Asymmetric synthesis of all stereoisomers of isofagomine using [2,3]-Wittig rearrangement

Article abstract of DOI:10.3987/com-07-s(k)58

The asymmetric synthesis of all stereoisomers of isofagomine from 5-hydroxymethyl-3-piperidene 6, which was prepared by [2,3 ]-Wittig rearrangement of O-alkylstannylmethyl compound 5 derived from readily available chiral 3-hydroxypiperidene 4, is describe

Full text of DOI:10.3987/com-07-s(k)58

HETEROCYCLES, Vol. 72, 2007
633
HETEROCYCLES, Vol. 72, 2007, pp. 633 - 645. © The Japan Institute of Heterocyclic Chemistry
Received, 9th January, 2007, Accepted, 21st February, 2007, Published online, 23rd February, 2007. COM-07-S(K)58
ASYMMETRIC SYNTHESIS OF ALL STEREOISOMERS OF
ISOFAGOMINE USING [2,3]-WITTIG REARRANGEMENT
a
a
a
a
Yukiko Mihara, Hidetomo Ojima, Tatsushi Imahori, Yuichi Yoshimura,
b
a
Hidekazu Ouchi, and Hiroki Takahata *
a
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai
981-8558, Japan:takahata@tohoku-pharm.ac.jp
b
Faculty of Pharmaceutical Sciences, Aomori University, Aomori, 030-0943,
Japan
Abstract – The asymmetric synthesis of all stereoisomers of isofagomine from
5
-hydroxymethyl-3-piperidene 6, which was prepared by [2,3]-Wittig
rearrangement of O-alkylstannylmethyl compound 5 derived from readily
available chiral 3-hydroxypiperidene 4, is described.
INTRODUCTION
Azasugars (or iminosugars), such as 1-deoxynojirimycin (1), are an important class of glycosidase
inhibitors and are currently attracting great interest as potential therapeutic agents such as antidiabetics,
1
-5
6
antiobesities, antivirals, and therapeutic agents for certain types of genetic disorders. Miglitol (Glyset)
has been approved as a second-generation ꢀ-glucosidase inhibitor for the treatment of type 2 diabetes,
7
-9
and N-butyl-1-deoxynojirimycin (Zavesca) has also been approved for use in patients with type 1
Gaucher disease in the European Union in 2002 and in the U.S. in 2003. The promising therapeutic
potential of iminosugars has led to an increased interest and demand. In the process of the design and
development of anomer-selective ꢁ-glycosidase inhibitors based on transition state mimics for hydrolysis
by a glycosidase, Bols and co-workers noticed a subtle change in glycosidase inhibitory activity when the
10
nitrogen atom of fagomine 2 was moved to the anomeric C position. This led to the development of
1
isofagomine 3 which showed stronger and more selective ꢁ-glucosidase inhibitory activity than
previously developed compounds. A number of isofagomine derivatives have been synthesized during the
1
1
last few years. Most of the syntheses start from carbohydrates and, in general, require numerous steps to
reach a specific target. The development of efficient and general procedures for their synthesis is still an

634
HETEROCYCLES, Vol. 72, 2007
area of great interest, not only for the synthesis of natural products, but also for chemically modified
analogues.
OH
OH
OH
N
OH
OH
HO
OH
OH
OH
HO
OH
OH
HO
OH
OH
OH
HO
OH
N
N
H
N
H
N
H
1
2
3
OH
miglitol
N-butyl-1-deoxynojirimycin
Figure 1
1
2
As a part of our ongoing interest in polyhydroxy piperidines, we envisioned the use of N-Boc-5-
hydroxy-3-piperidene (4) as a general representative chiral building block that might permit easy access
1
3
to these classes of compounds. We report herein on the asymmetric synthesis of all stereoisomers of the
1
4
1
-azasugars such as isofagomine (3), using the [2,3]-Wittig rearrangement as a key step starting from
the chiral N-Boc-5-hydroxy-3-piperidene (4) as depicted in Scheme 1.
OH OH
OH
HO
Bu SnH CO
3 2
LiH CO
2
n-BuLi
HO
N
Boc
N
Boc
N
Boc
N
Boc
N
H
4
5
3 isofagomine
[2,3]-Wittig rearrangement
6
7
8
9
3-epiisofagomine
4-epiisofagomine
3,4-diepiisofagomine
Scheme 1
RESULTS AND DISCUSSION
We began with the synthesis of a precursor 5 for the [2,3]-Wittig rearrangement from 4. O-Alkylation
1
2
15
of (S)-4 with tributyl(iodomethyl)stannane in the presence of KH and n-Bu NI gave the stannane
4
product (S)-5 in 98% yield.
With (S)-5 in hand, the [2,3]-Wittig rearrangement of (S)-5 by
1
6
transmetallation using n-BuLi to obtain the requisite hydroxymethyl substituent (R)-6 was examined.
