Divergent synthesis of L-sugars and L-iminosugars from D-sugars

Article abstract of DOI:10.1002/chem.200600268

An efficient divergent synthesis of L-sugars and L-iminosugars from D-sugars is described. The important intermediate. δ-hydroxyalkoxamate. prepared from D-glucono-/galactono-1,5-lactone, was cyclized under Mitsunobu conditions to give the O-cyclized oxim

Full text of DOI:10.1002/chem.200600268

DOI: 10.1002/chem.200600268
Divergent Synthesis of l-Sugars and l-Iminosugars from d-Sugars
Hideyo Takahashi, Tomomi Shida, Yuko Hitomi, Yoshinori Iwai, Namisa Miyama,
Kazusa Nishiyama, Daisuke Sawada, and Shiro Ikegami*[a]
Abstract: An efficient divergent syn-
thesis of l-sugars and l-iminosugars
from d-sugars is described. The impor-
tant intermediate, d-hydroxyalkoxa-
mate, prepared from d-glucono-/galac-
tono-1,5-lactone, was cyclized under
Mitsunobu conditions to give the O-cy-
clized oxime compound and the N-cy-
clized lactam compound as mixtures. A
more detailed investigation revealed
that the appropriate protecting groups
and solvents controlled the specificity
for the O-/N-cyclization of the d-hy-
droxyalkoxamate. Suitable protection
at the 6-position of d-hydroxyalkoxa-
mate, derived from d-glucono-1,5-lac-
tone, afforded the corresponding O-al-
kylation product alone. Thus we suc-
ceeded in applying this to the total syn-
thesis of l-iduronic acid. In contrast,
with both TBDMS as the protecting
group and RCN as the solvent the effi-
cient conversion of d-glucono/galacto-
no-1,5-lactone into the corresponding
l-iminosugars (l-idonolactam and l-al-
tronolactam) was achieved.
Keywords: azasugars
drates lactams
Mitsunobu reaction
·
carbohy-
lactones ·
·
·
Introduction
As a part of our program for the utilization of sugar de-
rivatives as synthetic tools,[37–41] we became interested in the
cyclization of hydroxyalkoxamates derived from natural d-
sugars. In fundamental research, efficient biomimetic meth-
ods for b-lactam syntheses were developed based on the in-
tramolecular N-alkylation of b-hydroxyalkoxamates derived
from amino acids.[42–45] In contrast, recent studies have re-
vealed that competitive O-alkylation occurs in several cases
with amides and carbamates.[46–52] We have therefore investi-
gated the intramolecular cyclization of d-hydroxyalkoxa-
mates derived from d-glycono-1,5-lactone under Mitsunobu
conditions.[53] It was found that the cyclization of d-hydrox-
yalkoxamates derived from d-glycono-1,5-lactone resulted
mainly in O-alkylation rather than N-alkylation. Taking ad-
vantage of the structural relationships between d-glucose
and l-idose, d-galactose and l-altrose, and d-mannose and
l-gulose, we utilized the O-alkylated products, which had in-
verted stereochemistry at C5, as precursors for the corre-
sponding l-sugars (Scheme 1).[54]
While d-sugars are abundant in nature and frequently used
as chiral resources in the synthesis of complex natural prod-
ucts, l-sugars are rare and have been overlooked in synthet-
ic organic chemistry. l-Sugars, however, play important roles
in the microbial world. They are key constituents of antibi-
otics,[1] oligosaccharides,[2–3] and clinically useful nucleo-
sides.[4–6] To take notable examples, l-gulose is a key build-
ing block of the carbohydrate moiety of the antitumor anti-
[7–14]
biotic bleomycin A2
and l-iduronic acid is also a typical
component of mammalian dermatan sulfate, heparan sulfate,
and heparin.[15–18] As the requirement for l-sugars increases
in scientific fields, it becomes necessary to develop an effi-
cient method that makes them readily available and thus nu-
merous synthetic routes for l-sugars have been reported re-
cently.[19–36]
While these results were successfully applied to the novel
and practical synthesis of rare l-sugars, we continued to in-
vestigate methods by which N-cyclized products could be
converted into precursors for the corresponding l-iminosu-
gars. Here we describe the divergent synthesis of l-sugars
and l-iminosugars based on the specifically controlled O-/N-
alkylation of d-hydroxyalkoxamate.
[a] Prof. H. Takahashi, T. Shida, Y. Hitomi, Y. Iwai, N. Miyama,
K. Nishiyama, Dr. D. Sawada, Prof. S. Ikegami
School of Pharmaceutical Sciences
Teikyo University, Sagamiko
Sagamihara, Kanagawa, 199-0195 (Japan)
Fax : (+81)426-85-3729
E-mail: hide-tak@pharm.teikyo-u.ac.jp
shi-ike@pharm.teikyo-u.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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FULL PAPER
Scheme 1. Synthesis of l-pyranose from d-glycono-1,5-lactone.
Results and Discussion
An approach to l-iduronic acid: As an extension of the pre-
vious work, we first reconsidered O-cyclization from a syn-
thetic point of view. In this case, we focused on the synthesis
of l-iduronic acid. Thus it was necessary to protect O6 of d-
glucono-1,5-lactone, so that subsequent oxidation of C6
could take place to provide uronic acid. Initially, the 6-ace-
tylated lactone 19[55] was examined (Scheme 2).
Scheme 3. Cyclization of 6-siloxy-d-hydroxyalkoxamate. a) K2CO3,
MeOH, 08C, 2 h, 87%; b) TBDMSCl, imidazole, DMF, RT, 2 h, 85%;
c) BnONH2, Me3Al, CH2Cl2, RT, 1.5 h, 92%; d) TPP, DEAD, THF, RT,
10 min, 95%; TBDMS=tert-butyldimethylsilyl.
product in 95% yield. No N-cyclized product was detected
in this case. The modification at the 6-position might affect
the stability of the intermediate, which leads to O-cycliza-
tion. So far we have only limited information on this specif-
icity for O-cyclization, although it should be investigated in
detail in future. After we had confirmed that O-cyclized 27
was obtained in good yield, the next step was to complete
the synthesis of l-iduronic acid (Scheme 4).
Scheme 2. Cyclization of 6-acetyloxy-d-hydroxyalkoxamate. a) BnONH2,
Me3Al, CH2Cl2, ꢀ408C, 1h, 52% ( 20/21 30:1); b) DEAD, TPP, THF, RT,
10 min, 96% (22/23 2.5:1); DEAD=diethylazodicarboxylate; TPP=tri-
phenylphosphine.
The O-cyclized compound 27 was hydrolyzed under acidic
conditions to give l-idonolactone 28. Acetylation of 28 and
the successive reduction of 29 with DIBAL-H gave l-idose
30 as an anomeric mixture. l-Idose 30[57] was treated with
MeOH under acidic conditions to give methyl l-idosides 31
and 32 (31/32 2.2:1). Oxidation of the b-anomer 31[58] with
chromium trioxide/H2SO4 (Jones reagent), followed by es-
terification of the intermediate acid provided methyl uron-
ate 34[59,60] in 72% yield. Finally, 34 was hydrogenolyzed
with Pd(OH)2/C to give unprotected methyl uronate 35.[60]
Thus the synthesis of l-iduronic acid from d-glucono-1,5-lac-
tone was achieved.
Treatment of 19 with BnONH2 and Me3Al at 08C prefer-
entially afforded d-hydroxyalkoxamate 21 with the expected
product 20 (20/21 1:3.9). To control the migration reaction,
several conditions were examined. It was found that a lower
temperature (ꢀ408C) decreased the migration of the acetyl
group and gave 20 selectively (20/21 30:1). Although 20
easily cyclized under Mitsunobu conditions, moderate selec-
tivity for O-cyclization was observed (96% yield, 22/23
2.5:1). Variations in the reaction conditions did not signifi-
cantly change the O-/N-alkylation ratio. As satisfactory re-
sults were not obtained with the 6-acetylated lactone, the
protecting group at O6 was changed to TBDMS (Scheme 3).
The 6-acetylated lactone 19 was hydrolyzed under basic
conditions to give 24,[56] which was successively protected at
O6 with TBDMS. Alkoxyamidation of 25 proceeded
smoothly and the expected d-hydroxyalkoxamate 26 was ob-
tained in 92% yield. Exceeding our expectations, 26 cyclized
easily under Mitsunobu conditions to give 27 as the sole
N-Cyclization of d-glucono/galactono-1,5-lactones: Since d-
iminosugars (for example, Nojirimycin) were discovered to
be potent glycosidase inhibitors in nature, numerous studies
have been performed to develop effective procedures for
the synthesis of various d-iminosugars and analogues.[61–71]
What appears lacking, however, is the synthesis of l-imino-
sugars,[72] which are enantiomers of d-iminosugars. To apply
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S. Ikegami et al.
pound 10 was obtained in all cases. In particular, toluene
gave the optimum ratio of O-alkylation (Table 1, entry 1).
CH2Cl2, DMSO, and cyclohexane gave similar results (en-
tries 3–5), although C6F6, EtCN, and MeCN gave the best
ratios of N-alkylation among the various solvents examined
(entries 6–8).
In expectation of the steric effect of the bulky protecting
group, we next examined the replacement of the benzyl-pro-
tecting group in 4 with TBDMS. The d-hydroxyalkoxamate
37, derived from silyl-protecting d-glucono-1,5-lactone 36,[74]
was prepared according to the previous procedure
(Scheme 5). Treatment of 36 with O-benzylhydroxyamine in
Scheme 5. Me3Al-mediated amidation of silyl-protected d-glucono-1,5-
lactone.
