Synthesis and glycosidase inhibitory activity of new penta-substituted C8-glycomimetics

Article abstract of DOI:10.1016/j.tet.2005.05.066

The syntheses of new C8-carbasugars and -aminocyclitols related to miglitol and voglibose are described. The key step involves the ring closing metathesis of 1,9-dienes derived from d-mannitol. Chemical transformations of the newly created double bond of the resulting cyclooctenes involved notably hydroboration and reductive amination. The inhibitory activity of the glycomimetics so-obtained has been evaluated towards 24 commercially available glycosidases.

Full text of DOI:10.1016/j.tet.2005.05.066

Tetrahedron 61 (2005) 7094–7104
Synthesis and glycosidase inhibitory activity of new
penta-substituted C8-glycomimetics
b
a,
Olivia Andriuzzi,a Christine Gravier-Pelletier,a, Pierre Vogel and Yves Le Merrer
*
*
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
´ ´
b
´ ´
Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de Lausanne, BCH, CH-1015 Lausanne, Switzerland
Received 15 April 2005; revised 13 May 2005; accepted 17 May 2005
Available online 15 June 2005
Abstract—The syntheses of new C8-carbasugars and -aminocyclitols related to miglitol and voglibose are described. The key step involves
the ring closing metathesis of 1,9-dienes derived from D-mannitol. Chemical transformations of the newly created double bond of the
resulting cyclooctenes involved notably hydroboration and reductive amination. The inhibitory activity of the glycomimetics so-obtained has
been evaluated towards 24 commercially available glycosidases.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
AO-128) (2),19 the synthetic piperidine derivatives such as 3
(miglitol)20 and 4 (1-deoxynojirimycin)21 or pyrrolidine
derivatives such as 5 (nectrisine)22,23 can have their amino
moiety protonated. The corresponding ammonium ions
mimick the charge of the presumed transition states or
intermediates of the enzymatic glycoside hydrolyses.21,22
The biological importance of oligosaccharides was first
recognized for their role in metabolism and energy storage.
More recently, it became clear that complex oligosacchar-
ides also regulate a large number of biological processes.
Most important are the oligosaccharides formed on the
surface of cells and their role on protein and glycoprotein
conformation. The cell-surface oligosaccharides are the
‘words’ used by cells to communicate with the outer
world.1–4 They guide their social behavior such as cell/cell
interactions, cell/invader interactions, including HIV/cell
penetration.5 These oligosaccharides are conjugated with
proteins (N-linked, O-linked glycoproteins), with phospha-
tidylinositol (GPI-anchored proteins) or with glycolipids.5–10
Carbohydrate mimetics are potential tools to study the
mechanisms of cellular interactions, the biosynthesis of
glycoproteins, the catabolism of glycoconjugates,11,12 and
the mechanisms of digestions.13,14 Inhibition of intestinal
a-glucosidases can be used to treat diabetes through the
lowering of blood glucose levels, and a-glucosidase
inhibitors1–3 are being marketed against type 2 (non-
insulinodependent mellitus) diabetes (Fig. 1).15–17
Furthermore, it has to be pointed out that carbasugars such
as valienamine (6) and its derivative 724 (Fig. 2), or polyol
825 and C7-aminocyclitols 926 (Fig. 2) can also present
potent glycosidase inhibitory activity.
In that context, new C8-glycomimetics27 have been targeted
The naturally occurring acarbose (1)18 and voglibose (or
Keywords: Carbasugars; Aminocyclitols; Glycomimetics; Ring closing
metathesis; Reductive amination; Glycosidases.
*
Corresponding authors. Tel.: C33 142862181; fax: C33 42868387
(C.G-P.); tel.: C33 142862176; fax: C33 42868387 (Y.Le M.);
e-mail
yves.le-merrer@univ-paris5.fr
addresses:
christine.gravier-pelletier@univ-paris5.fr;
Figure 1. Examples of glycosidase inhibitors.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.066

O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
7095
Figure 2. Examples of glycosidase inhibitors.
in order to study the effect of the enhanced flexibility and of
the new spatial distribution displayed by these structures on
their adaptability in the active site of the enzymes.
2. Results and discussion
Our retrosynthetic analysis (Fig. 3) involves the carbacy-
clisation of enantiomerically pure polyhydroxylated C2-
symmetric 1,9-dienes 13 by ring closing metathesis (RCM)
leading to a cyclooctenic structure 11.28 The synthetic
potentialities of the newly created double bond are then
explored to reach pentasubstituted C8-carbasugars and their
apparented aminocyclitols (10). Due to the different
configurations available, (D-manno and L-ido) of corre-
sponding presented bis-epoxides 14, the approach allows
access to various glycomimetics. Furthermore, the pinacolic
coupling (PC) of 1,8-dialdehyde 12, resulting from
oxidative cleavage of dienes 13, is proposed as a
complementary approach towards related hexasubstitued
C8-carbasugars of type 10.
Ring closing metathesis is a widespread method29 to reach
carba- or hetero-cyclic compounds and has been largely
applied to the synthesis of five to seven-membered rings. It
is less used for the preparation of eight-membered ring
systems,30 perhaps due to unfavorable thermodynamic
factors.31
Scheme 1. Reagents and conditions: (a) (CH2]CH)2CuCNLi2, THF,
K78 8C to 20 8C; (b) Grubbs I cat. 13 mol%, CH2Cl2, rt, 96 h; (c)
TBDMSCl, DMF, ImH, 50 8C; (d) Grubbs I cat. 2 mol%, CH2Cl2, rt,
30 min.
[(PCy3)2Cl2RuZCHPh] in dichloromethane (20 8C, 96 h)
gave the expected cyclooctene 17 in 87% yield. In order to
avoid subsequent side reactions of the free alcohol
functions, they were protected as their O-silylated derivative
19. The alternative way involving double-O-protection prior
to RCM was also carried out. In that case, the cyclisation
involving the di-O-silylated dienetetrol 18 was realized in
quantitative yield with 2 mol% of catalyst in much shorter
time (20 8C, 30 min).
The synthesis of protected polyhydroxylated cyclooctenes is
outlined in Scheme 1. First, the double opening of the C2-
symmetrical 3,4-O-methylethylidene-L-ido-bis-epoxide
1532 by an excess of lithium divinylcyanocuprate33 at
K78 8C cleanly afforded diene 16 in 92% yield. Thanks to
the stability of commercially available ruthenium Grubbs
catalyst and to its potential compatibility with free hydroxyl
groups, the RCM was first applied to unprotected diene-
diol 16. Thus, up to 13 mol% of ruthenium catalyst
The same sequence of reactions was applied to the D-manno
bis-epoxide 20 and afforded the protected cyclooctenetetrol
24. However, it has to be pointed out that the route involving
protection of the diol (21/23) followed by RCM (23/24)
was both more efficient and easier to carry out than that
involving first RCM (21/22/24) due to incomplete
reaction.
We explored further the efficiency of RCM with diene 26
and with the alcohol protected derivative 27 (Scheme 2)
resulting from opening of 3,4-di-O-benzyl-D-manno-bis-
epoxide 2534 by lithium divinylcyanocuprate (30% yield)35
and subsequent O-silylation. Under the same reaction
conditions as above the expected cyclooctene 28 was
obtained in 95% yield.
Figure 3. Retrosynthetic analysis.

7096
O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
Scheme 2. Reagents and conditions: (a) (CH2]CH)2CuCNLi2, THF,
K78 8C to rt; (b) TBDMSCl, DMF, ImH, 50 8C, 70%; (c) Grubbs I cat.
2 mol%, CH2Cl2, rt.
We next turned to the second proposed pathway that
involves the pinacolic coupling of 1,8-dialdehyde 29
(Scheme 3). For that purpose ozonolysis of both double
bonds of 18 in dichloromethane and methanol, followed by
the decomposition of the resulting ozonide by trimethylpho-
sphite, furnished the expected dialdehyde 29 in 70% yield.
Samarium diiodide (0.1 M in THF) reductive coupling of
the dialdehyde 29 in the presence of tert-butanol and
HMPA36 led to cyclization. However, a 1:1 diastereoiso-
meric mixture of polyhydroxylated cyclooctanes 30 and
31C32 was obtained. The poor diastereoselectivity and the
difficulty in separating the cis derivative 30 from the two
trans derivatives 31 and 32 led us to only perform the
synthesis of glycomimetics from the key cyclooctenes 19
and 24 obtained by RCM.
Scheme 4. Reagents and conditions: (a) BH3$THF, Et2O then NaOH,
EtOH, H2O2, 62, 30, 51 and 38% yield for 33, 34, 37 and 38; (b) TFA, H2O,
rt, 95–100%.
The first goal was the obtention of C8-carbasugars. Thus,
hydroboration of the protected D-manno-configurated
cyclooctenetetrol 24 by borane tetrahydrofuran complex37
in diethyl ether and subsequent oxidative cleavage by
alkaline hydrogen peroxide (Scheme 4) afforded a mixture
of the two epimers 33 and 34 in a 2:1 ratio38 in 92% overall
yield and that were separated by column chromatography.
moieties of 19 and 24 anti with respect to the oxygen atom
of the 1,3-dioxolane in g position. On one hand, the H
1
NMR spectrum of 33 showed relatively large coupling
constants between H1 and H8 (proS),39 H1 and H2 (proS),
H8 (proS) and H7 (proS) as expected for protons in pseudo-
3
Subsequent trifluoroacetic acid catalyzed hydrolysis of 33
and 34 gave the expected C8-carbasugar analogs 35 and 36,
respectively. In a similar manner, hydroboration of the L-ido
19, followed by oxidative cleavage and then acidic
hydrolysis led to the corresponding carbasugars 39 and
40. In the latter case, diastereoselectivity was only 3:2 ratio
for 37 and 38, and these compounds could be separated by
flash chromatography. The structures of 33, 34, 37 and 38
axial positions. On the other hand, small J1H,1H coupling
constants were observed between H1 and H8 (proR), H1 and
H2 (proR), as expected for protons in pseudo-equatorial
positions. Furthermore, prochiral H2 (proS) and H8 (proS)
both displayed strong NOEs with H4 and with each other,
thus indicating that these protons are close together and are
located on the same (upper) face. The 1H NMR signal of H7
(proS) displayed strong NOEs with H5 and H1. This shows
that these protons are on the other (lower) face of the C8
cycle (Fig. 4). These data allowed the structural determi-
nation of compound 33 which implies a (S)-configurated
alcohol moiety of the newly created stereogenic center.