After screening various reaction conditions, we were very pleased to find that the desired [2,3]-Wittig
1
7
rearrangement of (S)-5 proceeded smoothly to afford (R)-6 with no racemization. The results are shown
in Table 1. The use of less polar solvents such as n-pentane and n-hexane gave good results.

HETEROCYCLES, Vol. 72, 2007
635
Table 1. [2,3]-Wittig rearrangement of (S)-5
OH
Bu SnH CO
3
2
n-BuLi
N
Boc
dry solvent
N
Boc
-
80 °C (2 h)
(S)-5
(R)-6
to -40 °C (1~2 h)
Entry
Solvent
n-pentane
n-hexane
(R)-6a, Yield[%]
1
2
3
4
5
65
53
50
33
16
Et O
2
THF
DME
Having the key intermediate (R)-6 in hand, the stereoselective dihydroxylation of the double bond was
examined. Treatment of (R)-6 with a catalytic amount of OsO (5 mol %) and 4-methylmorphorine N-
4
oxide as a cooxidant gave an inseparable mixture of diastereomeric diols, which, after deprotection with
10% HCl in dioxane followed by silica gel column chromatography using a mixture eluent
(
methanol:10% NH OH), gave 3-epiisofagomine (7) (75%) and 4-epiisofagomine (8) (14%). The O-
4
TBDPS protected piperidene 10 was next dihydroxylated under similar conditions to give 11 (56%) and
1
2 (21%). Unfortunately, diastereoselectivity was not improved. The spectral data for 7 and 8 were found
1
1a,c
to be in good agreement with reported values from the literature.
Donohoe reported that osmium
tetroxide produces a bidentate and reactive complex with TMEDA, which can be used in the directed
1
8
dihydroxylation of cyclic homoallylic alcohols. Under the condition, hydrogen bonding control
preferentially led to the formation of the syn isomer in almost every case. However, the oxidation of (R)-6
with a combination of OsO with TMEDA gave 7 and 8 in 61% and 37% yields, respectively. Although
4
the yield of 8 was increased, inversion of the ratio did not occur.
We next set out to synthesize 3 and 9 from this advanced intermediate 11. Thus, the cis-diol 11 was
converted into the cyclic sulfate ester 13 in 76% yield in a two-step sequence, including cyclic sulfite
1
9
formation with SOCl and triethylamine followed by oxidation with RuCl /NaIO (Scheme 8).
2
3
4
Treatment of 13 with benzoic acid in the presence of cesium carbonate (DMF, 60 °C) resulted in the non-
regioselective substitution at the C and C positions to produce benzoates 14 and 15 in 46% and 42%
3
4
yields, respectively, after acid hydrolysis of the resultant sulfate esters. Finally, the deprotection of 14 and
5 by treatment with 6N hydrochloric acid at 120 °C gave 3 and 9 in 98% and 96% yields, respectively,
1

636
HETEROCYCLES, Vol. 72, 2007
1
1f
the spectral data for which were found to be in good agreement with reported values from the literature.
OH
OH
OH
OH
OH
HO
HO
(
a)
N
Boc
N
H
N
H
7
8
(R)-6
cat. OsO (75%)
(14%)
4
OsO -TMEDA (61%) (37%)
4
OTBDPS
(
OH
OH
OTBDPS
OTBDPS
HO
HO
b)
N
Boc
N
Boc
N
Boc
(R)-10
12
11
(56%)
(21%)
Scheme 2. (a) 1) cat. OsO , NMO, acetone; 2) 10% HCl, dioxane, reflux;
4
3
) NH OH; or 1) OsO -TMEDA, CH Cl ; 2) conc HCl, MeOH; 3) NH OH;
4
4
2
2
4
(
b) cat. OsO , NMO, acetone
4
OH
OH
OTBDPS
(
OH
PhOCO
HO
c)
O
O
N
N
H
S
OH
O
Boc
OTBDPS
a)
OTBDPS
b)
O
HO
14
46%)
3
(
(
(
N
Boc
N
Boc
OCOPh
OH
OH
OTBDPS
1
1
13
HO
HO
(
c)
N
Boc
N
H
9
1
5
(
42%)
Scheme 3. (a) 1) SOCl , Et N, CH Cl ; 2) cat. RuCl -3H O, NaIO , CCl -MeCN-H O;
2
3
2
2
3
2
4
4
2
(
b) 1) PhCOOH, CsCO , DMF; 2) conc H SO , H O, THF; (c) 1) 6N HCl; 2) NH OH
3 2 4 2 4
As an alternative synthesis of 3 and 9, we attempted an epoxidation of (R)-10 followed by cleavage. Thus,
2
0
the dioxirane, generated in situ from Oxone® by treatment with 1,1,1-trifluoroacetone was reacted with
R)-10 to give the anti epoxide 16 and the syn epoxide 17 in 52% and 34% yields, respectively, which
were tentatively assigned based on steric considerations between the allylic substitutent of the six
(
2
1
membered cyclic alkene and a substituent of dioxirane. Subsequently, basic cleavage of the epoxy ring
of 16 was accomplished using a mixture of KOH/1,4-dioxane/H O at reflux followed by a sequence of
2
deprotection with 6N hydrochloric acid and desalting to give 3 and 9, 28% and 62% yields, respectively.