Scheme 4. Synthesis of l-iduronic acid. a) TsOH, acetone, RT, 6 h, 79%;
b) Ac2O, pyridine, RT, 0.5 h, 99%; c) DIBAL-H, CH2Cl2, RT, 14 min,
88%; d) sat. HCl/MeOH, 508C, 5 h, 97% (31/32 2.2:1); e) CrO3/H2SO4
RT, 1.5 h; f) CH2N2, Et2O, 0 8C, 3 h, 72% (from 31); g) Pd(OH)2/C, H2,
MeOH, RT, 22 h, quant; Ts=p-toluenesulfonyl; DIBAL-H=diisobutyl-
aluminium hydride.
CH2Cl2 for 30 minutes, followed by the addition of Me3Al
at room temperature afforded the corresponding d-hydroxy-
benzyloxamate 37 in 83% yield. A summary of solvent ef-
fects in the cyclization of 37 under Mitsunobu conditions is
shown in Table 2.[75]
With bulky TBDMS-protecting groups, the effects of sol-
vent were seen more clearly than with other protectors.
While a higher ratio of O-cyclization was observed with
C6F6 and toluene (Table 2, entries 1and 2), N-cyclization
preferentially occurred with CH2Cl2, DMSO, MeCN, and
EtCN (entries 5–8). In particular, an excellent ratio of 39
was obtained with RCN as the solvent (entries 7 and 8). It is
noteworthy that the effects of RCN on N-cyclization were
divergent cyclization to the synthesis of l-iminosugars, it is
necessary to increase the ratio of the N-cyclized product,
which is a precursor of l-iminosugars. In the beginning, we
focused on the effects of the solvent on the cyclization of
the benzyl-protecting d-hydroxyalkoxamate 4,[73] derived
from d-glucono-1,5-lactone (Table 1). The reaction was car-
ried out with DEAD (3.0 equiv) and TPP (3.0 equiv) in a
suitable solvent at room temperature. Although the reac-
tions proceeded efficiently, contrary to our expectations the
O-cyclized compound 7 rather than the N-cyclized com-
Table 2. Cyclization of TBDMS-protected d-hydroxybenzyloxamate 37.
Table 1. Cyclization of benzyl-protected d-hydroxyalkoxamate.
Entry Solvent
1toluene
Yield of 7
Yield of 10
Ratio of 7/
Entry
Solvent
Yield [%][a]
Ratio of 38/39[b]
[%][a]
[%][a]
10[b]
1
2
3
4
5
6
7
8
C6F6
78
7122:1
50
79
62
63
611
73
27:1.0
78
0
1
7.8:1
toluene
cyclohexane
THF
CH2Cl2
DMSO
MeCN
EtCN
.0
2
3
4
5
6
7
8
THF
CH2Cl2
DMSO
cyclohexane
C6F6
EtCN
3
5.57:11
67
64
64
55
5.7:1.0
1.6:1.0
1.0:1.6
1.0:1.7
28
28
28
2.4:1
2.3:1
2.3:1
.8:1 311
.0:4.1
54
40
30
23
1.8:1
1.7:1
1.0:6.6
MeCN
[a] Isolated yield. [b] The ratio was determined by using NMR spectro-
scopic analysis.
[a] Isolated yield. [b] The ratio was based on isolated yields.
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Chem. Eur. J. 2006, 12, 5868 – 5877

l-Sugars and l-Iminosugars
FULL PAPER
seen in several cases (Table 1, entries 7 and 8; Table 2, en-
tries 7 and 8). One explanation for these results may be that
both bulky TBDMS-protecting groups and coordination of
the cyano group of RCN affect the conformation of the in-
termediate that is suitable for N-cyclization.
We further extended this to alkoxamate. To determine the
steric effect of the substitution of a hydroxamate, studies on
the formation of O-/N-alkylation products with various O-
substituted hydroxamate derivatives (40a–d) were carried
out (Table 3).[76]
clized product 42d in 81% yield with complete selectivity
(Table 4, entry 4).
After we had established efficient conditions for the N-
cyclization of d-hydroxyalkoxamate derived from d-gluco-
no-1,5-lactone, we examined the cyclization of d-galactono-
1,5-lactone. The TBDMS-protected d-hydroxyalkoxamate 44
derived from d-galactono-1,5-lactone 43[61] was employed in
this cyclization.
As observed in the case of d-glucose, the TBDMS-pro-
tecting group along with RCN as solvent increased the ratio
of N-cyclization (Table 5). Better selectivity for N-cycliza-
tion was observed for the reaction of 44b in RCN (Table 5,
entries 5, and 6).
Table 3. Effects of the alkoxy moiety of hydroxamate on the cyclization.
Table 5. Cyclization of TBDMS-protected d-hydroxyalkoxamate derived
from d-galactono-1,5-lactone 43.
Entry
X[a]
Yield [%][b]
Ratio of 41/42[c]
1Me
40a
Et 40b
tBu 40c
TBDMS 40d
99
76
56
69
1.3:1.0
1.0:1.2
1.0:1.3
1.0:1.8
2
3
4
[a] X denotes the alkoxamate-protective group. [b] Isolated yield. [c] The
ratio was determined by using NMR spectroscopic analysis.
Whilst the cyclization of 40a provided the O-alkylated
product 41a rather than the N-alkylated 42a (Table 3,
entry 1), cyclization of 40b–d resulted mainly in N-alkylated
42b–d[77] (entries 2–4). The results indicate that the steric re-
quirement of the hydroxamate moiety partly affected the
ratios of O-/N-alkylation: better selectivity for N-alkylation
was observed with the bulky TBDMS group (entry 4).
Considering the results obtained, we finally determined
the best approach to the N-cyclized product (Table 4). In
the optimized run, DEAD (8.0 equiv) and TPP (8.0 equiv)
were added at room temperature to a solution of the d-hy-
droxyalkoxamate 40d in EtCN, which provided the N-cy-
Entry
X[a]
Solvent
Yield [%][b]
45/46[c]
1Bn
44a
THF
80
73
82
69
80
75
1.6:1.0
1.0:1.7
1.0:3.3
1.0:1.2
1.0:7.1
1.0:7.8
2
3
4
5
6
MeCN
EtCN
THF
MeCN
EtCN
TBDMS 44b
[a] X denotes the alkoxamate-protective group. [b] Isolated yield. [c] The
ratio was determined by using NMR spectroscopic analysis.
As previously reported, the d-hydroxyalkoxamate 6 de-
rived from d-mannono-1,5-lactone 3 afforded the O-alkylat-
ed product as the sole product in excellent yield (Scheme 1).
We further investigated the cyclization of g-hydroxyalkoxa-
mates derived from readily available d-mannono-1,4-lac-
tone, but only the O-alkylation product was obtained. It is
noteworthy that no effect from the solvent and protecting
group was observed and hence no N-alkylation product was
detected in any case. It appears characteristic of d-mannose
derivatives to show this strange specificity for O-alkylation.
While this unique feature of mannose was successfully ap-
plied to the synthesis of l-ribose from d-mannono-1,4-lac-
tone,[78] we reluctantly abandoned attempts to obtain N-al-
kylated products from d-mannose derivatives.
Table 4. Cyclization of the fully TBDMS-protected d-hydroxyalkoxa-
mate.
Entry
Solvent
EtCN
TPP [equiv]
DEAD [equiv]
Yield [%][a]
1MeCN
6.0
6.0
61
2
3
4
8.0
6.0
8.0
8.0
6.0
8.0
78
78
81
[a] Isolated yield.
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S. Ikegami et al.
DIP-370 in a 1dm cell. Analytical and preparative TLC was conducted
on precoated TLC plates (silica gel 60 F254, Merck). Column chromatog-
raphy was performed by using Merck silica gel 60N (100–210 mm). All an-
hydrous solvents were purified according to standard methods.
Synthesis of l-iminosugars: To synthesize l-iminosugars, we
next examined the reduction of the N-alkylated products.
Of the methods examined, hydrogenolysis by using
Pd(OH)2/C as a catalyst gave the best results. Thus l-idono-
lactam 47[79,80] and l-altronolactam 48[80] were obtained in
good yields (Table 6).
General procedure for the cyclization of d-hydroxyalkoxamates: A mix-
ture of 4 (504 mg, 0.76 mmol), triphenylphosphine (594 mg, 2.27 mmol),
and DEAD (0.36 mL, 2.27 mmol) in THF (7.6 mL) was stirred at room
temperature for 30 min. After this time, the solvent was removed in
vacuo. The residue was chromatographed on silica gel (hexane/AcOEt
7:1) to give 7 (346 mg, 71%) and 10 (63 mg, 13%).
Table 6. Reduction of N-cyclization products.
General procedure for hydroxyamination:
A mixture of 1 (50 mg,
0.093 mmol) and benzylhydroxyamine (44.6 mg, 0.36 mmol) in CH2Cl2
(2 mL) was stirred at room temperature for 30 min and then a solution of
trimethylaluminum (0.34 mL of a 1.08m solution in n-hexane, 0.36 mmol)
was added. The resulting solution was stirred at room temperature for a
period of 1h. After this time, the reaction was quenched with pH 7 phos-
phate buffer and the product was extracted with CH2Cl2. The combined
organic phase was dried over Na2SO4, filtered, and the solvemt was re-
moved in vacuo. Purification by silica-gel chromatography (hexane/
AcOEt 3:1) gave 4 (57.1mg, 93%).