1
were unambiguously assigned by 2D H NMR studies and
NOE measurements. In each case the major isomer results
from the favored hydroboration of the face of the alkene
We next turned to the obtention of the corresponding
aminocyclitols. Their preparation was first attempted by
hydroboration of 19 and 24, followed by aminolysis with
sulfamic acid,40 but this reaction failed. Alternatively,
activation of the hydroxyl group of 33 or 37 as their triflate
derivatives, followed by in situ nucleophilic substitution
with sodium azide or ethanolamine (DMF, K78 8C to room
temperature) resulted in b-elimination and, consequently, to
recover the starting cyclooctene. To circumvent this
difficulty we have studied the reductive amination of
ketones resulting from oxidation of the alcohols 33, 34, 37
and 38. Treatment of the mixture 33 and 34 by Dess–Martin
periodinane41 in CH2Cl2/pyridine at room temperature
yielded ketone 41 (85% yield, Scheme 5). Alternatively,
Scheme 3. Reagents and conditions: (a) O3, CH2Cl2, K78 8C then
P(OMe)3, rt; (b) SmI2, HMPA, tBuOH, K40 8C to rt.

O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
7097
mine or bis-O-tert-butyldimethylsilylserinol43 in the
presence of titanium(IV) tetra-isopropoxide44 in dichloro-
methane followed by cyanoborohydride reduction of the
resulting imine intermediate. The expected aminocyclitols
42 and 43 were isolated in good yield (84 and 96%) as
unseparable 4:1 mixtures of 1S:1R epimers, respectively.
Simultaneous acidic hydrolysis of protected groups led to
the corresponding aminocyclitols 44 and 45. Similarly, the
aminocyclitol 48 displaying the aglycon part of miglitol was
obtained from the L-ido cyclooctene 19 by successive
hydroboration, oxidative cleavage, reductive amination
with ethanolamine and acidic hydrolysis (30% overall
yield from 19). In that sequence, the reductive amination led
to an unseparable mixture of epimers in a 3:1 ratio in favor
of the 1S stereoisomer.
The new C8-carbasugars 35, 36, 39 and 40 and C8-
aminocyclitols 44, 45 and 48 have been assayed for their
inhibitory activity towards 24 commercially available
glycosidases.45 They did not inhibit the following enzymes
at 1 mM concentration and optimal pH: a-glucosidase
(maltase) from yeast and rice, amyloglucosidase from
Aspergillus niger, b-glucosidase from Caldocellum sac-
charolyticum, a-L-fucosidases from bovine epididymis and
human placenta, a-galactosidases from coffee beans and
Escherichia coli, b-galactosidases from Escherichia coli,
bovine liver, Aspergillus niger and Aspergillus orizae, a-N-
acetylgalactosaminidase from chicken liver, b-N-acetylglu-
cosaminidases from Jack bean, bovine epididymis A and
bovine epididymis B, a-mannosidase from almonds, b-
mannosidase from Helix pomatia, and b-xylosidase from
Aspergillus niger. For other enzymes: amyloglucosidase
Rhizopus mold, a-D-glucosidase from Bacillus stearother-
mophilus, b-D-glucosidase from almonds, a-D-mannosidase
from Jack beans and a-L-fucosidase from bovine kidney, the
results are shown in Table 1. These new compounds
revealed weak inhibitions of the tested enzymes with a
percentage of inhibition not exceeding 33%. These results
show that the enhanced flexibility displayed by C8-
glycomimetics is not correlated with an increase of
glycosidase inhibitory activity. Indeed, we had previously
shown that the C7-aminocyclitol (see Fig. 2, (9) RZ
CH(CH2OH)2) exhibited interesting activity towards amy-
loglucosidases from Aspergillus niger and Rhizopus mold
(KiZ35 and 18 mM, respectively), while the corresponding
aminocyclitol 45 was almost inactive towards the same
enzymes.
Figure 4. Schematic representation of the NOEs (indicated with arrows)
found to deduce structure 33. Prochiral 1H of the CH2 groups are labelled
pR or pS.
Scheme 5. Reagents and conditions: (a) BH3$THF, Et2O then PCC, rt; (b)
Ti(OiPr)4, H2NCH2CH2OH or H2NCH(CH2CH2OTBDMS)2, CH2Cl2 then
NaBH3CN, EtOH; (c) TFA, H2O, rt, 60, 63 and 31% overall yield for 44, 45
and 48 from 41 and 46, respectively.
this ketone can be obtained in an one-pot reaction from the
cyclooctene 24 by hydroboration and in situ oxidation42 by
pyridinium chlorochromate (88% overall yield from 24).
Reductive amination to introduce either the aglycon part of
miglitol or voglibose was further performed by ethanola-
Table 1. Inhibitory activities for C8-carbasugars 35, 36, 39 and 40, and for C8-aminocyclitols 44 and 45
Enzymea
35
36
39
40
44b
45b
a-D-Glu
- Bac. Stearotherm.c
- Rhizopus mold
b-D-Gluc
15%
n.i.d
n.i.d
12%
6%
13%
n.i.d
n.i.d
8%
23%
n.i.d
n.i.d
n.i.d
16%
n.i.a
20%
5%
7%
n.i.d
17%
32%
n.i.d
17%
27%
15%
n.i.d
n.i.d
12%
33%
a-D-Manc
a-L-Fucc
29%
Percentage of inhibitions at 1 mM.
a See text.
b Tested as a mixture of epimers.
c See Ref. 46.
d No inhibition detected.

7098
O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
3. Conclusion
Flash chromatography of the crude led to pure diene
derivatives.
We have realized efficient and versatile syntheses of new
C8-glycomimetics using RCM methodology as the key step
to afford enantiomerically pure tetrahydroxylated cyclooc-
tenes with D-manno or L-ido configuration. Further
transformation of the cyclic double bond involved hydro-
boration and alkaline oxidation, followed by oxidation to a
ketone and reductive amination, then acidic hydrolysis.
According to this strategy and depending on the nature of
the amine involved in the reductive amination, various
aminocyclitols could be obtained. Thus, in this study, four
carbasugars and three aminocyclitols displaying the aglycon
part of miglitol or voglibose were obtained. These
compounds were evaluated for their inhibitory activity
towards 24 commercially available glycosidases. In the case
of the aminopolyols 44 and 45, spatial disposition of the
four hydroxy groups and the amino moiety departs probably
too much from that realized in glycomimetics such as
valiolamine, vogliobose and valienamine. The even weaker
inhibitory activities of pentols 35, 36, 39 and 40 can be
attributed to the fact that they lack a function (amino group)
that can imitate the glycosyl cation intermediate generated
during the glycosidase-catalyzed hydrolysis.
4.1.1. (4S,5R,6R,7S)-5,6-O-Methylethylidene-deca-1,9-
diene-4,5,6,7-tetrol (16). Isolated yield: 92%; Rf 0.3
(cyclohexane/EtOAc 7:3); [a]D C4 (c1.0, CH2Cl2); 1H
NMR d 5.83 (dddd, 2H, J2,1aZ17.2 Hz, J2,1bZ10.1 Hz,
J2,3aZJ2,3bZ7.1 Hz, H2,9), 5.12 (dd, 2H, J1a,2Z17.2 Hz,
J1a,1bZ1.1 Hz, H1a,10a), 5.10 (dd, 2H, J1b,1aZ1.1 Hz,
J1b,2Z10.1 Hz, H1b,10b), 4.00–3.90 (m, 2H, H5,6), 3.57
(ddd, 2H, J4,OHZ8.1 Hz, J4,3aZJ4,3bZ6.9 Hz, H4,7), 2.30
(AA0, XX0, 4H, J3a,2ZJ3b,2Z7.1 Hz, J3a,4ZJ3b,4Z6.9 Hz,
H3a,3b,8a,8b), 1.41 (s, 6H, CH3); 13C NMR d 134.2 (C2,9),
118.0 (C1,10), 109.4 (CMe2), 79.1, 69.3 (C4,5,6,7), 39.3 (C3,8),
27.2 (CMe2). Anal. Calcd for C13H22O4: C, 64.44; H, 9.15.
Found: C, 64.31; H, 9.35.
4.1.2. (4R,5R,6R,7R)-5,6-O-Methylethylidene-deca-1,9-
diene-4,5,6,7 tetrol (21). Isolated yield: 87%; Rf 0.2
(cyclohexane/EtOAc 8:2); [a]D C13 (c1.0, CH2Cl2); H
1
NMR d 5.88 (dddd, 2H, J2,1aZ17.1 Hz, J2,1bZ10.3 Hz,
J2,3aZ6.4 Hz, J2,3bZ7.9 Hz, H2,9), 5.17 (d, 2H, J1a,2
Z
17.1 Hz, H1a,10a), 5.16 (d, 2H, J1b,2Z10.3 Hz, H1b,10b),
3.78–3.58 (m, 4H, H4,5,6,7), 2.58 (ddd, 2H, J3a,3bZ14.2 Hz,
J3a,2Z6.4 Hz, J3a,4Z3.0 Hz, H3a,8a), 2.22 (ddd, 2H, J3b,3a
Z
14.2 Hz, J3b,2ZJ3b,4Z7.9 Hz, H3b,8b), 1.36 (s, 6H, CH3);
13C NMR d 134.2 (C2,9), 118.3 (C1,10), 108.9 (CMe2), 82.5
(C5,6), 72.0 (C4,7), 38.5 (C3,8), 26.8 (CMe2); HRMS for
C13H23O4 (MCC1): calcd 243.1596; found 243.1600.
