Total, asymmetric synthesis of methyl 3-deoxy-3-(1',2',6'-trideoxy- 2',6'-imino-D-galactitol-1-yl)-α-D-manno-pyranoside (A C-linked imino disaccharide): Conformational analysis and glycosidase inhibition

Article abstract of DOI:10.1055/s-1999-3645

The lithium enolate 16 derived in 5 steps from the Diels-Alder adduct of furan to 1-cyanovinyl (1S)-camphanate [(+)-12: a 'naked sugar' of the first generation] was reacted with (+)(1R, 4S,5S,6S)-6-endo-chloro-3-methylidene-5- exo-phenylseleno-7-oxabicyclo[2.2.1 ]heptan-2-one [(+)-8] to give a unique product of Michael addition after acidic quenching. This adduct (-)-18 was transformed into branched long-chain carbohydrate derivatives such as benzyl 5-deoxy-5-[(5'-O-acetyl-3'-deoxy-2'-O-methoxymethyl-D-manno-furanurono-6,1- lactone-3_-yl)methyl]-(tert- butyl)dimethylsilyl-2,3-di-O-methoxymethyl-α and β-L-gulo-furanosideuronate [(-)-27]. Hydrogenolysis, followed by a Curtius rearrangement permitted to construct the corresponding branched 5- amino-5,6-dideoxydodecose derivative (-)-30 which was converted into 5-O- acetyl-3-[5'-N-(benzyloxy)carbonyl-2',3'-di-O-methoxymethyl-α and β-D- manno-furanose]-2-O-methoxymethyl-D-manno-furanurono-6,1-lactone [(-)-31] and then into methyl 3-deoxy-3-(1',2',6'-trideoxy-2',6'-imino-D-galactitol-1'- yl)-α-D- manno-pyranoside [(-)-1]. Its ¹H NMR spectrum measured at variable temperature demonstrated that (-)-1 exist as a double equilibrium involving two pairs of rotamers about the σC(1')-C(2') and cvC(1')-C(3) bond [CH₂ bridge linking β-C(1) of the 1,5-dideoxy-1,5-imino-D-lyxitol unit at C(3) of methyl α-D-manno-pyranoside]. Rotamers B' in which C(3) is gauche with respect to C(3') is preferred to conformers C' in which C(3) is anti with respect to C(3'). An equilibrium constant K (B' = C') =- 0.35 (25 °C) was evaluated. Rotamers B [C(2) gauche with respect to C(2')] and C [C(2) anti with respect to C(2')] are equally populated. Disaccharide mimetic (-)-1 is a moderate inhibitor of α-L-fucosidases from bovine liver (K(i) = 100 μM) and human placenta.

Full text of DOI:10.1055/s-1999-3645

PAPER
1441
Total, Asymmetric Synthesis of Methyl 3-Deoxy-3-(1’,2’,6’-trideoxy-2’,6’-
imino-D-galactitol-1-yl)-a-D-manno-pyranoside (A C-Linked Imino
Disaccharide): Conformational Analysis and Glycosidase Inhibition1
Christian Marquis,a,b Sylviane Picasso,a Pierre Vogel*a
a Section de Chimie, Université de Lausanne, BCH, CH-1015 Lausanne-Dorigny, Switzerland
Fax +41(21)6923975; E-mail: pierre.vogel@ico.unil.ch
b Calbiochem-Novabiochem AG, Weidenmattweg 44, CH-4448 Läufelfingen, Switzerland
Received 10 March 1999
the C-linked imino disaccharides ("aza-C-disaccha-
rides")7,8 which contains not only the steric and charge in-
formation of the glycosyl moiety, which is liberated
during the enzyme-catalyzed hydrolysis, but also that of
Abstract: The lithium enolate 16 derived in 5 steps from the Diels–
Alder adduct of furan to 1-cyanovinyl (1S)-camphanate [(+)-12: a
"naked sugar" of the first generation] was reacted with (+)-
(1R,4S,5S,6S)-6-endo-chloro-3-methylidene-5-exo-phenylseleno-
7-oxabicyclo[2.2.1]heptan-2-one [(+)-8] to give a unique product of the aglycone to which the glycone is attached. The first
Michael addition after acidic quenching. This adduct (–)-18 was
transformed into branched long-chain carbohydrate derivatives
such as benzyl 5-deoxy-5-[(5"-O-acetyl-3"-deoxy-2"-O-meth-
through a CH2 unit] was prepared by Johnson and co-
oxymethyl-D-manno-furanurono-6,1-lactone-3"-yl)methyl]-(tert-
butyl)dimethylsilyl-2,3-di-O-methoxymethyl-a and b-L-gulo-fura-
