Synthesis and glycosidase inhibitory activity of aminocyclitols with a C6- or a C7-ring

Article abstract of DOI:10.1016/j.tet.2003.09.049

The synthesis of carbasugars and various aminocyclitols, related to voglibose and acarbose used in the treatment of non-insulino-dependant diabetes, is described from C₂-symmetrical bis-epoxides derived from D-mannitol. The methodology involves

Full text of DOI:10.1016/j.tet.2003.09.049

Tetrahedron 59 (2003) 8705–8720
Synthesis and glycosidase inhibitory activity of aminocyclitols
with a C6- or a C7-ring
Christine Gravier-Pelletier,a William Maton,a Thierry Dintinger,b Charles Tellierb
and Yves Le Merrera
,
*
a
´ ´
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Universite Rene Descartes, UMR 8601 CNRS,
`
45 rue des Saints-Peres, 75270 Paris Cedex 06, France
´ ´
Faculte des Sciences et des Techniques, Unite de Recherches en Biocatalyse, FRE 2230 CNRS, 2 rue de la Houssiniere, BP 92208,
b
`
44322 Nantes, France
Received 8 July 2003; revised 3 September 2003; accepted 15 September 2003
Abstract—The synthesis of carbasugars and various aminocyclitols, related to voglibose and acarbose used in the treatment of non-insulino-
dependant diabetes, is described from C2-symmetrical bis-epoxides derived from D-mannitol. The methodology involves two key steps: a
domino alkylation–cyclization with 2-lithio-1,3-dithiane derivatives, and reduction or reductive amination with a primary amine. These
compounds have been evaluated as inhibitors of several glycosidases, and this study indicates notably that the L-ido or D-manno
1-aminocycloheptane-3,4,5,6-tetrol are inhibitors of a-D-glucosidase with Ki in the micromolar range.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
related insulin secretagogues6 increase insulin release from
pancreatic islets; the biguanide metformin7 delays the
absorption of dietary carbohydrates by inhibiting
the glucose transporter found on the brush border of the
epithelial lining of the intestines and so acts to reduce
hepatic glucose production. Thiazolidinediones8 which are
peroxisome proliferator-activated receptor-g (PPArg)
agonists enhance insulin action. Insulin itself stops glucose
production and increases glucose utilization.9 Alpha-
glucosidase inhibitors such as the pseudo-oligosaccharide
acarbose10 can decrease post-prandial glucose elevation by
decreasing the intestinal absorption of glucose. However,
although these drugs are effective, due to the frequent need
of long-term therapies, they often have to be used
successively or simultaneously as the disease progresses
so that limited tolerability and side-effects may be
observed. In that context, it is obvious that there is still a
need for new therapies to complement and even improve on
existing ones.
Interest in diabetes is currently blowing up as the number of
people with diabetes is expected to rise from the current
estimate of 150 million to 220 million in 2010 and 300
million in 2025.1 There are two main forms of diabetes.
Type 1 diabetes2 is the most common chronic disease of
children and is due to auto-immune-mediated destruction of
pancreatic b-cell islets resulting in absolute insulin
deficiency. It can be treated by supplying exogenous
insulin. Type 2 diabetes or non-insulinodependant mellitus
diabetes (NIDMD), which represents 90% of cases, is a
multifactorial disease and is characterized by insulin
resistance in peripheral tissues and/or abnormal insulin
secretion from the pancreas and increasing blood glucose
levels.3 The NIDMD is taking an increasing place both in
developed and developing countries and is associated with
sedentary lifestyle and obesity.4 Many complications such
as retino-, neuro- and nephro-pathies are associated with
NIDMD and lowering blood glucose may be an effective
mechanism for preventing the development of diabetic
complications.5
Our investigations concern a-glucosidase inhibitors, the
activity of acarbose,11 voglibose12 and miglitol13 having
already been demonstrated as inhibitors of intestinal
digestive enzymes (Fig. 1) and these compounds being
approved for use in humans.14 Both the naturally occurring
voglibose and acarbose are believed, in the same way as
other carbohydrate mimics such as polyhydroxylated
piperidines (like miglitol), pyrrolidines, indolizidines and
pyrrolizidines, to mimic the charge of the presumed
transition state for enzymatic glycoside hydrolysis, due to
At present, therapies for NIDMD are directed towards the
reduction of hyperglycemia itself. Thus, sulfonylureas and
Keywords: aza-disaccharide; aminocyclitol; bis-epoxide; carbasugar;
cyclization; glycosidases; reductive amination.
*
Corresponding author. Tel.: þ33-1-42862176; fax: þ33-1-42868387;
e-mail: yves.le-merrer@univ-paris5.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.049

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C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
C2-symmetric bis-epoxides derived from D-mannitol by a
formal carbonyl dianion.18 Subsequent reduction or reduc-
tive amination of the introduced carbonyl group lead to the
corresponding cyclitols or aminocyclitols.
2. Results and discussion
We have studied the nucleophilic opening of the easily
available 1,2:5,6-dianhydro-3,4-O-methylethylidene-L-
iditol 1 or D-mannitol 2 and their 3,4-di-O-benzyl analogs
3 and 4 with lithiated derivatives of 1,3-dithiane. Treatment
of bis-epoxide 1 with lithiated 1,3-dithiane afforded the
C2-symmetric acyclic compound 5 (Scheme 1). The yield of
5 was improved to 90% with 2.4 equiv. of lithiated 1,3-
dithiane. This result proved that the alkoxide anion resulting
from the first epoxide opening by the organometallic is not
sufficiently basic to remove the second hydrogen atom of
the introduced 1,3-dithiane, and in this way to generate the
second nucleophily of the dihiane.
Figure 1. Inhibitors of a-glucosidases.
To circumvent this difficulty and to promote the C-cycliza-
tion we turned our attention to the use of 2-trimethylsilyl-
1,3-dithiane. An organometallic derivative of this com-
mercially available reagent has been recently used in a
bis-alkylation reaction with two equivalents of epoxide
through Brook’s rearrangement.19 Treatment of the bis-
epoxide 1 with the lithio derivative of 2-TMS-1,3-dithiane,
generated by LDA, afforded the expected carbocycles 6 and
7, in only 28 and 11% yield, respectively, after separation by
chromatography. This poor isolated yield was attributed to
partial hydrolysis of the O-silyl bond during the chroma-
tography. It should be noted that the desilylation of the
crude reaction mixture with tetrabutylammonium fluoride
afforded the corresponding diols, which could not be
separated by chromatography. Nevertheless, formation of
the C6- and C7-rings in this reaction confirms that the
expected 1,4-Brook rearrangement occurs, transferring the
Figure 2. Retrosynthetic analysis.
the protonation of their nitrogen atom in the enzyme active
site.
If considerable synthetic efforts have been devoted to the
synthesis of iminosugar analogs15 and have sometimes
shown interesting inhibitory activitiy,16 to our knowledge,
aminocyclitols with a C6- or C7-ring have been less studied
in the field of glycosidase inhibitors. We report here full
results concerning the synthesis of these compounds and
their evaluation as glycosidase inhibitors.17 To access to the
target molecules, our retrosynthetic analysis (Fig. 2)
involves the carbacyclization of enantiomerically pure
Scheme 1.

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8707
Scheme 2. Reagents and conditions: see Table 1.
silyl group to alkoxide and generating the second nucleo-
phile of the 1,3-dithiane. Subsequently, this anion promotes
the intramolecular opening of the second epoxide at the less
subsituted side (7-endo-tet process) and at the more
substituted side (6-exo-tet process). Furthermore, these
results show that the intramolecular silyl migration and
C-cyclization are faster than the intermolecular reaction
which should evolve towards the C2-symmetric acyclic
compound 5.
of the 2-metallated 2-TBDMS-1,3-dithiane, the yield was
comparable. However, it should be noted that with t-BuLi,
the reaction mixture was cleaner, justifying the use of these
conditions on a large scale of bis-epoxide (up to 4 g).
Results from the Table 1 show that, on one hand depending
on the 3,4-O-protective group of the bis-epoxide, benzyl
ether or acetonide, the cyclization is directed to the major
formation of either the C7- or the C6-ring, respectively. On
the other hand, analogous results are obtained independent
of the D-manno or L-ido configuration of the bis-epoxide.22
To increase the stability of the resulting O-silyl derivative,
we then turned our attention towards 2-tert-butyldimethyl-
silyl-1,3-dithiane for which the lithio derivative has already
been used in the sequential opening of two different
epoxides.20 Reactivity of this organometallic species has
been studied on bis-epoxides 1–4 (Scheme 2) under
different experimental conditions (Table 1).
Silylation of the free alcohol function of 8, 11 or 15
(Scheme 3) was accomplished by treatment with tert-
butyldimethylsilyl chloride in the presence of imidazole in
DMF at 708C. The 1H and 13C NMR spectra of the resulting
bis-silylated C7-cyclitols 17 and 18 exhibited a simplifica-
tion consistent with the presence of a C2-symmetric axis.
The conjugate base of 2-TBDMS-1,3-dithiane was
generated either at 2788C by addition of tert-butyllithium,
or at room temperature by addition of a mixture of
n-BuLi/n-Bu2Mg.21 In each case, the reaction was carried
out with the bis-epoxide in a THF/HMPA mixture and
afforded enantiomerically pure carbacycles, in good yield,
63 to 82%, for the main product (after chromatographic
purification). Whatever the method used for the formation
Next, attention was focused on the dithioketal hydrolysis
(Scheme 3). Treatment of 17 or 18 with bis(trifluoro-
acetoxy) iodobenzene23 in aqueous acetonitrile at 208C
yielded the corresponding cycloheptanone 21 or 22 in a
yield varying from 50 to 80% depending of the attempts
(Table 2, entries 1, 2). Furthermore, from 16, the
cyclohexanone 19b was isolated in only 34% yield (entry
3). Considerable effort was made to improve the yield of the
desired cycloalcanone by running the reaction under various
experimental conditions.
Table 1. Screening of conditions for the carbacyclization
bis-Epoxide
Conditions
Producta
For example, from dithioketal 16 we found that triethyl-
oxonium tetrafluoroborate24 (entry 4), or 2,3-dichloro-5,6-
dicyanobenzoquinone25 (entry 5) only led to decomposition
giving an inextractable mixture. Moreover, treatment with
mercury(II) perchlorate26 (entry 7) in the presence of
K2CO3 at room temperature afforded the expected cyclo-
hexanone 19b in a low yield (28%). A small amount of a
slightly higher running product was also isolated which
turned out to be enone 20, probably resulting from 19b by a
b-elimination. Reaction with N-bromosuccinimide27 at
room temperature in aqueous acetone (entry 8) resulted in
34% of the desired ketone 19b. When carried out at 2308C,
C6-ring
C7-ring
1
1
3
3
2
2
4
4
A
B
A
B
A
B
A
B
8 (72%)
8 (52%)
9 (15%)
9 (30%)
10 (21%)
10 (33%)
12 (39%)
12 (67%)
14 (13%)
14 (10%)
11 (43%)
11 (63%)
13 (13%)
13 (24%)
15 (73%)
15 (82%)
A: t-BuLi, THF, HMPA, 2788C then 2308C and bis-epoxide addition; B:
n-BuLi, n-Bu2Mg, THF, HMPA, rt, then bis-epoxide addition.
Isolated yield after flash chromatographic purification.
a

8708
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
Scheme 3. Reagents and conditions: (a) TBDMSCl, ImH, DMF, 708C; (b) see text.
the reaction proved to be more interesting and synthetically
useful. Indeed, we isolated the ketone 19b, 21 or 22 in an
excellent yield (80%, entries 9, 10 and 11).
presence of bulkier hydride sources such as di-iso-
butylaluminium hydride (DIBAL-H), L- or K-selectridew
in THF at 2788C. With DIBAL-H, we observed the
formation of the same major epimer as above (24/25
78:22, 43%), whereas with L- or K-selectridew we observed
the expected inversion of the diastereoselectivity (24/25
36:64, 50%). In order to examine the eventual influence of
the primary free alcohol function of 19a this compound was
submitted to NaBH4 reduction (EtOH at 2788C). A 75:25
mixture of the corresponding diols (like 24 and 25 with
P0¼H) revealing no significative modification of the
diastereoselectivity.
Having found suitable conditions for the dithioketal
hydrolysis, we now proceeded to the reduction of the
cycloalkanone (Scheme 4). Thus, reduction of 22 with
lithium aluminium hydride in refluxing THF, yielded the
corresponding alcohol 23 (50%). Fortunately, the reduction
performed with sodium borohydride in EtOH afforded 23 in
quantitative yield.
Reduction of the crude cyclohexanone 19b by NaBH4 in
EtOH at 208C afforded a 82:18 mixture of the alcohols 24/25
in 80% yield. These products were easily separated by flash
We next turned to the preparation of the targeted
aminocyclitols via the reductive amination of the cyclo-
alkanones with various primary amines such as benzyl-
chromatography and the absolute configuration at the newly
1
created asymmetric carbon was assigned by H NMR. The
observed coupling constants for the H-1 protons:
J1,2b¼J1,6¼9.1 Hz for 24 and J1,2b¼J1,6¼3.0 Hz for 25 are
consistent with an axial–axial and an axial–equatorial
relationship, respectively. The reduction of 19b with NaBH4
was also carried out at 2788C, and the diastereoselectivity
was improved up to 96:4 in favour of the equatorial
hydroxyl group in the same yield (80%) as above. To
reverse the diastereoselectivity, attempts were made in the
amine,
n-butylamine,
bis-O-tert-butyldimethyl
silylserinol28 or methyl 6-amino-6-deoxy-2,3,4-tri-O-
benzyl-a-D-glucopyranoside,29 respectively chosen to
afford unsubstituted aminocyclitols, N-butylaminocyclitols
Table 2. Deprotection of the dithioketal group
Entry
Thioketal
Conditions
Result
1
2
3
4
5
6
7
8
17
18
16
16
16
16
16
16
16
17
18
(CF3CO2)2PhI, MeCN, H2O
(CF3CO2)2PhI, MeCN, H2O
(CF3CO2)2PhI, MeCN, H2O
Et3OBF4, CH2Cl2, rt
DDQ, MeCN, H2O
HgCl2, K2CO3
Hg(ClO4)2, K2CO3
NBS, Me2CO, H2O, rt
NBS, Me2CO, H2O, 2308C
NBS, Me2CO, H2O, 2308C
NBS, Me2CO, H2O, 2308C
21 (63%)
22 (54%)
19b (34%)
Dec.a
Dec.a
n.r.b
19b (28%)þ20
19b (34%)
19b (77%)
21 (79%)
22 (77%)
9
10
11
a
Decomposition of the reaction mixture.
No reaction.
b
Scheme 4. Reduction of the cycloalkanones 19b and 22.

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8709
Scheme 5. Reagents and conditions: (a) RNH2, Ti(Oi-Pr)4, then NaBH3CN, EtOH, rt; (b) TBAF, THF, rt; (c) H2, Pd, AcOH for 30a,b,c or 31a,b,c, or Na, NH3,
2338C for 30d.
analogs of voglibose, or analogs of disaccharide displaying
partial acarbose structure. The reductive amination carried
out under the conditions of Mattson et al.30 involved imine
formation catalyzed by titanium(IV) isopropoxide
followed by in situ reduction with sodium cyanoboro-
hydride. In the cycloheptanone series (Scheme 5), the
expected N-substituted aminocycloheptanols (26a,b,c,d or
27a,b,c,d) were isolated after flash chromatographic
purification in yields ranging from 47 to 91%. In the
cyclohexanone series (Scheme 6), the reductive amination
provided a mixture of the two possible aminocyclitols 32/33
in moderate to good yield (61–82%), which could be easily
separated by flash chromatography. In all cases, the
diastereoselectivity (60:40 to 70:30) was in favor of 32
which presents the amino group in an equatorial direction,
as precedently observed for the NaBH4 reduction of the
Scheme 6. Reagents and conditions: (a) RNH2, Ti(Oi-Pr)4, then NaBH3CN, EtOH, rt; (b) TFA, H2O for 32d!34a, or for 32b!34b, or for 33b!35b, or TFA,
H2O, THF for 32c!34c; (c) H2, Pd(OH)2, EtOH for 32a!32d, (d) H2, Pd black, AcOH for 34c!34d.