Entry
X[a]
Yield [%][b]
1Bn
39
47 83
84
86
78
76
2
3
4
5
6
7
Me 42a
Et 42b
tBu 42c
TBDMS 42d
Bn 46a
6-O-Acetyl-1N-benzyloxy-2,3,4-tribenzyloxy-5-hydroxy-(2R,3R,4R,5R)-
hexanamide (20) and 5-O-acetyl-1N-benzyloxy-2,3,4-tribenzyloxy-6-hy-
droxy-(2R,3R,4R,5R)-hexanamide (21):
A mixture of 19 (51.9 mg,
48 86
79
0.106 mmol) and benzylhydroxyamine (26.3 mg, 0.212 mmol) in CH2Cl2
(2 mL) was stirred at room temperature for 30 min and then a solution of
trimethylaluminum (0.196 mL of 1.08m solution in n-hexane, 0.212 mmol)
was added at ꢀ408C. The resulting solution was stirred at ꢀ408C for a
period of 1h. After this time, the reaction was quenched with pH 7 phos-
phate buffer and the product was extracted with CH2Cl2. The combined
organic phase was dried over Na2SO4, filtered, and the solvent was re-
moved in vacuo. Purification by silica-gel chromatography (hexane/
AcOEt 3:1) gave products 20/21 30:1(33.7 mg, 52%).
TBDMS 46b
[a] X denotes the alkoxamate-protective group. [b] Isolated yield.
Conclusions
We have established a divergent synthesis of l-sugars and l-
iminosugars based on the O/N-alkylation of d-hydroxyalkox-
amates derived from d-sugars. It was found that the
TBDMS protection at position 6 of d-hydroxyalkoxamates
derived from d-glucono-1,5-lactones leads to complete O-
cyclization, which is the key step in the synthesis of l-idur-
onic acid. In the synthesis of l-iminosugars, both the use of
bulkier TBDMS as the protecting group and RCN as the
solvent are the key to the N-cyclization of d-glucose/galac-
tose derivatives. The N-alkylation products obtained could
be converted into various analogues of l-iminosugars, which
may represent an appealing route to potential glycosidase
inhibitors.[55] Unfortunately, we have not yet developed any
means to achieve N-cyclization in the case of d-mannose.
However, such complete selectivity for O-cyclization allows
us to synthesize l-gulose and l-ribose derivatives efficiently.
It should be emphasized that the divergent conversion of
commercially available d-sugars into valuable l-sugars and
l-iminosugars could benefit various studies in the field of
medicinal chemistry.
Compound (20): [a]2D4 =+58.5 (c=1.10 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=8.92 (s, 1H), 7.38–7.25 (m, 20H), 4.89 (s, 2H), 4.66 (d, J=
11.0 Hz, 1H), 4.61 (d, J=11.0 Hz, 1H), 4.56 (d, J=11.0 Hz, 1H), 4.46 (d,
J=11.0 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 4.41 (d, J=11.0 Hz, 1H), 4.30
(d, J=2.8 Hz, 1H), 4.28 (dd, J=2.8, 11.5 Hz, 1H), 4.09 (dd, J=2.8,
5.5 Hz, 1H), 4.08 (dd, J=5.5, 11.5 Hz, 1H), 3.91 (ddd, J=2.5, 5.5, 7.7 Hz,
1H), 3.70 (dd, J=5.5, 7.7 Hz, 1H), 2.98 (s, 1H), 2.04 ppm (s, 3H);
13C NMR (150 MHz, CD3OD): d=171.1, 169.4, 137.4, 136.0, 135.2, 128.9,
128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 79.6, 77.0, 76.8, 76.4,
75.1, 73.8, 74.0, 70.4, 65.6, 20.9 ppm; IR (neat): n˜ =3387, 1738, 1684 cmꢀ1
;
HRMS (FAB-Gly+NaI): calcd for C9H17O6: 617.2754; found: 617.2749.
Compound (21): [a]2D8 =+44.2 (c=1.10 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=8.89 (s, 1H), 7.23–7.41 (m, 20H), 4.95 (ddd, J=2.8, 3.9,
6.1Hz, 1H), 4.88 (s, 2H), 4.76 (d, J=11.5 Hz, 1H), 4.70 (d, J=10.4 Hz,
1H), 4.66 (d, J=11.5 Hz, 1H), 4.58 (d, J=10.4 Hz, 1H), 4.50 (d, J=
11.0 Hz, 1H), 4.43 (d, J=11.0 Hz, 1H), 4.17 (d, J=3.3, 1H), 4.02 (dd, J=
2.8, 7.7 Hz, 1H), 4.00 (dd, J=3.3, 7.7 Hz, 1H), 3.93 (dd, J=3.9, 12.1 Hz,
1H), 3.88 (dd, J=6.1, 12.1 Hz, 1H), 1.99 ppm (s, 3H); 13C NMR
(150 MHz, CD3OD): d=170.5, 138.0, 137.9, 137.1, 135.2, 129.2, 129.0,
128.9, 128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.0, 80.8, 78.2, 79.2, 74.2,
74.0, 73.3, 70.4, 65.7, 62.3, 20.1ppm; IR (neat): n˜ =3393, 1736, 1680 cmꢀ1
;
HRMS (FAB-Gly+NaI): calcd for C9H16O6Na: 636.2574; found:
636.2581.
2N-Benzyloxy-3,4,5-tris(benzyloxy)-6-acetoxymethyl-(3R,4S,5R,6S)-tetra-
hydo-2H-pyran-2-imine (22) and 1,3,4,5-tetrakis(benzyloxy)-6-acetoxy-
methyl-(3R,4S,5R,6S)-tetrahydropyridine-2(1H)-one (23): Compound 20
(271mg, 0.442 mmol) was converted into products 22/23 2.5:1(251mg,
0.422 mmol, 96%).
Experimental Section
General experimental: Melting points were determined with a Yanagimo-
to micro melting point apparatus and are uncorrected. IR spectra were
measured with a JASCO FTIR-8000 spectrometer. HRFABMS were
taken with a JEOL SX-102A spectrometer. 1H and 13C NMR spectra
were recorded with 400 and 600 MHz pulse Fourier transform NMR
spectrometers (JEOL AL-400, JEOL ECP-600) in CDCl3 solution with
TMS as an internal standard. Chemical shifts were reported in ppm
downfield from TMS. Optical rotations were measured by a JASCO
Compound (22): M.p. 1088C (hexane/AcOEt); [a]2D4 =+2.30 (c=1.00 in
CHCl3); 1H NMR (600 MHz, CDCl3): d=7.42–7.22 (m, 20H), 5.09 (s,
2H), 4.72 (d, J=11.5 Hz, 1H), 4.64 (d, J=12.1 Hz, 1H), 4.59 (d, J=
12.1 Hz, 1H), 4.49 (d, J=11.5 Hz, 1H), 4.48 (m, 1H), 4.43 (dd, J=7.2,
11.6 Hz, 1H), 4.42 (d, J=12.1 Hz, 1H), 4.38 (dd, J=4.4, 11.6 Hz, 1H),
4.37 (d, J=12.1, 1H), 4.07 (d, J=5.0, 1H), 3.88 (dd, J=4.4, 5.0 Hz, 1H),
3.67 (dd, J=2.8, 4.4 Hz, 1H), 1.99 ppm (s, 3H); 13C NMR (150 MHz,
CDCl3): d=170.6, 149.4, 138.3, 137.4, 137.2, 128.5, 128.4, 128.3, 128.2,
5872
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 5868 – 5877

l-Sugars and l-Iminosugars
FULL PAPER
128.1, 128.0, 127.9, 127.8, 127.7, 77.9, 76.8, 75.1, 71.6, 77.0, 74.9, 74.6, 71.7,
62.8, 20.8 ppm; IR (KBr): n˜ =1744, 1645 cmꢀ1; HRMS (EI): calcd for
C36H37NO7: 595.2570; found: 595.2582.
5.07 (d, J=11.48 Hz, 1H), 4.69–4.57 (m, 4H), 4.47 (m, 1H), 4.30 (d, J=
12.2 Hz, 1H), 4.20 (d, J=6.35 Hz, 1H), 3.97 (dd, J=6.84, 11.96 Hz, 1H),
3.92 (dd, J=1.22, 6.35 Hz, 1H), 3.72 (dd, J=1.22, 1.46 Hz, 1H), 3.65 ppm
(dd, J=4.88, 11.96 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=169.30,
137.07, 136.81, 136.53, 136.96, 128.47, 128.44, 128.42, 128.40, 128.05,
128.02, 127.95, 127.92, 127.84, 127.82, 79.84, 78.54, 75.10, 73.43, 64.51,
72.60, 72.59, 71.17 ppm; IR (KBr): n˜ =3357, 1746 cmꢀ1; HRMS (EI):
calcd for C27H28O6: 448.1886; found: 448.1891.
Compound (23): [a]2D4 =+26.4 (c=1.00 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=7.42–7.19 (m, 20H), 5.27 (d, J=11.0 Hz, 1H), 4.92 (d, J=
11.0 Hz, 1H), 4.86 (d, J=11.0 Hz, 1H), 4.79 (d, J=11.0 Hz, 1H), 4.75 (s,
2H); 4.54 (d, J=11.5 Hz, 1H), 4.49 (d, J=3.3, 11.5 Hz, 1H), 4.42 (d, J=
11.5 Hz, 1H), 4.12 (dd, J=2.2, 11.5 Hz, 1H), 3.98–3.94 (m, 2H), 3.62 (m,
1H), 3.39 (ddd, J=2.2, 3.3, 5.5 Hz, 1H), 1.97 ppm (s, 3H); 13C NMR
(150 MHz, CDCl3): d=170.1, 169.0, 138.1, 137.2, 135.2, 129.6, 128.9,
128.6, 128.5, 128.3, 128.1, 128.0, 84.5, 79.2, 77.2, 75.7, 75.0, 74.9, 73.3, 64.2,
58.1, 20.8 ppm; IR (neat): n˜ =1748, 1703 cmꢀ1; HRMS (EI): calcd for
C36H37NO7: 595.2570; found: 595.2566.