HETEROCYCLES, Vol. 72, 2007
637
OTBDPS
O
OH
OH
OH
OH
HO
HO
(
b)
N
OTBDPS
Boc
N
H
N
H
(
a)
16
52%)
(
3
9
N
Boc
(28%)
(62%)
OTBDPS
O
(
R)-10
(
b)
3
9
N
Boc
(
53%)
(37%)
17
(34%)
ꢀ
Scheme 4. (a) Oxone , CF COCH , Na EDTA(aq.), NaHCO , MeCN;
3
3
2
3
(
b) 1) 0.3M KOH, 1,4-dioxane; 2) 6N HCl; 3) NH OH
4
The regiochemistry of the nucleophilic opening of the epoxide on a six-membered ring is mainly subject
2
2
to trans diaxial opening (Fürst-Plattner rule). Consequently, this regioselectivity would result, if the
opening proceeded through the two possible half chair conformations (A and B) in the following
explanation. A substituent at C-3 would preferentially occupy a pseudoequatrial orientation compared
with a pseudoaxial one. Thus, the somewhat preferential attack of the hydroxide anion at C-4 through
conformer A would occur with trans diaxial opening. On the other hand, a similar reaction using 17
somewhat preferentially gave 3 (53%) together with 9 (37%). On the basis of the above reasoning, the
existence of conformer D would be major species and conformer C, the minor species.
OH
OH
4
(R)5-6
Boc
OTBDPS
N
5
OTBDPS
4
3
3
H
N
O
H
O
Boc
conformer A
conformer B
Boc
Boc
OH
N
N
OTBDPS
OTBDPS
HO
OH
OH
C-4 product
C-5 product
OH
OH
Boc
H
5
N
5
4
H
4
3
3
N
O
O
OTBDPS
Boc
OTBDPS
conformer D
conformer C
Scheme 5

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HETEROCYCLES, Vol. 72, 2007
In addition, four enantiomers of 3, 7, 8, and 9 were prepared from (R)-4 according to the above described
procedure (Scheme 6).
OH OH
OH
HO
HO
N
Boc
N
H
N
Boc
ent-3, ent-7,
ent-8 ,ent-9
(
R)-4
(S)-6
Scheme 6
In summary, the asymmetric synthesis of all stereoisomers 3, 7, 8, and 9 of isofagomine is described
using the [2,3]-Wittig rearrangement as a key step starting from the chiral N-Boc-5-hydroxy-3-piperidene
(
4).
This rearrangement of 5 by transmetallation using n-BuLi proceeded smoothly in nonpolar
solvents such as n-pentane with no racemization. Thus, the prepared hydoxymethylpiperidene 6 was
transformed by dihydroxylation, cyclic sulfenylation, and epoxidation into stereoisomers of isofagomine,
although their diastereoselectivities were not always high.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. Mass spectra
(
MS) were recorded on a JEOL JMN-DX 303/JMA-DA 5000 spectrometer. Microanalyses were
performed on a Perkin-Elmer CHN 2400 Elemental Analyzer. Optical rotations were measured with a
1
JASCO DIP-360 or JASCO P-1020 digital polarimeter. Proton nuclear magnetic resonance ( H NMR)
spectra were recorded on JEOL JNM-EX 270 (270 MHz) or JEOL JNM-AL 400 (400 MHz) or JNM-LA
(
600 MHz) spectrometer, using tetramethylsilane as an internal standard. The following abbreviations are
used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Column chromatography
was carried out on Merck Silica gel 60 (230-400 mesh) or KANTO Silica Gel 60N (40-50 mm) for flash
chromatography.
(
S)-N-tert-Butoxycarbonyl-5-(tributylstannyl)methoxy-3-piperidene [(S)-5]
A solution of (S)-4 (995 mg, 5 mmol) in THF (5 mL) was added to a suspension of KH (860 mg, 35
wt% in oil, 7.5 mmol) in THF (20 mL) and DMF (5 mL) at 0 °C and the whole was stirred for 1 h. A
solution of Bu SnCH I (3.235 g, 7.5 mmol) in THF (5 mL) was added to the reaction mixture at 0 °C and
3
2
the whole was stirred overnight. Ice water was added to the reaction mixture and the whole was extracted
with Et O (50 mL) three times. The extracts were washed with brine, dried over MgSO , and evaporated.