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C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
Table 3. Comparison of inhibitory activities for aminocyclitols 30, 31, 34 and 35 and iminosugars 36–38. Percentage of inhibitions at 1 mM and Ki in mM (in
bold) when measured33
Enzyme
30a
30b
30c
30d
31a
31b
31c
34a
34b
34d
35b
36
37
38
a-D-Glu
b-D-Glu
a-D-Man
a-L-Fuc
25 mM
n.i.a
37%
21%
33%
n.i.a
8%
n.i.a
4%
n.i.a
7%
70 mM
11%
39%
4%
16%
15%
n.i.a
19%
5%
7%
8%
2%
15%
6%
n.i.a
12%
15%
9%
n.i.a
4%
n.i.a
30%
n.i.a
10%
4.8 mM
17 mM
25%
70 mM
1%
1%
0.44 mM
8%
3%
n.i.a
11%
n.i.a
n.i.a
14%
10%
10%
4%
28 mM
a
No inhibition detected.
cyclohexanone 19. The axial or equatorial position of the
amino group was determined by the coupling constants
between the H-1 and the H-neighbors, for example
J1,2b¼10 Hz, J1,2a¼4.5 Hz, J1,6¼11.8 Hz for 32a, and
J1,2b¼J1,2a¼J1,6¼3.0 Hz for 33a. No evidence for epimer-
ization adjacent to the ketone was observed in each case.
results are for the N-unsubstituted aminocycloheptanols 30a
and 31a which competitively inhibits the a-D-glucosidase
(Ki¼25 and 70 mM, respectively). However, no significative
difference was observed, on one hand between the L-ido or
D-manno configuration, and on the other hand by compari-
son with the parent iminosugars (Ki¼4.8 and 70 mM for 36
and 37, respectively). N-substitution of these compounds by
a n-butyl group, a bis-hydroxymethylmethylene, the
aglycon part of the voglibose, or a methyl glucoside reduce
or prevent inhibition. Furthermore, the aminocyclohexanols
(34, 35) are weak inhibitors or inactive towards all
glycosidases studied.
Finally, the following steps concerned the removal of the
protecting groups. In the C7-series, removal of the tert-
butyldimethylsilyl groups was achieved by an excess of
n-tetrabutylammonium fluoride in THF to give the corre-
sponding alcohols 28 or 29, and the deprotection of benzyl
ethers, and N-benzyl amines for 28a and 29a, involved
hydrogenolysis in the presence of palladium black in acetic
acid. For compounds 28d and 29d, the last reaction was
carried out by sodium in liquid ammonia. In the C6-series,
acidic hydrolysis (TFA, H2O) of both acetonide and silyl
ether of 32b or 33b led to the aminocyclitol 34b or 35b.
Hydrogenolysis of 32a in the presence of Pearlman catalyst
(32a!32d), followed by acidic hydrolysis (TFA, H2O)
furnished the N-unsubstituted aminocyclitol 34a while for
the disaccharide analog 32c, deprotections required acidic
hydrolysis (TFA, THF, H2O) of both acetonide and the silyl
ethers (32c!34c), then hydrogenolysis of the benzyl ethers
(Pd black, AcOH) to give 34d. In all cases, subsequent
purification by ion exchange chromatography afforded the
targeted pure aminocyclitols.
In order to extend the biological evaluation of the precedent
aminocyclitols, they were also tested on a-D-galactosidase
from green coffee beans, b-D-galactosidase from Thermus
thermophilus, and on pancreatic porcine a-amylase. The
synthesized aminocyclitols were totally inactive towards
these latter enzymes, except N-unsubstituted amino-L-
idocycloheptane-tetrol 30a and the structural analog of
voglibose 34b which were weak inhibitors of b-D-
galactosidase (Ki¼200 and 600 mM, respectively), and
N-butylamino-L-idocycloheptane-tetrol 30b which
moderately inhibits a-amylase (IC50¼600 mM). Finally,
even if voglibose, actually used in the treatment of diabetes
NID, is a powerful inhibitor of intestinal sucrase
(Ki¼67 nM), its activity on b-D-glucosidase from almonds
is weak (IC50 ( 1.5 mM). In this context, evaluation of the
synthetized aminocyclitols on such an enzyme will later be
performed.
3. Inhibition studies
The new aminocyclitols (30, 31, 34 and 35) were screened
against four common glycosidases (a-D-glucosidase from
baker’s yeast, b-D-glucosidase from almonds, a-D-manno-
sidase from Jack beans and a-L-fucosidase from bovine
kidney). The observed results are gathered in Table 3 and
compared with the reported activity of the parent imino-
sugar:31 3,4,5,6-tetrahydroxy-L-ido- or D-mannoazepane,
36 or 37, or 1-deoxynojirimycin 38 (Fig. 3).
4. Conclusion
In conclusion, we have developed an efficient and versatile
synthetic strategy for the preparation of enantiopure
carbasugars and aminocyclitols with a C6- or C7-ring,
from easily available bis-epoxides. The key steps involved
the one-pot domino alkylation–cyclization which can be
directed either to the C6 or C7 polyhydroxylated cyclo-
alkanone by selecting the appropriate O-protecting groups
of the bis-epoxide derived from D-mannitol, and the
reduction or the reductive amination in the presence of a
primary amine. According to this strategy, the synthesized
aminocyclitols can be N-substituted by various R groups,
notably R¼CH(CH2OH)2 or methyl glucoside as,
respectively, voglibose or acarbose analogs or unsubstituted
to serve as a reference concerning the biological effect of
N-substitution. Interestingly, biological studies indicate that
the L-ido or D-manno 1-aminocycloheptane-3,4,5,6-tetrol
are inhibitors of a-D-glucosidase with the Ki values in the
low micromolar range.
The aminocyclitols are weakly or no-potent on the four
commercially available enzymes. Among them, the best
Figure 3.

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8711
5. Experimental
(C4), 76.7 (C5), 69.0 (C3), 62.7 (C7), 51.7 (C1,6), 46.2 (C2),
0
0
0
27.0, 25.8 (CMe2), 26.8, 25.8, 25.5 (C1 ,2 ,3 ), 25.8, 18.3
(tBu), 24.6, 24.8 (SiMe2); MS (CI, CH4) 421 (Mþþ1);
HRMS for C19H37O4S2Si (Mþþ1) calcd 421.1902; found
421.1898. Anal. calcd for C19H36O4S2Si: C, 54.25; H, 8.63;
found: C, 54.17, H, 8.72.
1H NMR (250 MHz) and 13C NMR (63 MHz) spectra were
recorded on a Bruker AM250 in CDCl3 (unless indicated).
Chemical shifts (d) are reported in ppm and coupling
constants are given in Hz. IR spectra were recorded on a
Perkin–Elmer 783 Infrared Spectrophotometer. Optical
rotations were measured on a Perkin–Elmer 241C polari-
meter with sodium (589 nm) or mercury (365 nm) lamp.
Mass spectra, chemical ionization (CI), and high resolution
5.1.2. [3S,4S,5R,6S]-3-O-tert-Butyldimethylsilyl-4,5-O-
methylethylidene-3,4,5,6-tetrahydroxycycloheptan-1-
one 1,3-propanedithioketal (9). Rf 0.25 (cyclohexane/
EtOAc 8:2); [a]D¼þ14 (c 0.5, CH2Cl2); 1H NMR d 4.01–
3.98 (m, 3H, H3,5,6), 3.85 (dd, 1H, J4,5¼J4,3¼9.0 Hz, H4),
´
(HRMS) were recorded by the Service de Spectrometrie de
Masse, Ecole Normale Superieure, Paris. All reactions were
´
0
0
0
0
carried out under an argon atmosphere, and were monitored
by thin-layer chromatography with Merck 60F–254 pre-
coated silica (0.2 mm) on glass. Flash chromatography was
performed with Merck Kieselgel 60 (200–500 mm); the
solvent system were given v/v spectroscopic (1H and 13C
NMR, MS) and/or analytical data were obtained using
chromatography homogeneous samples.
2.90–2.84 (m, 4H, H1 a,1 b,3 a,3 b), 2.52 (dd, 1H, J2a,2b
¼
14.7 Hz, J2a,3¼5.4 Hz, H2a), 2.36 (dd, 1H, J7b,7a¼15.0 Hz,
J7b,6¼5.0 Hz, H7b), 2.26 (dd, 1H, J7a,7b¼15.0 Hz, J7a,6
¼
4.8 Hz, H7a), 2.10 (dd, 1H, J2b,2a¼14.7 Hz, J2b,3¼7.0 Hz,
0
0
H2b), 2.00–1.90 (m, 3H, H2 a,2 b,OH), 1.36 (s, 6H, CMe2); 0.90
(s, 9H, tBu), 0.08 (s, 6H, SiMe2); 13C NMR d 109.0 (CMe2),
80.5 (C4,5), 71.7, 71.0 (C3,6), 48.0 (C1), 47.5, 45.5 (C2,7), 27.2,
0
0
0
27.0, 24.9 (C1 ,2 ,3 ), 27.1 (CMe2), 25.8, 18.2 (tBu), 24.4, 24.7
(SiMe2); MS (CI, CH4) 421 (Mþþ1); HRMS for
C19H37O4S2Si (Mþþ1) calcd 421.1902; found 421.1890.
5.1. General procedure for carbacyclization
Method A. To a 2788C cooled solution of 2-tert-
butyldimethylsilyl-1,3-dithiane (34.2 g, 146.2 mmol,
5.2 equiv.) in a 9:1 mixture of THF/HMPA (887 mL) was
slowly added tert-butyllithium (1.5 M in hexanes, 97.5 mL,
146.2 mmol, 5.2 equiv.). The temperature was then
increased to 2308C and a solution of the epoxide 1, 2, 3
or 4 (5.23 g, 28.1 mmol) in THF (86 mL) was added. After
stirring at 2308C for 15 min, a saturated NH4Cl aqueous
solution was added. After ether extractions, the combined
organic layers were dried (MgSO4), filtered and concen-
trated in vacuo. Flash chromatography of the crude
(cyclohexane/EtOAc) afforded the expected carbacycles.
5.1.3. [3S,4S,5R,6R]-4,5-Di-O-benzyl-3-O-tert-butyl-
dimethylsilyl-6-hydroxymethyl-3,4,5-trihydroxycyclo-
hexan-1-one 1,3-propanedithioketal (10). Rf 0.4
(cyclohexane/EtOAc 85:15); [a]D¼þ23 (c 0.67, CH2Cl2);
1H NMR (500 MHz) d 7.39–7.28 (m, 10H, Har), 5.01, 4.75
(AB, 2H, JAB¼11.5 Hz, OCH2Ph), 4.92, 4.89 (AB, 2H,
JAB¼10.8 Hz, O–CH2–Ph), 4.28 (d, 1H, J7a,7b¼10.5 Hz,
H7a), 4.12 (dd, 1H, J7b,7a¼10.5 Hz, J7b,6¼4.0 Hz, H7b), 4.07
(dd, 1H, J5,6¼J5,4¼9.2 Hz, H5), 3.98 (ddd, 1H,
J3,2b¼11.6 Hz, J3,4¼9.2 Hz, J3,2a¼4.1 Hz, H3), 3.46 (dd,
0
1H, J4,5¼J4,3¼9.2 Hz, H4), 3.30–3.19 (m, 1H, H1 a), 3.14
(dd, 1H, J2a,2b¼13.5 Hz, J2a,3¼4.1 Hz, H2a), 3.03–3.00 (m,
0 0
1H, H3 a), 2.78–2.68 (m, 1H, H1 b), 2.60–2.52 (m, 1H,
Method B. To a solution of 2-tert-butyldimethylsilyl-1,3-
dithiane (3.6 g, 15.3 mmol, 4.7 equiv.) in a 9:1 mixture of
THF/HMPA (92.5 mL), at 208C, was slowly added a
mixture of n-butyllithium (1.6 M in hexanes, 9.6 mL,
15.3 mmol, 4.7 equiv.) and dibutylmagnesium (1.0 M in
hexane, 3.8 mL, 3.8 mmol, 1.2 equiv.). The mixture was
stirred for 1 h at 208C prior to the addition of a solution of the
epoxide 1, 2, 3 or 4 (607 mg, 3.3 mmol) in THF (7.7 mL).
After stirring for 15 min, a saturated NH4Cl aqueous solution
was added and the same protocol as above was followed.
0
0
0
H3 b), 2.15–2.08 (m, 1H, H2 a), 1.92–1.80 (m, 2H, H6,2 b),
1.75 (dd, 1H, J2b,2a¼13.5 Hz, J2b,3¼11.7 Hz, H2b), 0.96 (s,
9H, tBu); 0.21, 0.15 (s, 6H, SiMe2); 13C NMR d 138.9,
138.8, 128.6, 128.4, 127.8, 127.5 (Car), 89.7 (C4), 77.5 (C5),
75.3, 74.6 (OCH2Ph), 69.4 (C3), 59.1 (C7), 54.4 (C6), 51.9
0
0
0
(C1), 42.2 (C2), 27.0, 25.7 (C1 ,2 ,3 ), 26.2, 18.3 (tBu), 24.9,
25.1 (SiMe2).
5.1.4. [3S,4S,5R,6S]-4,5-Di-O-benzyl-3-O-tert-butyl-
dimethylsilyl-3,4,5,6-tetrahydroxycycloheptan-1-one
1,3-propanedithioketal (11). Rf 0.3 (cyclohexane/EtOAc
5.1.1. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
hydroxymethyl-4,5-O-methylethylidene-3,4,5-tri-
hydroxycyclohexan-1-one 1,3-propanedithioketal (8). Rf
0.35 (cyclohexane/EtOAc 8:2); mp 958C; [a]D¼þ15 (c
0.81, CH2Cl2); 1H NMR (500 MHz) d 4.21 (ddd, 1H,
J7a,7b¼11.6 Hz, J7a,OH¼10.0 Hz, J7a,6¼4.0 Hz, H7a), 4.06
(ddd, 1H, J7b,7a¼11.6 Hz, J7b,6¼7.3 Hz, J7b,OH¼3.4 Hz,
H7b), 4.02 (ddd, 1H, J3,4¼J3,2b¼9.2 Hz, J3,2a,4.0 Hz, H3),
3.76 (dd, 1H, J5,6¼11.3 Hz, J5,4¼9.2 Hz, H5), 3.44 (dd, 1H,
1
85:15); [a]D¼þ11 (c 1.1, CH2Cl2); H NMR d 7.30–7.20
(m, 10H, Har), 4.96, 4.56 (AB, 2H, JAB¼11.2 Hz, OCH2Ph),
4.84, 4.75 (AB, 2H, JAB¼11.9 Hz, OCH2Ph), 4.00–3.94 (m,
1H, H3), 3.83–3.76 (m, 1H, H6), 3.70–3.60 (m, 2H, H4,5),
0
3.07–2.86 (m, 2H, H1 a,3 a), 2.80–2.70 (m, 2H, H1 b,3 b),
0
0
0
2.55 (dd, 1H, J2a,2b¼15 Hz, J2b,3¼10.5 Hz, H2b), 2.21 (d,
0
0
1H, J2a,2b¼15 Hz, H2a), 2.12–1.80 (m, 4H, H2 a,2 b,7a,7b),
0.91 (s, 9H, tBu), 0.13, 0.08 (2s, 6H, SiMe2); 13C NMR d
138.9, 138.2, 128.5, 128.2, 127.8, 127.7, 127.1, 126.4 (Car),
88.9, 88.0 (C4,5), 75.5, 75.0 (OCH2Ph), 69.5, 67.7 (C3,6),
0
J4,5¼J4,3¼9.2 Hz, H4), 3.25–3.17 (m, 1H, H1 a), 3.02 (dd,
1H, J2a,2b¼14.0 Hz, J2a,3¼4.0 Hz, H2a), 3.06–2.98 (m, 1H,
0
H3 a), 2.76–2.67 (m, 2H, H1 b,3 b), 2.62 (dd, 1H, J7a,OH
0
0
0
47.2 (C1), 46.0, 42.2 (C2,7), 26.7, 25.1 (C1 ,2 ,3 ), 26.0, 17.9
0
0
¼
0
10.0 Hz, J7b,OH¼3.4 Hz, OH), 2.18–2.11 (m, 1H, H2 a),
2.07 (ddd, 1H, J5,6¼11.3 Hz, J7b,6¼7.3 Hz, J7a,6¼4.0 Hz,
(tBu), 24.3, 24.5 (SiMe2).
0
H6), 1.95–1.82 (m, 1H, H2 b), 1.88 (dd, 1H, J2b,2a¼14 Hz,
5.1.5. [3R,4S,5R,6S]-3-O-tert-Butyldimethylsilyl-6-
hydroxymethyl-4,5-O-methylethylidene-3,4,5-tri-
hydroxycyclohexan-1-one 1,3-propanedithioketal (12).
J2b,3¼10 Hz, H2b), 1.44, 1.43 (2s, 6H, CMe2), 0.94 (s, 9H,
tBu); 0.15 (s, 6H, SiMe2); 13C NMR d 109.4 (CMe2), 84.7