6-O-Acetyl-2,3,4-tri-O-benzyl-l-idono-1,5-lactone (29): Excess acetic an-
hydride (0.1mL) was added to a solution of 28 (5.0 mg, 0.011 mmol) in
pyridine (0.1mL) at RT. The solution was stirred at RT for 12 h and was
then poured into water. The aqueous layer was extracted with CH2Cl2
and the combined organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by chromatography on
silica gel with (hexane/AcOEt 2:1) to give 29 (5.4 mg, 0.011 mmol,
99.1%) as a white solid. M.p. 99 8C (hexane/AcOEt); [a]2D6 =+35.3 (c=
0.94 in CHCl3); 1H NMR (600 MHz, CDCl3): d=7.43–7.21(m, 51H),
5.06 (d, J=11.5 Hz, 1H), 4.67 (d, J=12.1 Hz, 1H), 4.65 (d, J=11.5 Hz,
1H), 4.60 (d, J=12.1 Hz, 1H), 4.57 (d, J=12.1 Hz, 1H), 4.56 (m, 1H),
4.33 (dd, J=7.2, 11.6 Hz, 1H), 4.30 (d, J=12.1, 1H), 4.20–4.17 (m, 2H),
3.91(dd, J=1.7, 6.6 Hz, 1H), 3.69 (dd, J=1.7, 1.7 Hz, 1H), 1.99 ppm (s,
3H); 13C NMR (150 MHz, CDCl3): d=170.4, 169.0, 137.2, 136.9, 136.5,
128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 79.5, 78.4, 74.9, 74.6, 73.4, 72.6,
62.4, 20.7 ppm; IR (KBr): n˜ =1750 cmꢀ1; HRMS (EI): calcd for C29H30O7:
490.1991; found: 490.1981.
2,3,4-Tri-O-benzyl-6-O-[tert-butylACHTREU(NG dimethyl)silyl]-d-glucono-1,5-lactone
(25): Imidazole (31.8 mg, 0.467 mmol) and TBDMSCl (70.42 mg,
0.467 mmol) were added to a solution of 24 (69.8 mg, 0.156 mmol) in
DMF (1.5 mL) at 08C. The solution was stirred at RT for 2 h and was
then poured into water. The aqueous layer was extracted with CH2Cl2
and the combined organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by chromatography on
silica gel with (hexane/AcOEt 3:1) to give the lactone compound 25
(74.8 mg, 0.133 mmol, 85.4%). [a]2D4 =+76.0 (c=1.00 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.27–7.11 (m, 15H); 4.87 (s, 2H); 4.89
(d, J=11.2 Hz, 1H); 4.64 (d, J=10.8 Hz, 1H); 4.28 (d, J=11.2 Hz, 1H);
4.54–4.47 (m, 3H); 4.16 (m, 1H); 3.94 (d, J=7.2 Hz, 1H); 3.83 (dd, J=
7.2, 7.2 Hz, 1H); 3.78 (dd, J=7.2, 7.2 Hz, 1H); 3.73 (dd, J=2.4, 11.6 Hz,
1H); 3.65 (dd, J=2.4, 11.6 Hz, 1H); 0.74 (s, 9H); ꢀ0.08 ppm (s, 6H);
13C NMR (150 MHz, CDCl3): d=169.6, 137.7, 137.6, 137.1, 128.5, 128.5,
128.4, 128.3, 128.1, 128.1, 128.0, 127.9, 81.0, 79.4, 77.8, 75.7, 74.2, 74.05,
2,3,4-Tri-O-benzyl-l-idose (30): DIBAL-H (0.45 mL, 0.43 mmol, 0.95m in
n-hexane) was added to a solution of 29 (70.3 mg, 0.14 mmol) in CH2Cl2
(1.4 mL) at 08C. The solution was stirred at RT for 15 min and was then
poured into saturated NH4Cl. The aqueous layer was extracted with
CH2Cl2 and the combined extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by chromatography on
silica gel with (hexane/AcOEt 2:1) to give 56.8 mg (0.13 mmol, 88%) of
73.92, 61.62, 25.83, 18.24, ꢀ5.48, ꢀ5.28 ppm. IR (neat): n˜ =1757 cmꢀ1
;
HRMS (EI): calcd for C33H42O6Si: 562.2751; found: 562.2775.
1N-Benzyloxy-2,3,4-tribenzyloxy-6-tert-butyldimethylsilyloxy-5-hydroxy-
1
the l-idose derivative 30 as the a/b-mixture. H NMR (600 MHz, CDCl3)
(2R,3S,4R,5R)-hexanamide (26): Compound 25 (30.9 mg, 0.06 mmol) was
converted into 26 (34.6 mg, 0.05 mmol, 92%). [a]2D4 =+29.4 (c=1.00 in
EtOH); 1H NMR (400 MHz, CDCl3): d=7.36–7.13 (m, 20H), 4.87 (s,
2H), 4.78 (d, J=11.6 Hz, 1H), 4.70 (d, J=10.8 Hz, 1H), 4.56 (m, 2H),
4.46 (s, 2H), 4.32 (d, J=3.6 Hz, 1H), 4.06 (dd, J=3.6, 6.0 Hz, 1H), 3.80
(dd, J=6.0, 7.6 Hz, 1H), 3.76 (d, J=3.2, 9.6 Hz, 1H), 3.72 (m, 1H); 3.62
(dd, J=5.2, 9.6 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 ppm (s, 3H);
13C NMR (150 MHz, [D6]acetone): d=168.78, 138.24, 137.64, 136.59,
135.37, 128.94, 128.66, 128.61, 128.51, 128.49, 128.40, 128.38, 128.33,
128.19, 128.01, 127.85, 127.67, 80.83, 79.60, 78.15, 77.69, 75.59, 74.33,
73.78, 72.19, 64.04, 25.90, 18.41, ꢀ5.37, ꢀ5.31ppm. IR (neat): n˜ =3378,
major: d=7.43–7.19 (m, 15H), 4.95 (s, 1H), 4.64 (d, J=12.1 Hz, 1H),
4.61(d, J=12.1 Hz, 1H), 4.56 (d, J=12.1 Hz, 1H), 4.43 (d, J=12.1 Hz,
1H), 4.40 (d, J=12.1 Hz, 1H), 4.33 (d, J=12.1 Hz, 1H), 3.94 (dd, J=7.7,
11.5, 1H), 3.92–3.90 (m, 1H), 3.76 (dd, J=3.3, 3.9 Hz, 1H), 3.56 (dd, J=
3.9, 11.5 Hz, 1H), 3.45–3.43 (m, 1H), 3.33–3.32 ppm (m, 1H); minor: d=
7.43–7.19 (m, 15H), 4.68 (d, J=12.1 1H), 4.63 (d, J=11.5 Hz, 1H), 4.58
(d, J=12.1 Hz, 1H), 4.54 (d, J=11.5 Hz, 1H), 4.47 (d, J=11.5 Hz, 1H),
4.39 (d, J=11.5 Hz, 1H), 4.19 (ddd, J=2.8, 5.0, 7.7 Hz, 1H), 3.97–3.92
(m, 1H), 3.79–3.77 (m, 1H), 3.69 (dd, J=4.8, 11.6 Hz, 1H), 3.51–3.50 (m,
1H), 3.46–3.45 (m, 1H), 3.33–3.32 ppm (m, 1H); HRMS (EI): calcd for
C27H30O6: 450.2040; found: 450.2044.
1680 cmꢀ1
;
HRMS (FAB-NBA+NaI): calcd for C40H51O7NSiNa:
708.3332; found: 708.3328.
Methyl 2,3,4-tri-O-benzyl-b-l-idopyranoside (31) and methyl 2,3,4-tri-O-
benzyl-a-l-idopyranoside (32): Saturated HCl in MeOH (1.33 mL) was
added to a solution of 30 (530 mg, 1.18 mmol) in MeOH (10 mL) at RT.
The solution was stirred at reflux for 5 h and was then poured into satu-
rated NaHCO3. The aqueous layer was extracted with CH2Cl2 and the
combined organic extracts were dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by chromatography on silica gel
with (hexane/AcOEt 2:1) to give b-anomer 31 (289.2 mg, 0.62 mmol,
53%) and a-anomer 32 (243.8 mg, 0.55 mmol, 45%).
2N-Benzyloxy-3,4,5-tris(benzyloxy)-6-tert-butyldimethylsilyloxymethyl-
(3R,4S,5R,6S)-tetrahydro-2H-pyran-2-imine
(27):
Compound
26
(32.6 mg, 0.05 mmol) was converted into 27 (30.3 mg, 0.045 mmol, 95%).
[a]2D4 =+20.9 (c=0.35 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35–
7.23 (m, 20H), 5.09 (s, 2H), 4.75 (d, J=11.72 Hz, 1H), 4.62 (d, J=
11.72 Hz, 1H), 4.57 (d, J=11.72 Hz, 1H), 4.49 (d, J=11.96 Hz, 2H), 4.41
(d, J=11.96 Hz, 1H), 4.32 (m, 1H), 4.10 (d, J=5.37 Hz, 1H), 3.95 (m,
2H), 3.89 (dd, J=3.17, 5.37 Hz, 1H), 3.78 (dd, J=3.17, 2.69 Hz, 1H),
0.89 (s, 9H), 0.06 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=150.22, 138.66, 137.85, 137.82, 128.57, 128.48, 128.39, 128.36, 128.30,
128.04, 128.02, 127.91, 127.80, 127.69, 78.73, 76.47, 75.43, 72.35, 61.26,
77.43, 75.01, 72.75, 72.32, 26.35, 26.34, 26.31, 18.68, ꢀ4.85, ꢀ4.93 ppm; IR
(neat): n˜ =3387, 1738, 1684 cmꢀ1; HRMS (EI): calcd for C40H49NO6Si:
667.3329; found: 667.3333.
