 (dd, J 12.5, 10.5 Hz, 1H), 2.41 (s, 3H),
1.93–1.97 (m, 1H), 1.09 (d, J 2.0 Hz, 3H), 1.08 (d, J
2.0 Hz, 3H); 13C NMR(CD OD, 125 MHz): d 144.79
3
(C), 139.46 (C), 130.60 (two CH), 128.56 (two CH),

B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
2467
73.49 (CH), 69.25 (CH), 67.22 (CH2), 66.28 (CH), 60.62
(CH), 48.49 (CH2), 42.55 (CH2), 42.09 (CH), 22.32
(CH3), 22.27 (CH3), 21.45 (CH3); HREIMS: Calcd for
C17H29N2O5S (M+ꢀHCl+1): m/z 373.1792. Found: m/
z 373.1797.
3.55–3.71 (m, 4H), 2.76–2.83 (m, 2H), 2.53 (q, J 6.5 Hz,
1H), 2.40 (s, 3H), 1.79–1.83 (m, 1H); 13C NMR(CD 3OD,
125 MHz): d 144.52 (C), 139.56 (C), 130.47 (two CH),
128.70 (two CH), 71.54 (CH), 68.95 (CH), 62.74 (CH),
60.87 (CH2), 44.79 (CH2), 43.09 (CH2), 38.67 (CH),
21.45 (CH3); HREIMS: Calcd for C14H23N2O5S
(M+ꢀHCl+1): m/z 331.1322. Found: m/z 331.1328.
For 25: Colorless liquid: yield 3.3 mg, 15%; Rf 0.14
in 1:4 MeOH–CH2Cl2 (1% NH4OH); 1H NMR
(CD3OD, 500 MHz): d 7.80 (d, J 8.0 Hz, 2H), 7.35 (d,
J 8.0 Hz, 2H), 4.12 (t, J 6.0 Hz, 1H), 4.05 (s, 1H),
3.65–3.73 (m, 2H), 3.44–3.55 (m, 3H), 2.94–3.06 (m,
2H), 2.82 (t, J 11.0 Hz, 1H), 2.41 (s, 3H), 1.71–1.75
(m, 1H), 1.09 (d, J 1.5 Hz, 3H), 1.08 (d, J 1.5 Hz, 3H);
13C NMR(CD 3OD, 125 MHz): d 144.73 (C), 139.53
(C), 130.56 (two CH), 128.59 (two CH), 73.43 (CH),
69.13 (CH), 66.94 (CH2), 66.09 (CH), 60.72 (CH),
48.49 (CH2), 44.07 (CH), 42.45 (CH2), 22.30 (CH3),
22.23 (CH3), 21.43 (CH3); HREIMS: Calcd
for C17H29N2O5S (M+ꢀHCl+1): m/z 373.1792. Found:
m/z 373.1801.
3.32. 5-Aminomethyl-2-hydroxymethylpiperidine-3,4-diol
(27)
Small pieces of sodium metal were added to a solution
of 26 (37.6 mg, 0.10 mmol) in liquid ammonia (20 mL)
at ꢀ78 ꢁC, until a blue color persisted for 5 min. The
solution was then warmed to ambient temperature,
and the ammonia was allowed to evaporate. The crude
residue was purified by flash chromatography with 3:7
NH4OH–MeOH. (Rf 0.31 in 3:7 NH4OH–MeOH) to
1
give 27 as a colorless liquid (18.1 mg; 83% yield). H
For 26: Colorless liquid: yield 6.4 mg, 32%; Rf 0.14 in
NMR(D O, 500 MHz): d 3.98 (t, J 4.0 Hz, 1H), 3.84
2
1
MeOH (1% NH4OH); H NMR(CD OD, 500 MHz): d
(td, J 7.5, 4.0 Hz, 1H), 3.60–3.63 (m, 2H), 3.14 (dd, J
13.0, 6.0 Hz, 1H), 3.04 (dd, J 13.0, 6.0 Hz, 1H), 2.88–
2.91 (m, 1H), 2.83 (dd, J 13.5, 3.5 Hz, 1H), 2.63 (dd, J
3
7.79 (d, J 8.5 Hz, 2H), 7.34 (d, J 7.5 Hz, 2H), 4.13 (s, 1H),
4.07 (t, J 6.5 Hz, 1H), 3.63–3.73 (m, 3H), 3.54–3.57 (m,
1H), 3.09–3.19 (m, 2H), 2.82 (t, J 13.0 Hz, 1H), 2.41
(s, 3H), 1.93–2.02 (m, 1H); 13C NMR(CD 3OD,
125 MHz): d 144.7 (C), 139.5 (C), 130.6 (two CH),
128.6 (two CH), 67.9 (CH), 66.2 (CH), 62.3 (CH), 60.4
(CH2), 48.1 (CH2), 42.2 (CH2), 41.9 (CH), 21.4 (CH3);
HREIMS: Calcd for C14H23N2O5S (M+ꢀHCl+1): m/z
331.1322. Found: m/z 331.1326.
13.5, 7.5 Hz, 1H), 1.98–2.03 (m, 1H); 13C NMR(D O,
2
125 MHz): d 66.16 (CH), 65.98 (CH), 58.92 (CH2),
57.95 (CH), 44.88 (CH2), 41.24 (CH), 39.16 (CH2);