8712
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
Rf 0.2 (cyclohexane/EtOAc 8:2); [a]D¼228 (c 1.05,
CH2Cl2); 1H NMR d 4.82 (dd, 1H, J5,4¼10.2 Hz,
J5,6¼4.6 Hz, H5), 4.35–4.31 (m, 1H, H3), 4.01–3.88 (m,
2H, H7a,7b), 3.71 (dd, 1H, J4,5¼10.2 Hz, J4,3¼2.5 Hz, H4),
(131 mL) at 208C, were successively added imidazole
(22.1 mmol, 3.7 equiv.) and tert-butyldimethylsilyl chloride
(15.6 mmol, 2.7 equiv.). The temperature was then raised to
708C and the mixture was stirred for 24 h. After cooling to
208C, a saturated NH4Cl aqueous solution was added and
the mixture was extracted with CH2Cl2. The combined
organic layers were then dried (MgSO4), filtered and
concentated in vacuo. Flash chromatography of the crude
led to the pure silylated derivatives.
0
0
3.28–3.20 (m, 1H, H6), 3.15–3.04 (m, 2H, H1 a,3 a), 2.69–
0
0
2.57 (m, 2H, H1 b,3 b), 2.20 (dd, 1H, J2a,2b¼15.1 Hz,
0
J2a,3¼1.5 Hz, H2a), 2.15–2.06 (m, 1H, H2 a), 1.88 (dd, 1H,
J2b,2a¼15.1 Hz, J2b,3¼2.6 Hz, H2b), 1.87–1.81 (m, 1H,
0
H2 b), 1.47, 1.45 (2s, 6H, CMe2), 0.94 (s, 9H, tBu), 0.11,
0.10 (2s, 6H, SiMe2); 13C NMR d 109.8 (CMe2), 75.8 (C4),
73.5 (C5), 67.4 (C3), 61.0 (C7), 50.7 (C1), 43.8 (C6), 43.7
5.2.1. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-tert-
butyldimethylsilyloxymethyl-4,5-O-methylethylidene-
3,4,5-trihydroxycyclohexan-1-one 1,3-propanedithio-
ketal (16). Isolated yield: 88%; Rf 0.4 (cyclohexane/
EtOAc 97.5:2.5); mp 778C; [a]D¼þ17 (c 1.0, CH2Cl2);
1H NMR d 4.12 (dd, 1H, J7a,7b¼10.0 Hz, J7a,6¼4.3 Hz,
H7a), 4.05–3.90 (m, 2H, H7b,3), 3.76 (dd, 1H, J5,6¼11.3 Hz,
J5,4¼9.2 Hz, H5), 3.35 (dd, 1H, J4,5¼J4,3¼9.2 Hz, H4),
0
0
0
(C2), 27.1, 24.5 (C1 ,2 ,3 ), 26.8, 26.6 (CMe2), 25.8, 18.2
(tBu), 24.6, 25.1 (SiMe2); MS (CI, CH4) 421 (Mþþ1);
HRMS for C19H37O4S2Si (Mþþ1) calcd 421.1902; found
421.1897.
5.1.6. [3R,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-4,5-O-
methylethylidene-3,4,5,6-tetrahydroxycycloheptan-1-
one 1,3-propanedithioketal (13). Rf 0.4 (cyclohexane/
0
0
3.30–3.01 (m, 1H, H1 a), 3.05–2.85 (m, 2H, H2a,3 a), 2.71–
1
0
2.55 (m, 2H, H1 b,3 b), 2.13–2.03 (m, 1H, H2 a), 2.00–1.75
0
0
EtOAc 8:2); [a]D¼þ48 (c 0.97, CH2Cl2); H NMR d 4.78
0
(dd, 1H, J5,4¼9.7 Hz, J5,6¼5 Hz, H5), 4.35–4.26 (m, 1H,
H3), 4.25–3.14 (m, 1H, H6), 4.09 (dd, 1H, J4,5¼9.7 Hz,
(m, 3H, H2 a,2b,6), 1.41, 1.36 (2s, 6H, CMe2), 0.90, 0.89 (2s,
18H, tBu), 0.11, 0.08, 0.07 (3s, 12H, SiMe2); 13C NMR d
110.8 (CMe2), 84.7 (C4), 74.9 (C5), 69.1 (C3), 61.0 (C7),
52.7 (C1), 52.2 (C6), 45.9 (C2), 26.9, 25.9 (CMe2), 26.9, 25.9
0
0
J4,3¼1.8 Hz, H4), 3.32–3.08 (m, 2H, H1 a,3 a), 2.87–2.53
0
(m, 4H, H1 b,3 b,2a,OH), 2.25–2.15 (m, 1H, H7a), 2.12–1.99
0
0
0
0
0
0
(m, 1H, H2 b), 1.98–1.77 (m, 3H, H2 a, 2b, 7b), 1.43, 1.41 (2s,
6H, CMe2), 0.97 (s, 9H, tBu), 0.11, 0.08 (2s, 6H, SiMe2);
13C NMR d 109.4 (CMe2), 78.2 (C4), 76.0 (C5), 75.1 (C3),
73.8 (C6), 48.4 (C2), 48.4 (C1), 42.7 (C2), 27.4, 26.8, 25.6
(C1 ,2 ,3 ), 25.9, 18.3 (tBu), 24.5, 24.7, 25.2 (SiMe2). Anal.
calcd for C25H50O4S2Si2: C, 56.13; H, 9.42; found: C,
56.23; H, 9.47.
0
(C1 ,2 ,3 ), 27.1 (CMe2), 25.8, 18.2 (tBu), 24.4, 24.7
(SiMe2).
0
0
5.2.2. [3S,4S,5S,6S]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxycycloheptan-1-one 1,3-propanedithio-
ketal (17). Isolated yield: 100%; Rf 0.5 (cyclohexane/
1
5.1.7. [3R,4S,5R,6S]-4,5-Di-O-benzyl-3-O-tert-butyl-
dimethylsilyl-6-hydroxymethyl-3,4,5-trihydroxycyclo-
hexan-1-one 1,3-propanedithioketal (14). Rf 0.3
(cyclohexane/EtOAc 8:2); [a]D¼þ23 (c 0.67, CH2Cl2);
1H NMR d 7.45–7.05 (m, 10H, Har), 4.93–4.25 (m, 4H,
OCH2Ph), 4.30–3.60 (m, 5H, H7a, 7b,3,4,5), 3.35–3.40 (m,
EtOAc 95:5); mp 1048C; [a]D¼29 (c 0.98, CH2Cl2); H
RMN d 7.24–7.16 (m, 10H, Har), 4.76, 4.66 (AB, 4H,
JAB¼11.6 Hz, OCH2Ph), 4.05 (dd, 1H, J3,2b¼9.3 Hz,
J3,4¼7.0 Hz, H3,6), 3.51–3.42 (m, 2H, H4,5), 2.93–2.71
0
0
0
0
(m, 4H, H1 a,1 b,3 a,3 b), 2.38 (d, 2H, J2a,2b¼15.1 Hz, H2a,7a),
2.13 (dd, 2H, J2a,2b¼15 Hz, J2b,3¼9.3 Hz, H2b,7b), 2.06–
0
0
0
0
0
0
0
0
5H, H2a,1 a,1 b,3 a,3 b), 2.18–1.63 (m, 4H, H2b,6,2 a,2 b), 0.91 (s,
9H, t-Bu), 0.10, 0.09 (2s, 6H, SiMe2); 13C NMR d 139.1,
138.3, 128.4, 128.3, 127.8, 127.4 (Car), 89.7 (C4),77.5 (C5),
68.5 (C3), 74.4, 72.8 (OCH2Ph), 60.6 (C7), 52.2 (C1), 47.8
1.93 (m, 2H, H2 a,2 b), 0.88 (s, 18H, t-Bu), 0.14, 20.02 (2s,
12H, SiMe2); 13C NMR d 139.0, 128.0, 127.0 (Car), 87.6
(C4,5), 74.4 (OCH2Ph), 70.1 (C3,6), 47.9 (C1), 44.8 (C2,7),
0
0
0
26.9, 25.3 (C1 ,2 ,3 ), 26.0, 18.0 (t-Bu), 24.3, 24.6 (SiMe2).
0
0
0
(C6), 39.8 (C2), 26.6, 25.0 (C1 ,2 ,3 ), 26.0, 18.3 (t-Bu), 23.6,
24.7 (SiMe2).
5.2.3. [3R,4S,5S,6R]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxycycloheptan-1-one 1,3-propanedithio-
ketal (18). Isolated yield: 100%; Rf 0.5 (cyclohexane/
EtOAc 95:5); [a]D¼220 (c 0.96, CH2Cl2); 1H NMR d
7.39–7.24 (m, 10H, Har), 4.85, 4.58 (AB, 4H, JAB¼12.2 Hz,
OCH2Ph), 4.15–3.96 (m, 2H, H3,6), 3.62 (s, 2H, H4,5),
5.1.8. [3R,4S,5R,6R]-4,5-Di-O-benzyl-3-O-tert-butyl-
dimethylsilyl-3,4,5,6-tetrahydroxycycloheptan-1-one
1,3-propanedithioketal (15). Rf 0.35 (cyclohexane/EtOAc
1
8:2); [a]D¼220 (c 0.96, CH2Cl2); H NMR d 7.35–7.25
0
2.93–2.82 (m, 4H, H1 a,1 b,3 a,3 b), 2.76 (dd, 2H, J2a,2b
0
0
0
(m, 10H, Har), 4.85, 4.44 (AB, 2H, JAB¼12 Hz, OCH2Ph),
4.60, 4.57 (AB, 2H, JAB¼12 Hz, OCH2Ph), 4.16–4.08 (m,
1H, H3), 4.00–3.90 (m, 1H, H6), 3.70–3.60 (m, 2H, H4,5),
¼
J7a,7b¼15.3 Hz, J2b,3¼J7b,6¼10.1 Hz, H2b,7b), 2.17 (d, 2H,
0
0
J2a,2b¼J7a,7b¼15.3 Hz, H2a,7a), 2.08–1.96 (m, 2H, H2 a,2 b),
0.95 (s, 18H, tBu), 0.18, 0.14 (2s, 12H, SiMe2); 13C NMR d
139.1, 128.2, 127.4 (Car), 81.8 (C4,5), 73.9 (OCH2Ph), 68.0
0
3.01–2.62 (m, 5H, H1 a,1 b,3 a,3 b,OH), 2.55 (dd, 1H,
0
0
0
J2a,2b¼15 Hz, J2b,3¼10.5 Hz, H2b), 2.21 (d, 1H, J2a,2b
¼
0
0
0
0
0
15 Hz, H2a), 2.12–1.80 (m, 4H, H2 a,2 b,7a,7b), 0.91 (s, 9H,
tBu), 0.13, 0.08 (2s, 6H, SiMe2), 13C NMR d 138.9, 138.3,
128.6, 128.4, 127.8, 127.7, 126.4 (Car), 81.5 (C4), 80.2 (C5),
74.0, 73.2 (OCH2Ph), 68.1, 67.0 (C3,6), 47.3 (C1), 42.1, 41.5
(C3,6), 47.5 (C1), 41.6 (C2,7), 26.9, 25.4 (C1 ,2 ,3 ), 25.9, 18.0
(tBu), 24.8 (SiMe2). Anal. calcd for C36H58O4S2Si: C,
64.04; H, 8.66; found: C, 64.05, H, 8.79.
0
(C2,7), 27.0, 25.3 (C1 ,2 ,3 ), 26.0, 18.0 (tBu), 24.5, 24.7
0
0
5.3. General procedure for dithioketal hydrolysis
(SiMe2).
To a 2258C cooled solution of N-bromosuccinimide
(2.66 g, 14.96 mmol, 8 equiv.) in a 98:2 mixture of
acetone/H2O (80 mL), was added the dithioketal (1.00 g,
1.87 mmol) in acetone (27 mL) and the mixture was stirred
5.2. General procedure for silylation
To a solution of cycloalcanol (5.82 mmol) in DMF