2
4
The residue was purified by flash column chromatography on silica gel (n-hexane : AcOEt = 15 : 1) to
2
5
1
give (S)-5 (2.46 g, 98 %) as an oil; [ꢀ]D +45.7° (c 5.10, CHCl ). H NMR (600 MHz,CDCl ) d 0.86–0.94
3
3

HETEROCYCLES, Vol. 72, 2007
639
(
m, 15H), 1.25–1.35 (m, 6H), 1.46–1.56 (m, 15H), 3.11 (br s
,
0.5H), 3.31 (br s
,
0.5H), 3.63–4.00 (m, 6H),
1
3
5
1
5
.71–5.92 (m, 2H). C NMR (67.8 MHz, CDCl ) d 9.0, 13.7, 27.2, 28.4, 29.1, 43.6, 44.5, 59.4, 74.6, 79.5,
3
-
1
+
25.8, 126.9, 154.5. IR (neat) cm : 1703, 758. EI-MS (m/z): 502 (M –1). HRMS calcd for C H NO Sn:
2
3
45
3
03.2422, found: 503.2367.
2
6
(
(
R)-5 : (99%) [ꢀ]D –43.9° (c 1.08, CHCl3)
R)-N-tert-Butoxycarbonyl-5-(hydroxymethyl)-3-piperidene [(R)-6]
n-BuLi (4.5 mL, 1.6M in n-hexane, 6.98 mmol) was dropwise added to a solution of
(S)-5 (2.12 g,
4.23 mmol) in dry pentane (85 mL) at –80 °C and stirred for 1 h at the same temperature, and
subsequently stirred at –40 °C for 2 h.
sat. aqueous NH Cl (20 mL) was added the reaction mixture
4
and the whole was separated. The organic layer was dried over Na SO , and evaporated. The residue was
2
4
purified by flash column chromatography on silica gel (n-hexane : AcOEt = 15 : 1~ 2 : 1) to give (R)-6
2
4
1
(
582 mg, 65%) as an oil; [ꢀ]D –92.1° (c 1.10, CHCl ). H NMR (600 MHz, CDCl ) ꢁ 1.46 (s, 9H), 2.11
3 3
(
br s, 0.5H), 2.38 (br s, 1H), 2.96 (br s, 0.5H), 3.21–3.83 (m, 5H), 4.03 (d, J = 18.3Hz, 1H), 5.73 (br s,
1
3
-1
2
H). C NMR (67.8 MHz, CDCl ) d 28.4, 38.1, 41.3, 44.2, 63.1, 79.9, 125.8, 126.2, 154.9. IR (neat) cm :
3
+
3
435, 1698. EI-MS (m/z): 213 (M ). HRMS calcd for C H NO : 213.1365, found: 213.1361.
1
1
19
3
2
2
(
(
S)-6 (65%); [ꢀ]D +89.1° (c 1.50, CHCl ).
3
3S,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)piperidine [(+)-3-epiisofagomine (7)] and (3R,4S,5R)-
,4-Dihydroxy-5-(hydroxymethyl)piperidine ((-)-4-epiisofagomine (8) )
To a solution of (R)-6 (200 mg, 0.94 mmol) in acetone (6 mL) was added an aqueous 4% OsO solution
3
4
(
130 mL, 0.02 mmol). After 10 min, an aqueous 50% NMO solution (352 mg, 1.5 mmol) was added and
the mixture was stirred overnight. To the solution were added Na SO and Na SO . The mixture was
2
3
2
4
filtered through a Celite pad and the filtrate was evaporated. The residue was chromatographed on silica
gel (CHCl : MeOH = 10 : 1) to give a diastereoisomeric mixture of tert-butyl 3,4-dihydroxy-5-
3
(
(
hydroxymethyl)piperidine-1-carboxylates (210 mg, 90 %). To a solution of the above diol in 1,4-dioxane
6 mL) was added 10% HCl (15 mL). The reaction mixture was refluxed for 1 h and evaporated. 28%
NH OH was added to the residue and evaporated. The residue was chromatographed on silica gel
4
(
MeOH : 10% NH OH = 10 : 1) to give 7 (104 mg, 83%) and 8 (20 mg, 16%) as oils;
4
2
4
1
7
2
1
; [ꢀ]D +85.2° (c 1.04, EtOH). H NMR (270 MHz, D O) ꢁ 1.72–1.88 (m, 1H), 2.22 (t, J = 12.1 Hz, 1H),
2
.54 (d, J = 14.2 Hz, 1 H), 2.80–2.98 (m, 2H), 3,42–3.54 (m, 2H), 3.61 (dd, J = 11.4, 3.8 Hz, 1H), 3.73 (s,
1
3
+
H). C NMR (67.8 MHz, D O) ꢁ 39.0, 44.9, 48.1, 60.3, 66.8, 69.2. EI-MS (m/z): 147 (M ). HRMS calcd
2
for C H NO : 147.0895, found: 147.0894.