Compound (31): M.p. 978C (hexane/AcOEt); [a]2D3 =ꢀ10.1 (c=0.96 in
1
CHCl3); H NMR (600 MHz, CDCl3): d=7.34–7.23 (m, 15H), 4.75 (d, J=
3.3 Hz 1H), 4.74 (d, J=11.5 Hz, 1H), 4.70 (d, J=12.1 Hz, 1H), 4.69 (d,
J=12.1 Hz, 1H), 4.59 (d, J=12.1 Hz, 1H), 4.57 (d, J=11.5 Hz, 1H), 4.45
(d, J=12.1 Hz, 1H), 4.05 (ddd, J=4.4, 6.6, 7.7 Hz, 1H), 3.90 (dd, J=6.6,
12.1 Hz, 1H), 3.78 (dd, J=5.5, 6.6 Hz, 1H), 3.71 (dd, J=4.4, 12.1 Hz,
1H), 3.63 (dd, J=5.5, 7.7 Hz, 1H), 3.61 (dd, J=3.3, 6.6 Hz, 1H), 3.43 (s,
3H), 1.92 ppm (s, 1H); 13C NMR (150 MHz, CDCl3): d=138.1, 138.0,
137.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 101.7, 78.6, 77.2, 73.6,
73.3, 73.2, 69.6, 62.1, 55.6 ppm; IR (KBr): n˜ =3308 cmꢀ1; HRMS (EI):
calcd for C28H32O6: 464.2199; found: 464.2198.
Compound (32): [a]2D3 =+30.2 (c=1.02 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=7.36–7.27 (m, 15H), 4.80 (d, J=12.1 Hz, 1H), 4.76 (d, J=
12.1 Hz, 1H), 4.75 (d, J=12.1 Hz, 1H), 4.72 (d, J=11.5 Hz, 1H), 4.68 (d,
J=12.1 Hz, 1H), 4.56 (d, J=12.1 Hz, 1H), 4.54 (d, J=3.9 Hz, 1H), 4.04
2,3,4-Tri-O-benzyl-l-idono-1,5-lactone (28): p-TsOH·H2O (7.5 mg,
0.04 mmol) was added to a solution of 27 (26.4 mg, 0.04 mmol) in acetone
(2.8 mL) at 08C. The solution was stirred at RT for 6.5 d and was then
poured into saturated NaHCO3. The aqueous layer was extracted with
CH2Cl2 and the combined organic extracts were dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by chromatog-
raphy on silica gel with (hexane/AcOEt 1:1) to give 28 (14.1 mg
0.03 mmol) as a white solid. M.p. 1078C (hexane/AcOEt); [a]2D4 =+45.6
1
(c=0.98 in CHCl3); H NMR (400 MHz, CDCl3): d=7.44–7.22 (m, 15H),
Chem. Eur. J. 2006, 12, 5868 – 5877
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5873

S. Ikegami et al.
(dd, J=7.7, 8.3 Hz, 1H), 3.97 (dd, J=5.5, 11.0 Hz, 1H), 3.89 (dd, J=5.5,
12.1 Hz, 1H), 3.83 (dd, J=5.5, 12.1 Hz, 1H), 3.63 (dd, J=5.5, 7.7 Hz,
1H), 3.48 (s, 3H), 3.47 ppm (dd, J=3.9, 8.3 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d=138.4, 138.2, 137.8, 128.5, 128.4, 128.1, 128.0,
127.9, 127.8, 99.0, 78.1, 77.8, 74.9, 73.7, 75.0, 73.8, 63.1, 56.9 ppm; IR
(KBr): n˜ =3467 cmꢀ1; HRMS (FAB-NBA+NaI): calcd for C28H32O6NaI:
487.2097; found: 487.2099.
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by
chromatography on silica gel with (hexane/AcOEt 10:1!4:1) to give the
lactone compound 38’, which was derived from 38, and remaining 39.
Compound (38’): [a]2D4 =+10.1 (c=0.72 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.62 (dd, J=5.12, 7.57 Hz, 1H), 4.08 (d, J=1.47 Hz, 1H),
3.92 (dd, J=7.57, 11.47 Hz 1H), 3.84 (m, 1H), 3.71 (d, J=2.93 Hz, 1H),
3.64 (dd, J=5.12, 11.47 Hz, 1H), 0.91 (s, 9H), 0.90 (s, 9H), 0.87 (s, 9H),
0.18 (s, 3H), 0.14 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=170.90, 78.67, 77.36, 75.80, 69.32, 62.36,
26.03, 25.81, 25.77, 25.63, 18.46, 18.06, 17.93, ꢀ3.89, ꢀ3.93, ꢀ4.03, ꢀ4.42,
ꢀ4.77, ꢀ5.22 ppm; IR (neat): n˜ =3411, 1750 cmꢀ1; HRMS (FAB-NBA+
NaI): exact mass calcd for C24H52O6Si3: 520.3072; found: 520.3063.
Compound (39): [a]2D4 =+13.4 (c=0.36 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.35–7.20 (m, 5H), 5.19 (dd, J=7.81, 11.72 Hz, 1H), 4.98 (d,
J=15.13 Hz, 1H), 4.94 (d, J=15.13 Hz, 1H), 4.27 (d, J=5.13 Hz, 1H),
3.92 (m, 1H), 3.85 (m, 1H), 3.78–3.76 (m, 2H), 0.91 (s, 9H), 0.89 (s, 9H),
0.83 (s, 18H), 0.12 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s,
3H), 0.02 (s, 3H), 0.01(s, 3H), ꢀ0.02 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=153.24, 138.74, 127.89, 127.01, 78.58, 75.75, 75.51, 73.12,
71.71, 67.98, 26.25, 26.22, 26.06, 25.72, 18.52, 18.42, 18.40, 18.02, ꢀ3.67,
ꢀ4.35, ꢀ4.37, ꢀ4.59, ꢀ4.62, ꢀ4.73, ꢀ5.00, ꢀ5.08 ppm; IR (neat): n˜ =
1642 cmꢀ1; HRMS (EI): exact mass calcd for C37H73NO6Si4: 739.4515;
found: 739.4520 [M]+.
Methyl 2,3,4-tri-O-benzyl-b-l-idopyranosiduronate (33): CrO3 69.7 mg
(0.70 mmol) dissolved in H2SO4 (3.5m, 1mL) was added to a solution of
31 (120 mg, 1.18 mmol) in acetone (3 mL). The solution was stirred at
08C for 10 min before being filtered. The aqueous layer was extracted
with CHCl3 and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo to give the crude product 33 (76.3 mg,
0.16 mmol, 60%), which was applied to the next reaction without further
purification.
Dimethyl 2,3,4-tri-O-benzyl-b-l-idopyranosiduronate (34): Excess CH2N2
in Et2O was added to a solution of 33 (104.5 mg, 0.22 mmol) in CH2Cl2
(2 mL) at 08C. The solution was stirred at RT for 2 h and was then con-
centrated in vacuo. The residue was purified by chromatography on silica
gel with (hexane/AcOEt 10:1) to give the l-idose derivative 34 (76.3 mg,
0.16 mmol, 60%). [a]2D6 =+29.0 (c=1.10 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=7.26–7.15 (m, 15H), 4.68 (d, J=12.7 Hz 1H), 4.58 (d, J=
12.7 Hz, 1H), 4.57 (d, J=12.1 Hz, 1H), 4.50–4.48 (m, 3H), 4.41 (d, J=
12.1 Hz, 1H), 4.23 (d, J=3.6 Hz, 1H), 3.97–3.95 (dd, J=5.5, 7.6 Hz, 1H),
3.65 (s, 3H), 3.61(dd, J=3.6, 5.5 Hz, 1H), 3.41–3.39 ppm (m, 4H);
13C NMR (150 MHz, CDCl3): d=169.5, 138.5, 138.0, 137.9, 128.5, 128.3,
128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 100.9, 75.7, 74.5, 73.7, 73.5,
72.9, 56.92, 51.87 ppm; IR (neat): n˜ =1688 cmꢀ1; HRMS (EI): calcd for
C29H32O7: 492.2148; found: 492.2132.
1N-Methoxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-hydroxy-
(2R,3S,4R,5R)-hexanamide (40a): Compound 36 (68.9 mg, 0.10 mmol)
was converted into 40a (46.4 mg, 0.068 mmol, 63%). M.p. 878C (hexane/
AcOEt); [a]2D4 =+75.3 (c=1.03 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=8.58 (s, 1H), 4.61 (s, 1H), 4.03 (d, J=4.63 Hz, 1H), 3.90 (dd, J=4.63,
9.28 Hz, 1H), 3.87 (m, 1H), 3.79 (s, 3H), 3.70–3.67 (m, 2H), 3.53 (s, 1H),
0.99 (s, 9H), 0.93 (s, 9H), 0.92 (s, 1H), 0.90 (m, 9H), 0.16 (s, 12H), 0.12
(s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=170.50, 76.58, 74.14, 72.47, 68.82, 64.27, 64.24, 26.16, 25.99,
25.98, 25.96, 25.89, 18.66, 18.11, 18.05, 18.01, ꢀ3.88, ꢀ4.01, ꢀ4.74, ꢀ4.76,
ꢀ4.78, ꢀ5.10, ꢀ5.46 ppm; IR (KBr): n˜ =3418, 1711, 1468 cmꢀ1; HRMS
(FAB-NBA+NaI): calcd for C31H72NO7Si4: 682.4386; found: 682.4391.