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8713
for 30 min prior to the addition, at 2258C, of a saturated
Na2S2O3 aqueous solution (17.8 mL). After increasing the
temperature to 208C and removing the acetone in vacuo, the
resulting residue was extracted with ether and the combined
organic layers were dried (MgSO4), filtered and concen-
trated in vacuo. The crude ketone was then purified by flash
chromatography.
16 (0.17 mmol)) in THF (4 mL) at 2788C was added
K-selectridew (1 M in THF, 1.1 mL, 1.1 mmol, 6.5 equiv.)
and the mixture was stirred for 1.5 h prior to the addition of
a saturated NH4Cl aqueous solution. After ether extractions,
the combined organic layers were then dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatographic
purification of the crude (cyclohexane/EtOAc 95:5) led to
the alcohols 24 (5.6 mg) and 25 (16.9 mg) as colorless oils
in 50% yield.
5.3.1. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-tert-
butyldimethylsilyloxymethyl-4,5-O-methylethylidene-
3,4,5-trihydroxycyclohexan-1-one (19b). Isolated yield:
77%; Rf 0.43 (cyclohexane/EtOAc 95:5); mp 468C;
[a]D¼þ7 (c 1.03, CH2Cl2); 1H NMR d 4.10 (dd, 1H,
J7a,7b¼9.9 Hz, J7a,6¼2.2 Hz, H7a), 4.05–3.95 (m, 1H, H3),
3.90–3.65 (m, 3H, H4,5,7b), 2.74 (dd, 1H, J2a,2b¼16.8 Hz,
J2a,3¼6.8 Hz, H2a), 2.41–2.29 (m, 1H, H6), 2.34 (dd, 1H,
J2b,2a¼16.8 Hz, J2b,3¼8.0 Hz, H2b), 1.41, 1.43 (2s, 6H,
CMe2), 0.87, 0.85 (2s, 18H, tBu), 0.11, 0.10, 0.04, 0.03 (4s,
12H, SiMe2); 13C NMR d 205.7 (C1), 111.7 (CMe2), 83.6
(C4), 73.3 (C5), 67.6 (C3), 58.4 (C7), 55.5 (C6), 49.6 (C2),
29.7, 25.8 (CMe2), 27.1, 27.0, 18.3, 18.1 (tBu), 24.6, 25.0,
25.6 (SiMe2). Anal. calcd for C22H44O5Si2: C, 59.41; H,
9.97; found: C, 59.34; H, 10.00.
5.4.1. [3R,4S,5S,6R]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-cycloheptanol (23). Prepared accord-
ing to the method A. Rf 0.4 (cyclohexane/EtOAc 95:5); 1H
NMR d 7.28–7.25 (m, 10H, Har); 4.78, 4.77, 4.60, 4.58
(2AB, 4H, JA,B¼11.8 Hz, OCH2Ph), 4.35–4.25 (m, 1H,
H3), 4.23–4.15 (m, 1H, H6), 4.10–3.95 (m, 1H, H1), 3.65–
3.55 (m, 2H, H4,5), 2.40–2.35 (m, 1H, H2b), 2.35–2.10 (m,
1H, H7b), 2.00–1.90 (m, 1H, H7a), 1.70–1.60 (m, 1H, H2a),
0.88 (s, 18H, tBu), 0.06 (s, 12H, SiMe2); 13C NMR d 139.0,
138.8, 128.2, 127.7, 127.6, 127.4, 127.3 (Car), 83.2, 83.0
(C4,5), 74.0, 73.8 (OCH2Ph), 70.2, 68.1, 66.4 (C1,3,6), 39.6,
39.4 (C2,7), 25.9, 18.1 (tBu), 24.6, 24.7, 24.9 (SiMe2).
5.4.2. [1R,3S,4S,5R,6S]-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idenecyclohexan-1,3,4,5-tetrol (24). Prepared according to
the method A, excepted that the reaction was carried out at
2788C (80% yield Rf 0.2 (cyclohexane/EtOAc 95:5);
[a]D¼þ29 (c 1.0, CH2Cl2); 1H NMR d 4.07 (dd, 1H,
J7a,b¼10.0 Hz, J6,7b¼9.1 Hz, H7b), 3.98 (s, 1H, OH), 3.79–
3.63 (m, 2H, H3,1), 3.63 (dd, 1H, J7a,b¼10.0 Hz,
J6,7a¼3.7 Hz, H7a), 3.42 (dd, 1H, J4,3¼J4,5¼9.1 Hz, H4),
2.97 (dd, 1H, J5,6¼11.1 Hz, J5,4¼9.1 Hz, H5), 2.17 (ddd,
1H, J2a,b¼13.1 Hz, J2a,3¼J2a,1¼4.9 Hz, H2a), 1.83 (dddd,
1H, J6,5¼11.1 Hz, J6,7b¼J6,1¼9.1 Hz, J6,7a¼3.7 Hz, H6),
1.61 (ddd, 1H, J2b,2a¼13.1 Hz, J2b,3¼J2b,1¼11.1 Hz, H2b),
1.37, 1.34 (2s, 6H, CMe2), 0.88, 0.87 (2s, 18H, tBu), 0.09,
0.08, 0.07, 0.06 (4s, 12H, SiMe2); 13C NMR d 110.8
(CMe2), 83.9 (C4), 77.0 (C5), 75.1 (C3), 71.5 (C1), 65.3 (C7),
46.9 (C6), 42.2 (C2), 30.1, 26.9 (CMe2), 25.7, 18.2, 18.0
(tBu), 24.6, 24.9, 25.6, 25.7 (SiMe2); MS (CI, CH4) 446
(Mþ); HRMS for C22H46O5Si2 (Mþþ1) calcd 446.2884;
found 446.2884.
5.3.2. [3S,4S,5S,6S]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxycycloheptan-1-one (21). Isolated yield:
79%; Rf 0.3 (cyclohexane/EtOAc 95:5); [a]D¼218 (c 1.03,
1
CH2Cl2); H NMR d 7.40–7.20 (m, 10H, Har), 4.57, 4.49
(AB, 4H, JAB¼11.9 Hz, OCH2Ph), 4.15 (ddd, 2H,
J3,2a¼7.9 Hz, J3,4¼5.3 Hz, J3,2b¼1.6 Hz, H3), 3.68 (d, 1H,
J4,3¼5.3 Hz, H4), 2.95 (dd, 2H, J2a,2b¼14.8 Hz, J2a,3
H2b), 0.83 (s, 18H, tBu), 0.00, 20.04 (2s, 12H, SiMe2); 13
¼
1.6 Hz, H2a), 2.61 (dd, 1H, J2b,2a¼14.8 Hz, J2b,3¼7.9 Hz,
C
NMR d 208.1 (C1), 138.3, 128.3, 127.8, 127.7 (Car), 82.9
(C4,5), 72.9 (OCH2Ph), 69.1 (C3,6), 47.7 (C2,7), 25.2, 17.9
(tBu), 25.0, 25.2 (SiMe2). Anal. calcd for C33H52O5Si2: C,
67.76; H, 8.96; found: C, 67.65; H, 9.09.
5.3.3. [3R,4S,5S,6R]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxycycloheptan-1-one (22). Isolated yield:
77%; Rf 0.38 (cyclohexane/EtOAc 95:5); mp 528C;
[a]D¼213 (c 1.1, CH2Cl2); 1H NMR d 7.40–7.23 (m,
10H, Har); 4.70 (s, 4H, OCH2Ph), 4.29–4.20 (m, 2H, H3,6),
3.76 (s, 2H, H4,5), 2.72–2.70 (m, 2H, H2a,7a), 2.63–2.49 (m,
2H, H2b,7b), 0.83 (s, 18H, tBu), 0.05, 0.02 (2s, 12H, SiMe2);
13C NMR d 207.9 (C1), 145.1, 138.7, 128.2, 127.8, 127.4
(Car), 82.9 (C4,5), 73.8 (OCH2Ph), 68.6 (C3,6), 47.5 (C2,7),
25.8, 18.0 (tBu), 24.6, 25.2 (SiMe2). Anal. calcd for
C33H52O5Si2: C, 67.76; H, 8.96; found: C, 67.13; H, 9.20.
5.4.3. [1S,3S,4S,5R,6S]-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idenecyclohexan-1,3,4,5-tetrol (25). Prepared according to
the method B; Rf 0.4 (cyclohexane/EtOAc 95:5); [a]D¼þ12
1
(c 0.6, CH2Cl2); H NMR d 4.31 (d, 1H, J1,2¼2.6 Hz, H1),
4.13 (ddd, 1H, J3,2a¼J3,4¼9.1 Hz, J3,2b¼4.8 Hz, H3), 4.06
(dd, 1H, J7a,b¼10.4 Hz, J7a,6¼3.0 Hz, H7a), 3.97 (dd, 1H,
J7a,b¼10.4 Hz, J7b,6¼3.0 Hz, H7b), 3.88 (s, 1H, OH), 3.83
(dd, 1H, J5,6¼11.6 Hz, J5,4¼9.1 Hz, H5), 3.25 (dd, 1H,
J4,3¼J4,5¼9.1 Hz, H4), 2.11 (ddd, 1H, J2a,b¼16.1 Hz,
5.4. Reduction of cycloalkanone
Method A. To a solution of the cycloheptanol 22 (119.9 mg,
0.21 mmol) in absolute ethanol (3.9 mL), at 08C, was added
sodium cyanoborohydride (15.5 mg, 0.72 mmol, 3.4 equiv.)
and the mixture was stirred at 208C for 2 h. A saturated
NH4Cl aqueous solution was then added and the mixture
was extracted with CH2Cl2. The combined organic layers
were then dried (MgSO4), filtered and concentrated in vacuo
to give the cyclitol 23 (123.1 mg) as an oil, in quantitative
yield.
J2a,3¼4.8 Hz, J2a,1¼2.6 Hz, H2a), 1.83 (dddd, 1H, J6,5
¼
11.1 Hz, J6,7b¼J6,1¼J6,7a¼3.0 Hz, H6), 1.47–1.38 (m, 1H,
H2b), 1.38, 1.37 (2s, 6H, CMe2), 0.89, 0.88 (2s, 18H, tBu),
0.09, 0.08, 0.06, 0.05 (4s, 12H, SiMe2); 13C NMR d 109.3
(CMe2), 84.9 (C4), 72.6 (C5), 71.4 (C3), 68.7 (C1), 63.0 (C7),
44.5 (C6), 41.3 (C2), 27.0, 26.8 (CMe2), 25.9, 25.7, 18.3,
18.1 (tBu), 24.6, 24.9, 25.6, 25.7 (SiMe2); MS (CI,
NH3) 446 (Mþ); HRMS for C22H46NO5Si2 (Mþþ1) calcd
446.2884; found 446.2883.
Method B. To the crude cyclohexanone 19b (obtained from

8714
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
5.5. Reductive amination in C7 series
128.0, 127.8, 127.4, 127.1 (Car), 88.3, 82.0 (C4,5), 73.5, 71.7
0
0
0
(OCH2Ph), 72.6, 69.7 (C3,6), 62.9, 62.0 (C1 ,3 ), 58.6 (C2 ),
49.2 (C1), 42.1, 37.4 (C2,7), 25.9, 25.8, 18.2, 18.1 (tBu),
24.4, 24.6, 25.2, 25.4 (SiMe2); MS (CI, CH4) 888
(Mþþ1); HRMS for C48H90NO6Si4 (Mþþ1) calcd
888.5877; found 888.5845.
To the neat cycloalkanone (0.53 mmol) at 208C, were
successively added titanium tetra-isopropoxide (0.66 mmol,
1.25 equiv.) and the primary amine (1.06 mmol, 2 equiv.).
After 2 h stirring, absolute ethanol (500 mL) and sodium
cyanoborohydride (2.79 mmol, 5.3 equiv.) were added and
the resulting mixture was further stirred for 14 h. Addition
of H2O (300 mL) resulted in the formation of a off-white
precipitate which was filtered off and washed with absolute
ethanol. Concentration of the filtrate was followed by
extraction of the resulting residue with ethyl acetate,
filtration and concentration in vacuo. The oily residue was
then dissolved in CH2Cl2 and stirred in the presence of
sodium hydrogencarbonate. Filtration and concentration in
vacuo afforded the crude aminocyclitol which was then
purified by flash chromatography.
5.5.4. Methyl [30S,40S,50S,60S]-6-deoxy-(40,50-dibenzyl-
oxy-30,60-di-tert-butyldimethylsilyloxy-cycloheptanyl)-
amino-2,3,4-tri-O-benzyl-D-glucopyranoside
Isolated yield: 43%; Rf 0.3 (cyclohexane/EtOAc 7:3);
(26d).
1
[a]D¼þ0.3 (c 2.0, CH2Cl2); H NMR d 7.34–7.22 (m,
25H, Har), 5.00–4.20 (m, 10H, OCH2Ph), 4.53 (d, 1H,
0
0
J1,2¼3.5 Hz, H1), 4.21–4.05 (m, 2H, H3 ,6 ), 3.97 (dd, 1H,
J3,2¼J3,4¼9.2 Hz, H3), 3.80–3.70 (m, 1H, H5), 3.62–3.40
0
(m, 4H, H4,5 ,4 ,2), 3.37 (s, 3H, OMe), 3.06 (dd, 1H,
0
J6a,b¼12.0 Hz, J6a,5¼2.7 Hz, H6a), 2.95–2.80 (m, 1H,
0
H1 ), 2.68 (dd, 1H, J6a,b¼12.0 Hz, J6b,5¼5.8 Hz, H6b),
0
0
5.5.1. [3S,4S,5R,6S]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-N-cycloheptanyl-N-benzylamine
(26a). Isolated yield: 80%; Rf 0.3 (cyclohexane/EtOAc
95:5); [a]D¼21 (c 1.0, CH2Cl2); 1H NMR d 7.50–7.10 (m,
15H, Har), 4.78, 4.35 (AB, 2H, JAB¼12.1 Hz, OCH2Ph),
4.56, 4.52 (AB, 2H, JAB¼11.8 Hz, OCH2Ph), 4.20–4.02 (m,
2H, H3,6), 3.87, 3.78 (AB, 2H, JAB¼13.3 Hz, NHCH2Ph),
3.56 (dd, 1H, J4,5¼1.3 Hz, J4,3¼6.1 Hz, H4), 3.45 (dd, 1H,
J5,4¼1.3 Hz, J5,6¼8.2 Hz, H5), 3.03–2.80 (m, 1H, H1),
2.04–1.66 (m, 4H, H7a,2a,2b,7b), 0.89, 0.83 (2s, 18H, tBu),
0.05, 0.01, 20.04 (3s, 12H, SiMe2); 13C NMR d 139.7,
139.2, 138.4, 128.5, 128.3, 128.0, 127.8, 127.5, 127.1, 127.0
(Car), 88.0, 82.3 (C4,5), 73.9, 72.9 (OCH2Ph), 71.8, 69.5
(C3,6), 50.9 (NHCH2Ph), 50.5 (C1), 40.6, 36.4 (C2,7), 26.0,
25.8, 18.1, 17.9 (tBu), 24.4, 24.7, 25.2 (SiMe2).
1.90–1.60 (m, 4H, H2 a,b,7 a,b), 0.86, 0.84 (2s, 18H, tBu),
0.03 (s, 12H, SiMe2); 13C NMR d 139.3, 138.9, 138.5,
138.4, 138.3, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9,
0
0
127.6, 127.5, 127.2 (Car), 98.1 (C1), 88.0, 82.0 (C4 ,5 ), 82.3,
80.1, 73.3 (C2,3,4), 75.7, 75.1, 73.5, 73.4, 71.8 (OCH2Ph),
0
0
0
72.6, 69.7 (C3 ,6 ), 70.1 (C5), 55.3 (OMe), 51.7 (C1 ), 47.6
0
0
(C6), 40.8, 36.8 (C2 ,7 ), 26.0, 25.0, 18.1, 18.0 (tBu), 24.5,
24.6, 25.1 (SiMe2); MS (CI, CH4) 1032 (Mþþ1); HRMS
for C61H86NO9Si2 (Mþþ1) calcd 1032.5841; found
1032.5824.
5.5.5. [3R,4S,5S,6R]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-N-cycloheptanyl-N-benzylamine
(27a). Isolated yield: 93%; Rf 0.3 (cyclohexane/EtOAc
1
95:5); [a]D¼216 (c 1.09, CH2Cl2); H NMR d 7.47–7.10
(m, 15H, Har), 4.84, 4.59 (AB, 2H, JAB¼11.8 Hz, OCH2Ph),
4.76, 4.57 (AB, 2H, JAB¼12.0 Hz, OCH2Ph), 4.56–4.20 (m,
1H, H3), 4.18–4.08 (m, 1H, H6), 3.79 (s, 2H, NHCH2Ph),
3.64 (dd, 1H, J4,5¼5.5 Hz, J4,3¼1.1 Hz, H4), 3.58 (dd, 1H,
J5,4¼5.5 Hz, J5,6¼1.9 Hz, H5), 3.06–2.89 (m, 1H, H1), 2.23
(ddd, 1H, J2a,b¼14.3 Hz, J2a,3¼9.4 Hz, J2a,1¼5.8 Hz, H2a),
2.10 (ddd, 1H, J7b,a¼14.0 Hz, J7b,6¼J7b,1¼9.8 Hz, H7b),
1.84–1.71 (m, 1H, H7a), 1.53 (ddd, 1H, J2b,a¼14.3 Hz,
J2b,1¼6.5 Hz, J2b,3¼2.2 Hz, H2b), 0.89, 0.87 (2s, 18H, tBu),
0.04, 0.03 (2s, 12H, SiMe2); 13C NMR d 139.7, 139.2,
138.4, 128.5, 128.3, 128.0, 127.8, 127.5, 127.1, 127.0 (Car),
88.0, 82.3 (C4,5), 73.9, 72.9 (OCH2Ph), 71.8, 69.5 (C3,6),
50.9 (NHCH2Ph), 50.5 (C1), 40.6, 36.4 (C2,7), 26.0, 25.8,
18.1, 17.9 (tBu), 24.4, 24.7, 25.2 (SiMe2); MS (CI, CH4)
676 (Mþþ1); HRMS for C40H62NO4Si2 (Mþþ1) calcd
676.4217; found 676.4202.
5.5.2. [3S,4S,5S,6S]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-N-cycloheptanyl-N-butylamine
(26b). Isolated yield: 63%; Rf 0.2 (cyclohexane/EtOAc 8:2);
1
[a]D¼þ5 (c 1.0, CH2Cl2); H NMR d 7.34–7.22 (m, 10H,
Har); 4.68, 4.56 (AB, 2H, JAB¼11.9 Hz, OCH2Ph), 4.50,
4.33 (AB, 2H, JAB¼11.6 Hz, OCH2Ph), 4.21–4.05 (m, 2H,
H3,6), 3.56 (dd, 1H, J4,3¼6.2 Hz, J4,5¼1.5 Hz, H4), 3.58 (dd,
1H, J5,6¼8.2 Hz, J5,4¼1.5 Hz, H5), 2.95–2.76 (m, 1H, H1),
0
2.73–2.48 (m, 2H, H1 ), 1.95–1.54 (m, 4H, H2a,b,7a,b),
0
0
0
1.53–1.23 (m, 4H, H2 ,3 ), 0.99–0.75 (m, 21H, tBu, H4 ),
0.06, 0.01, 20.02 (3s, 12H, SiMe2); 13C NMR d 139.3,
138.5, 128.3, 128.0, 127.8, 127.5, 127.2 (Car), 88.0, 82.3
(C4,5), 74.1, 73.2 (OCH2Ph), 72.8, 69.8 (C3,6), 51.5 (C1),
0
47.1 (C1 ), 40.8, 36.9 (C2,7), 32.5 (C2 ), 26.0, 25.8, 18.1, 18.0
0
0
0
(tBu), 20.6 (C3 ), 14.0 (C4 ), 24.4, 24.8, 25.0 (SiMe2); MS
(CI, CH4) 642 (Mþþ1); HRMS for C37H64NO4Si2 (Mþþ1)
calcd 642.4374; found 642.4371.
5.5.6. [3R,4S,5S,6R]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-N-cycloheptanyl-N-butylamine
(27b). Isolated yield: 47%; Rf 0.2 (cyclohexane/EtOAc
75:25); [a]D¼221 (c 1.03, CH2Cl2); 1H NMR d 7.30–7.20
(m, 10H, Har), 4.83, 4.58 (AB, 2H, JAB¼11.9 Hz, OCH2Ph),
4.74, 4.57 (AB, 2H, JAB¼12.0 Hz, OCH2Ph), 4.28–4.05 (m,
2H, H3,6), 3.63 (dd, 1H, J4,5¼5.4 Hz, H4), 3.56 (d, 1H,
J5,4¼5.4 Hz, H5), 2.98–2.74 (m, 1H, H1), 2.56 (t, 2H,
5.5.3. [3S,4S,5S,6S]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-N-cycloheptanyl-N-(10,20-di-tert-
butyldimethylsilyloxy)-20-propylamine (26c). Isolated
yield: 72%; Rf 0.46 (cyclohexane/EtOAc 9:1); [a]D¼þ0
1
(c 1.0, CH2Cl2); [a]Hg¼þ0 (c 1.0, CH2Cl2); H NMR d
7.40–7.15 (m, 10H, Har), 4.68, 4.55 (AB, 2H, JAB¼11.8 Hz,
OCH2Ph), 4.50, 4.21 (AB, 2H, JAB¼11.9 Hz, OCH2Ph),
0
0
0
J1 ,2 ¼7.0 Hz, H1 ), 2.19 (ddd, 1H, J2a,b¼14.6 Hz,
0
4.20–4.02 (m, 2H, H3,6), 3.67–3.39 (m, 6H, H4,5,1 ,3 ),
0
J2a,3¼9.3 Hz, J2a,1¼6.0 Hz, H2a), 1.99 (ddd, 1H, J7b,a¼
0
2.98–2.81 (m, 1H, H1), 2.75–2.62 (m, 1H, H2 ), 1.88–1.62
(m, 4H, H2a,b,7a,b), 0.88 (s, 36H, tBu), 0.06, 0.03, 0.00,
20.03 (4s, 24H, SiMe2); 13C NMR d 139.3, 138.5, 128.3,
13.9 Hz, J7b,6¼J7b,1¼9.9 Hz, H7b), 1.80–1.55 (m, 1H, H7a),
0 0 0
1.55–1.23 (m, 5H, H2b,2 ,3 ), 0.94–0.82 (m, 21H, tBu, H4 ),
0.06, 0.04 (2s, 12H, SiMe2); 13C NMR d 139.4, 139.1,