6
13
3
2
5
1
8
2
3
; [ꢀ]D –5.1° (c 0.98, EtOH). H NMR (270 MHz, D O) ꢁ 1.64–1.78 (m, 1H), 2.33 (t, J = 12.3 Hz, 1H),
2
.53 (t, J = 11.6 Hz, 1 H), 2.63 (dd, J = 12.9, 4.5 Hz, 1H), 2.72 (dd, J = 12.1, 4.9 Hz, 1H), 3.36–3.57 (m,
1
3
+
H), 4.61 (s, 1H). C NMR (67.8 MHz, D O) ꢁ 39.9, 41.5, 43.5, 60.1, 67.1, 68.1. EI-MS (m/z): 147 (M ).
2

640
HETEROCYCLES, Vol. 72, 2007
HRMS calcd for C H NO : 147.0895, found: 147.0887.
6
13
3
An alternative synthesis of 7 and 8 using OsO -TMEDA complex.
4
A solution of OsO (245.2 mg, 0.95 mmol) in CH Cl (2 mL) was added to a solution of (R)-6 (186 mg,
4
2
2
0
.87 mmol) and TMEDA (111.6 mg, 0.95 mmol) in CH Cl (15 mL) at –78 °C. The mixture was stirred at
2 2
the same temperature for 2 h, warmed to rt, and stirred for 1 h. The reaction mixture was evaporated. The
residue was dissolved in MeOH (10 mL), 35% HCl (1 mL) was added, and the mixture was stirred at rt
for 2 h, and then evaporated. The residue was treated with 28% NH OH and evaporated. The residue was
4
chromatographed on silica gel (MeOH : 10% NH OH = 10 : 1) to give 7 (78 mg, 61%) and 8 (47 mg,
4
3
7%) as oils;
ent-7 (71%); [ꢀ]D –83.7° (c 1.06, EtOH). and ent-8 (20%); [ꢀ]D +3.5° (c 1.02, EtOH).
R)-N-tert-Butoxycarbonyl-5-((tert-butyldiphenylsilyloxy)methyl)-3-piperidene [(R)-10]
To a solution of (R)-6 (507 mg, 2.38 mmol) in CH Cl (15 mL) was added imidazole (243 mg, 3.57
2
5
25
(
2
2
mmol), DMAP (5.8 mg, 0.05 mmol), and tert-butylchlorodiphenylsilane (720 mg, 2.62 mmol). The
mixture was stirred at rt for 3 h. The reaction mixture was filtered through a Celite pad. The filtrate was
washed with brine (10 ml), dried over MgSO , and concentrated under reduced pressure. The residue was
4
purified by flash column chromatography on silica gel (n-hexane : AcOEt = 15 : 1) to give (R)-10 (1.06 g,
2
1
1
9
8 %) as a colorless oil; [ꢀ]D –82.9° (c 1.20, CHCl ). H NMR (600 MHz, CDCl ) ꢁ: 1.08 (s, 9H), 1.49
3 3
(
s, 9H), 2.44-2.54 (m, 1H), 3.30– 3.59 (m, 3H), 3.70–3.89 (m, 2H), 3.94 (dd, J= 18.7, 2.0 Hz, 1H), 5.61
1
3
(
br s, 1H), 5.71 (br s, 1H), 7.38-7.45 (m, 6H), 7.67-7.70 (m, 4H). C NMR (150 MHz, CDCl ) ꢁ19.2, 26.8,
3
-
1
2
8.4, 38.4, 43.3, 64.9, 79.4, 126.0, 127.6, 129.6, 133.6, 134.8, 135.5, 155.1. IR (KBr) cm : 1699. EI-MS
(
(
(
(
m/z): 452 (M+1). HRMS calcd for C H NO Si: 451.2543, Found: 451.2578.
27 37 3
2
1
S)-10 (99%); [ꢀ]D +85.4° (c 1.30, CHCl ).