HREIMS: Calcd for C7H16N2O3ÆHCl (M+ÆHCl): m/z
176.1161. Found: m/z 176.1159.
3.33. 5-Aminomethyl-2-hydroxymethylpiperidine-3,4-
diol (32)
3.31. 4,5-Dihydroxy-6-isopropoxymethyl-1-(toluene-4-
sulfonyl)piperidin-3-ylmethylammonium chloride (29),
and 5-aminomethyl-2-hydroxymethyl-1-(toluene-4-sulfon-
yl)piperidine-3,4-diol (31)
Prepared from 31 according to procedure 3.32. Colorless
oil: 87% yield; Rf 0.32 in 3:7 NH4OH–MeOH. 1H NMR
(D2O, 500 MHz): d 3.72 (dd, J 7.0, 3.0 Hz, 1H), 3.56–
3.61 (m, 3H), 2.97–3.01 (m, 2H), 2.86–2.91 (m, 2H),
2.57 (dd, J 13.5, 7.5 Hz, 1H), 2.03–2.10 (m, 1H); 13C
NMR(D 2O, 125 MHz): d 69.57 (CH), 66.96 (CH),
59.44 (CH2), 58.14 (CH), 40.65 (CH2), 40.05 (CH2),
37.20 (CH); HREIMS: Calcd for C7H16N2O3ÆHCl
(M+ꢀHCl): m/z 176.1161. Found: m/z 176.1163.
Prepared from 28 according to procedure 3.30. For 29:
Colorless solid: yield 10.7 mg, 48%; Rf 0.29 in 1:4
MeOH–CH2Cl2 (1% NH4OH); mp 162–164 ꢁC; 1H
NMR(CD OD, 500 MHz): d 7.82 (d, J 8.0 Hz, 2H),
3
7.35 (d, J 8.5 Hz, 2H), 4.25 (br s, 1H), 3.93 (s, 1H),
3.81 (dd, J 11.0, 3.0 Hz, 1H), 3.74 (dd, J 13.0, 5.0 Hz,
1H), 3.53–3.56 (m, 1H), 3.46–3.48 (m, 1H), 3.04 (dd, J
13.0, 8.0 Hz, 1H), 2.94 (t, J 13.0 Hz, 1H), 2.83 (dd, J
13.0, 5.0 Hz, 1H), 2.41 (s, 3H), 2.07–2.18 (m, 1H), 1.07
(d, J 6.0 Hz, 3H), 1.05 (d, J 6.5 Hz, 3H); 13C NMR
(CD3OD, 125 MHz): d 144.73 (C), 139.51 (C), 130.62
(two CH), 128.57 (two CH), 73.43 (CH), 72.33 (CH),
69.82 (CH), 67.78 (CH2), 60.89 (CH), 44.77 (CH2),
42.18 (CH2), 35.47 (CH), 22.28 (CH3), 22.25 (CH3),
21.44 (CH3); HREIMS: Calcd for C17H29N2O5S
(M+ꢀHCl+1): m/z 373.1792. Found: m/z 373.1801.
For 31: Colorless solid: yield 8.6 mg, 43%; Rf 0.17 in
MeOH (1% NH4OH); mp 158–160 ꢁC; 1H NMR
(CD3OD, 500 MHz): d 7.83 (d, J 6.0 Hz, 2H), 7.33 (d, J
7.5 Hz, 2H), 4.19–4.21 (m, 1H), 3.95 (t, J 2.5 Hz, 1H),
Acknowledgments
Financial support from Auspex Pharmaceutical Inc. for
this work is gratefully acknowledged.
Supplementary data
Crystal information files (CIF) have been deposited with
the Cambridge Crystallographic Data Centre. These
data may be obtained, on request, from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (Tel.:
+44-1223-336408; fax: +44-1223-336033; e-mail:

2468
B.-C. Hong et al. / Carbohydrate Research 340 (2005) 2457–2468
Lee, G.-H.; Sarshar, S. Tetrahedron Lett. 2005, 46, 1281–
1285; (b) Hong, B.-C.; Chen, Z.-Y.; Nagarajan, A.;
Rudresha, K.; Chavan, V. P.; Sarshar, S. PCT Int. Appl.
WO 2004/0647445; Chem. Abstr. 2004, 141, 174075.
7. (a) Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org. Chem.
2003, 68, 62–69; (b) Hoffmann, T.; Gmeiner, P. Synlett
2002, 1014–1016; (c) Reichwein, J. F.; Liskamp, R. M. J.
Eur. J. Org. Chem. 2000, 2335–2344; (d) Grigg, R.;
Coulter, T. Tetrahedron Lett. 1991, 32, 1359–1362; (e)
Suzuki, A.; Hyeon, S. B.; Nagai, I.; Iesaka, H.; Kajita, T.;
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Appl. EP 181494 A1 19860521, 1986.
deposit@ccdc.cam.ac.uk) on quoting CCDC-280748 for
trans-2,2-dimethyl-5-(toluene-4-sulfonyl)-4a,5,6,8a-tetra-
hydro-4H-[1,3]dioxino[5,4-b]pyridine (7) and CCDC-
280749 for 1,5-deoxy-2,3:4,6-di-O-isopropylidene-1,5-
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