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8715
128.1, 127.5, 127.4, 127.2 (Car), 83.7, 82.7 (C4,5), 74.1, 73.2
0
(OCH2Ph), 70.7, 68.8 (C3,6), 51.9 (C1), 47.0 (C1 ), 37.4, 37.0
J5,4¼J5,6¼5.3 Hz, H5), 3.45 (dd, 1H, J4,5¼5.3 Hz,
J4,3¼8.5 Hz, H4), 3.17–3.02 (m, 1H, H1), 2.79–2.50 (m,
0
(C2,7), 32.5 (C2 ), 26.0, 25.9, 18.1, 18.0 (tBu), 20.6 (C3 ),
0
0
2H, H1 ), 2.21–1.74 (m, 4H, H2a,b,7a,b), 1.63–1.20 (m, 4H,
14.1 (C4 ), 24.7, 24.8, 25.0 (SiMe2); MS (CI, CH4) 642
H2 ,3 ), 0.91 (t, 3H, J4 ,3 ¼7.1 Hz, H4 ); 13C NMR d 138.2,
0
0
0
0
0
0
(Mþþ1); HRMS for C37H64NO4Si2 (Mþþ1) calcd
128.5, 127.9, 127.8 (Car), 88.6, 86.2 (C4,5), 73.8, 73.0
0
(OCH2Ph), 71.0, 66.1 (C3,6), 52.7 (C1), 47.0 (C1 ), 39.2
642.4374; found 642.4371.
0
0
0
(C2 ), 32.1, 31.1 (C2,7), 20.4 (C3 ), 14.0 (C4 ); MS (CI, CH4)
414 (Mþþ1); HRMS for C25H36NO4 (Mþþ1) calcd
414.2644; found 414.2640.
5.5.7. [3R,4S,5S,6R]-4,5-Dibenzyloxy-3,6-di-tert-butyl-
dimethylsilyloxy-1-N-cycloheptanyl-N-(10,30-di-tert-
butyldimethylsilyloxy)-20-propylamine (27c). Isolated
yield: 91%; Rf 0.56 (cyclohexane/EtOAc 9:1); [a]D¼213
(c 1.0, CH2Cl2); 1H NMR d 7.40–7.10 (m, 10H, Har), 4.86,
4.59 (AB, 2H, JAB¼11.9 Hz, OCH2Ph), 4.72, 4.55 (AB, 2H,
JAB¼12.0 Hz, OCH2Ph), 4.32–4.18 (m, 1H, H3), 4.16–4.04
5.6.3. [3S,4R,5R,6S]-4,5-Di-O-benzyloxy-1-N-(10,30-di-
hydroxycycloheptanyl-N-(10,20-dihydroxy)-20-propyl-
amine (28c). This product was submitted without
purification to the hydrogenolysis reaction.
0
0
(m, 1H, H6), 3.70–3.40 (m, 6H, H4,5,1 a,b,3 a,b), 3.07–2.89
5.6.4. Methyl [30S,40R,50R,60S]-6-deoxy-(40,50-dibenzyl-
oxy-30,60-dihydroxycycloheptanyl)-amino-2,3,4-tri-O-
benzyl-D-glucopyranoside (28d). Isolated yield: 87%; Rf
0
(m, 1H, H2 ), 2.75–2.60 (m, 1H, H1), 2.14 (ddd, 1H,
J2a,b¼14.5 Hz, J2a,3¼8.7 Hz, J2a,1¼5.5 Hz, H2a), 2.01 (ddd,
1H, J7b,a¼13.5 Hz, J7b,6¼J7b,1¼10.5 Hz, H7b), 1.71–1.48
(m, 2H, H2b,7a), 0.88, 0.87 (2s, 36H, tBu), 0.06, 0.04, 0.03,
0.02 (4s, 24H, SiMe2); 13C NMR d 139.5, 139.2, 128.2,
128.1, 127.6, 127.4, 127.2 (Car), 84.0, 82.8 (C4,5), 74.3, 73.2
1
0.2 (EtOAc/EtOH 95:5); [a]D¼þ0.5 (c 0.2, CH2Cl2); H
NMR d 7.32–7.20 (m, 25H, Har), 5.00–4.52 (m, 10H,
OCH2Ph), 4.53 (d, 1H, J1,2¼3.5 Hz, H1), 4.15–3.90 (m, 3H,
0
0
0
0
H3 ,6 ,3), 3.79–3.62 (m, 2H, H5,5 ), 3.46 (dd, 1H, J2,3
0
0
(OCH2Ph), 70.5, 68.9 (C3,6), 62.1, 61.6 (C1 ,3 ), 57.7 (C2 ),
49.0 (C1), 38.6, 38.1 (C2,7), 25.9, 18.3, 18.1 (tBu), 24.7,
25.4 (SiMe2); MS (CI, CH4) 888 (Mþþ1); HRMS for
C48H90NO6Si4 (Mþþ1): calcd 888.5877; found 888.5855.
¼
0
9.6 Hz, J2,1¼3.5 Hz, H2), 3.42–3.30 (m, 2H, H4,4 ), 3.33 (s,
0
3H, OMe), 3.00–2.95 (m, 1H, H1 ), 2.90 (dd, 1H,
J6a,6b¼12.0 Hz, J6a,5¼2.7 Hz, H6a), 2.58 (dd, 1H, J6b,6a
¼
0
0
12.0 Hz, J6b,5¼7.1 Hz, H6b), 1.90–1.60 (m, 4H, H2 a,b,7 a,b);
13C NMR d 138.8, 138.3, 138.1, 128.6, 128.5, 128.1, 128.0,
127.9, 127.8, 127.6, 126.8 (Car), 98.0 (C1), 88.5, 86.2
5.6. General procedure for the hydrolysis of the silyl
ethers (26) or (27)
0
(C4 ,5 ), 82.0, 80.1, 79.4 (C2,3,4), 75.7, 75.0, 74.0, 73.4
0
0
0
0
To a solution of the silylated diol 26 (or 27) (0.47 mmol) in
THF (11.8 mL) was added tetra-n-butylammonium fluoride
(1 M in THF, 1.64 mL, 1.64 mmol, 3.5 equiv.). After 24 h
stirring at 208C, the mixture was concentrated in vacuo and
the crude diol 28 (or 29) was purified by flash
chromatography.
(OCH2Ph), 70.5, 69.3, 66.2 (C3 ,6 ,5), 55.3 (OMe), 53.4þ(C1 ),
0 0
48.0 (C6), 38.1, 32.4 (C2 ,7 ); MS (CI, CH4) 804 (M þ1);
HRMS for C49H57NO9 (Mþþ1) calcd 804.4105; found
804.4111.
5.6.5. [3R,4R,5R,6R]-4,5-Di-O-benzyl-1-N-(-3,4,5,6-
tetrahydroxycycloheptanyl)-N-benzylamine
(29a).
5.6.1. [3S,4R,5R,6S]-4,5-Di-O-benzyl-1-N-(-3,4,5,6-tetra-
hydroxycycloheptanyl)-N-benzylamine (28a). Isolated
yield: 100%; Rf 0.3 (CH2Cl2/MeOH 96:4); [a]D¼22 (c
Isolated yield: 74%; Rf 0.3 (CH2Cl2/MeOH 96:4);
[a]D¼28 (c 1.0, CH2Cl2); 1H NMR d 7.34–7.21 (m,
15H, Har), 4.72, 4.70, 4.62 (AB, 4H, JAB¼11.6 Hz,
OCH2Ph), 4.28 (ddd, 1H, J3,2a¼8.9 Hz, J3,2b¼J3,4¼2.3 Hz,
H3), 4.15 (ddd, 1H, J6,7b¼8.9 Hz, J6,7a¼J6,5¼2.6 Hz, H6),
3.81 (dd, 1H, J4,5¼6.1 Hz, J4,3¼2.3 Hz, H4), 3.81, 3.74
1
0.93, CH2Cl2); H NMR d 7.50–7.10 (m, 15H, Har), 4.85,
4.61 (AB, 2H, JAB¼11.3 Hz, OCH2Ph), 4.75, 4.64 (AB, 2H,
JAB¼11.4 Hz, OCH2Ph), 4.19 (ddd, 1H, J3,2b¼J3,4¼8.6 Hz,
J3,2a¼2.3 Hz, H3), 4.05 (ddd, 1H, J6,7b¼8.7 Hz,
J6,5¼5.6 Hz, J6,7a¼3.0 Hz, H6), 3.91, 3.77 (AB, 2H,
(AB, 2H, JAB¼13.0 Hz, NHCH2Ph), 3.67 (dd, 1H, J5,4
¼
6.1 Hz, J5,6¼2.6 Hz, H5), 3.07 (dddd, 1H, J1,2b¼7.3 Hz,
J1,7b¼6.2 Hz, J1,2a¼5.5 Hz, J1,7a¼4.4 Hz, H1), 2.24 (ddd,
1H, J2a,b¼14.3 Hz, J2a,3¼8.9 Hz, J2a,1¼5.5 Hz, H2a), 2.00
(ddd, 1H, J7b,a¼14.1 Hz, J7b,6¼8.9 Hz, J7b,1¼6.2 Hz, H7b),
1.84 (ddd, 1H, J7a,b¼14.1 Hz, J7a,1¼4.4 Hz, J7a,6¼2.6 Hz,
H2a), 1.65 (ddd, 1H, J2b,a¼14.3 Hz, J2b,1¼7.3 Hz,
J2b,3¼2.3 Hz, H2b); 13C NMR d 138.4, 138.3, 136.0,
129.1, 128.8, 128.5, 128.0, 127.8 (Car), 82.3, 82.0 (C4,5),
73.4, 73.1 (OCH2Ph), 68.7, 66.9 (C3,6), 51.1 (NH–CH2–
Ph), 50.9 (C1), 34.8, 33.9 (C2,7).
JAB¼12.7 Hz, NHCH2Ph), 3.74 (dd, 1H, J5,4¼J5,6
¼
5.6 Hz, H5), 3.46 (dd, 1H, J4,5¼5.6 Hz, J4,3¼8.6 Hz, H4),
3.23–3.07 (m, 1H, H1), 2.14–1.76 (m, 2H, H2a,7a), 1.42–
1.20 (m, 2H, H2b,7b); 13C NMR d 139.7, 139.2, 138.4, 128.5,
128.3, 128.0, 127.8, 127.5, 127.1, 127.0 (Car), 88.0, 82.3
(C4,5), 73.9, 72.9 (OCH2Ph), 71.8, 69.5 (C3,6), 50.9
(NHCH2Ph), 50.5 (C1), 40.6, 36.4 (C2,7), 26.0, 25.8, 18.1,
17.9 (tBu), 24.4, 24.7, 25.2 (SiMe2); MS (CI, CH4) 448
(Mþþ1); HRMS for C28H34NO4 (Mþþ1) calcd 448.2488;
found 448.2483.
5.6.6. [3R,4R,5R,6R]-4,5-Di-O-benzyl-1-N-(3,4,5,6-tetra-
hydroxycycloheptanyl)-N-butylamine (29b). Isolated
yield: 88%; Rf 0.3 (EtOAc/EtOH 95:5); [a]D¼228 (c 1.0,
5.6.2. [3S,4R,5R,6S]-4,5-Di-O-benzyl-1-N-(3,4,5,6-tetra-
hydroxycycloheptanyl)-N-butylamine (28b). Isolated
yield: 85%; Rf 0.3 (EtOAc/EtOH 95:5); [a]D¼þ21 (c 1.0,
1
CH2Cl2); H NMR d 7.30–7.26 (m, 10H, Har), 4.72, 4.67,
1
CH2Cl2); H NMR d 7.37–7.23 (m, 10H, Har), 4.85, 4.60
4.62 (AB, 2H, JAB¼11.6 Hz, OCH2Ph), 4.27 (ddd, 1H,
0
(AB, 2H, JAB¼11.2 Hz, OCH2Ph), 4.71, 4.63 (AB, 2H,
J3,2a¼8.9 Hz, J3,2b¼J3,4¼2.3 Hz, H3 ), 4.17 (ddd, 1H, J6,7b
¼
JAB¼11.3 Hz, OCH2Ph), 4.19 (ddd, 1H, J3,2b¼10.4 Hz,
8.9 Hz, J6,7a¼J6,5¼2.5 Hz, H6), 3.81 (dd, 1H, J4,5¼6.1 Hz,
J4,3¼2.5 Hz, H4), 3.65 (dd, 1H, J5,4¼6.1 Hz, J5,6¼2.5 Hz,
H5), 3.11–2.96 (m, 1H, H1), 2.90–2.70 (m, 2H, OH),
J3,4¼8.5 Hz, J3,2a¼1.9 Hz, H3), 4.09 (ddd, 1H, J6,7b
¼
7.3 Hz, J6,5¼5.3 Hz, J6,7a¼1.8 Hz, H6), 3.76 (dd, 1H,