3
3R,4R,5S)-N-tert-Butoxycarbonyl-3-(tert-butyldiphenylsilyloxymethyl)-4,5-dihydroxypiperidine
11) and (3R,4S,5R)-N-tert-Butoxycarbonyl-3-(tert-butyldiphenylsilyloxymethyl)-4,5-dihydroxy-
piperidine (12)
To a solution of (R)-10 (1.05 g, 2.3 mmol) in acetone(18 mL) was added an aqueous 4% OsO solution
4
(
335 mL, 0.05 mmol). After 10 min, an aqueous 50% NMO solution (905 mL mg, 3.8 mmol) was added
and the mixture was stirred overnight. To the solution were added Na SO and Na SO . The mixture was
2
3
2
4
filtered through a Celite pad and the filtrate was evaporated. The residue was chromatographed on silica
gel (n-hexane : AcOEt = 1 : 1 ~ 1 : 2) to give a diastereoisomeric mixture of 11 (637 mg, 57 %) and
1
1
2 (208 mg, 19%) as oils;
2
1
1
1: [ꢀ] D –8.9° (c 2.5, CHCl ). H NMR (270 MHz, CDCl ) ꢁ 1.05 (s, 9H), 1.43 (s, 9H), 2.05 – 2.18
3
3
(
m, 1H), 2.57 (br s, 1H), 2.86 (d, J= 13.7 Hz, 1H), 3.39 – 3.97 (m, 4H), 3.97 – 4.06 (m, 1H), 4.14 (d, J=
1
3
1
6.0 Hz, 1H), 7.30 – 7.48 (m, 6H), 7.60 – 7.81 (m, 4H). C NMR(100 MHz, CDCl ) ꢁ 19.1, 26.8, 28.4,
3

HETEROCYCLES, Vol. 72, 2007
641
-
1
3
1
1
9.4, 44.5, 47.5, 65.3, 67.6, 74.1, 79.9, 128.0, 129.9, 132.6, 135.6, 155.9. IR (KBr) cm : 3438, 1697,
+
669. EI-MS (m/z): 486 (M +1). HRMS calcd for C H NO Si: 485.2598, Found: 485.2524.
2
7
39
5
2
0
1
2: [ꢀ]D –32.0° (c 1.1, CHCl ). H NMR (270 MHz, CDCl ) ꢁ 1.05 (s, 9H), 1.43 (s, 9H), 1.70 – 1.83
3
3
(
m, 1H), 2.78 – 3.00 (m, 2H), 3.21 – 3.64 (m, 3H), 3.67 – 3.88 (m, 2H), 3.91 – 4.05 (br, 1H), 7.26 – 7.50
1
3
(
m, 6H), 7.59 – 7.84 (m, 4H). C NMR(100 MHz, CDCl ) ꢁ 19.1, 26.7, 28.4, 40.8, 42.5, 43.6, 63.8, 66.2,
3
-
1
+
6
8.8, 79.9, 127.7, 129.9, 133.1, 135.5, 154.8. IR (KBr) cm : 3436, 1697, 1674. EI-MS (m/z): 486 (M +1).
HRMS calcd for C H NO Si: 485.2598, Found: 485.2590.
2
7
39
5
2
5
24
ent-11 (56%); [ꢀ]D +9.7° (c 1.1, CHCl ). ent-12 (21%); [ꢀ]D +32.2° (c 1.0, CHCl ).
3
3
(
3aS,7R,7aR)-Hexahydro-N-tert-butoxycarbonyl-7-(tert-butyldiphenyl-silyloxymethyl)-1,3-dioxa-2-
thia-5-azaindene 2,2-dioxide (13)
To a solution of diol 11 (437 mg, 0.9 mmol) in CH Cl (11.0 mL) at –15 °C were added Et N (0.45 mL,
2
2
3
3
.24 mmol) and thionyl chloride (99 μL, 1.35 mmol). The resultant mixture was stirred at –15 °C for 30
min and then poured into ice-water (20 mL). The mixture was extracted with CHCl (3 x 20 mL), and the
3
combined organic layers were washed with brine (10 mL), dried over MgSO , filtered, and concentrated
4
under reduced pressure to give a cyclic sulfite (500 mg) as an oil. To a solution of the above cyclic sulfite
in MeCN/CCl /H O (2:2:3, v/v, 21.0 mL) at rt were added NaIO (339 mg, 1.6 mmol) and RuCl (12 mg,
4
2
4
3
4
5 μmol) followed by water (4.0 mL). The resultant mixture was stirred at rt for 1 h and then extracted
with Et O (60 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO ,
2
4
filtered, and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (n-hexane : AcOEt = 2 : 1) to give 13 (417 mg,76 %) as a colorless oil; [ꢀ]
2
6
1
+
12.7° (c 1.3, CHCl ). H NMR (270 MHz, CDCl ) ꢁ 1.07 (s, 9H), 1.45 (s, 9H), 2.32 – 2.48 (m, 1H),
D
3
3
2
.97 (dd, J = 13.4, 11.2 Hz, 1H), 3.36 (d, J = 15.7 Hz, 1H), 3.72 (dd, J= 10.8, 3.4 Hz, 1H), 3.84 (br s, 1H),
4
7
1
.07 (br s, 1H), 4.45 (br d, J = 15.2 Hz, 1H), 4.97 (br s, 1H), 5.16 (br s, 1H), 7.37 – 7.47 (m, 6H), 7.59 –
1
3
.63 (m, 4H). C NMR(100 MHz, CDCl ) ꢁ 19.1, 26.8, 28.1, 39.3, 42.6, 43.9, 60.9, 78.2, 81.0, 81.4,
3
-
1
+
27.8, 130.0, 132.4, 135.4, 154.3. IR (KBr) cm : 1703. EI-MS (m/z): 546 (M -1). HRMS calcd for
C H NO SSi: 547.2060, Found: 547.2103.