nosideuronate [(–)-27]. Hydrogenolysis, followed by a Curtius rear-
rangement permitted to construct the corresponding branched 5-
amino-5,6-dideoxydodecose derivative (–)-30 which was converted
example of a C-linked imino disaccharide [1,5-dideoxy-
1,5-imino-D-mannitol linked at C(6) of D-galactose
workers.9 Other examples of "linear" C-linked imino dis-
accharides were obtained by the groups of Martin10 and
Van Boom.11 We have prepared the first examples of
"branched" disaccharides.1,7,12 Further examples were re-
ported by Johnson and coworkers8 and Zhu et al.13 We de-
scribe here the synthesis of a (1Æ3)-C-linked imino
disaccharide which links 1,5-dideoxy-1,5-imino-D-lyxitol
at C(3) of methyl a-D-manno-pyranoside [(–)-1]. This dis-
accharide mimetic was expected to imitate b-D-manno-
pyranosyl-(1Æ3)-b-D-manno-pyranosides (2) as well as
b-D-lyxo-pyranosyl-(1Æ3)-a-D-manno-pyranosides (3).
As we shall show, this "aza-C-disaccharide" is not an in-
hibitor of Helix pomatia b-mannosidase. It is a moderate
inhibitor a-L-fucosidase from bovine epididymis and
from human placenta. As very little is known about the
conformation about C-linked iminodisaccharide,12b we
into
5-O-acetyl-3-[5'-N-(benzyloxy)carbonyl-2',3'-di-O-meth-
oxymethyl-a and b-D-manno-furanose]-2-O-methoxymethyl-D-
manno-furanurono-6,1-lactone [(–)-31] and then into methyl
3-deoxy-3-(1',2',6'-trideoxy-2',6'-imino-D-galactitol-1'-yl)-a-D-
manno-pyranoside [(–)-1]. Its 1H NMR spectrum measured at vari-
able temperature demonstrated that (–)-1 exist as a double equilib-
rium involving two pairs of rotamers about the sC(1')–C(2') and
sC(1')–C(3) bond [CH2 bridge linking b-C(1) of the 1,5-dideoxy-
1,5-imino-D-lyxitol unit at C(3) of methyl a-D-manno-pyranoside].
Rotamers B’ in which C(3) is gauche with respect to C(3') is pre-
ferred to conformers C’ in which C(3) is anti with respect to C(3').
An equilibrium constant K (B’ = C’) @ 0.35 (25 °C) was evaluated.
Rotamers B [C(2) gauche with respect to C(2')] and C [C(2) anti
with respect to C(2')] are equally populated. Disaccharide mimetic
(–)-1 is a moderate inhibitor of a-L-fucosidases from bovine liver
(Ki = 100 mM) and human placenta.
1
have studied the effect of pH and temperature on the H
NMR spectrum of (–)-1. Our synthesis uses the "naked
sugar" methodology14 and it is highly stereoselective.
Key words: 5-amino-5,6-dideoxydodecose, branched long-chain
carbohydrates, a-L-fucosidase inhibitor, van't Hoff plot for rotam-
ers, "naked sugars", C-glycosides, trihydroxypiperidine, 7-oxabicy-
clo[2.2.1]heptyl derivatives
OH
OH
O
O
H
H
OH
OH
O
HO
HO
R
OMe
OR'
H
N
O
Introduction
OH
OH
OH
OH
HO
HO
The interaction between cell surface carbohydrates and
their protein receptors is implied in several important bio-
logical events.2 Carbohydrate mimetics are potential tools
to study the mechanisms of cellular interactions, the bio-
synthesis of glycoproteins, the catabolism of glycoconju-
gates,3 and the mechanisms of digestion.4 Inhibitors of
enzymes involved in these processes such as the glycosi-
dases and glycosyltransferases are potential antibacterial,
antiviral, antimetastatic, antidiabetes, antihyperglycemic,
antiadhesive, or immunostimulatory agents.5,6 A new
class of selective glycosidase inhibitors has emerged with
(-)-1
2 R = CH2OH
3 R = H
Retrosynthetic Analysis
Johnson et al.8,9 have used the Suzuki coupling of bromo-
conduramine derivatives with alkylboranes derived from
methylenehexopyranosides to generate the C-linker be-
tween two hexose subunits. Martin et al.10 have coupled a
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