4. Experimental
1H NMR (250 or 500 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. Optical rotations were
measured on a Perkin-Elmer 241C polarimeter with sodium
(589 nm) or mercury (365 nm) lamp. Mass spectra,
chemical ionization (CI), and high resolution (HRMS)
4.1.3. (4R,5R,6R,7R)-5,6-Di-O-benzyl-deca-1,9-diene-
4,5,6,7-tetrol (26). Isolated yield: 30%; Rf 0.3 (cyclo-
hexane/EtOAc 7:3); [a]Hg K10 (c1.0, CH2Cl2); 1H NMR d
7.37–7.24 (m, 10H, HAr), 5.88 (dddd, 2H, J2,1aZ17.2 Hz,
J2,1bZ10.0 Hz, J2,3aZ6.2 Hz, J2,3bZ8.1 Hz, H2,9), 5.13 (d,
2H, J1a,2Z17.2 Hz, H1a,10a), 5.12 (d, 2H, J1b,2Z10.0 Hz,
H1b,10b), 4.66 (s, 4H, CH2Ph), 4.02 (ddd, 2H, J4,3aZ1.2 Hz,
´
were recorded by the Service de Spectrometrie de Masse,
Ecole Normale Superieure, Paris. All reactions were carried
´
J4,3bZ7.8 Hz, J4,5Z6.1 Hz, H4,7), 3.68 (d, 2H, J5,4
6.1 Hz, H5,6), 2.49 (ddd, 2H, J3a,2Z6.2 Hz, J3a,3b
14.1 Hz, J3a,4Z1.2 Hz, H3a,8a), 2.28 (ddd, 2H, J3b,2
Z
Z
Z
out under an argon atmosphere, and were monitored by thin-
layer chromatography with Merck 60F-254 precoated silica
(0.2 mm) on glass. Flash chromatography was performed
with Merck Kieselgel 60 (0.2–0.5 mm); the solvent system
were given v/v spectroscopic (1H and 13C NMR, MS) and/or
analytical data were obtained using chromatographically
homogeneous samples.
8.1 Hz, J3b,3aZ14.1 Hz, J3b,4Z7.8 Hz, H3b,8b); 13C NMR
d 137.3 (C2,9), 134.7, 128.5, 128.3, 128.1 (CAr), 117.9
(C1,10), 79.5, 70.3 (C4,5,6,7), 73.1 (CH2Ph), 38.3 (C3,8);
HRMS for C24H31O4 (MCC1): calcd 383.2222; found
383.2222.
4.2. General procedure for ring closing metathesis of
diene-diols
4.1. General procedure for bis-epoxides opening
To a solution of vinylbromide (48.4 mmol) in diethyl ether
(12 mL) at K78 8C was slowly added tert-butyllithium
(1.7 M in pentane, 96.8 mmol, 2 equiv). The temperature
was then raised from K78 8C to 20 8C. This solution was
slowly added to a suspension of copper(I) cyanide (2.16 g,
24.2 mmol) in THF (24 mL) at K78 8C. The temperature
was then slowly raised from K78 to 0 8C. After addition of
a solution of bis-epoxide (5.38 mmol) in THF (10 mL) at
K78 8C, the temperature was allowed to raise to 20 8C
overnight. A saturated NH4Cl aqueous solution containing
10% of NH4OH (250 mL) was added and after stirring for
30 min, the mixture was filtered through celite. After
extraction of the mixture with diethyl ether, the combined
organic layers were washed with a saturated NH4Cl aqueous
solution, dried (MgSO4), filtered and concentrated in vacuo.
To a solution of diene-diol (4.42 mmol) in CH2Cl2
(800 mL) was added Grubbs’ catalyst (0.22 mmol, 5.0 mol
%). After stirring at 20 8C for 24, 48 and 72 h, 2.5 mol % of
catalyst (0.11 mmol) were successively added. After stirring
for 4 days, DMSO (1.96 mL, 27.6 mmol, 50 equiv relative
to the catalyst) was added and the mixture was stirred
overnight before concentration in vacuo. Flash chromato-
graphy of the crude led to pure cyclooctene derivatives.
4.2.1.
(Z)-(1S,2R,3R,4S)-2,3-O-Methylethylidene-
cyclooct-6-ene-1,2,3,4-tetrol (17). Isolated yield: 87%; Rf
0.3 (cyclohexane/EtOAc 5:5); mp 102 8C; [a]D C60 (c1.0,
CH2Cl2); 1H NMR d 5.78–5.73 (m, 2H, H1,8), 3.80 (dd, 1H,
J4,3ZJ4,5Z5.9 Hz, H4), 3.76 (dd, 1H, J5,4ZJ5,6Z5.9 Hz,

O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
7099
H5), 3.71–3.57 (m, 2H, H3,6), 2.41 (ddd, 2H, J2a,1Z5.4 Hz,
J2a,2bZ13.9 Hz, J2a,3Z3.5 Hz, H2a,7a), 2.30 (ddd, 2H,
J2b,1Z6.8 Hz, J2a,2bZ13.9 Hz, J2b,3Z6.8 Hz, H2b,7b), 1.34
(s, 6H, CH3); 13C NMR d 127.7 (C1,8), 108.9 (CMe2), 82.2
(C4,5), 72.5 (C3,6), 30.3 (C2,7), 26.8 (CMe2). Anal. Calcd for
C11H18O4: C, 61.66; H, 8.47. Found: C, 61.48; H, 8.66.
6.1 Hz, J4,3bZ7.3 Hz, H4,7), 2.45 (ddd, 2H, J3a,3bZ13.5 Hz,
J3a,4Z6.1 Hz, J3a,2Z7.1 Hz, H3a,8a), 2.24 (ddd, 2H, J3b,3a
13.5 Hz, J3b,4Z7.3 Hz, J3b,2Z7.1 Hz, H3b,8b), 1.38 (s, 6H,
CH3), 0.88 (s, 18H, SitBu), 0.06, 0.04 (2 s, 12H, SiMe2); 13
NMR d 134.7 (C2,9), 117.5 (C1,10), 108.8 (CMe2), 78.4 (C5,6),
71.9 (C4,7), 39.1 (C3,8), 27.4 (CMe2), 25.9 (SiC(CH3)3), 18.2
(SiC(CH3)3), K4.1, K4.3 (SiMe2); HRMS for C25H51O4Si2
(MCC1): calcd 471.3326; found 471.3321.
Z
C
4.2.2.
(Z)-(1R,2R,3R,4R)-2,3-O-Methylethylidene-
cyclooct-6-ene-1,2,3,4-tetrol (22). Isolated yield: 62%; Rf
0.2 (cyclohexane/EtOAc 6:4); [a]D K87 (c1.0, CH2Cl2); 1H
NMR d 5.81–5.67 (m, 2H, H1,8), 4.23 (sl, 2H, H4,5), 4.14
(dd, 2H, J3,2aZ4.6 Hz, J3,2bZ7.6 Hz, H3,6), 2.50–2.31 (m,
4H, H2a,2b,7a,7b), 1.42 (s, 6H, CH3); 13C NMR d 128.0 (C1,8),
108.2 (CMe2), 77.0 (C4,5), 67.4 (C3,6), 29.0 (C2,7), 27.2
(CMe2); HRMS for C11H19O4 (MCC1): calcd 215.1283;
found 215.1278.
4.3.4. (4R,5S,6S,7R)-4,7-Di-O-tert-butyldimethylsilyl-
5,6-O-methylethylidene-deca-1,9-diene-4,5,6,7-tetrol
(23). Isolated yield: 96%; Rf 0.3 (cyclohexane/CH2Cl2 9:1);
[a]D K8 (c1.0, CH2Cl2); 1H NMR d 5.85 (dddd, 2H, J2,1a
Z
17.2 Hz, J2,1bZ10.3 Hz, J2,3aZ6.7 Hz, J2,3bZ7.4 Hz, H2,9),
5.07 (d, 2H, J1a,2Z17.2 Hz, H1a,10a), 5.06 (d, 2H, J1b,2
Z
10.3 Hz, H1b,10b), 4.00 (dd, 1H, J5,6Z3.8 Hz, J5,4Z4.8 Hz,
H5), 3.99 (dd, 1H, J6,5Z3.8 Hz, J6,7Z4.8 Hz, H6), 3.82
(ddd, 2H, J4,5Z4.8 Hz, J4,3aZ5.4 Hz, J4,3bZ5.1 Hz, H4,7),
4.3. General procedure for silylation of alcohols
2.41 (ddd, 2H, J3a,2Z6.7 Hz, J3a,3bZ14.2 Hz, J3a,4
5.4 Hz, H3a,8a), 2.28 (ddd, 2H, J3b,2Z7.4 Hz, J3b,3a
Z
Z
To a solution of diol (4.46 mmol) in DMF (6 mL) at 20 8C
were successively added imidazole (23.2 mmol, 5.2 equiv)
and tert-butyldimethylsilyl chloride (11.2 mmol, 2.5 equiv).
The temperature was then raised to 50 8C and the mixture was
stirred for 4 h. After cooling at 20 8C, a saturated NH4Cl
aqueous solution was added and the mixture was extracted
with CH2Cl2. The combined organic layers were then dried
(MgSO4), filtered and concentrated in vacuo. Flash chroma-
tography of the crude led to pure silylated derivatives.
14.2 Hz, J3b,4Z5.1 Hz, H3b,8b), 1.36 (s, 6H, CH3), 0.88 (s,
18H, SitBu), 0.08, 0.07 (2 s, 12H, SiMe2); 13C NMR d 134.6
(C2,9), 117.4 (C1,10), 109.0 (CMe2), 79.8 (C5,6), 71.9 (C4,7),
37.7 (C3,8), 28.4 (CMe2), 25.9 (SiC(CH3)3), 18.1
(SiC(CH3)3), K4.2, K4.4 (SiMe2). Anal. Calcd for
C25H50O4Si2: C, 63.77; H, 10.70. Found: C, 63.84; H, 10.69.