2
7
37
7
(
3R,4R,5R)-3,4-Dihydroxy-5-hydroxymethylpiperidine [(+)-isofagomine (3)] and (3S,4S,5R)-3,4-
Dihydroxy-5-hydroxymethylpiperidine [(+)-3,4-di-epiisofagomin (9)]
To a solution of cyclic sulfate 13 (164 mg, 0.3 mmol) in DMF (3.0 mL) at rt were added cesium
carbonate (150 mg, 0.465 mmol) and PhCOOH (63 mg, 0.54 mmol). The resultant suspension was stirred
at 60 °C for 4 h and then concentrated under reduced pressure to give an benzoxy sulfate as a pale yellow
solid. To a stirred suspension of the above benzoxy sulfate in THF (6.0 mL) at rt were added concentrated
H SO (4 drops) and H O (6 drops). The mixture was stirred at rt for 22 h and then partitioned between
2
4
2

642
HETEROCYCLES, Vol. 72, 2007
CHCl (30 mL) and sat. aq. NaHCO (10 mL). The organic layer was separated, and the aqueous layer
3
3
was extracted with CHCl . The combined organic layers were washed with brine, dried over MgSO ,
3
4
filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (n-
hexane : AcOEt = 1 : 1) to give (3R,4R,5R)-N-tert-butoxycarbonyl-3-benzoyloxy-5-(tert-butyldiphenyl-
silyloxymethyl)-4-hydroxypiperidine 14 (82 mg, 46 %) and (3R,4S,5S)-N-tert-butoxycarbonyl-4-
benzoyloxy-5-(tert-butyldiphenylsilyloxymethyl)-3-hydroxypiperidine 15 (75.0 mg, 42 %) as oils. A
solution of 14 (49.5 mg. 0.084 mmol) was dissolved in 6N HCl (10 mL) was heated at 120 °C for 12 h.
and then washed with CHCl . The aqueous layer was evaporated and the residue was treated with 28%
3
NH OH and evaporated. The residue was chromatographed on silica gel (MeOH : 10% NH OH = 10 : 1)
4
4
to give 3 (12 mg, 98%). According to the procedure described for 3, 15 (41 mg. 0.0695 mmol) gave (+)-
3
,4-di-epi-isofagomine, 9 (9.8 mg, 96 %).
25
1
3
: [ꢀ]D +25.4° (c 1.30, EtOH). H NMR (600 MHz, D O) ꢁ 1.61–1.68 (m, 1H), 2.33–2.38 (m, 2
2
H), 3.05 (dd, J = 13.0, 3.5 Hz, 1H), 3.10 (dd, J = 12.1, 4.8 Hz, 1H), 3.27 (t, J = 9.9 Hz, 1H),
1
3
3
.43–3.48 (m, 1H), 3.59 (dd, J = 11.4, 7.0 Hz, 1H), 3.78 (dd, J = 11.4, 3.3 Hz, 1H). C NMR
+
(
67.8 MHz, D O) ꢁ: 43.9, 45.7, 48.8, 59.8, 71.4, 73.1. EI-MS (m/z): 147 (M ). HRMS calcd for
2
C H NO : 147.0895, found: 147.0845.
6
13
3
1
9
1
9
: [ꢀ]D +18.4° (c 0.96, EtOH). H NMR (270 MHz, D O) ꢁ 1.90–2.02 (m, 1H), 2.47–2.65 (m, 3H), 2.84
2
(
dd, J = 13.8, 2.9 Hz, 1H), 3.42 (dd, J = 11.1, 8.0 Hz, 1H), 3.48–3.68 (m, 2H), 3.69 (dd, J = 5.6, 3.6 Hz,
1
3
+
1
H). C NMR (67.8 MHz, D O) ꢁ 38.2, 41.4, 45.7, 59.3, 66.8, 68.7. EI-MS (m/z): 147 (M ). HRMS calcd
2
for C H NO : 147.0895, found: 147.0926.
6
13
3
(
3S,4R,5S)-N-tert-Butoxycarbonyl-3-(tert-butyldiphenylsilyloxymethyl)-4,5-epoxypiperidine
and (3S,4S,5R)-N-tert-Butoxycarbonyl-3-(tert-butyldiphenylsilyloxymethyl)-4,5-epoxypiperidine
17)
(16)
(
To a cooled (0 °C) solution of (R)-10 (433 mg, 0.96 mmol) in MeCN (10 mL) was added 4 mmol/L aq.