1442
C. Marquis et al.
PAPER
protected
2,6-dideoxy-2,6-imino-1-iodoheptitol
to with (Me3Si)2NLi reacted with enone (+)-8 (THF, –70 °C)
giving an intermediate enolate 17 that was quenched with
1,2:3,4-O-di(isopropylidene)-a-D-galactodialdo-1,5-pyr-
anose with SmI2. On our part we have applied cross-al- a solution of MeOH/AcOH in THF at –78 °C. This fur-
dolization between enolates that are hexose precursors nished a single product (–)-18 (90%) the structure of
and 2,n-dideoxy-2,n-iminoaldoses12,13 or aldehydes that which was established by its spectral data and elemental
are then converted into the iminoalditol moiety.7 In this analyses. In particular, the absence of coupling between
report we present an alternative approach which relies on vicinal protons H-1' and H-2' confirmed the endo relative
the Michael addition between an 1,4-anhydro-5-deoxyu- configuration of the alkyl substituent at C(2').21 The ob-
3
ronolactone (Michael donor, e.g. 10) and a 3-meth- servation of J(H-4, H-5) = 6 Hz is consistent only with
ylidene-7-oxabicyclo[2.2.1]heptan-2-one
[Michael the relative exo configuration of the 4-alkyl substituent.
acceptor, e.g. (+)-8] as shown in Scheme 1. The amino The high double diastereoselectivity of the Michael addi-
function (as in 4) is introduced via a Curtius rearrange- tion (–)-15+(+)-8 Æ (–)-18 can be interpreted in terms of
ment exploiting the carboxylic moiety of uronolactone 6 steric factors that make the exo face of the uronolactone-
once it is converted into the corresponding uronic acid 5. derived enolate 16 more accessible than its endo face
This route is analogous to that used previously to prepare leading to the irreversible protonation of enolate 17
rare 5-aminohexoses15 and 5-aminooctoses16 starting which is favored on its exo face. When the Michael addi-
from enantiomerically pure 7-oxabicyclo[2.2.1]hept-5- tion was performed with racemic lactone ( )-15 [derived
en-2-yl derivatives17 ("naked sugars" of the first from ( )-19 (Scheme 1) and (+)-8], a 1:1 mixture of (–)-
generation14).
18 and 20 (85%) that could not be separated was obtained.
Reduction of ketone (–)-18 with NaBH4 was highly exo
face selective (steric factor) giving endo-alcohol 21 (91%)
which was not purified and used as such in the next step;
that is the oxidative elimination of the benzeneselenyl
group with metachloroperbenzoic acid, providing the 6-
chloro-7-oxabicyclo[2.2.1]hept-5-en-2-ol (–)-22 (86%).
Protection of the endo alcohol as a methoxymethyl ether
gave (–)-23 (89%). The same reaction sequence applied
to a 1:1 mixture of (–)-18 and 20 led to a 1:1 mixture of
(–)-23 and (–)-23b (Scheme 2). Uronolactone (–)-23b
could be isolated from that mixture by several recrystalli-
zations from CH2Cl2 and light petroleum in 16% yield.
Mother liquor delivered (–)-23 in 10% yield after three re-
crystallizations. Addition of lithium benzylate to urono-
lactone (–)-23 generates a mixture of a- and b-L-gulo-
furanose 24 which was silylated with (t-
Bu)Me2SiOSO2CF3 to give a 3:1 mixture of a- and b-fura-
noside (–)-25 (75%). Double hydroxylation (Me3NO,
OsO4, NaHCO3 THF/H2O 5:1) of the chloroalkene moiety
Synthesis
Enone (+)-8 was prepared as already described18 in three
steps from (–)-11, a Diels–Alder adduct of furan to 1'-cy-
anovinyl (1S, 5R, 7S)-3-ethyl-2-oxo-6,8-dioxa-3-azabicy-
clo[3.2.1]octane-7-exo-carboxylate.17b Epoxidation of
"naked sugar" (+)-12,17a followed by treatment with 70%
aqueous HClO4 in hexafluoroisopropanol provided (–)-
1319 in 60% yield. Acetalization of (+)-13 with
(MeO)2CH2/P2O5 in CH2Cl2, followed by methanolysis
with MeOH and DBU (recovery of the chiral auxiliary:
methyl camphanate) and treatment with (MeO)2CH2 and
P2O5 in CH2Cl2 gave ketone (+)-14 in 80% yield. Baeyer–
Villiger oxidation of (+)-14 with metachloroperbenzoic
acid and NaHCO3 was, as expected,14,20 highly regioselec-
tive, producing uronolactone (–)-15 (90%) (Scheme 2).