Dimethyl b-l-idopyranosiduronate (35): Pd(OH)2/C (14.4 mg) was added
to a solution of 34 (71.9 mg, 0.15 mmol) in MeOH (1.5 mL) and the mix-
ture was stirred under a H2 atmosphere for 22 h at RT. After this time,
the mixture was filtered and concentrated to give 35 (31.9 mg, 0.15 mmol,
quant). [a]2D2 =+80.7 (c=0.23 in MeOH); 1H NMR (600 MHz, CDCl3):
d=4.67 (d, J=1.7 Hz, 1H), 4.54 (d, J=2.2 Hz, 1H), 4.00 (dd, J=3.3,
3.9 Hz, 1H), 3.81–3.79 (m, 1H), 3.77 (s, 3H), 3.61 (dd, J=1.7, 3.9 Hz,
1H), 3.55 ppm (s, 3H); 13C NMR (150 MHz, CD3OD): d=171.8, 101.7,
1N-Ethoxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-hydroxy-
(2R,3S,4R,5R)-hexanamide (40b): Compound 36 (83.4 mg, 0.12 mmol)
75.1, 71.6, 71.3, 70.7, 57.4, 52.5 ppm; IR (neat): n˜ =3488, 1734 cmꢀ1
;
was converted into 40b (56.7 mg, 0.081mmol, 74%). [ a]2D4 =+86.4 (c=
1
HRMS (EI): calcd for C8H14O7: 222.0740; found: 222.0739.
1.02 in CHCl3); H NMR (400 MHz, CDCl3): d=8.51(s, 1H), 4.60 (d, J=
1.10 Hz, 1H), 4.03 (dd, J=1.10, 6.88 Hz, 1H), 3.89 (dd, J=6.88, 9.07 Hz,
1H), 3.87–3.85 (m, 3H), 3.68 (dd, J=1.92, 10.72 Hz, 1H), 3.64 (dd, J=
3.58, 10.72 Hz, 1H), 2.69 (s, 1H), 1.27 (dd, J=6.6, 6.6 Hz, 1H), 0.98 (s,
9H), 0.91 (s, 18H), 0.89 (s, 9H), 0.14 (s, 12H), 0.12 (s, 3H), 0.07 (s, 3H),
0.05 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=170.64, 76.61, 74.08,
72.43, 72.13, 64.21, 60.38, 13.73, 26.13, 25.96, 25.93, 25.85, 21.14, 18.62,
17.96, 17.93, ꢀ3.87, ꢀ3.91, ꢀ4.05, ꢀ4.08, ꢀ4.77, ꢀ4.81, ꢀ4.95, ꢀ5.13 ppm;
IR (neat): n˜ =3416, 1709, 1464 cmꢀ1; HRMS (FAB-NBA+NaI): calcd for
C32H73NO7Si4Na: 718.4362; found: 718.4363.
1N-Benzyloxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-hydroxy-
(2R,3S,4R,5R)-hexanamide (37): A mixture of 36 (790 mg, 1.25 mmol)
and benzylhydroxyamine (1.23 g, 9.96 mmol) in CH2Cl2 (10 mL) was stir-
red at room temperature for 30 min, after which time, a solution of trime-
thylaluminum (9.96 mL of 1.00m solution in n-hexane, 9.96 mmol) was
added. The resulting solution was stirred at room temperature for a
period of 2 h. The reaction was quenched with pH 7 phosphate buffer
and the product was extracted with CH2Cl2. The combined organic phase
was dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Purification by silica-gel chromatography (hexane/Et2O 10:1) gave 37
814 mg (86%). [a]2D4 =+98.5 (c=0.85 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.62 (s, 1H), 7.36–7.30 (m, 5H), 5.06 (d, J=11.96 Hz, 1H),
4.82 (d, J=11.96 Hz, 1H), 4.58 (s, 1H), 4.02 (d, J=4.63 Hz, 1H), 3.86
(dd, 1H, J=4.63, 9.28 Hz, 1H), 3.81 (m, 1H), 3.63 (m, 2H), 3.49 (s, 1H),
0.91 (s, 9H), 0.90 (s, 9H), 0.87 (s, 9H), 0.79 (s, 9H), 0.15 (s, 3H), 0.14 (s,
3H), 0.11 (s, 3H), 0.07 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H), ꢀ0.07 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=170.86, 135.63, 128.47, 128.32,
127.86, 77.98, 76.72, 74.05, 72.48, 68.85, 64.21, 26.15, 25.98, 25.96, 25.67,
18.63, 18.10, 18.04, 17.78, ꢀ3.84, ꢀ4.20, ꢀ4.75, ꢀ4.77, ꢀ4.78, ꢀ5.11,
ꢀ5.41ppm; IR (neat): n˜ =3416, 1711 cmꢀ1; HRMS (FAB-NBA+NaI):
exact mass calcd for C37H75NO7Si4Na: 780.4518; found: 780.4515
[M+Na]+.
1N-tert-Butoxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-hydroxy-
(2R,3S,4R,5R)-hexanamide (40c): Compound 36 (114 mg, 0.18 mmol)
was converted into 40c (82.4 mg, 0.11 mmol, 63%). [a]2D4 =+71.5 (c=
0.12 in CHCl3); 1H NMR (400 MHz, CDCl3): d=8.14 (s, 1H), 4.69 (s,
1H), 4.08 (d, J=3.66, 1H), 3.96–3.92 (m, 2H), 3.76–3.69 (m, 2H), 3.62 (s,
1H), 1.33 (s, 9H), 1.05 (s, 9H), 0.98 (s, 18H), 0.98 (s, 9H), 0.95 (s, 9H),
0.24 (s, 3H), 0.22 (s, 9H), 0.17 (s, 3H), 0.12 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=177.94, 77.11, 74.01, 72.72, 68.95, 64.30, 29.07,
26.59, 26.20, 26.19, 26.06, 26.05, 25.96, 25.95, 25.89, 25.88, ꢀ81.24, 18.69,
18.14, 18.04, 17.91, ꢀ3.50, ꢀ3.57, ꢀ3.77, ꢀ4.66, ꢀ4.74, ꢀ5.06, ꢀ5.56 ppm;
IR (neat): n˜ =3382, 1719, 1464 cmꢀ1; HRMS (FAB-NBA+NaI): calcd for
C34H78NO7Si4: 724.4855; found: 724.4857.
1N-tert-Butoxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-hydroxy-
2,3,4-Tri-O-tert-butyldimethylsilyl-l-idono-1,5-lactone (38’) and 3,4,5-
tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxymethyl-1-(ben-
zyloxy)-(3R,4S,5R,6S)-tetrahydropyridin-2(1H)-one (39): p-TsOH·H2O
(17.5 mg, 0.09 mmol) was added to a mixture of 38 and 39 (67.9 mg, 38/39
1.4:1) in acetone (4.5 mL) at 08C. The solution was stirred at 58C for 6 d
and was then poured into saturated NaHCO3. The aqueous layer was ex-
tracted with CH2Cl2 and the combined organic extracts were dried over
(2R,3S,4R,5R)-hexanamide (40d): Compound 36 (542 mg, 0.10 mmol)
was converted into 40d (553 mg, 0.71mmol, 83%). [ a]2D4 =+56.8 (c=1.32
in CHCl3); 1H NMR (400 MHz, CDCl3): d=8.38 (s, 1H), 4.63 (s, 1H),
4.06 (dd, J=1.22, 4.44 Hz, 1H), 3.95 (m, 1H), 3.92 (dd, J=4.44, 9.28 Hz,
1H), 3.71–3.66 (m, 2H), 3.61 (s, 1H), 1.00 (s, 9H), 0.97 (s, 9H), 0.94 (s,
18H), 0.92 (s, 9H), 0.23 (s, 3H), 0.18 (s, 3H), 0.17 (s, 6H), 0.16 (s, 3H),
0.14 (s, 3H), 0.10 (s, 6H), 0.09 (s, 3H), 0.08 ppm (s, 3H); 13C NMR
5874
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 5868 – 5877

l-Sugars and l-Iminosugars
FULL PAPER
(100 MHz, CDCl3): d=180.39, 85.04, 84.73, 82.14, 81.03, 72.33, 29.09,
28.94, 28.88, 28.80, 28.76, 21.57, 21.02, 20.96, 20.89, 20.83, ꢀ0.77, ꢀ0.82,
ꢀ0.94, ꢀ1.73, ꢀ1.85, ꢀ1.87, ꢀ1.98, ꢀ2.18, ꢀ2.25 ppm; IR (neat): n˜ =3387,
1719, 1464 cmꢀ1; HRMS (EI): calcd for C36H83NO7Si5: 781.5016; found:
781.4999.
5.13 (dd, J=7.57, 11.72 Hz, 1H), 4.36 (d, J=4.64, 1H), 3.86–3.83 (m,
2H), 3.80 (dd, J=2.69, 4.64, 1H), 3.77 (d, J=11.72, 1H), 0.93–0.87 (m,
45H), 0.12–0.00 ppm (m, 30H); 13C NMR (100 MHz, CDCl3): d=180.39,
85.04, 84.73, 82.14, 81.03, 72.33, 29.09, 28.94, 28.88, 28.76, 21.57, 21.02,
20.96, 20.89, 20.83, ꢀ0.77, ꢀ0.82, 0.94, ꢀ1.73, ꢀ1.85, ꢀ1.87, ꢀ1.98, ꢀ2.18,
ꢀ2.25 ppm; IR (neat): n˜ =1634 cmꢀ1; HRMS (EI): exact mass calcd for
C36H81NO6Si5: 763.4910; found: 763.4918.
3,4,5-Tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxymethyl-
1-methoxy-(3R,4S,5R,6S)-tetrahydropyridin-2(1H)-one
(42a):
p-
TsOH·H2O (11.6 mg, 0.06 mmol) was added to a mixture of 41a and 42a
(40.2 mg, 41a/42a 1.3:1) in acetone (3.0 mL) at 08C. The solution was
stirred at 58C for 4 d and was then poured into saturated NaHCO3. The
aqueous layer was extracted with CH2Cl2 and the combined extracts
were dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by chromatography on silica gel with (hexane/AcOEt 10:1~
4:1) to give the lactone compound (38’) (21.2 mg, 0.03 mmol), which was
derived from 41a, and unreacted 42a (11.9 mg, 0.02 mmol).