8716
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
0
2.70–2.48 (m, 2H, H1 ), 2.22 (ddd, 1H, J2a,b¼14.2 Hz,
J2a,3¼8.9 Hz, J2a,1¼5.5 Hz, H2a), 2.07–1.88 (m, 1H, H7b),
1.79 (ddd, 1H, J7a,b¼14.2 Hz, J7a,1¼3.9 Hz, J7a,6¼2.0 Hz,
H2a), 1.63 (ddd, 1H, J2b,a¼14.2 Hz, J2b,1¼7.4 Hz,
HRMS for C11H24O4N (Mþþ1) calcd 234.1705; found
234.1709.
5.7.3. [3S,4R,5R,6S]-1-N-(10,30-Dihydroxy-20-N-propyl)-
3,4,5,6-tetrahydroxycycloheptylamine (30c). Overall
0
0
J2b,3¼2.0 Hz, H2b), 1.52–1.20 (m, 4H, H2 ,3 ), 0.90 (t, 3H,
1
J4 ,3 ¼7.1 Hz, H4 ); 13C NMR d 138.4, 128.5, 127.8 (Car),
yield from 26c: 50%; [a]D¼þ5 (c 1.0, H2O); H NMR
0
0
0
83.2, 82.8 (C4,5), 73.5, 72.9 (OCH2Ph), 69.3, 67.1 (C3,6),
0
(D2O) d 3.85–3.73 (m, 1H, H6), 3.72–3.47 (m, 5H,
0
0
0
H3,1 a,b,3 a,b), 3.40–3.23 (m, 2H, H4,5), 3.20–3.04 (m, 1H,
0
51.7 (C1), 46.8 (C1 ), 36.6 (C2 ), 34.8, 32þ.0 (C2,7), 20.4 (C3 ),
0
0
13.9 (C4 ); MS (CI, CH4) 414 (M þ1); HRMS for
H1), 2.93–2.81 (m, 1H, H2 ), 2.06 (ddd, 1H, J2a,b¼13.6 Hz,
C25H36NO4 (Mþþ1) calcd 414.2644; found 414.2646.
J2a,3¼4.2 Hz, J2a,1¼2.4 Hz, H2a), 1.92–1.77 (m, 2H, H7a,b),
1.45 (dt, 1H, J2b,a¼13.6 Hz, J2b,3¼J2b,1¼11.2 Hz, H2b); 13
C
NMR (D2O) d 80.7, 80.2 (C4,5), 72.6, 70.9 (C3,6), 63.2, 62.8
5.6.7. [3R,4R,5R,6R]-4,5-Di-O-benzyloxy-1-N-(10,30-di-
hydroxycycloheptanyl-N-(10,20-dihydroxy)-20-propyl-
amine (29c). This product was submitted without
purification to the hydrogenolysis reaction.
0
0
0
(C1 ,3 ), 59.2 (C2 ), 49.6 (C1), 40.7, 39.2 (C2,7); SM (CI, CH4)
252 (Mþþ1); HRMS for C10H22NO6 (Mþþ1) calcd
252.1447; found 252.1445.
5.7. Hydrogenolysis in the C7 series
5.7.4. Methyl [30S,40R,50R,60S]-6-deoxy-(30,40,50,60-tetra-
hydroxycycloheptanyl)-6-amino-D-glucopyranoside
1
For 28a,b,c or 29a,b,c. A suspension of palladium black
(37.3 mg) in acetic acid (1 mL) was saturated with
dihydrogen. A solution of the substrate (90 mmol) in acetic
acid (2 mL) was then added and was followed by 14 h
stirring. The catalyst was removed by filtration through a
Celite pad and the filtrate was concentrated in vacuo.
Subsequent purification by ion exchange chromatography
(Dowexw 50X8-100, 3% aqueous ammonium hydroxide)
afforded the pure targeted aminocyclitol.
(30d). Isolated yield: 43%; [a]D¼þ71 (c 0.7, H2O); H
NMR (D2O) d 4.87 (d, 1H, J1,2¼3.6 Hz, H1), 3.92–3.67 (m,
0
0
4H, H3 ,6 ,5,3), 3.62 (dd, 1H, J2,3¼9.8 Hz, J2,1¼3.6 Hz, H2),
0
3.49 (s, 3H, OMe), 3.45–3.20 (m, 4H, H4,5 ,4 ,1 ), 3.21 (dd,
0
0
1H, J6a,6b¼12.7 Hz, J6a,5¼2.2 Hz, H6a), 2.94 (dd, 1H,
0
J6b,a¼12.7 Hz, J6b,5¼9.1 Hz, H6b), 2.19 (ddd, 1H, J2 a,b
¼
0
0
0
0
0
13.6 Hz, J2 a,3 ¼4.6 Hz, J2 a,1 ¼2.5 Hz, H2 a), 2.08–1.93 (m,
0
0
0
0
2H, H7 a,b), 1.65 (ddd, 1H, J2 b,a¼13.6 Hz, J2 b,3
¼
J2 b,1 ¼11.0 Hz, H2 b); 13C NMR (D2O) d 102.2 (C1), 80.8,
0
0
0
0
80.1 (C4 ,5 ), 75.7, 74.7, 74.0 (C2,3,4), 72.5, 71.8, 70.8
0
0
(C3 ,6 ,5), 58.2 (OMe), 52.7 (C1 ), 49.5 (C6), 39.0, 38.0
0
0
For 28d. To a solution of the benzylated derivative 28
(93 mg, 11.6 mmol) in THF (500 mL) was condensed liquid
ammonia (60 mL) at 2788C. Sodium was then added until
persistance of a dark blue color and the mixture was stirred
in refluxing ammonia for 6 h. After careful addition of solid
ammonium chloride until decoloration, ammonia was
evaporated and the solid residue was washed with CH2Cl2
and extracted with MeOH. The combined alcoholic layers
were then concentrated in vacuo, and purification by ion-
exchange chromatography (Dowexw 50X8-100, 1%
aqueous ammonium hydroxide) gave the expected 30d
(17.5 mg) as a hygroscopic solid, in 43% yield.
þ
0
0
(C2 ,7 ); SM (CI, CH4) 354 (M þ1); HRMS for C14H28NO9
(Mþþ1) calcd 354.1764; found 354.1768.
5.7.5. [3R,4R,5R,6R]-1-Aminocycloheptane-3,4,5,6-tetrol
1
(31a). Isolated yield: 85%; [a]D¼22 (c 0.93, H2O); H
NMR (D2O) d 4.31–4.21 (m, 1H, H3), 4.19–4.08 (m, 1H,
H6), 3.96–3.86 (m, 2H, H4,5), 2.38 (ddd, 1H, J2a,b¼14.5 Hz,
J2a,3¼8.8 Hz, J2a,1¼6.3 Hz, H2a), 2.20–1.92 (m, 2H, H7a,b),
1.81 (ddd, 1H, J2b,a¼14.5 Hz, J2b,1¼7.8, J2b,3¼2.5 Hz,
H2b); 13C NMR (D2O) d 77.6, 76.3 (C4,5); 70.4, 69.8
(C3,6); 47.8 (C1); 36.7, 36.1 (C2,7); SM (CI, CH4) 178
(Mþþ1); HRMS for C7H16O4N (Mþþ1) calcd 178.1079;
found 178.1080.
5.7.1. [3S,4R,5R,6S]-1-Aminocycloheptane-3,4,5,6-tetrol
1
(30a). Isolated yield: 60%; [a]D¼þ9 (c 1, H2O); H NMR
(D2O) d 3.98–3.84 (m, 1H, H6), 3.76–3.53 (m, 2H, H3,1),
3.49–3.35 (m, 2H, H4,5), 2.21 (ddd, 1H, J2a,b¼13.5 Hz,
J2a,1¼5 Hz, J2a,3¼2.4 Hz, H2a), 2.15–1.93 (m, 2H, H7a,b),
1.73 (ddd, 1H, J2b,a¼13.5 Hz, J2b,1¼J2b,3¼11.2 Hz, H2b);
13C NMR (D2O) 80.8, 80.1 (C4,5), 72.0, 70.5 (C3,6), 46.7
(C1), 40.4, 39.4 (C2,7); SM (CI, CH4) 178 (Mþþ1); HRMS
for C7H16O4N (Mþþ1) calcd 178.1079, found 178.1084.
5.7.6. [3R,4R,5R,6R]-1-N-(3,4,5,6-Tetrahydroxycyclo-
heptanyl)-N-butylamine (31b). Isolated yield: 50%;
1
[a]D¼22 (c 0.9, H2O); H NMR (D2O) d 4.34–4.25 (m,
1H, H3), 4.17–4.09 (m, 1H, H6), 3.92 (s, 2H, H4,5), 3.71–
0
0
0
3.55 (m, 1H, H1), 3.13 (t, 2H, J1 ,2 ¼7.7 Hz, H1 ), 2.44 (ddd,
1H, J2a,b¼15 Hz, J2a,3¼9.2 Hz, J2a,1¼6.7 Hz, H2a), 2.33–
2.00 (m, 2H, H7a,b), 1.89 (ddd, 1H, J2b,a¼15 Hz,
0
J2b,1¼7.6 Hz, J2b,3¼3.8 Hz, H2b), 1.80–1.62 (m, 2H, H2 ),
0
0
0
0
0
5.7.2. [3S,4R,5R,6S]-1-N-(3,4,5,6-Tetrahydroxycyclo-
heptanyl)-N-butylamine (30b). Isolated yield: 62%;
1.68 (qt, 2H, J3 ,4 ¼J3 ,2 ¼7.3 Hz, H3 ), 0.99 (t, 3H,
J4 ,3 ¼7.3 Hz, H4 ); 13C NMR (D2O) d 77.9, 76.3 (C4,5),
0
0
0
1
0
70.8, 69.9 (C3,6), 54.8 (C1), 48.0 (C1 ), 35.0, 34.5 (C2,7), 31.0
[a]D¼þ1 (c 1.0, H2O); H NMR (D2O) d 3.92 (ddd, 1H,
þ
0
0
0
J3,2b¼J3,4¼11.2 Hz, J3,2a¼3.8 Hz, H3), 3.80–3.62 (m, 1H,
(C2 ), 22.2 (C3 ), 15.6 (C4 ); SM (CI, CH4) 234 (M þ1);
HRMS for C11H24O4N (Mþþ1) calcd 234.1705; found
234.1704.
0
0
H6), 3.57–3.34 (m, 3H, H1,4,5), 3.13 (t, 2H, J1 ,2 ¼7.7 Hz,
0
H1 ), 2.27 (ddd, 1H, J2a,b¼13.5 Hz, J2a,3¼3.8 Hz,
J2a,1¼2.4 Hz, H2a), 2.15–2.03 (m, 2H, H7a,b), 1.78 (ddd,
1H, J2b,a¼13.5 Hz, J2b,1¼J2b,3¼11.2 Hz, H2b), 1.71–1.56
5.7.7. [3R,4R,5R,6R]-1-N-(10,30-Dihydroxy-20-N-propyl)-
3,4,5,6-tetrahydroxycycloheptylamine (31c). Overall
0
0
0
0
0
0
(m, 2H, H2 ), 1.43 (qt, 2H, J3 ,4 ¼J3 ,2 ¼7.3 Hz, H3 ), 0.97 (t,
1
3H, J4 ,3 ¼7.3 Hz, H4 ); 13C NMR (D2O) 82.4, 81.6 (C4,5),
yield from 27c: 75%; [a]D¼25 (c 1.0, H2O); H NMR
0
0
0
0
74.1, 72.5 (C3,6), 55.6 (C1), 48.5 (C1 ), 41.5, 40.2 (C2,7), 34.3
(D2O) d 4.25 (dd, 1H, J3,2a¼8.8 Hz, J3,2b¼2.8 Hz, H3),
4.18–4.06 (m, 1H, H6), 3.92 (d, 2H, J4,5¼7.6 Hz, H4,5), 3.80
þ
0
0
0
(C2 ), 23.9 (C3 ), 16.7 (C4 ); SM (CI, CH4) 234 (M þ1);