4.3.5. (4R,5S,6S,7R)-5,6-Di-O-benzyl-4,7-di-O-tert-butyl-
dimethylsilyl-deca-1,9-diene-4,5,6,7-tetrol (27). Isolated
yield: 70%; Rf 0.3 (cyclohexane/CH2Cl2 8:2); [a]D C21
4.3.1. (Z)-(1S,2S,3S,4S)-1,4-Di-O-tert-butyldimethylsilyl-
2,3-O-methylethylidene-cyclooct-6-ene-1,2,3,4-tetrol
(19). Isolated yield: 97%; Rf 0.3 (cyclohexane/CH2Cl2 8:2);
mp 44 8C; [a]D C76 (c1.0, CH2Cl2); 1H NMR d 5.78–5.64
(m, 2H, H1,8), 3.75 (dd, 1H, J4,3ZJ4,5Z5.8 Hz, H4), 3.72
(dd, 1H, J5,4ZJ5,6Z5.8 Hz, H5), 3.68–3.52 (m, 2H, H3,6),
2.45–2.20 (m, 4H, H2a,2b,7a,7b), 1.31 (s, 6H, CH3), 0.88 (s,
18H, SitBu), 0.06 (s, 12H, SiMe2); 13C NMR d 127.6 (C1,8),
107.4 (CMe2), 82.3 (C4,5), 73.6 (C3,6), 32.8 (C2,7), 26.9
(CMe2), 25.9 (SiC(CH3)3), 18.3 (SiC(CH3)3), K4.3, K5.1
(SiMe2); HRMS for C23H47O4Si2 (MCC1): calcd
443.3013; found 443.3013.
1
(c1.0, CH2Cl2); H NMR d 7.55–7.20 (m, 10H, CH2Ph),
5.89 (dddd, 2H, J2,1aZ17.2 Hz, J2,1bZ9.9 Hz, J2,3a
J2,3bZ7.1 Hz, H2,9), 5.07 (d, 2H, J1a,2Z17.2 Hz, H1a,10a),
5.06 (d, 2H, J1b,2Z9.9 Hz, H1b,10b), 4.85, 4.68 (AB, JAB
Z
Z
11.1 Hz, CH2Ph), 3.80 (d, 2H, J4,3aZ7.0 Hz, J4,3bZ5.1 Hz,
H4,7) 3.62 (sl, 2H, H5,6), 2.55 (ddd, 2H, J3a,2Z7.1 Hz,
J3a,3bZ14.2 Hz, J3a,4Z7.0 Hz, H3a,8a), 2.28 (ddd, 2H,
J3b,2Z7.1 Hz, J3b,3aZ14.2 Hz, J3b,4Z5.1 Hz, H3b,8b), 0.91
(s, 18H, SitBu), 0.07 (s, 12H, SiMe2); 13C NMR d 139.3,
128.2, 127.8, 127.3 (CH2Ph), 136.1 (C2,9), 116.8 (C1,10),
84.4 (C5,6), 75.0 (CH2Ph), 74.0 (C4,7), 37.1 (C3,8), 26.0
(SiC(CH3)3), 18.1 (SiC(CH3)3), K4.2, K4.4 (SiMe2);
HRMS for C36H58O4Si2 (MCC1): calcd 611.3952; found
611.3945.
4.3.2. (Z)-(1R,2S,3S,4R)-1,4-Di-O-tert-butyldimethylsi-
lyl-2,3-O-methylethylidene-cyclooct-6-ene-1,2,3,4-tetrol
(24). Isolated yield: 74%; Rf 0.25 (cyclohexane/CH2Cl2
1
4.4. General procedure for ring closing metathesis of
dienes-diols silylated derivatives
8:2); mp 87 8C; [a]D K126 (c1.0, CH2Cl2); H NMR d
5.70–5.55 (m, 2H, H1,8), 4.26 (sl, 2H, H4,5), 4.14 (dd, 2H,
J3,2aZ4.5 Hz, J3,2bZ7.9 Hz, H3,6), 2.40–2.28 (m, 4H,
H2a,7a), 2.23 (ddd, 2H, J2b,1Z2.4 Hz, J2b,2aZ16.0 Hz,
J2b,3Z7.8 Hz, H2b,7b), 1.36 (s, 6H, CH3), 0.89 (s, 18H,
SitBu), 0.08, 0.06 (2 s, 12H, SiMe2); 13C NMR d 127.9
(C1,8), 108.5 (CMe2), 77.6 (C4,5), 68.7 (C3,6), 31.7 (C2,7),
27.6 (CMe2), 26.0 (SiC(CH3)3), 18.3 (SiC(CH3)3), K4.2,
K5.0 (SiMe2). Anal. Calcd for C23H46O4Si2: C, 62.39; H,
10.48. Found: C, 62.39; H, 10.57.
To a solution of diene (2.12 mmol) in CH2Cl2 (10 mL) was
added Grubbs’ catalyst (0.04 mmol, 2.0 mol %). After
stirring at 20 8C for 30 min was added lead tetraacetate47
(0.06 mmol, 1.5 equiv relative to the catalyst). After stirring
overnight, the mixture was filtered through celite and
concentrated in vacuo. Flash chromatography of the crude
led to pure cyclooctene derivatives.
4.4.1. (Z)-(1S,2S,3S,4S)-1,4-Di-O-tert-butyldimethylsilyl-
2,3-O-methylethylidene-cyclooct-6-ene-1,2,3,4-tetrol
(19). Isolated yield: 100%. Physical data: see Section 4.3.1.
4.3.3. (4S,5S,6S,7S)-4,7-Di-O-tert-butyldimethylsilyl-5,6-
O-methylethylidene-deca-1,9-diene-4,5,6,7-tetrol (18).
Isolated yield: 94%; Rf 0.25 (cyclohexane/CH2Cl2 8:2);
[a]D C18 (c1.0, CH2Cl2); 1H NMR d 5.78 (dddd, 2H,
J2,1aZ17.2 Hz, J2,1bZ10.0 Hz, J2,3aZJ2,3bZ7.1 Hz, H2,9),
4.4.2. (Z)-(1R,2S,3S,4R)-1,4-Di-O-tert-butyldimethylsi-
lyl-2,3-O-methylethylidene-cyclooct-6-ene-1,2,3,4-tetrol
(24). Isolated yield: 95%. Physical data: see Section 4.3.2.
5.09 (d, 2H, J1a,2Z17.2 Hz, H1a,10a), 5.03 (d, 2H, J1b,2
Z
Z
10.0 Hz, H1b,10b), 3.98 (sl, 2H, H5,6), 3.62 (dd, 2H, J4,3a

7100
O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
4.4.3. (Z)-(1R,2S,3S,4R)-2,3-Di-O-benzyl-1,4-di-O-tert-
butyldimethylsilyl-cyclooct-6-ene-1,2,3,4-tetrol (28). Iso-
lated yield: 95%; Rf 0.3 (cyclohexane/CH2Cl2 8:2); [a]D
C21 (c1.0, CH2Cl2); 1H NMR d 7.35–7.15 (m, 10H,
5.4 Hz, J8a,7bZ10.0 Hz, J8a,8bZ13.4 Hz, H8a), 1.96 (dddd,
1H, J7a,6Z7.7 Hz, J7a,7bZ15.0 Hz, J7a,8aZ5.4 Hz, J7a,8b
Z
10.1 Hz, H7a), 1.74 (dd, 1H, J2b,1Z9.8 Hz, J2b,2aZ14.1 Hz,
4
H2b), 1.64 (dddd, 1H, J8b,1Z1.0 Hz, J8b,2aZ1.9 Hz,
CH2Ph), 5.75–5.55 (m, 2H, H1,8), 4.86, 4.45 (AB, JA,B
Z
J8b,7aZ10.1 Hz, J8b,8aZ13.4 Hz, H8b), 1.56 (dd, 1H,
J7b,7aZ15.0 Hz, J7b,8aZ10.0 Hz, H7b), 1.34 (s, 6H, CH3),
0.92, 0.91, 0.90 (3 s, 18H, SitBu), 0.09, 0.07, 0.05, 0.04 (4 s,
12H, SiMe2); 13C NMR d 106.1 (CMe2), 78.3, 78.2 (C4,5),
69.1 (C1), 68.3, 68.2 (C3,6), 45.0 (C2), 31.4 (C8), 31.0 (C7),
27.3 (CMe2), 26.0 (SiC(CH3)3), 18.1 (SiC(CH3)3), K4.5,
K4.6, K4.8, K4.9 (SiMe2). Anal. Calcd for C23H48O5Si2:
C, 59.95; H, 10.50. Found: C, 59.79; H, 10.66.
10.9 Hz, CH2Ph), 4.30–4.13 (m, 2H, H3,6), 3.90 (sl, 2H,
H4,5), 2.40–2.15 (m, 4H, H2a,2b,7a,7b), 0.91 (s, 18H, SitBu),
0.10, 0.09, 0.07 (3 s, 12H, SiMe2); 13C NMR d 140.0, 128.3,
127.9, 127.5 (CH2Ph), 126.8 (C1,8), 77.6 (C4,5), 73.8
(CH2Ph), 72.4 (C3,6), 32.7 (C2,7), 26.0 (SiC(CH3)3), 18.3
(SiC(CH3)3), 1.0, –4.0, –5.0 (SiMe2); HRMS for
C34H55O4Si2 (MCC1): calcd 583.3639; found 583.3633.
4.5. 2,5-Di-O-tert-butyldimethylsilyl-1,6-didesoxy-1,6-
diformyl-3,4-O-methylethylidene-L-iditol (29)
4.6.2. (1R,2S,3S,4R,6R)-1,4-Di-O-tert-butyldimethylsilyl-
2,3-O-methylethylidene-cyclooctane-1,2,3,4,6-pentol
(34). Isolated yield: 30%; Rf 0.2 (cyclohexane/EtOAc 9:1);
1
By using an ozone generator, a stream of O3/O2 was passed
through a solution of diene (1.62 mmol) in CH2Cl2 (24 mL)
and methanol (4 mL) at K78 8C, until a slight blue color
developed. After 30 min, O3 in excess was removed by a
stream of argon in the solution until decoloration.