The lithium enolate 16 generated by treatment of (–)-15
Scheme 1
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conformational Analysis and Glycosidase Inhibition
1443
Scheme 2
of (–)-25 provided the corresponding exo-a-hydroxy ke- its 13C NMR spectrum which showed for its anomeric cen-
1
tones which were acetylated under standard conditions ter d(C-1) = 101.0 ppm and J(C, H) = 170 Hz, values
(Ac2O, Et3N, DMAP) to produce a 3:1 mixture of acetates quite similar to those [d(C-1) = 101.5 ppm, 1J (C,H) = 171
(–)-26 (97%). Baeyer–Villiger oxidation of (–)-26 with Hz] reported for methyl a-D-manno-pyranoside itself.23
metachloroperbenzoic acid and NaHCO3 gave the corre-
sponding uronolactones (–)-27 (80%). Debenzylation [H2,
Pd(OH)2/charcoal] liberated a mixture of uronic acids 28
which reacted with diphenyloxyphosphoryle azide and
triethylamine. This generated the corresponding acylazide
Conformational Analysis of C-Linked Imino Disac-
charide
29 which underwent a Curtius rearrangement. The inter- The coupling constants (Table 1) between vicinal protons
mediate isocyanates were quenched with benzyl alcohol demonstrate that both the methyl pyranoside and trihy-
to form the benzyl carbamate (–)-30 (85%, 3:1 mixture of droxypiperidine moieties of (–)-1 adopt chair conforma-
a- and b-furanosides). Desilylation of the silyl furano- tions (Scheme 3). They were confirmed by the 2D
sides (HF•pyridine) liberated a 3:1 mixture of anomeric NOESY 1H NMR spectrum of (–)-1 which showed strong
furanoses (–)-31 (90%). Hydrogenolysis [H2, Pd(OH)2/ NOE's between proton pairs indicated with curved arrows
charcoal] of the benzylcarbamate generated the primary in the structure (–)-1 shown in Scheme 3.
amine 32 which underwent intramolecular condensation
with the aldose moiety to form the imine 33. Hydrogena-
tion of 33 afforded (–)-34 (80%). Methanolysis of the
uronolactone unit of (–)-34 under acidic conditions
Table 1 Coupling Constants Between Vicinal Protons of (–)-1
Vicinal Protonsa
3JH,H (Hz)
(MeOH/SOCl222) produced (+)-35 which was reduced
(NaBH4/EtOH) to the targeted imino-C-disaccharide (–)-
1 in 61% (2 steps) (Scheme 3). Only the a-D-manno-pyr-
anoside was obtained under our conditions, no trace of
methyl b-D-manno-pyranoside or a- and b-D-manno-fura-
noside were detected in the 1H NMR spectrum of (–)-1.
He-1, He-2
He-2, Ha-3
Ha-3, Ha-4
Ha-4, He-5
Ha-2, He-3
He-3′, Ha-4′
Ha-4′, Ha-5′
Ha-5′, He-6′
Ha-5′, Ha-6′
1.4
2.9
11.3
8.4
1.3
3.2
9.7
5.4
10.8
The structures of all the new compounds presented above
were confirmed by their spectral data, including 2D NOE-
SY and COSY 90 or 45 1H NMR spectra. The methyl a-
D-manno-pyranoside structure of (–)-1 was indicated by
a He = H-equatorial, Ha = H-axial.