Na EDTA (5 mL, 0.02 mmol) and 1,1,1-trifluoroacetone (1 mL). The mixture of NaHCO (630 mg, 7.5
2
3
®
mmol) and Oxone (3.07 g，5.0 mmol) as a solid were added slowly over a period of 1 h at 0 °C. After
being stirred at 0 °C overnight, the solution was quenched by adding water (30 mL), and extracted with
CHCl (30 mL x 3). The organic extracts were combined, dried over Na SO , filtered, and concentrated
3
2
4
under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-
2
2
hexane : AcOEt = 11 : 1) to give 16 (231 mg, 52 %) and 17 (152 mg, 34 %) as colorless oils. 16: [ꢀ] D
1
-
41.7 ° (c 1.23, CHCl ). H NMR (600 MHz, CDCl ) ꢁ 1.06 (s, 9H), 1.41 (br d, J = 28.9Hz, 9H), 2.33 (br
3
3
d, J = 25.0 Hz, 1H), 3.06-3.28 (m, 3H), 3.37-3.77 (m, 4H), 3.93 (dd, J = 52.4, 14.5 Hz, 1H), 7.30-7.45 (m,
1
ꢂ
6
H), 7.65 (d, J = 7.7 Hz, 4H). H NMR (400 MHz, C D 60 C) ꢁ 1.17 (s, 9H), 1.45 (s, 9H), 2.31 (t, J =
6 6,
5.9 Hz, 1H), 2.68 (t, J = 3.2 Hz, 1H), 2.96 (s, 1H), 3.10 (dd, J = 13.4, 6.8 Hz, 1H), 3.35 (br s, 1H), 3.57-

HETEROCYCLES, Vol. 72, 2007
643
1
3
3
.67 (m, 3H), 3.89 (d, J = 15.1 Hz, 1H), 7.26-7.30 (m, 6H), 7.72-7.75 (m, 4H). C NMR (100
MHz,C D 60 °C) ꢀ 19.5, 27.1, 28.5, 37.1, 40.9, 42.9, 49.8, 52.3, 63.9, 79.2, 127.8, 128.1, 128.3, 128.5,
6
6,
-
1
1
1
4
1
1
4
30.1, 133.9, 133.9, 135.9, 136.0, 155.1. IR (neat) cm : 2962, 2931, 2859, 1696, 1473, 1461, 1428, 1392,
+
366, 1248, 1174, 1113. EI-MS (m/z): 468 (M +1). HRMS calcd for C H NO Si: 467.2492, found:
2
7
37
4
67.2465.
2
2
1
7: [ꢁ]D -32.7 ° (c 1.10, CHCl ). H NMR (400 MHz, CDCl ) ꢀ 1.07 (s, 9H), 1.44 (s, 9H), 2.27-2.32 (m,
3
3
H), 2.70-2.72 (m, 1H), 3.25 (br s, 1H), 3.25-3.30 (m, 2H), 3.43-3.51 (m, 1H), 3.64-3.80 (m, 3H), 3.92-
1
3
.06 (m, 1H), 7.38-7.45 (m, 6H), 7.66-7.69 (m, 4H). C NMR (150 MHz, CDCl ) ꢀ 19.2, 26.8, 28.4, 38.2,
3
-
4
0.1, 40.7, 41.7, 50.7, 51.9, 63.7, 79.8, 127.7, 129.7, 133.4, 133.4, 135.5, 135.6, 154.7. IR (neat) cm
1
:
2962, 2932, 2859, 1695, 1473, 1462, 1428, 1392, 1366, 1247, 1174, 1152, 1113, 1083. EI-MS (m/z):
+
4
68 (M +1). HRMS calcd for C H NO Si: 467.2492, found: 467.2580.
2
7
37
4
2
2
22
ent-16 (40%); [ꢁ]D +41.3 ° (c 1.26, CHCl ). ent-17 (21%); [ꢁ]D +30.5 ° (c 1.33, CHCl ).
3
3
An Alternative synthesis of 3 and 9 from 16 and 17.
A mixture of 16 (103 mg，0.22 mmol), 1,4-dioxane (5.6 mL), and 3ꢀM KOH (11.2 mL) was refluxed
overnight. After evaporation, MeOH (2ꢀmL) and 6ꢀN HCl (6.2mL) were added to the residue. The mixture
was heated at 60ꢀ°C for 1ꢀh and evaporated. The residue was treated with 28% NH OH and evaporated.
4
The residue was chromatographed on silica gel (MeOH : 10% NH OH = 10 : 1) to give 3 (9 mg, 28%)
4
and 9 (20 mg, 62%). By similar procedure described the above, 17 (104 mg，0.22 mmol) gave 3 (17 mg,
53%) and 9 (12 mg, 37%).
ACKNOWLEDGEMENTS
This research was supported by the Uehara Memorial Foundation and a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-Element Cyclic Molecules’ from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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