Trimethylphosphite (14.6 mmol, 9 equiv) was then added
at K78 8C and the mixture was stirred for 10 min from
K78 8C to 20 8C, then overnight at 20 8C. After concen-
tration in vacuo, flash chromatography of the crude led to
pure dialdehyde derivative. Isolated yield: 70%; Rf 0.2
mp 55–60 8C; [a]D K36 (c1.0, CH2Cl2); H NMR d 4.35
(ddl, 1H, J3,2aZ6.8 Hz, J3,4Z1.7 Hz, H3), 4.20 (ddl, 1H,
J6,5Z1.3 Hz, J6,7aZ6.9 Hz, H6), 4.16 (dd, 1H, J5,4Z8.6 Hz,
J5,6Z1.3 Hz, H5), 4.06 (dd, 1H, J4,3Z1.7 Hz, J4,5Z8.6 Hz,
H4), 4.11–4.01 (m, 1H, H1), 2.29 (ddd, 1H, J2a,1Z7.4 Hz,
J2a,2bZ14.8 Hz, J2a,3Z6.8 Hz, H2a), 2.03–1.86 (m, 2H,
H8a,8b), 1.80–1.60 (m, 3H, H2b,7a,7b), 1.35, 1.34 (2 s, 6H,
CH3), 0.90, 0.89 (2 s, 18H, SitBu), 0.13, 0.12, 0.07, 0.05 (4
s, 12H, SiMe2); 13C NMR d 106.2 (CMe2), 78.6, 77.3 (C4,5),
70.9 (C3), 68.4 (C1), 68.2 (C6), 39.3 (C2), 27.3 (CMe2), 27.2
(C7), 26.0, 25.9 (SiC(CH3)3), 25.6 (C8), 18.2, 18.0
(SiC(CH3)3), K4.4, K4.8 (SiMe2); HRMS for
C23H49O5Si2 (MCC1): calcd 461.3119; found 461.3116.
1
(cyclohexane/CH2Cl2 1:9); [a]D C16 (c1.0, CH2Cl2); H
NMR d 9.81 (dd, 2H, J1,2aZ1.5 Hz, J1,2bZ2.3 Hz, H1,8),
4.23 (ddd, 2H, J3,4Z1.2 Hz, J3,2aZ6.6 Hz, J3,2bZ4.8 Hz,
H3,6), 4.03 (dd, 2H, J4,3Z1.2 Hz, J4,5Z1.8 Hz, H4,5), 2.81
(ddd, 2H, J2a,1Z1.5 Hz, J2a,2bZ14.2 Hz, J2a,3Z6.6 Hz,
H2a,7a), 2.55 (ddd, 2H, J2b,1Z2.3 Hz, J2b,2aZ14.2 Hz,
J2b,3Z4.8 Hz, H2b,7b), 1.37 (s, 6H, CH3), 0.88 (s, 18H,
SitBu), 0.09, 0.08 (2 s, 12H, SiMe2); 13C NMR d 200.6
(C1,8), 110.0 (CMe2), 79.6 (C4,5), 67.7 (C3,6), 48.3 (C2,7),
27.2 (CMe2), 25.8 (SiC(CH3)3), 18.1 (SiC(CH3)3), K4.5
(SiMe2); HRMS for C23H47O6Si2 (MCC1): calcd
475.2911; found 475.2917.
4.6.3. (1S,2S,3S,4S,6S)-1,4-Di-O-tert-butyldimethylsilyl-
2,3-O-methylethylidene-cyclooctane-1,2,3,4,6-pentol
(37). Isolated yield: 51%; Rf 0.35 (cyclohexane/EtOAc 9:1);
1
mp 62–65 8C; [a]D C37 (c1.0, CH2Cl2); H NMR d 4.10
(dd, 1H, J4,3Z7.6 Hz, J4,5Z8.0 Hz, H4), 4.03 (ddd, 1H,
J3,2aZ5.8 Hz, J3,2bZ2.3 Hz, J3,4Z7.4 Hz, H3), 3.87–3.74
(m, 1H, H1), 3.67 (ddd, 1H, J6,5Z8.2 Hz, J6,7aZ4.3 Hz,
J6,7bZ8.3 Hz, H6), 3.58 (dd, 1H, J5,4Z8.0 Hz, J5,6Z8.2 Hz,
H5), 2.17 (dd, 1H, J8a,7bZ6.5 Hz, J8a,8bZ13.6 Hz, H8a),
4.6. General procedure for oxidative hydroboration
2.10 (ddd, 1H, J2a,1Z4.8 Hz, J2a,2bZ15.0 Hz, J2a,3
5.8 Hz, H2a), 1.91 (ddd, 1H, J2b,1Z2.2 Hz, J2b,2a
Z
Z
To a solution of cyclooctene (1.03 mmol) in diethyl ether
(4 mL) was added at 0 8C BH3$THF complex (1 M in THF,
1 mmol, 1 equiv). After stirring at 20 8C for 1 h 30 min the
mixture was oxidized by adding successively ethanol
(1.2 mL), 3 M NaOH (0.25 mL) and 30% hydrogen
peroxide (0.25 mL). After stirring overnight at 20 8C,
water (20 mL) was added and the reaction mixture was
extracted with diethyl ether. The combined organic layer
were washed with water, then with brine, dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatography of
the crude led to pure cyclooctanol derivatives.
15.0 Hz, J2b,3Z2.3 Hz, H2b), 1.80 (dd, 1H, J7a,6Z4.3 Hz,
J7a,7bZ13.6 Hz, H7a), 1.39–1.22 (m, 2H, H7b,8b), 1.34, 1.31
(2 s, 6H, CH3), 0.88, 0.86 (2 s, 18H, SitBu), 0.12, 0.11, 0.07,
0.06 (4 s, 12H, SiMe2); 13C NMR d 107.7 (CMe2), 81.8,
81.7 (C4,5), 77.2, 76.1 (C3,6), 70.4 (C1), 35.4 (C2), 31.1 (C8),
29.6 (C7), 27.0, 26.7 (CMe2), 25.9, 25.8 (SiC(CH3)3), 18.2,
18.0 (SiC(CH3)3), K4.3, K4.4, K5.0, K5.3 (SiMe2). Anal.
Calcd for C23H48O5Si2: C, 59.95; H, 10.50. Found C, 59.92;
H, 10.54.
4.6.4. (1S,2S,3S,4S,6R)-1,4-Di-O-tert-butyldimethylsilyl-
2,3-O-methylethylidene-cyclooctane-1,2,3,4,6-pentol
(38). Isolated yield: 38%; Rf10.25 (cyclohexane/EtOAc 9:1);
[a]D C26 (c1.0, CH2Cl2); H NMR d 4.23–4.13 (m, 1H,
H1), 3.88–3.78 (m, 2H, H3,4), 3.68–3.53 (m, 2H, H5,6), 1.93–
1.53 (m, 6H, H2a,2b,7a,7b,8a,8b), 1.32, 1.30 (2 s, 6H, CH3),
0.87 (3 s, 18H, SitBu), 0.07, 0.06 (4 s, 12H, SiMe2); 13C
NMR d 107.5 (CMe2), 81.7, 81.6 (C4,5), 76.4 (C6), 73.3
(C3), 65.9 (C1), 38.2 (C2), 30.2 (C8), 27.0, 26.7 (CMe2), 26.9
(C7), 25.9, 25.8 (SiC(CH3)3), 18.3, 18.1 (SiC(CH3)3), K4.3,
K4.5, K5.0, K5.2 (SiMe2); HRMS for C23H49O5Si2
(MCC1): calcd 461.3119; found 461.3121.
4.6.1. (1R,2S,3S,4R,6S)-1,4-Di-O-tert-butyldimethylsilyl-
2,3-O-methylethylidene-cyclooctane-1,2,3,4,6-pentol
(33). Isolated yield: 62%; Rf 0.15 (cyclohexane/EtOAc 9:1);
1
[a]D K28 (c1.0, CH2Cl2); H NMR d 4.27 (d, 1H, J3,2a
Z
7.8 Hz, H3), 4.15 (dd, 1H, J6,5Z1.5 Hz, J6,7aZ7.7 Hz, H6),
4.11 (d, 1H, J4,5Z8.5 Hz, H4), 4.01 (dd, 1H, J5,4Z8.5 Hz,
J5,6Z1.5 Hz, H5), 3.90 (dddd, 1H, J1,2aZ1.9 Hz, J1,2b
Z
9.8 Hz, J1,8aZ9.6 Hz, J1,8bZ1.0 Hz, H1), 2.12 (dddd, 1H,
4
J2a,1Z1.9 Hz, J2a,2bZ14.1 Hz, J2a,3Z7.8 Hz, J2a,8b
1.9 Hz, H2a), 2.00 (dddd, 1H, J8a,1Z9.6 Hz, J8a,7a
Z
Z

O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
7101
4.7. General procedure for ketone formation
hydrogencarbonate, filtered and concentrated in vacuo.
Flash chromatography of the crude led to a mixture of two
epimers.
To a solution of cyclooctene (1.0 mmol) in diethylether
(6 mL) was added at 0 8C BH3$THF complex (1 M in THF,
1 mmol, 1 equiv). After stirring at 20 8C for 2 h the mixture
was oxidized by adding pyridinium chlorochromate (36 mg,
0.17 mmol, 6 equiv). After stirring overnight at 20 8C the
mixture was filtered through celite and concentrated in
vacuo. Flash chromatography of the crude led to pure ketone
derivatives.