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8717
0
0
0
0
0
0
0
(dd, 2H, J1 a,b¼J3 a,b¼11.9 Hz, J1 a,2 ¼J3 a,2 ¼5.2 Hz,
J3,2¼J3,4¼9.2 Hz, H3), 3.87 (dd, 1H, J7 a,b¼10 Hz,
0
0
0
0
0
0
0
0
0
0
0
H1 a,3 a), 3.71 (dd, 2H, J1 b,a¼J3 b,a¼11.9 Hz, J1 b,2
¼
¼
0
J7 a,6 ¼2 Hz, H7 a), 3.78–3.62 (m, 3H, H5,7 b,3 ), 3.51 (dd,
1H, J4,3¼J4,5¼9.2 Hz, H4), 3.45 (dd, 1H, J2,3¼9.6 Hz,
J2,1¼3.5 Hz, H2), 3.34 (s, 3H, OMe), 3.31–3.28 (m, 2H,
0
0
0
0
J3 b,2 ¼5.4 Hz, H1 b,3 b), 3.44 (dddd, 1H, J1,2a¼J1,7b
7.8 Hz, J1,2a¼J1,7b¼5.8 Hz, H1), 3.24–3.09 (m, 1H, H2 ),
2.30 (ddd, 1H, J2a,2b¼14.5 Hz, J2a,3¼8.8 Hz, J2a,1¼5.8 Hz,
0
0
H4 ,5 ), 2.93 (dd, 1H, J6a,b¼11.7 Hz, J6a,5¼2.9 Hz, H6a),
0
H2a), 2.06–1.91 (m, 2H, H7a,b), 1.75 (ddd, 1H, J2b,a
¼
2.74–2.58 (m, 1H, H1 ), 2.61 (dd, 1H, J6a,b¼11.7 Hz,
14.5 Hz, J2b,1¼7.8 Hz, J2b,3¼2.8 Hz, H2b); 13C NMR (D2O)
J6b,5¼5.7 Hz, H6b), 2.13 (ddd, 1H, J2 a,b¼12.8 Hz, J2 a,3
¼
0
0
0
0
0
d 78.3, 76.4 (C4,5), 71.0, 70.2 (C3,6), 62.6, 62.4 (C1 ,3 ), 59.9
0
0
0
0
J2 a,1 ¼4.4 Hz, H2 a), 1.55–1.44 (m, 1H, H6 ), 1.36, 1.32 (2s,
0
0
(C2 ), 51.6 (C1), 37.1, 36.5 (C2,7); SM (CI, CH4) 252
6H, CMe2), 1.28–0.93 (m, 1H, H2 b), 0.87, 0.80 (2s, 18H,
(Mþþ1); HRMS for C10H22NO6 (Mþþ1) calcd 252.1447;
tBu), 0.07, 0.05, 20.01, 20.06 (4s, 12H, SiMe2); 13C NMR
d 138.9, 138.3, 128.4, 128.1, 128.0, 127.7, 127.6 (Car),109.9
found 252.1449.
0
(CMe2), 97.9 (C1), 84.1, 80.1, 79.1 (C2,3,4,4 ), 75.7, 75.1,
0 0 0
73.4 (OCH2Ph), 75.1 (C5 ), 70.3, 69.5 (C3 ,5), 59.1 (C7 ),
5.8. Reductive amination in C6 series
0
55.2 (OMe), 53.0 (C6 ), 47.1 (C6), 46.1 (C1 ), 40.5 (C2 ), 27.0
0
0
The reductive amination was performed according to the
procedure described above in C7 series.
(CMe2), 25.9, 18.3 (tBu), 24.4, 24.8, 25.6 (SiMe2).
5.8.4. (1S,3S,4S,5R,6S)-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idene-1-N-(3,4,5-trihydroxycyclohexanyl)-N-benzyl-
amine (33a). Isolated yield: 20%; Rf 0.6 (cyclohexane/
EtOAc 95:5); [a]D¼þ33 (c 1.3, CH2Cl2); 1H NMR d 7.40–
7.20 (m, 5H, Har), 4.10 (ddd, 1H, J3,2b¼10.1 Hz,
J3,4¼9.1 Hz, J3,2a¼4.4 Hz, H3), 3.84, 3.61 (AB, 2H,
JAB¼15.2 Hz, NCH2Ph), 3.75–3.59 (m, 2H, H7a,b), 3.74
(dd, 1H, J5,6¼11.5 Hz, J5,4¼9.1 Hz, H5), 3.29 (dd, 1H,
J4,3¼J4,5¼9.1 Hz, H4), 3.24–3.15 (m, 1H, H1), 2.14 (ddd,
1H, J2a,b¼14.0 Hz, J2a,3¼4.4 Hz, J2a,1¼2.7 Hz, H2a), 1.81
(dddd, 1H, J6,5¼11.5 Hz, J6,7b¼8.2 Hz, J6,7a¼6.6 Hz,
J6,1¼4.4 Hz, H6), 1.37, 1.34 (2s, 6H, CMe2), 1.31–1.22
(m, 1H, H2b), 0.91, 0.84 (2s, 18H, tBu), 0.1, 0.02 (2s, 12H,
SiMe2); 13C NMR d 140.7, 128.3, 128.2, 126.8 (Car), 110.0
(CMe2), 85.2 (C4), 74.3 (C5), 68.8 (C3), 61.8 (C7), 55.2 (C1),
52.3 (NCH2Ph), 45.6 (C6), 37.6 (C2), 26.9 (CMe2), 25.9,
18.1 (tBu), 24.5, 24.7, 25.5, 25.6 (SiMe2); SM (CI, CH4)
536 (Mþþ1); HRMS for C29H54NO4Si2 (Mþþ1) calcd
536.3591; found 536.3587.
5.8.1. (1R,3S,4S,5R,6S)-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idene-1-N-(3,4,5-trihydroxycyclohexanyl)-N-benzyl-
amine (32a). Isolated yield: 54%; Rf 0.22 (cyclohexane/
EtOAc 95:5); [a]Hg¼217 (c 1.1, CH2Cl2); 1H NMR d
7.40–7.20 (m, 5H, Har), 3.98 (dd, 1H, J7a,b¼10.2 Hz,
J7a,6¼2.4 Hz, H7a), 3.88, 3.69 (AB, 2H, JAB¼13 Hz,
NCH2Ph), 3.75–3.59 (m, 2H, H3,7b), 3.34 (dd, 1H, J4,3
¼
J4,5¼9.0 Hz, H4), 3.21 (dd, 1H, J5,6¼10.6 Hz, J5,4¼9.0 Hz,
H5), 2.74 (ddd, 1H, J1,6¼11.8 Hz, J1,2b¼10 Hz, J1,2a
4.5 Hz, H1), 2.24 (ddd, 1H, J2a,b¼13 Hz, J2a,3¼J2a,1
¼
¼
4.5 Hz, H2a), 1.66–1.52 (m, 1H, H6), 1.38, 1.33 (2s, 6H,
CMe2), 1.31–1.22 (m, 1H, H2b), 0.88, 0.87 (2s, 18H, tBu),
0.08, 0.07, 0.03, 0.02 (4s, 12H, SiMe2); 13C NMR d 140.7,
128.4, 128.1, 126.9 (Car), 110.0 (CMe2), 84.1 (C4), 75.3
(C5), 69.5 (C3), 60.5 (C7), 54.0 (C1), 51.8 (NCH2Ph), 46.6
(C6), 40.5 (C2), 26.9 (CMe2), 25.8, 18.2 (tBu), 24.5, 24.8,
25.5 (SiMe2); SM (CI, CH4) 536 (Mþþ1); HRMS for
C29H54NO4Si2 (Mþþ1) calcd 536.3591; found 536.3597.
5.8.2. (1R,3S,4S,5R,6S)-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idene-1-N-(3,4,5-trihydroxycyclohexanyl)-N-(10,30-di-
5.8.5. (1S,3S,4S,5R,6S)-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idene-1-N-(3,4,5-trihydroxycyclohexanyl)-N-(10,30-di-
tert-butyldimethylsilyloxy)-200-propylamine
(32b).
tert-butyldimethylsilyloxy)-20-propylamine
(33b).
Isolated yield: 28%; Rf 0.62 (cyclohexane/EtOAc 95:5);
Isolated yield: 28%; Rf 0.4 (cyclohexane/EtOAc 97:3);
[a]D¼29 (c 1.0, CH2Cl2); 1H NMR d 3.95 (dd, 1H,
J7a,b¼9.9 Hz, J7a,6¼1.8 Hz, H7a), 3.75–3.60 (m, 3H,
1
[a]D¼213 (c 1.0, CH2Cl2); H NMR d 3.95 (ddd, 1H,
J3,2b¼10.2 Hz, J3,4¼9.0 Hz, J3,2a¼4.4 Hz, H3), 3.75 (dd,
1H, J7a,b¼14.2 Hz, J7a,6¼5.5 Hz, H7a), 3.74 (dd, 1H,
J7b,a¼14.2 Hz, J7b,6¼10.2 Hz, H7b), 3.62–3.42 (m, 5H,
0
0
0
0
0
H3,7b,3 a), 3.56 (dd, 1H, J1 a,b¼10 Hz, J1 a,2 ¼4.8 Hz, H1 a),
0
0
0
0
3.44 (dd, 1H, J1 a,b¼10 Hz, J1 b,2 ¼6.1 Hz, H1 b), 3.39–3.25
0
(m, 2H, H4,5), 2.80–2.63 (m, 2H, H1,2 ), 2.29–2.17 (m, 1H,
0
0
H1 ,3 ,5); 3.32–3.25 (m, 1H, H1), 3.20 (dd, 1H,
0
H2a), 1.42–1.30 (m, 1H, H6), 1.37, 1.33 (2s, 6H, CMe2),
1.26–1.20 (m, 1H, H2b), 0.87 (s, 36H, tBu), 0.08, 0.03, 0.02
(3s, 24H, SiMe2); 13C NMR d 109.9 (CMe2), 84.1 (C4), 74.9
J4,3¼J4,5¼9.0 Hz, H4), 2.76–2.64 (m, 1H, H2 ), 1.98 (ddd,
1H, J2a,b¼14.2 Hz, J2a,3¼4.4 Hz, J2a,1¼2.6 Hz, H2a), 1.83–
1.60 (m, 2H, H6,2b), 1.36, 1.34 (2s, 6H, CMe2), 0.88, 0.87
0
0
0
(C5), 69.5 (C3), 63.2 (C1 ,3 ), 59.6 (C2 ), 58.2 (C7), 50.6 (C6),
47.9 (C1), 42.0 (C2), 27.1 (CMe2), 25.8, 18.2 (tBu), 24.5,
24.9, 25.4 (SiMe2). Anal. calcd for C37H81NO6Si4: C,
59.38; H, 10.91; N, 1.87; found: C, 59.24; H, 10.84; N, 1.95.
(2s, 36H, tBu), 0.08, 0.07, 0.03, 0.02 (4s, 24H, SiMe2); 13
C
NMR d 109.2 (CMe2), 85.1 (C4), 74.8 (C5), 69.0 (C3), 62.2,
0
0
0
61.9 (C1 ,3 ), 60.8 (C7), 58.7 (C2 ), 51.3 (C6), 46.9 (C1), 39.8
(C2), 26.9 (CMe2), 25.9, 18.2, 18.1 (tBu), 24.4, 24.8
(SiMe2). Anal. calcd for C37H81NO6Si4: C, 59.38; H, 10.91;
N, 1.87; found: C, 59.42; H, 10.74; N, 1.71.
5.8.3. Methyl [10R,30S,40S,50R,60S]-6-Deoxy-6-[30-tert-
butyldimethylsilyloxy-60-tert-butyldimethylsilyloxy-
methyl-40,50-O-methylethylidene-10-N-(30,40,50-tri-
hydroxycyclohexanyl)]-amino-2,3,4-tri-O-benzyl-D-
glucopyranoside (32c). Isolated yield: 46%; Rf 0.16
(cyclohexane/EtOAc 85:15); [a]D¼þ27 (c 1.0, CH2Cl2);
1H NMR d 7.40–7.12 (m, 15H, Har), 5.01–4.55 (m, 6H,
OCH2Ph), 4.50 (d, 1H, J1,2¼3.5 Hz, H1), 3.95 (dd, 1H,
5.8.6. Methyl [10S,30S,40S,50R,60S]-6-Deoxy-6-[30-tert-
butyldimethylsilyloxy-60-tert-butyldimethylsilyloxy-
methyl-40,50-O-methylethylidene-10-N-(30,40,50-tri-
hydroxycyclohexanyl)]-amino-2,3,4-tri-O-benzyl-D-
glucopyranoside (33c). Isolated yield: 13%; Rf 0.46
(cyclohexane/EtOAc 85:15); [a]D¼þ51 (c 1.0, CH2Cl2);

8718
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
1H NMR d 7.36–7.23 (m, 15H, Har), 4.84 (AB, 2H,
JAB¼10.7 Hz, OCH2Ph), 4.76 (AB, 2H, JAB¼10.9 Hz,
OCH2Ph), 4.71 (AB, 2H, JAB¼12.2 Hz, OCH2Ph), 4.50
J2b,3¼J2b,1¼11.4 Hz, H2b); 13C NMR (D2O) d 81.8 (C4),
73.3 (C5), 72.3 (C3), 61.0 (C7), 52.6 (C1), 47.7 (C6), 42.3
(C2); SM (CI, NH3) 178 (Mþþ1); HRMS for C7H16NO4
(Mþþ1) calcd 178.1079; found 178.1075.
0
(d, 1H, J1,2¼3.5 Hz, H1), 4.02–3.89 (m, 2H, H3,3 ), 3.85–
0
3.65 (m, 3H, H5,7 a,b), 3.59 (dd, 1H, J4,3¼J4,5¼9.3 Hz, H4),
3.58 (dd, 1H, J5 ,6 ¼11.3 Hz, J5 ,4 ¼9.0 Hz, H5 ), 3.45 (dd,
5.9.3. (1R,3S,4R,5R,6R)-1-(10,30-Dihydroxy-20-propyl-
amine)-6-hydroxymethylcyclohexane-3,4,5-triol (34b).
The protected aminocyclitol 32b (97 mg, 0.13 mmol) was
reacted under the same conditions as above to afford the
aminocyclitol 34b (28 mg) as a brownish solid in 86% yield.
0
0
0
0
0
1H, J2,3¼9.6 Hz, J2,1¼3.5 Hz, H2), 3.34 (s, 3H, OMe), 3.22
0
0
0
0
0
0
(dd, 1H, J4 ,3 ¼J4 ,5 ¼9.0 Hz, H4 ), 3.15–3.07 (m, 1H, H1 ),
2.90 (dd, 1H, J6a,b¼11.9 Hz, J6a,5¼4.7 Hz, H6a), 2.73 (dd,
1H, J6a,b¼11.9 Hz, J6b,5¼2.6 Hz, H6b), 2.10 (ddd, 1H,
1
0
0
0
0
0
0
J2 a,b¼14.2 Hz, J2 a,3 ¼4.8 Hz, J2 a,1 ¼3.0 Hz, H2 a), 1.92–
[a]D¼223 (c 1.4, H2O); H NMR (D2O) d 4.05 (dd, 1H,
0
1.79 (m, 1H, H6 ), 1.35 (s, 6H, CMe2), 1.30–1.20 (m, 1H,
J7a,b¼11.4 Hz, J7a,6¼2.9 Hz, H7a), 3.84 (dd, 1H, J7b,a¼
0 0
0
H2 b), 0.84, 0.77 (2s, 18H, tBu), 0.00, 20.02, 20.03 (3s,
11.4 Hz, J7b,6¼6.4 Hz, H7b), 3.79–3.59 (m, 4H, H1 a,b,3 a,b),
3.52 (ddd, 1H, J3,2b¼11.5 Hz, J3,4¼8.8 Hz, J3,2a¼3.7 Hz,
12H, SiMe2); 13C NMR d 138.8, 138.4, 128.4, 128.1, 127.9,
127.7 (Car), 109.2 (CMe2), 97.9 (C1), 85.3, 82.2, 80.1, 78.6
0
H3), 3.41–3.22 (m, 2H, H4,5); 3.07–2.94 (m, 1H, H2 ), 2.92
0
(C2,3,4,4 ), 75.9, 74.9, 73.4 (OCH2Ph), 74.5 (C5 ), 69.5, 69.0
0
(ddd, 1H, J1,6¼J1,2b¼11.4 Hz, J1,2a¼3.7 Hz, H1), 2.39 (ddd,
1H, J2a,b¼12.3 Hz, J2a,3¼J2a,1¼3.7 Hz, H2a), 1.71–1.53 (m,
11.4 Hz, H2b); 13C NMR (D2O) d 81.6 (C4), 73.6 (C5),
0
(C3 ,5), 61.7 (C7 ), 55.1 (OMe), 55.0 (C6 ), 48.4 (C6), 45.9
0
0
0
0
(C1 ), 37.6 (C2 ), 27.0 (CMe2), 25.8, 18.2 (tBu), 24.3, 24.8,
25.5, 25.6 (SiMe2). Anal. calcd for C50H77NO9Si2: C,
67.30; H, 8.70; N, 1.57; found: C, 67.31; H, 8.83; N, 1.52.
1H, H6), 1.48 (ddd, 1H, J2b,a¼12.3 Hz, J2b,3¼J2b,1¼
0
0
0
72.3 (C3), 64.5, 63.7, 63.3 (C7,1 ,3 ), 60.2 (C2 ), 54.8 (C1),
51.0 (C6), 40.2 (C2); SM (CI, CH4) 252 (Mþþ1); HRMS for
C10H22NO6 (Mþþ1) calcd 252.1447; found 252.1443.
5.9. Deprotection of the aminocyclohexanols
5.9.1. (1R,3S,4S,5R,6S)-3-O-tert-Butyldimethylsilyl-6-
tert-butyldimethylsilyloxymethyl-4,5-O-methylethyl-
idene-3,4,5-trihydroxy-1-cyclohexylamine (32d). To a
suspension of palladium hydroxide (58 mg) in absolute
ethanol (2 mL) saturated with dihydrogen was added a
solution of the N-benzylamine 32a (144 mg, 0.269 mmol) in
EtOAc (0.7 mL). After stirring for 14 h, the catalyst was
removed by filtration through a Celite pad and the filtrate
was concentrated in vacuo. Flash chromatographic purifi-
cation (CH2Cl2/MeOH 98:2) led to amine 32d (71.9 mg) as
an oil in 60% yield. Rf 0.3 (CH2Cl2/MeOH 98:2);
[a]D¼þ24 (c 1.0, CH2Cl2); 1H NMR d 3.91 (dd, 1H,
5.9.4. (1S,3S,4R,5R,6R)-1-(10,30-Dihydroxy-20-propyl-
amine)-6-hydroxymethylcyclohexane-3,4,5-triol (35b).
The protected aminocyclitol 33b (99 mg, 0.132 mmol)
was reacted under the same conditions as above to afford
the aminocyclitol 35b (32.2 mg) as a brownish solid in 98%
yield. [a]D¼þ58 (c 1.0, H2O); 1H NMR (D2O) d 3.90 (dd,
1H, J7a,b¼11.4 Hz, J7a,6¼3.7 Hz, H7a), 3.86 (dd, 1H, J7b,a
¼
11.4 Hz, J7b,6¼5.9 Hz, H7b), 3.76 (dd, 1H, J3,2b¼13.2 Hz,
0
J3,4¼9.4 Hz, J3,2a¼3.7 Hz, H3), 3.68 (dd, 1H, J1 a,b
¼
0
0
0
11.4 Hz, J1 a,2 ¼5.0 Hz, H1 a), 3.63 (dd, 1H, J5,6¼11.4 Hz,
J5,4¼9.4 Hz, H5), 3.62 (dd, 1H, J3 b,a¼11.5 Hz, J3 b,2
0
0
0
¼
0
0
0
0
5.5 Hz, H3 b), 3.57 (dd, 1H, J3 a,b¼11.5 Hz, J3 a,2 ¼4.9 Hz,
0
0
0
0
0
J7a,b¼10.4 Hz, J7a,6¼2.6 Hz, H7a), 3.74 (dd, 1H, J7b,a
¼
H3 a), 3.50 (dd, 1H, J1 b,a¼11.4 Hz, J1 b,2 ¼6.9 Hz, H1 b),
10.4 Hz, J7b,6¼4.1 Hz, H7b), 3.89–3.75 (m, 1H, H3), 3.34
(dd, 1H, J4,3¼J4,5¼9.1 Hz, H4), 3.21 (dd, 1H, J5,6¼10.6 Hz,
J5,4¼9.1 Hz, H5), 2.89 (ddd, 1H, J1,6¼12 Hz, J1,2b¼9.6 Hz,
J1,2a¼4.5 Hz, H1), 2.07 (ddd, 1H, J2a,b¼13.1 Hz,
J2a,3¼J2a,1¼4.5 Hz, H2a), 1.63–1.20 (m, 1H, H6,2b), 1.38,
1.36 (2s, 6H, CMe2), 0.88, 0.87 (2s, 36H, tBu), 0.08, 0.07,
0.06, 0.05 (4s, 24H, SiMe2); 13C NMR d 110.2 (CMe2), 84.2
(C4), 75.2 (C5), 69.4 (C3), 60.2 (C7), 48.9, 48.1 (C1,6), 43.9
(C2), 27.0, 26.9 (CMe2), 25.8, 18.2 (tBu), 24.5, 24.9, 25.5,
25.6 (SiMe2); SM (CI, CH4) 446 (Mþþ1); HRMS for
C22H48NO4Si2 (Mþþ1) calcd 446.3122; found 446.3128.
3.32–3.27 (m, 1H, H1), 3.28 (dd, 1H, J4,3¼J4,5¼9.4 Hz,
0
H4); 2.88–2.78 (m, 1H, H2 ), 2.16 (ddd, 1H, J2a,b¼13.2 Hz,
J2a,3¼J2a,1¼3.7 Hz, H2a), 1.71 (dddd, 1H, J6,5¼11.4 Hz,
J6,7b¼5.9 Hz, J6,7a¼J6,1¼3.7 Hz, H6), 1.48 (ddd, 1H, J2b,a
¼
J2b,3¼13.2 Hz, J2b,1¼3.4 Hz, H2b); 13C NMR (D2O) d 82.3
0
0
0
(C4), 72.3 (C5), 71.3 (C3), 64.2, 63.4 (C7,1 ,3 ), 61.4 (C2 ),
55.3 (C1), 48.6 (C6), 37.5 (C2); SM (CI, CH4) 252 (Mþþ1);
HRMS for C10H22NO6 (Mþþ1) calcd 252.1447; found
252.1446.
5.9.5. Methyl [10R,30S,40R,50R,60R]-6-Deoxy-6-[60-hydro-
xymethyl-10-N-(30,40,50-trihydroxycyclohexanyl)]-amino-
2,3,4-tri-O-benzyl-D-glucopyranoside (34c). To a cooled
solution of the silylated diol 32c (90 mg, 99 mmol) in THF
(2.7 mL) at 08C were successively added H2O (0.9 mL) and
trifluoroacetic acid (0.9 mL). After stirring for 40 h at 208C,
CH2Cl2 (3 mL) and a saturated NaHCO3 aqueous solution
(0.9 mL) were added, then the pH was adjusted to 7 by
addition of K2CO3. The mixture was extracted with CH2Cl2,
and the organic layers were dried (MgSO4) and concen-
trated in vacuo. After flash chromatography (CH2Cl2/
MeOH 85:15), the compound 34c was obtained in
quantitative yield as an yellow oil. Rf 0.44 (CH2Cl2/
MeOH 8:2); [a]D¼þ28 (c 1.1, CH2Cl2); 1H NMR d
7.30–7.20 (m, 15H, Har), 5.00–4.56 (m, 7H, OCH2Ph,
5.9.2. (1R,3S,4R,5R,6R)-1-Amino-6-hydroxymethyl-
cyclohexane-3,4,5-triol (34a). The acetonide 32d
(69.3 mg, 0.16 mmol) was stirred in a 9:1 solution of
trifluoroacetic acid/H2O at 208C for 15 h. After concen-
trating in vacuo, the resulting oil was triturated in diethyl
ether and the supernatant was discarded to afford a brownish
solid which was then purified by ion-exchange chromato-
graphy (Dowexw 5 X8-100, 3% aqueous ammonium
hydroxide) to give the aminocyclitol 34a (25 mg) as a
solid in 90% yield. [a]D¼þ11 (c 1.0, H2O); 1H NMR (D2O)
d 4.01–3.86 (m, 2H, H7a,b), 3.58 (ddd, 1H, J3,2b¼11.4 Hz,
J3,4¼9.0 Hz, J3,2a¼3.7 Hz, H3), 3.46–3.26 (m, 2H, H4,5),
2.93 (ddd, 1H, J1,6¼J1,2b¼11.4 Hz, J1,2a¼3.7 Hz, H1), 2.20
(ddd, 1H, J2a,b¼12.1 Hz, J2a,3¼J2a,1¼3.7 Hz, H2a), 1.57–
1.26 (m, 1H, H6), 1.39 (ddd, 1H, J2b,a¼12.1 Hz,
0
0
0
H1), 4.08–3.83 (m, 2H, H3,7 a), 3.72–3.52 (m, 3H, H5,7 b,3 ),
3.50–3.40 (m, 2H, H4,2), 3.29 (s, 3H, OMe), 3.17–2.95 (m,