Compound (42a): M.p. 658C (hexane/AcOEt); [a]2D4 =+13.4 (c=0.36 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35–7.20 (m, 5H), 5.19 (dd,
J=7.81, 11.72 Hz, 1H), 4.98 (d, J=15.13 Hz, 1H), 4.94 (d, J=15.13 Hz,
1H), 4.27 (d, J=5.13 Hz, 1H), 3.92 (m, 1H), 3.85 (m, 1H), 3.78–3.76 (m,
2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.83 (s, 18H), 0.12 (s, 3H), 0.10 (s, 3H),
0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.02 (s, 3H), 0.01(s, 3H),
ꢀ0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=153.24, 138.74,
127.89, 127.01, 78.58, 75.75, 75.51, 73.12, 71.71, 67.98, 26.25, 26.22, 26.06,
25.72, 18.52, 18.42, 18.40, 18.02, ꢀ3.67, ꢀ4.35, ꢀ4.37, ꢀ4.59, ꢀ4.62, ꢀ4.73,
ꢀ5.00, ꢀ5.08 ppm; IR (neat): n˜ =1642 cmꢀ1; HRMS (FAB): exact mass
calcd for C41H42NO6: 644.3012; found: 644.3011 [M+H]+.
1,3,4,5-Tetrakis(tert-butyldimethylsilyloxy)-6-hydroxymethyl-
(3R,4S,5R,6S)-2-piperidinone (42d’): p-TsOH·H2O (10.6 mg, 0.06 mmol)
was added to a mixture of 41d and 42d (42.7 mg, 41d/42d 1:1.8) in ace-
tone (2.8 mL) at 08C. The solution was stirred at 58C for 6.5 d and was
then poured into saturated NaHCO3. The aqueous layer was extracted
with CH2Cl2 and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by chroma-
tography on silica gel with (hexane/AcOEt 10:1!4:1) to give the lactone
compound 38’ (6.9 mg, 0.01mmol), which was derived from 41d, and de-
silylated 42d’ (18.7 mg, 0.03 mmol).
1
Compound (42d’): [a]2D4 =+8.56 (c=0.33 in CHCl3); H NMR (400 MHz,
CDCl3): d=5.25 (dd, J=7.81, 11.72 Hz, 1H), 4.37 (dd, J=0.98, 5.13, 1H),
3.94–3.81(m, 4H), 0.93–0.90 (m, 36H), 02.1–0.09 ppm (m, 24H);
13C NMR (100 MHz, CDCl3): d=154.54, 78.50, 75.45, 73.02, 71.54, 68.14,
26.25, 26.20, 26.08, 25.80, 18.52, 18.46, 18.42, 18.03, ꢀ3.63, ꢀ4.31, ꢀ4.42,
ꢀ4.60, ꢀ4.65, ꢀ4.74, ꢀ4.94, ꢀ5.03 ppm; IR (neat): n˜ =1680, 3349 cmꢀ1
;
HRMS (EI): exact mass calcd for C30H67NO6Si4: 649.4045; found:
649.4042.
1N-Benzyloxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-hydroxy-
3,4,5-Tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxymethyl-
(2R,3S,4S,5R)-hexanamide (44a): Compound 43 (324 mg, 0.51mmol)
was converted into 44a (335 mg, 0.44 mmol, 87%). [a]2D4 =+16.4 (c=0.47
in CHCl3); 1H NMR (400 MHz, CDCl3): d=8.71(s, 1H), 7.40–7.33 (m,
5H), 4.93 (s, 2H), 4.14 (d, J=4.64 Hz, 1H), 4.04 (dd, J=2.68, 4.39 Hz,
1H), 4.00 (dd, J=2.68, 4.64 Hz, 1H), 3.79 (m, 1H), 3.59 (dd, J=5.86,
9.52 Hz, 1H), 3.55 (dd, J=8.06, 9.52 Hz, 1H), 2.99 (s, 1H), 0.92 (s, 9H),
0.90 (s, 9H), 0.89 (s, 9H), 0.86 (s, 9H), 0.14 (s, 9H), 0.10 (s, 3H), 0.09 (s,
3H), 0.06 (s, 6H), 0.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
169.83, 135.73, 128.55, 128.34, 128.27, 78.47, 77.88, 71.14, 71.03, 63.41,
73.31, 26.32, 26.12, 26.02, 25.87, 18.66, 18.39, 18.30, 18.22, ꢀ2.89, ꢀ4.21,
ꢀ4.54, ꢀ4.63, ꢀ4.79, ꢀ4.87, ꢀ5.15, ꢀ5.21ppm; IR (neat): n˜ =3418, 1705,
1-ethoxy-(3R,4S,5R,6S)-tetrahydropyridin-2(1H)-one
(42b):
p-
TsOH·H2O (9.2 mg, 0.04 mmol) was added to a mixture of 41b and 42b
(32.5 mg, 41b/42b 1.1:1) in acetone (2.5 mL) at 08C. The solution was
stirred at 58C for 5 d and was then poured into saturated NaHCO3. The
aqueous layer was extracted with CH2Cl2 and the combined organic ex-
tracts were dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by chromatography on silica gel with (hexane/
AcOEt 10:1!4:1) to give the lactone compound 38’ (9.4 mg, 0.02 mmol),
which was derived from 41b, and unreacted 42b (12.4 mg, 0.02 mmol).
Compound (42b): [a]2D4 =+16.8 (c=0.98 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.19 (dd, J=7.81, 11.47 Hz, 1H), 4.34 (d, J=5.13, 1H), 4.00
(q, 2H), 3.92 (m, 1H), 3.87 (m, 1H), 3.81 (dd, J=3.17, 5.13 Hz, 1H), 3.76
(m, 1H), 1.25 (t, 3H), 0.92–0.90 (m, 36H), 0.12–0.07 ppm (m, 24H);
13C NMR (100 MHz, CDCl3): d=152.69, 78.55, 75.66, 73.10, 71.68, 69.37,
67.84, 15.07, 26.26, 26.21, 26.13, 25.77, 18.51, 18.48, 18.43, 18.06, ꢀ3.64,
ꢀ4.27, ꢀ4.38, ꢀ4.59, ꢀ4.60, ꢀ4.69, ꢀ4.93, ꢀ4.93 ppm; IR (neat): n˜ =
1639 cmꢀ1; HRMS (EI): exact mass calcd for C32H71NO6Si4: 677.4358;
found: 677.4362.
1472 cmꢀ1
;
HRMS (FAB-NBA+NaI): exact mass calcd for
C37H75NO7Si4Na: 780.4518; found: 780.4517 [M+Na]+.
1N-tert-Butyldimethylsilyloxy-2,3,4,6-tetra-tert-butyldimethylsilyloxy-5-
hydroxy-(2R,3S,4S,5R)-hexanamide (44b): Compound 43 (165 mg,
0.26 mmol) was converted into 44b (179 mg, 0.23 mmol, 88%). [a]D24
=
ꢀ7.10 (c=1.01 in CHCl3); 1H NMR (400 MHz, CDCl3): d=8.36 (s, 1H),
4.15 (d, J=4.40 Hz, 1H), 4.05 (dd, J=2.44, 4.64 Hz, 1H), 3.95 (dd, J=
2.44, 4.40 Hz, 1H), 3.75 (dd, J=5.37, 10.01 Hz, 1H), 3.62 (dd, J=8.06,
10.01Hz, 1H), 3.55 (m, 1H), 3.09 (s, 1H), 0.97 (s, 9H), 0.96 (s, 9H), 0.95
(s, 9H), 0.93 (s, 9H), 0.90 (s, 9H), 0.19 (s, 3H), 0.16 (s, 15H), 0.14 (s,
3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.06 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=171.49, 78.40, 72.96, 72.46, 71.14, 63.38, 26.46, 26.14, 26.10,
26.01, 25.95, 18.80, 18.44, 18.39, 18.36, 18.19, ꢀ2.98, ꢀ4.00, ꢀ4.61, ꢀ4.69,
ꢀ4.88, ꢀ5.07, ꢀ5.10, ꢀ5.15, ꢀ5.26, ꢀ5.28 ppm; IR (neat): n˜ =1740,
1472 cmꢀ1; HRMS (FAB-NBA+NaI): calcd for C36H84NO7Si5: 782.5094;
found: 782.5087 [M+Na]+.
3,4,5-Tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxymethyl-
1-(benzyloxy)-(3R,4S,5R,6S)-tetrahydropyridin-2(1H)-one
(42c):
p-
TsOH·H2O (13.5 mg, 0.04 mmol) was added to a mixture of 41c and 42c
(49.1mg, 41c/42c 1:5.1) in acetone (3.6 mL) at 0 8C. The solution was stir-
red at 58C for 6 d and was then poured into saturated NaHCO3. The
aqueous layer was extracted with CH2Cl2 and the combined extracts
were dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by chromatography on silica gel with (hexane/AcOEt 10:1!
4:1) to give the lactone compound 38’ (6.4 mg, 0.02 mmol), which was de-
rived from 41b, and unreacted 42c (38.4 mg, 0.056 mmol).
2N-Benzyloxy-3,4,5-tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsi-
lyloxymethyl-(3R,4S,5S,6S)-tetrahydro-2H-pyran-2-imine (45a) and 3,4,5-
tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxymethyl-1-(ben-
zyloxy)-(3R,4S,5S,6S)-tetrahydropyridin-2(1H)-one (46a): Compound
44a (68.9 mg, 0.442 mmol) was converted into products 45a/46a 1.6:1
(54.0 mg, 0.07 mmol, 80%).