4.8.1. (1R,2S,3S,4R)-1,4-Di-O-tert-butyldimethylsilyl-6-
(2-hydroxyethylamino)-2,3-O-methylethylidene-cyclooc-
tane-1,2,3,4-tetrol (42). Isolated yield: 84% (unseparable
4:1 mixture of 6S:6R epimers); Rf 0.2 (CH2Cl2/MeOH 9:1);
1H NMR d 4.30–3.96 (m, 4H, H3,4,5,6), 3.66–3.52 (m, 2H,
0
0
0
0
H2 a,2 b), 2.82–2.65 (m, 3H, H1,1 a,1 b), 2.06–1.42 (m, 6H,
H2a,2b,7a,7b,8a,8b), 1.34 (s, 6H, CH3), 0.90 (s, 18H, SitBu),
0.09, 0.07, 0.03 (3 s, 12H, SiMe2); 13C NMR d 106.1
4.7.1. (3R,4S,5S,6R)-3,6-Di-O-tert-butyldimethylsilyl-
4,5-O-methylethylidene-3,4,5,6-tetrahydroxy cycloocta-
none (41). Isolated yield: 88%; Rf 0.4 (cyclohexane/
EtOAc 9:1); mp 69 8C; [a]D K59 (c1.0, CH2Cl2); 1H
NMR d 4.31 (ddd, 1H, J3,2aZJ3,2bZ5.6 Hz, J3,4Z1.1 Hz,
H3), 4.26–4.20 (m, 1H, H6), 4.21 (dd, 1H, J4,3Z1.1 Hz,
J4,5Z8.2 Hz, H4), 4.10 (dd, 1H, J5,4Z8.2 Hz, J5,6Z1.0 Hz,
0
(CMe2), 78.6, 78.1 (C4,5), 68.6, 68.4 (C3,6), 60.9 (C2 ), 54.3
0
(C1), 48.5 (C1 ), 37.7 (C2), 32.5 (C8), 27.9 (C7), 27.3
(CMe2), 26.0 (SiC(CH3)3), 18.2 (SiC(CH3)3), K4.5, K4.8
(SiMe2); HRMS for C25H54NO5Si2 (MCC1): calcd
504.3541; found 504.3537.
H5), 2.76–2.56 (m, 3H, H2a,2b,8a), 2.31 (ddd, 1H, J8b,7a
Z
4.8.2. (1R,2S,3S,4R)-1,4-Di-O-tert-butyldimethylsilyl-6-
[2-silyloxy-1-silyloxymethylethylamino]-2,3-O-methyl-
ethylidene-cyclooctane-1,2,3,4-tetrol (43). Isolated yield:
96% (unseparable 4:1 mixture of 6S:6R epimers); Rf 0.2
(CH2Cl2/MeOH 9:1); 1H NMR d 4.30–4.02 (m, 4H,
7.5 Hz, J8b,7bZ3.8 Hz, J8b,8aZ15.0 Hz, H8b), 2.08–1.88 (m,
2H, H7a,7b), 1.36, 1.35 (2 s, 6H, CH3), 0.90 (s, 18H, SitBu),
0.10, 0.08, 0.04 (3 s, 12H, SiMe2); 13C NMR d 210.4 (C1),
107.7 (CMe2), 78.0 (C5), 77.0 (C4), 68.6 (C6), 68.2 (C3),
47.0 (C2), 36.8 (C8), 30.4 (C7), 27.5, 27.3 (CMe2), 26.0
(SiC(CH3)3), 18.1 (SiC(CH3)3), K4.4, K4.8, K4.9
(SiMe2); HRMS for C23H47O5Si2 (MCC1): calcd
459.2962; found 459.2958.
0
H3,4,5,6), 3.65–3.40 (m, 4H, H1 a,1 b,3 a,3 b), 2.91–2.82 (m,
0
0
0
0
1H, H1), 2.70–2.60 (m, 1H, H2 ), 2.00–1.40, 1.29–1.18 (m,
6H, H2a,2b,7a,7b,8a,8b), 1.34, 1.33 (2 s, 6H, CH3), 0.90, 0.88,
0.87 (3 s, 18H, SitBu), 0.10, 0.09, 0.06, 0.05, 0.04, 0.03 (6 s,
24H, SiMe2); 13C NMR d 106.1 (CMe2), 78.0 (C4,5), 68.6
0
0
0
(C3,6), 64.5, 62.2 (C1 ,3 ), 54.3 (C1), 52.0 (C2 ), 37.7 (C2),
29.7 (C8), 28.1 (C7), 27.4, 27.3 (CMe2), 26.0, 25.9
(SiC(CH3)3), 18.2 (SiC(CH3)3), K4.5, K4.9, K5.5
(SiMe2); SM (CI, NH3) 763 (MCC1).
4.7.2. (3S,4S,5S,6S)-3,6-Di-O-tert-butyldimethylsilyl-4,5-
O-methylethylidene-3,4,5,6-tetrahydroxy cyclooctanone
(46). Isolated yield: 97%; Rf 0.6 (cyclohexane/EtOAc 9:1);
mp 99–100 8C; [a]D C26 (c1.0, CH2Cl2); 1H NMR d 3.90–
3.80 (m,1H, H6), 3.82 (ddd, 1H, J3,2aZ10.9 Hz, J3,2b
Z
4.5 Hz, J3,4Z8.2 Hz, H3), 3.72 (dd, 1H, J4,3ZJ4,5Z8.2 Hz,
H4), 3.44 (dd, 1H, J5,4ZJ5,6Z8.2 Hz, H5), 2.95 (dd, 1H,
J2a,2bZ11.1 Hz, J2a,3Z10.9 Hz, H2a), 2.75 (ddd, 1H,
J8a,7aZ13.0 Hz, J8a,7bZ2.9 Hz, J8a,8bZ16.2 Hz, H8a),
2.41 (dd, 1H, J2b,2aZ11.1 Hz, J2b,3Z4.5 Hz, H2b), 2.27
(ddd, 1H, J7a,7bZ15.2 Hz, J7a,8aZ13.0 Hz, J7a,8bZ2.2 Hz,
4.8.3. (1S,2S,3S,4S)-1,4-Di-O-tert-butyldimethylsilyl-6-
(2-hydroxyethylamino)-2,3-O-methylethylidene-cyclooc-
tane-1,2,3,4-tetrol (47). Isolated yield: 61% (unseparable
3:1 mixture of 6S:6R epimers); Rf 0.2 (CH2Cl2/MeOH 9:1);
1H NMR d 3.91–3.50 (m, 6H, H3,4,5,6,2 a,2 b), 2.80–2.65 (m,
0
0
0
0
2H, H1 a,1 b), 2.65–2.41 (m, 1H, H1), 2.22–2.02 (m, 1H,
H8a), 1.90–1.38 (m, 4H, H2a,2b,7a,8b), 1.30, 1.29 (2 s, 6H,
CH3), 1.17–0.98 (m, 1H, H7b), 0.85 (s, 18H, SitBu), 0.09,
0.05, 0.03 (3 s, 12H, SiMe2); 13C NMR d 107.6 (CMe2),
H7a), 2.13 (ddd, 1H, J8b,7aZ2.2 Hz, J8b,7bZ5.9 Hz, J8b,8a
16.2 Hz, H8b), 1.89 (ddd, 1H, J7b,7aZ15.2 Hz, J7b,8a
Z
Z
2.9 Hz, J7b,8bZ5.9 Hz, H7b), 1.32, 1.29 (2 s, 6H, CH3), 0.86,
0.85 (2 s, 18H, SitBu), 0.09, 0.03 (2 s, 12H, SiMe2); 13C
NMR d 210.4 (C1), 108.7 (CMe2), 81.9 (C4), 80.1 (C5), 74.9
(C3), 74.0 (C6), 46.3 (C2), 39.0 (C8), 28.9 (C7), 26.9 (CMe2),
25.8 (SiC(CH3)3), 18.2, 18.1 (SiC(CH3)3), K4.3, K5.0,
K5.2 (SiMe2); Anal. Calcd for C23H46O5Si2: C, 60.21; H,
10.11; found C, 59.89; H, 10.40.
0
81.9, 81.5 (C4,5), 76.3, 75.3 (C3,6), 60.9 (C2 ), 54.2 (C1), 48.7
0
(C1 ), 36.5 (C2), 29.4 (C7), 29.0 (C8), 27.0, 26.8 (CMe2),
25.9 (SiC(CH3)3), 18.2 (SiC(CH3)3), K4.4, K4.8, K5.1
(SiMe2); HRMS for C25H54NO5Si2 (MCC1): calcd
504.3541; found 504.3537.
4.9. Deprotection of the cyclooctanols
4.8. Reductive amination
The substrate (0.43 mmol) was stirred in a 9:1 solution of
trifluoroacetic acid/H2O at 20 8C for 15 h. After concen-
tration in vacuo, the resulting oily residue was triturated in
diethyl ether and the supernatant was discarded to afford a
brownish solid which was then purified by reverse phase
chromatography (Sep-Pakw Cartridges, H2O/MeOH 1:1 to
1:5).
To the cycloalkanone (0.33 mmol) at 20 8C, were succes-
sively added titanium(IV) tetra-isopropoxide (0.41 mmol,
1.25 equiv) and the primary amine (0.66 mmol, 2 equiv).
After stirring for 2 h, absolute ethanol (0.3 mL) and sodium
cyanoborohydride (1.75 mmol, 5.3 equiv) were added and
the mixture was stirred overnight at 20 8C. Addition of
water (0.2 mL) resulted in the formation of a white
precipitate which was filtered and washed with absolute
ethanol. Concentration of the filtrate was followed by
extraction of the residue with ethyl acetate, filtration and
concentration in vacuo. The oily residue was then dissolved
in CH2Cl2, stirred in the presence of sodium
4.9.1. (1R,2R,3R,4R,6S)-Cyclooctane-1,2,3,4,6-pentol
(35). Isolated yield: 100%; [a]Hg K12 (c1.0, MeOH); H
1
NMR (D2O) d 4.35 (ddd, 1H, J3,2aZ8.7 Hz, J3,2bZ2.3 Hz,
J3,4Z2.4 Hz, H3), 4.18–4.06 (m, 2H, H1,6), 3.97 (dd, 1H,
J4,3Z2.4 Hz, J4,5Z8.2 Hz, H4), 3.77 (dd, 1H, J5,4Z8.2 Hz,

7102
O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
0
0
0
0
J5,6Z1.9 Hz, H5), 2.18 (ddd, 1H, J2a,1Z2.8 Hz, J2a,2b
Z
7.7 Hz, J5,6Z1.7 Hz, H5), 3.72 (dd, 1H, J2 ,1 aZJ2 ,1 b
Z
0
5.6 Hz, H2 ), 3.03–2.97 (m, 1H, H1), 2.91–2.81 (m, 2H, H1 ),
2.06 (ddd, 1H, J2a,1Z3.5 Hz, J2a,2bZ14.5 Hz, J2a,3
8.6 Hz, H2a), 1.89–1.70 (m, 3H, H7a,7b,8a), 1.74 (ddd,
J2b,1Z9.1 Hz, J2b,2aZ14.5 Hz, J2b,3Z2.5 Hz, H2b), 1.70–
1.60 (m, 1H, H8b); 13C NMR (D2O) d 76.4 (C4,5), 74.3 (C6),
0
15.3 Hz, J2a,3Z8.7 Hz, H2a), 2.10–1.60 (m, 5H,
H2b,7a,7b,8a,8b); 13C NMR (D2O) d 76.4 (C5), 75.9 (C4),
74.1 (C1), 69.5 (C6), 68.8 (C3), 40.6 (C2), 31.9, 29.1 (C7,8);
HRMS for C8H17O5 (MCC1): calcd 210.1341; found
210.1345.