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

1444
C. Marquis et al.
PAPER
Scheme 3
A priori, (–)-1 could adopt three staggered conformations with temperature can be interpreted in terms of C’ being
about the s(C-1', C-2') bond designated by A’, B’ and C’. more populated at higher temperature than at lower tem-
Conformation A’ is expected to be the least populated, be- perature, indicating that C’ is slightly less stable than B’.
cause of gauche interactions between C-3/C-3' and C-3/ This finding is interesting because for other b C-glyco-
NH. Coupling constants of 3–4 Hz24 would be expected sides, Kishi and coworkers have reported that conformers
for conformer A’ between proton pairs Hb-1'/H-2' and Ha- of type C’ in which C(n)–C(1') and C(2')–C(3') are anti-
1'/H-2', what is quite different from the values observed periplanar are more stable than other conformers.24 This is
3
(Table 2). The coupling constants J(Ha-1', H-2') and also the case with a-D-GalpCH2(1Æ3)-a-D-ManOMe.25 If
3J(Hb-1', H-2') vary significantly with temperature (3.4- the NH unit and the alcoholic moieties at C-2 in conform-
85.2 °C, D2O+0.5% CD3OD). This indicates that (–)-1 ex- er B, or at C-4 in conformer C were forming hydrogen
ists as an equilibrium of conformers B’ = C’. The fact that bonds (see e.g. Scheme 3), the “standard” conformation
3
3J(Hb-1', H-2') increases while J(Ha-1', H-2') decreases C’ would have been expected to be made more stable than
Table 2 Selected 1H NMR Data of (–)-1 as a Function of Temperature
Temp.
(°C)
d,a) J (Hz)b
Ha-1
Hb-1'
Ha-1',Hb-1'
Ha-1',H-2'
Hb-1',H-2'
Ha-1',H-3
Hb-1',H-3
3.4
20
38.8
62.2
85.2
1.84
1.82
1.82
1.80
1.79
1.70
1.71
1.72
1.73
1.73
14.6
14.6
14.7
14.7
14.8
10.1
9.9
9.8
9.6
9.4
3.0
3.2
3.3
3.5
3.7
6.1
6.0
6.0
6.0
6.0
6.9
6.7
6.7
6.6
6.6
a Relative to internal CD2HOD (d = 3.43, at all temperatures).
b
0.1 Hz.
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

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Conformational Analysis and Glycosidase Inhibition
1445
Table 3 Estimated Equilibrium Constants K'(B’ = C’) and K(B = C)
H
H
H
Ha
C(3)
HO
Hb
Ha
C(3)
NH
as a Function of Temperature
Hb
3'
2'
HO
HO
HO
HO
K' ≈ 0.35
K'>>1
NH
NH
Temp. (K)
K' (B’ = C’)a
K(B = C)b
3'
C(3)
Ha
Hb
(25oC)
6'
4'
HO
276.5
293.1
311.8
335.2
358.2
0.297 ± 0.013
0.323 ± 0.014
0.337 ± 0.014
0.364 ± 0.015
0.394 ± 0.016
0.884 ± 0.036
0.895 ± 0.037
0.895 ± 0.037
0.909 ± 0.038
0.909 ± 0.038
5'
OH
OH
OH
C' ("anti")
A'
B'
a Given by Jobs(Hb-1', H-2')/Jobs(Ha-1', H-2').
b Given by Jobs(Ha-1', H-3)/Jobs(Hb-1', H-3).
B’ in which such hydrogen bonds are not possible. Our re-
sults therefore demonstrate that more subtle interactions
than interglycosidic hydrogen bridging intervene and
make conformer B’ more stable than C’.
van't Hoff plot of the values reported for K' (B’ = C’) led
to = +0.7 kcal/mol 0.1 kcal/mol and
@ 0. calK–1mol–1 (Figure 1).
∆H (B’= C’)
r
Dissacharide mimetic (–)-1 can adopt three conforma-
tions around s(C-1',C-3) bond designated by A, B and C.
Again for steric reasons conformer A is expected to be the
less populated. The observed coupling constants 3J(Ha-1',
H-3) = 6.0 0.1 Hz and 3J(Hb-1', H-3) = 6.7 0.2 Hz (Ta-
ble 2) are not consistent with conformation A as lower
values would have been expected (3–4 Hz24) for these
coupling constants. The fact that the observed coupling
constants are similar and do not vary significantly with
temperature suggests that conformations B and C are
equally populated (equilibrium constant K @ 1 for equilib-
rium B = C). These findings are consistent with the 2D
NOESY 1H NMR spectrum of (–)-1 that showed a strong
NOE between proton pair H-2' and H-3, on the one hand,
and a weaker NOE between proton pair Hb-1' and H-2, on
the other hand. A NOE is also observed between Ha-1' and
H-4.