Compound (45a): [a]2D4 =ꢀ41.6 (c=0.78 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.46–7.32 (m, 5H), 5.12 (d, J=12.70 Hz, 1H), 5.06 (d, J=
12.70 Hz, 1H), 4.59 (dd, J=1.95, 9.52 Hz, 1H), 4.25 (d, J=9.28, Hz, 1H),
4.16 (d, J=3.91Hz, 1H), 4.19 (dd, J=1.95, 11.96 Hz, 1H), 3.98–3.95 (m,
2H), 1.02 (s, 9H), 1.00 (s, 9H), 0.96 (s, 18H), 0.26 (s, 3H), 0.22 (s, 6H),
0.18 (s, 6H), 0.17 (s, 3H), 0.15 (s, 3H), 0.04 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=152.41, 138.62, 127.85, 127.80, 127.06, 77.97, 75.80,
73.12, 70.63, 64.21, 61.36, 26.17, 26.09, 25.82, 18.68, 18.22, 18.18, 18.14,
ꢀ3.52, ꢀ4.30, ꢀ4.33, ꢀ4.57, ꢀ4.66, ꢀ4.82, ꢀ5.23, ꢀ5.27 ppm; IR (neat):
Compound (42c): [a]2D4 =+3.78 (c=0.43 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.13 (dd, J=7.81, 11.72 Hz, 1H), 4.36 (d, J=4.89, 1H), 3.89
(m, 1H), 3.84 (m, 1H), 3.79 (dd, J=2.93, 4.89 Hz, 1H), 3.75 (m, 1H),
1.25 (s, 9H), 0.90–0.88 (m, 36H), 0.10–0.07 ppm (m, 24H); 13C NMR
(100 MHz, CDCl3): d=151.46, 77.71, 76.08, 73.62, 71.85, 67.60, 27.71,
26.25, 26.21, 26.13, 25.83, 78.76, 18.54, 18.50, 18.42, 18.10, ꢀ3.73, ꢀ4.38,
ꢀ4.44, ꢀ4.57, ꢀ4.63, ꢀ4.69, ꢀ4.72, ꢀ4.97 ppm; IR (KBr): n˜ =1638 cmꢀ1
;
HRMS (EI): exact mass calcd for C34H75NO6Si4: 705.4671; found:
705.4672.
1,3,4,5-Tetrakis(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxy-
methyl-(3R,4S,5R,6S)-tetrahydropyridin-2(1H)-one (42d): Compound
40d (65.5 mg, 0.08 mmol) was converted into 42d (39.4 mg, 0.05 mmol,
1
61%). [a]2D4 =+6.50 (c=0.37 in CHCl3); H NMR (400 MHz, CDCl3): d=
Chem. Eur. J. 2006, 12, 5868 – 5877
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5875

S. Ikegami et al.
n˜ =1649 cmꢀ1; HRMS (EI): exact mass calcd for C37H73NO6Si4: 739.4515;
found: 739.4519 [M]+.
Acknowledgements
Compound (46a): [a]2D4 =ꢀ4.82 (c=1.03 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.34–7.25 (m, 5H), 4.99 (s, 2H), 4.57 (dd, J=3.66, 6.10 Hz,
1H), 4.37 (d, J=3.66 Hz, 1H), 4.15 (dd, J=3.18, 6.10 Hz, 1H), 4.10 (m,
1H), 3.90 (dd, J=3.66, 10.99, 1H), 3.76 (dd, J=4.88, 10.99 Hz, 1H), 0.89
(s, 9H), 0.88 (s, 18H), 0.84 (s, 9H), 0.15–0.01 ppm (s, 24H); 13C NMR
(100 MHz, CDCl3): d=157.30, 138.34, 127.89, 127.18, 76.17, 75.95, 75.09,
69.99. 64.39, 56.35, 26.06, 26.02, 25.97, 25.72, 18.49, 18.33, 18.12, 18.06,
ꢀ3.76, ꢀ4.04, ꢀ4.09, ꢀ4.32, ꢀ4.34, ꢀ4.63, ꢀ5.20 ppm; IR (neat): n˜ =
1741 cmꢀ1; HRMS (EI): exact mass calcd for C37H73NO6Si4: 739.4515;
found: 739.4520.
We wish to thank Misses J. Shimode and A. Tonoki for spectroscopic
measurements. This work was partially supported by a Grant-in-Aid for
scientific research from the Japan Society for the Promotion of Science.
Support from the Takeda Science Foundation, Uehara Memorial Founda-
tion, and the Research Foundation for Pharmaceutical Sciences to H.T.
are gratefully acknowledged.
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2N-tert-Butyldimethylsilyloxy-3,4,5-tris(tert-butyldimethylsilyloxy)-6-tert-
butyldimethylsilyloxymethyl-(3R,4S,5S,6S)-tetrahydro-2H-pyran-2-imine
(45b) and 1,3,4,5-tetrakis(tert-butyldimethylsilyloxy)-6-tert-butyldime-
thylsilyloxymethyl-(3R,4S,5S,6S)-tetrahydropyridin-2(1H)-one
(46b):
Compound 44b (162 mg, 0.442 mmol) was converted into products 45b/
46b 1.6:1 (111 mg, 0.15 mmol, 70%).
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Compound (45b): [a]2D4 =+2.11 (c=0.59 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.14 (dd, J=7.56, 11.72 Hz, 1H), 4.35 (d, J=4.64 Hz, 1H),
3.86–3.83 (m, 2H), 3.79 (dd, J=4.64, 2.69 Hz, 1H), 3.76 (d, J=11.72, Hz,
1H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 18H), 0.87 (s, 9H), 0.12–0.02 ppm
(m, 30H); 13C NMR (100 MHz, CDCl3): d=156.54, 78.94, 75.91, 74.16,
71.90, 67.66, 26.47, 26.24, 26.22, 26.09, 26.00, 26.20, 18.62, 18.44, 18.43,
18.33, ꢀ3.77, ꢀ4.37, ꢀ4.49, ꢀ4.52, ꢀ4.67, ꢀ4.72, ꢀ4.90, 4.96 ppm; IR
(neat): n˜ =1636 cmꢀ1; HRMS (EI): exact mass calcd for C36H81NO6Si5:
763.4910; found: 763.4918 [M]+.
Compound (46b): [a]2D4 =ꢀ7.42 (c=0.19 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.54 (dd, J=3.17, 5.61 Hz, 1H); 4.33 (d, J=1.71 Hz, 1H);
4.16–4.10 (m, 2H); 3.91 (dd, J=3.17, 10.99 Hz, 1H); 3.78 (dd, J=5.61,
10.99 Hz, 1H); 0.92–0.87 (m, 45H); 0.17–0.07 ppm (m, 30H); 13C NMR
(100 MHz, CDCl3): d=160.37, 76.05, 75.26, 71.71, 64.93, 26.41, 26.14,
26.09, 25.77, 25.82, 18.54, 18.39, 18.16, 18.09, ꢀ4.01, ꢀ4.29, ꢀ4.86, ꢀ5.08,
ꢀ5.10 ppm, IR (neat): n˜ =1746 cmꢀ1; HRMS (EI): exact mass calcd for
C36H81NO6Si5: 763.4910; found: 763.4908.
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General procedure for the reduction of 39, 42, and 46: Pd(OH)2/C
(67.6 mg) was added to a solution of 42d (67.6 mg, 0.09 mmol) in MeOH
(5.0 mL) and the resulting mixture was stirred under a H2 atmosphere for
12 h at RT. After this time, the mixture was filtered and concentrated.
Purification by column chromatography on silica gel (hexane/Et2O 4:1)
afforded 47 (42.3 mg, 0.07 mmol, 76%).
3,4,5-Tris(tert-butyldimethylsilyloxy)-6-tert-butyldimethylsilyloxymethyl-
(3R,4S,5R,6S)-2-piperidinone (47): [a]2D4 =+6.12 (c=1.07 in CHCl3);
1H NMR (400 MHz, CDCl3): d=6.29 (s, 1H), 5.21 (dd, J=8.06, 11.72 Hz,
1H), 4.37 (dd, J=0.98, 5.13 Hz, 1H), 3.88 (m, 1H), 3.84 (m, 1H), 3.80–
3.78 (m, 2H), 0.93 (s, 9H), 0.92 (s, 18H), 0.91 (s, 9H), 0.17 (s, 3H), 0.16
(s, 3H), 0.15 (m, 9H), 0.13 (s, 3H), 0.11 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=158.58, 76.10, 75.09, 71.40, 64.50, 26.06, 26.03,
25.93, 25.73, 18.50, 18.38, 18.16, 18.05, ꢀ3.54, ꢀ3.98, ꢀ4.30, ꢀ4.70, ꢀ5.19,
ꢀ5.24 ppm; IR (neat): n˜ =1752, 1472 cmꢀ1; HRMS (EI): exact mass calcd
for C30H67NO5Si4: 633.4096; found: 633.4094.
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in CHCl3); 1H NMR (600 MHz, CDCl3): d=7.1(s, 1H), 4.61(dd,
J=
3.18, 6.59 Hz, 1H), 4.35 (m, 1H), 4.17–4.13 (m, 2H), 3.90 (dd, J=3.18,
10.99 Hz, 1H), 3.80 (dd, J=4.64, 10.99 Hz, 1H), 0.90 (s, 9H), 0.89 (s,
18H), 0.88 (s, 9H), 0.14–0.10 ppm (m, 24H); 13C NMR (150 MHz,
CDCl3): d=158.64, 76.05, 75.04, 71.38, 64.47, 60.43, 26.05, 26.02, 25.93,
25.69, 18.49, 18.37, 18.16, 8.05, ꢀ3.57, ꢀ3.99, ꢀ4.02, ꢀ4.32, ꢀ4.71, ꢀ5.21,
ꢀ5.25 ppm; IR (neat): n˜ =1703 cmꢀ1; HRMS (EI): exact mass calcd for
C30H67NO5Si4: 633.4096; found: 633.4087.
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5876
www.chemeurj.org
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Chem. Eur. J. 2006, 12, 5868 – 5877

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Received: February 25, 2006
Published online: May 23, 2006
Chem. Eur. J. 2006, 12, 5868 – 5877
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5877