Z
0
0
71.2 (C3), 62.7 (C2 ), 58.5 (C1), 50.3 (C1 ), 38.0 (C7), 31.7,
29.9 (C1,8); HRMS for C10H22NO5 (MCC1): calcd
236.1498; found 236.1492.
4.9.2. (1R,2R,3R,4R,6R)-Cyclooctane-1,2,3,4,6-pentol
(36). Isolated yield: 100%; [a]Hg K15 (c1.0, MeOH); H
1
NMR (D2O) d 4.17–4.07 (m, 1H, H1), 4.11 (ddd, 1H, J3,2a
Z
8.4 Hz, J3,2bZ2.8 Hz, J3,4Z2.6 Hz, H3), 4.01–3.91 (m, 1H,
H6), 3.87 (dd, 1H, J4,3Z2.6 Hz, J4,5Z8.8 Hz, H4), 3.83 (dd,
1H, J5,4Z8.8 Hz, J5,6Z2.0 Hz, H5), 2.13–1.92 (m, 3H,
H2a,7a,8a), 1.91 (ddd, 1H, J2b,1Z3.7 Hz, J2b,2aZ14.6 Hz,
J2b,3Z2.8 Hz, H2b), 1.71–1.45 (m, 2H, H7b,8b); 13C NMR
(D2O) d 76.0, 75.6 (C5,4), 74.0 (C1), 72.5, 69.7 (C3,6), 42.0
(C2), 34.0, 29.4 (C7,8); HRMS for C8H17O5 (MCC1): calcd
210.1341; found 210.1344.
4.10.2. (1R,2R,3R,4R)-6-(2-Hydroxy-1-hydroxymethyl-
ethylamino)-cyclooctane-1,2,3,4-tetrol (45). Isolated
yield: 63% (unseparable 4:1 mixture of 6S:6R epimers);
1H NMR (D2O) d 4.38–4.30 (m, 1H, H3), 4.22–4.12 (m, 1H,
H6), 3.96 (dd, 1H, J4,3Z1.7 Hz, J4,5Z7.8 Hz, H4), 3.88 (dd,
1H, J5,4Z7.8 Hz, J5,6Z1.4 Hz, H5), 3.80–3.60 (m, 4H,
0
0
0
H1 ,3 ), 3.12–3.00 (m, 1H, H1), 2.98–2.88 (m, 1H, H2 ),
0
0
2.13–1.98 (m, 1H, H2a), 1.83–1.60 (m, 5H, H2b,7a,7b,8 a,8 b);
13C NMR (D2O) d 76.5, 76.2 (C4,5), 74.3 (C6), 71.1 (C3),
4.9.3. (1S,2R,3R,4S,6S)-Cyclooctane-1,2,3,4,6-pentol
(39). Isolated yield: 100%; [a]HgZC11 (c1.0, MeOH);
0
0
0
64.5, 63.7 (C1 ,3 ), 59.4 (C2 ), 52.3 (C1), 38.7 (C7), 31.8, 30.9
(C1,8); HRMS for C11H24NO6 (MCC1): calcd 265.1604;
found 265.1600.
1H NMR (D2O) d 3.97 (ddd, 1H, J1,2aZ3.8 Hz, J1,8a
Z
5.6 Hz, J1,8bZ9.4 Hz, H1), 3.76 (ddd, 1H, J6,5Z7.8 Hz,
J6,7aZ3.0 Hz, J6,7bZ7.1 Hz, H6), 3.67 (ddd, 1H, J3,2a
8.4 Hz, J3,2bZ4.8 Hz, J3,4Z8.4 Hz, H3), 3.43 (dd, 1H,
J4,3ZJ4,5Z8.4 Hz, H4), 3.40 (dd, 1H, J5,4Z8.4 Hz, J5,6
Z
4.10.3. (1S,2R,3R,4S)-6-(2-Hydroxyethylamino)-cyclo-
octane-1,2,3,4-tetrol (48). Isolated yield: 31% (unseparable
3:1 mixture of 6S:6R epimers); 1H NMR (D2O) d 3.88–3.50
Z
7.8 Hz, H5), 2.10 (dddd, 1H, J8a,1Z5.6 Hz, J8a,8bZ14.4 Hz,
J8a,7aZ13.0 Hz, J8a,7bZ2.8 Hz, H8a), 2.03–1.94 (m, 2H,
H2a,2b), 1.93 (dddd, 1H, J7a,6Z3.0 Hz, J7a,7bZ15.8 Hz,
J7a,8aZ13.0 Hz, J7a,8bZ3.4 Hz, H7a), 1.71 (dddd, 1H,
0
(m, 4H, H3,4,5,6), 3.50–3.30 (m, 1H, H2 ), 2.95–2.73 (m, 3H,
0
H1,1 ), 2.28–2.08 (m, 1H, H2a), 2.08–1.80 (m, 4H,
H2b,7a,7b,8a), 1.80–1.60 (m, 1H, H8b); 13C NMR (D2O) d
0
78.3, 77.4 (C4,5), 77.1, 76.6 (C3,6), 63.2 (C2 ), 57.3 (C1), 50.4
J7b,6Z7.1 Hz, J7b,7aZ15.8 Hz, J7b,8aZ2.8 Hz, J7b,8b
6.0 Hz, H7b), 1.44 (dddd, 1H, J8b,1Z9.4 Hz, J8b,8a
Z
Z
0
(C1 ), 39.1 (C7), 30.1, 29.4 (C1,8); HRMS for C10H22NO5
(MCC1): calcd 236.1498; found 236.1492.
14.4 Hz, J8b,7aZ3.4 Hz, J8b,7bZ6.0 Hz, H8b); 13C NMR
(D2O) d 77.1 (C4), 76.2 (C5,6), 75.7 (C3), 70.1 (C1), 42.4
(C2), 32.4 (C8), 29.4 (C7); HRMS for C8H17O5 (MCC1):
calcd 210.1341; found 210.1339.
Acknowledgements
We gratefully acknowledge Dr. G. Bertho (LCBPT) for his
expertise in NMR studies and Ms. C. Schuetz for the
enzymatic studies.
4.9.4. (1S,2R,3R,4S,6R)-Cyclooctane-1,2,3,4,6-pentol
(40). Isolated yield: 95%; [a]Hg C16 (c1.0, MeOH); H
1
NMR (D2O) d 4.20–4.06 (m, 1H, H1), 3.93–3.80 (m, 1H,
H3), 3.72–3.55 (m, 1H, H6), 3.60 (dd, 1H, J4,3ZJ4,5
Z
8.4 Hz, H4), 3.48 (dd, 1H, J5,4ZJ5,6Z8.4 Hz, H5), 2.16–
1.65 (m, 6H, H2a,2b,7a,7b,8a,8b); 13C NMR (D2O) d 77.0 (C4),
76.2 (C5), 75.9 (C6), 74.6 (C3), 68.8 (C1), 39.0 (C2), 32.0
(C7), 28.9 (C8); HRMS for C8H17O5 (MCC1): calcd
210.1341; found 210.1344.
References and notes
1. Varki, S. A. Glycobiology 1993, 3, 97–130.
2. Roth, J. Chem. Rev. 2002, 102, 285–303.
4.10. Deprotection of the aminocyclooctanols
3. Chrispeels, M.; Hindsgaul, O.; Paulson, J. C.; Lowe, J.; Manzi,
A.; Powell, L.; van Halbeek, H. In Essentials of Glycobiology;
Varki, A., Cummings, R., Esko, J., Freeze, H., Hart, G. G.,
Marth, J., Eds.; Cold Spring Harbor Laboratory: Cold Spring
Harbor, New York, 1999.
The substrate (0.43 mmol) was stirred in a 9:1 solution of
trifluoroacetic acid/H2O at 20 8C for 15 h. After concen-
tration in vacuo, the resulting oily residue was triturated in
diethyl ether and the supernatant was discarded to afford a
brownish solid which was then purified by ion-exchange
chromatography (Dowexw 50!8-100, 1% aqueous
ammonium hydroxide).
4. Puri, A.; Rawat, S. S.; Lin, H-M. J. ; Finnegan, C. M.;
Mikovits, J.; Ruscetti, F. W.; Blumenthal, R. AIDS 2004, 18,
849–858.
5. Feizi, T. In Earnst, B., Hart, G. W., Sinay, P., Eds.;
Glycobiology of AIDS in Carbohydrates in Chemistry and
Biology; Wiley-VCH Verlag GmbH: D-69469 Weinheim,
2000; 52, Chapter 52, pp 851–866.
4.10.1. (1R,2R,3R,4R)-6-(2-Hydroxyethylamino)-cyclo-
octane-1,2,3,4-tetrol (44). Isolated yield: 60% (unseparable
4:1 mixture of 6S:6R epimers); 1H NMR (D2O) d 4.30 (ddd,
1H, J3,2aZ8.6 Hz, J3,2bZJ3,4Z2.5 Hz, H3), 4.12 (ddd, 1H,
J6,5Z1.7 Hz, J6,7aZ5.5 Hz, J6,7bZ6.8 Hz, H6), 3.90 (dd,
6. Rudd, P. M.; Dwek, R. A. Crit. Rev. Biochem. Mol. Biol. 1997,
32, 1–100.