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
8719
0
0
0
3H, H4 ,5 ,6a), 2.47–2.29 (m, 2H, H6b,1 ), 2.24–2.11 (m, 1H,
0
plate reader (iEMS-Labsystems) for 7 min. a-D-Galacto-
sidase and b-D-galactosidase kinetics were performed
likewise in 50 mM phosphate buffer pH 7.0 by monitoring
the release of 2-nitrophenol and 4-nitrophenol from the
corresponding 2- or 4-nitrophenyl substrates, respectively.
The potential inhibitors were tested at a final concentration
of 1 mM and the amount of enzyme in each assay was
adjusted so that less than 10% of the substrate would be
consummed. When the percentage of inhibition was higher
than 70 %, the Ki was determined according to the
Lineweaver-Burk method. Substrates were at a concen-
tration range of 0.2–5 KM and inhibitors were added to final
concentration between 1023 and 1028 M. In all cases, the
inhibitors displayed typical competitive inhibition kinetics.
The Ki was then calculated from the two Michaelis–Menten
H2 a), 1.72–1.51 (m, 1H, H6 ), 1.37–1.15 (m, 1H, H2 b); 13
NMR d 129.9, 128.6, 128.5, 128.4, 128.2, 128.0, 127.7
0
(Car), 98.0 (C1), 81.8, 80.0, 79.3, 78.9 (C2,3,4,4 ), 76.0, 75.1,
C
0
0
0
74.3 (OCH2Ph), 71.8 (C5 ), 69.2, 69.0 (C3 ,5), 64.3 (C7 ),
0
0
0
0
0
57.7 (C6 ), 55.5 (OMe), 47.6 (C1 ), 47.2 (C6), 37.0 (C2 ); SM
(CI, CH4) 624 (Mþþ1); HRMS for C35H46NO9 (Mþþ1)
calcd 624.3173; found 624.3170.
5.9.6. Methyl [10R,30S,40R,50R,60R]-6-Deoxy-6-[60-hydro-
xymethyl-10-N-(30,40,50-trihydroxycyclohexanyl)]-amino-
D-glucopyranoside (34d). To a suspension of palladium
black (37.3 mg) in acetic acid (1 mL) saturated with
dihydrogen was added a solution of the benzylated
derivative 34c (74.1 mg, 90 mmol) in acetic acid (2 mL).
After stirring for 14 h, the catalyst was removed by filtration
through a Celite pad and the filtrate was concentrated in
vacuo. Purification by ion-exchange chromatography
(Dowexw 5X8-100, 3% aqueous ammonium hydroxide)
gave the aminocyclitol 34d (29.3 mg) as an ocher solid in 70
% yield. [a]D¼þ15 (c 1.1, H2O); 1H NMR (D2O) d 4.87 (d,
0
(KM and KM ) constants obtained in the absence or presence
of inhibitor.
Acknowledgements
0
0
0
1H, J1,2¼3.4 Hz, H1), 4.12 (dd, 1H, J7 a,b¼11.4 Hz, J7 a,6
¼
0
0
0
0
The authors are grateful to Dr G. Bertho (LCBPT) for his
assistance in NMR studies.
3 Hz, H7 a), 3.82 (dd, 1H, J7 b,a¼11.4 Hz, J7 b,6 ¼7.9 Hz,
0
H7 b), 3.79–3.66 (m, 2H, H3,5), 3.63 (dd, 1H, J2,3¼9.7 Hz,
0
J2,1¼3.4 Hz, H2), 3.58–3.48 (m, 1H, H3 ), 3.45 (s, 3H,
OMe), 3.37 (dd, 1H, J6a,b¼11.5 Hz, J6a,5¼4.1 Hz, H6a), 3.36
0
0
0
0
0
(dd, 1H, J4 ,3 ¼J4 ,5 ¼9.1 Hz, H4 ), 3.35 (dd, 1H, J4,3
¼
0
0
0
J4,5¼9.3 Hz, H4), 3.25 (dd, 1H, J5 ,6¼10.1 Hz, J5 ,4 ¼9.1 Hz,
H5 ), 3.04–2.87 (m, 1H, H1 ), 2.78 (dd, 1H, J6a,b¼J6b,5¼11.7
Hz, H6b), 2.13 (ddd, 1H, J2 a,b¼12.8 Hz, J2 a,3 ¼J2 a,1 ¼4.2
References
0
0
0
0
0
0
0
1. King, H.; Aubert, R.; Herman, W. Diabetes Care 1988, 21,
1414.
2. Tish, R.; McDevitt, H. Cell 1996, 85, 291.
0
0
Hz, H2 a), 1.84–1.60 (m, 1H, H6 ), 1.45 (ddd, 1H,
J2 a,b¼12.8 Hz, J2 b,3 ¼J2 b,1 ¼10.9 Hz, H2 b); 13C NMR
0
0
0
0
0
0
0
(D2O) d 98.0 (C1), 81.8, 80.0, 79.3, 78.9 (C2,3,4,4 ), 71.8
3. Atkinson, M. A.; Eisenbarth, G. S. Lancet 2001, 358, 221.
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0
(C5 ), 69.2, 69.0 (C3 ,5), 64.3 (C7 ), 57.7 (C6 ), 55.5 (OMe),
0
0
0
þ
0
0
47.6 (C1 ), 47.2 (C6), 37.0 (C2 ); SM (CI, NH3) 354 (M þ1);
HRMS for C14H28NO9 (Mþþ1) calcd 354.1754; found
354.1769.
6. United Kingdom Prospective Diabetes Study Group, Lancet
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5.10. Inhibition studies32
8. Bailey, C. J.; Turner, R. C. N. Engl. J. Med. 1996, 334, 574.
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T. M.; Kliewer, S. A. J. Biol. Chem. 1995, 270, 12953.
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a-D-Glucosidase from Bacillus stearothermophilus (EC
3.2.1.20), b-D-glucosidase from almonds (EC 3.2.1.21),
a-D-mannosidase from Jack beans (EC 3.2.1.24), a-L-
fucosidase from bovine kidney (EC 3.2.1.51), a-D-galacto-
sidase from green coffee bean (EC 3.2.1.22), and pancreatic
porcine a-amylase (EC 3.2.1.1) and all substrates were
purchased from Sigma. b-D-galactosidase from Thermus
thermophilus33 was a generous gift from Dr M. Dion.
Inhibition studies with a-D-glucosidase, b-D-glucosidase,
a-D-mannosidase and a-L-fucosidase were displayed as
previously reported.31 Briefly, assays were run at 378C in
50 mM citrate-phosphate buffer, pH 6.8, 5.0, 4.5 and 5.5
respectively, according to the enzyme, using the corre-
sponding 4-nitrophenyl-glycoside in a total volume of
0.1 mL. After an incubation time of 10 min at 378C, the
reaction was quenched by the addition of a 0.2 M glycine-
sodium hydroxide buffer at pH 10 (0.1 mL). The optical
absorbance at 400 nm was measured to determine the
amount of liberated 4-nitrophenol and the percentage of
inhibition was calculated. a-Amylase kinetics were per-
formed in MES buffer 100 mM, NaCl 100 mM, CaCl2
10 mM, NaN3 1.6 g L21, KSCN 0.8 M, pH 6.0 by
monitoring the release of CNP at 405 nm on an ELISA
11. Chiasson, J. L.; Josse, R. G.; Hunt, A. H.; Palmason, C.;
Roger, N. W.; Ross, S. A.; Ryan, E. A.; Tan, M. H.; Wolever,
T. M. S. Ann. Intern. Med. 1994, 121, 928.
12. Holman, R. R.; Cull, C. C.; Tyrner, R. C. Diabetes Care 1998,
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13. Matsumoto, K.; Yano, M.; Miyake, S.; Ueki, Y.; Yamaguchi,
Y.; Akazawa, S.; Tominaga, Y. Diabetes Care 1998, 21, 256.
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Pi-Sunyer, F. X.; Krol, A. Diabetes Care 1994, 17, 20.
`
15. Gaudilliere, B. Annual Reports in Medicinal Chemistry;
Bristol, J. A., Ed.; Academic: San Diego, 1999; Vol. 34, p 325.
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Merrer, Y. Tetrahedron Lett. 2001, 42, 4475. (b) Gravier-
Pelletier, C.; Maton, W.; Le Merrer, Y. Tetrahedron Lett.
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18. Le Merrer, Y.; Gravier-Pelletier, C.; Maton, W.; Numa, M.;
Depezay, J. C. Synlett 1999, 1322.

8720
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8705–8720
19. Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett
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successively added Et3N (1 mL, 7.17 mmol), DMAP (23 mg,
0.19 mmol) and TBDMSCl (1.2 g, 7.96 mmol). After stirring
at 20 (C for 17 h, H2O was added and the mixture was
extracted with CH2Cl2 and purified by chromatography.
Isolated yield: 70%, Rf 0.2 (cyclohexane/EtOAc 85:15), 1H
20. Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119,
6925.
21. Ide, M.; Yasuda, M.; Nakata, M. Synlett 1998, 936.
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been reported by Brau¨er, N.; Dreessen, S.; Schaumann, E.
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the lithio derivative of the trimethylsilylformaldehyde dithio-
ketal on D-mannitol bis-epoxides. However, the isolated yield
in carbacycles never exceeded 30% and furthermore hetero-
cyclization was also observed.
NMR d 3.59 (dd, 2H, J1a,1b¼J3a,3b¼9.7 Hz, J1a,2¼J3a,2
5.2 Hz, H2a,3a), 3.49 (dd, 2H, J1a,1b¼J3a,3b¼9.7 Hz, J1b,2
¼
¼
J3b,2¼5.7 Hz, H1b,3b), 2.98–2.70 (m, 1H, H2), 0.88 (s, 18H,
t-Bu), 0.39 (s, 12H, SiMe2), 13C NMR ( 64.7 (C1,3), 54.2 (C2),
25.8, 18.1 (t-Bu), 25.6 (C SiMe2).
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28. Preparation of the bis-O-tert-butyldimethysilyserinol: to a
suspension of serinol (285 mg, 3.13 mmol) in CH2Cl2 were
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