7. Van den Steen, P.; Rudd, P. M.; Dwek, R. A.; Opddenakker, G.
Crit. Rev. Biochem. Mol. Biol. 1998, 33, 151–208.
1H, J4,3Z2.5 Hz, J4,5Z7.7 Hz, H4), 3.83 (dd, 1H, J5,4
Z

O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
7103
8. Lis, H.; Sharon, N. Eur. J. Biochem. 1993, 218, 1–27.
9. Bill, R.; Revers, L.; Wilson, I. B. H. Protein Glycosylation;
Klumer Academic: Boston, 1998.
C. A. A.; van Boom, J. H. Org. Lett. 2001, 3, 731–733. (e)
McNulty, J.; Grunner, V.; Mao, J. Tetrahedron Lett. 2001, 42,
5609–5612. (f) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J. Org.
Chem. 2001, 66, 4094–4096. (g) Marco-Contelles, J.; de
10. Hirschberg, C. B.; Snider, M. D. Annu. Rev. Biochem. 1987,
56, 63–87.
´
Opazo, E. J. Org. Chem. 2002, 67, 3705–3717. (h) Bleriot, Y.;
11. Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985, 54,
631–664.
Giroult, A.; Mallet, J.-M.; Rodriguez, E.; Vogel, P.; Sinay¨, P.
Tetrahedron: Asymmetry 2002, 13, 2553–2565. (i) Mehta, G.;
Pallavi, K. Chem. Commun. 2002, 2828–2829. (j) Paquette,
L. A.; Zhang, Y. Org. Lett. 2005, 7, 511–513.
12. Lal, A.; Pang, P.; Kalelkar, S.; Romero, P. A.; Herscovics, A.;
Moremen, K. W. Glycobiology 1998, 8, 981–995 and ref. cited
therein.
28. Preliminary results (a): Gravier-Pelletier, C.; Andriuzzi, O.; Le
Merrer, Y. Tetrahedron Lett. 2002, 43, 245–248. b Andriuzzi,
O.; Gravier-Pelletier, C.; Le Merrer, Y. Tetrahedron Lett.
2004, 45, 8043–8046.
13. Marshall, J. J. Adv. Carbohydr. Chem. Biochem. 1974, 30,
257–370.
14. Schmidt, D. D.; Frommer, W.; Junge, B.; Mu¨ller, L.;
Wingender, W.; Truscheit, E.; Schefer, D. Naturwissenschaf-
ten 1977, 64, 535–536.
29. For recent reviews on olefin metathesis, see (a): Grubbs, R. H.
Tetrahedron 2004, 60, 7117–7140. (b) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18–29. (c) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
15. Truscheit, E.; Hillebrand, I.; Junge, B.; Mu¨ller, L.; Puls, W.;
Schmidt, D. Prog. Clin. Biochem. Med. 1988, 7, 17–23.
16. Treadway, J. L.; Mendys, P.; Hoover, D. J. Expert Opin Invest-
Drugs 2001, 10, 439–454.
30. For cyclooctene by RCM synthesis, see for example Ref. 11a,
b,e–h and: (a) : Bourgeois, D.; Pancrazi, A.; Ricard, L.; Prunet,
J. Angew. Chem., Int. Ed. 2000, 39, 725–728. (b) Krafft, M. E.;
Cheung, Y. Y.; Abboud, K. A. J. Org. Chem. 2001, 66,
7443–7448. (c) Kariuki, B. M.; Owton, W. M.; Percy, J. M.;
Pintat, S.; Smith, C. A.; Spencer, N. S.; Thomas, A. C.;
Watson, M. Chem. Commun. 2002, 228–229. (d) Michaut, A.;
17. Johnson, P. S.; Coniff, R. F.; Hoogwerf, B. J.; Santiago, J. V.;
Pi-Sunyer, F. X.; Krol, A. Diabetes Care 1994, 17, 20–29.
18. (a) Schoffling, K.; Hillebrand, I. Deutsche med. Wochenschrift
1981, 106, 1083–1084. (b) 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. Interm. Med. 1994, 121,
928–935.
´
Miranda-Garcia, S.; Menedez, J. C.; Rodriguez, J. Org. Lett.
2004, 6, 3075–3078. (e) Braddock, D. C.; Cansell, G.;
Hermitage, S. A.; White, A. J. P. Tetrahedron: Asymmetry
2004, 15, 3123–3129. (f) Michalak, K.; Michalak, M.; Wicha,
J. Tetrahedron Lett. 2005, 46, 1149–1153.
19. (a) Kobatake, T.; Matsuzawa, Y.; Tokunaga, K.; Fujioka, S.;
Kawamoto, T.; Keno, Y.; Inui, Y.; Odaka, H.; Matsuo, T.;
Tarui, S. Int. J. Obesity 1989, 13, 147–154. (b) Matsuo, T.;
Odaka, H.; Ikeda, H. Am. J. Clin. Nutr. 1992, 55, 3145–3175.
(c) Holman, R. R.; Cull, C. C.; Tyrner, R. C. Diabetes Care
1999, 22, 960–964.
31. Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am.
Chem. Soc. 1995, 117, 2108–2109.
´
32. Le Merrer, Y.; Dureault, A.; Greck, C.; Micas-Languin, D.;
Gravier, C.; Depezay, J.-C. Heterocycles 1987, 25, 541–547.
`
33. Saniere, M.; Le Merrer, Y.; Barbe, B.; Koscielniak, T.; Micas-
Languin, D.; Dumas, J.; Depezay, J.-C. Angew. Chem., Int. Ed.
Engl. 1989, 28, 614–616.
20. (a) Lembcke, B.; Folsch, U. R.; Creutzfeldt, W. Digestion
1985, 31, 120–127. (b) Hillebrand, I.; Boehme, K.; Graefe,
K. H.; Wehling, K. Klinische Wochenscrift 1985, 64, 393–396.
(c) Matsumoto, K.; Yano, M.; Miyake, S.; Ueki, Y.;
Yamaguchi, Y.; Akazawa, S.; Tominaga, Y. Diabetes Care
1998, 21, 256–260.
34. Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett.
1995, 36, 6887–6890.
21. (a) Stu¨tz, A. E. Iminosugars as Glycosidane Inhibitors; Wiley-
VCH: Weinheim, 1999. (b) Chapleur, Y. Carbohydrates
Mimics, Concepts and Methods; Wiley-VCH: Weinheim,
1998.
35. The low yield obtained for this reaction is due to competitive
O-cyclisation involving the alcoholate resulting from the
nucleophilic opening of a single epoxide moiety, see Ref. 34.
36. Riber, D.; Hazell, R.; Skrydstrup, T. J. Org. Chem. 2000, 65,
5382–5390.
22. Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev.
2002, 102, 515–553 and ref. cited therein.
37. Brown, J. M.; Kim, K.-W.; Cole, T. E.; Singaram, B. J. Am.
Chem. Soc 1986, 108, 6761–6763.
23. (a) Shibata, T.; Nakayama, O.; Tsurumi, Y.; Okuhara, M.;
Terano, H.; Kohsaka, M. J. Antibiot. 1988, 41, 296–301. (b)
Kayakiri, H.; Nakamura, K.; Takase, S.; Setoi, H.; Uchida, I.;
Terano, H.; Hashimoto, M.; Tada, T.; Koda, S. Chem. Pharm.
Bull. 1991, 39, 2807–2812. (c) Tsuji, E.; Muroi, M.;
Shiragami, N.; Takatsuki, A. Biochem. Biophys. Res.
Commun. 1996, 220, 459–466.
38. A modification of the diastereoselectivity was tentatively
carried out in the presence of bulky borane such as 9-BBN or
catechol borane, but revealed unsuccessful.
39. The NMR description are related to numbering of the
corresponding compounds 10 shown in Figure 2.
40. Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M.
Chem. Eur. J. 2000, 6, 1840–1846.
24. Chen, X.; Fan, Y.; Zheng, Y.; Chen, Y. Chem. Rev. 2003, 103,
1955–1977.
41. Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron
2002, 58, 1983–1995.
25. Mehta, G.; Ramesh, S. S. Chem. Commun. 2000, 2429–2430.
26. Gravier-Pelletier, C.; Maton, W.; Dintinger, T.; Tellier, C.; le
Merrer, Y. Tetrahedron 2003, 59, 8705–8720.
42. Jones, T. H.; Blum, M. S. Tetrahedron Lett. 1981, 22,
4373–4377.
27. For C8-cyclitols or analogs synthesis, see for example: (a):
Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651–2654. (b) Wang,
W.; Zhang, Y.; Sollogoub, M.; Sinay¨, P. Angew. Chem., Int.
Ed. 2000, 39, 2466–2467. (c) van Hooft, P. A. V.; van der
Marel, G. A.; van Boeckel, C. A. A.; van Boom, J. H.
Tetrahedron Lett. 2001, 42, 1769–1772. (d) van Hooft,
P. A. V.; Litjens, E. J. N.; van der Marel, G. A.; van Boeckel,
43. The bis-O-TBDMS-serinol was prepared from commercially
available serinol: TBDMSCl, Et3N, DMAP, CH2Cl2.
44. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 53, 2552–2554.
45. A known protocol was applied (a) : Saul, R.; Chambers, J. P.;
Molyneux, R. J.; Elbein, A. D. Arch. Biochem. Biophys. 1983,
221, 593–597. Brandi, A.; Cicchi, S.; Codero, F. M.; Frignoli,

7104
O. Andriuzzi et al. / Tetrahedron 61 (2005) 7094–7104
B.; Goti, A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60,
explained in: Gavier-Pelletier, C.; Maton, W.; Dintinger, I.;
Tellier, C.; Le Merrer, Y. Tetrahedron 2003, 59, 8705–8720.
47. Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou,
6806–6812. We verified that the delay of inhibitor/enzyme
incubation did not affect the inhibition measurements. Under
standard conditions optimal inhibitory activities were
measured after five minutes of incubation.
´
F.; Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2,
1259–1261.
46. For these enzymes, the biological tests have been carried out as