∆S (B’= C’)
r
H
OH
O
MeO
H
Hb
2
Ha
4
1'
H
5
OH
Ha
HO
OH
K>>1
HO
Hb
Figure 1 van’t Hoff plot of lnK’(B’ = C’)
1
O
4
2
K
1
Ha
Hb
C(2')
O
H
5
1
OMe
MeO
We have measured the 1H NMR spectrum of (–)-1 in D2O
as a function of pH. at 40 °C, a pKa value of 7.4 has been
evaluated (Figure 2).
6
H
C(2')
(2')C
OH
OH
OH
OH
C
A
B
Equilibrium constant K' (A’ = B’) can be calculated by
K' = (Jav – DJ)/(Jav+DJ) where Jav = the average coupling
constant observed for J(Ha-1', H-2') = ½(3J(Ha-1',
H-2')+3J(Hb-1', H-2') = 6.55 Hz and DJ the difference be-
tween Jav and the observed coupling constant 3J(Ha-1', H-
3
2') or J(Hb-1', H-2'). This implies that in conformer B’
3J(Ha-1', H-2') = 3J(Hb-1', H-2) of conformer C’, and that
3J(Hb-1', H-2') for B’ equals 3J(Ha-1',H-2') in C’. For equi-
3
librium B’ = C’, Jobs for J(Ha-1', H-2') = Jav+DJ and Jobs
for 3J(Hb-1', H-2') = Jav – DJ. This allows one to evaluate
the equilibrium constants K' (B’ = C’) shown in Table 3.
The same calculation method applied to equilibrium K
(B = C) leads to the values reported for B = C shown in
Table 3.
Figure 2 Chemical shift of Hb-C(6') of (–)-1 in D2O+0.5% vol.
CD3OD at 40 °C as a function of pH.
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

1446
C. Marquis et al.
PAPER
(–)-1 capable to inhibit b-mannosidase from Helix poma-
tia or other glycosidases.
Enzymatic Assays
1
Compound (–)-1 was tested for its inhibitory activity to-
ward two a-L-fucosidases (from bovine epididymis, hu-
General: see Ref. 7b): 600 MHz H NMR spectra: Bruker AMX-
600 FT. Optical rotations at different wavelengths were recorded at
man placenta), three a-galactosidases (from coffee bean, 25 °C. Flash chromatography (FC) was carried out on silica gel
Merck No 9385, 240–400 mesh. Light petroleum refers to the frac-
Aspergillus niger, Escherichia coli), five b-galactosidases
tion boiling at 40-60 °C. Enzymatic Assays: see Refs 27 and 29.
(bovine liver, E. coli, Aspergillus niger, Aspergillus
orizae, jack bean), three a-glucosidases (maltases from
(+)-(1R,4R,5R,6S)-5-exo,6-endo-Bis(methoxymethoxy)-7-
yeast, from rice, isomaltase from baker yeast), two amy-
oxabicyclo[2.2.1]heptan-2-one [(+)-14]
loglucosidases (from Aspergillus niger, Rhizopus mold,
two b-glucosidases (from almond, caldocellum saccharo-
lyticum), two a-mannosidases (from jack bean, almond),
one b-mannosidase (from Helix pomatia), one b-xylosi-
dase (from Aspergillus niger), one a-N-acetylgalac-
tosaminidase (from chicken liver), three b-N-acetyl-
glucosaminidases (from jack bean, bovine epididymis A
and B). At 1 mM concentration of (–)-1 and under optimal
pH conditions27 no inhibition was observed exept for a-L-
fucosidase from bovine liver (78% inhibition, Ki = 100
mM) and a-L-fucosidase from human placenta (58% inhi-
bition, Ki not evaluated).
P4O10 (9 g) was added portionwise to a stirred mixture of (–)-1319
(2.91 g, 15.66 mmol), dimethoxymethane (60 mL) and CH2Cl2 (60
mL). After stirring at 20 °C for 10 min the solution was filtered and
the residue rinsed with CH2Cl2 (600 mL). The solution was washed
with aq satd NaHCO3 solution (100 mL) and brine (100 mL). After
drying (MgSO4) the solvent was evaporated, the residue taken in
MeOH (10 mL) and DBU (1.32 mL, 8.25 mmol) was added. After
stirring at 20 °C for 10 min the solvent was evaporated to dryness in
vacuo. The residue was dissolved in CH2Cl2 (45 mL) and
dimethoxymethane (45 mL). To this solution was added P4O10 (7.5
g) portionwise under stirring. After 10 min at 20 °C, the mixture
was filtered and the precipitate rinsed with CH2Cl2 (600 mL). The
organic phases were united and washed with aq satd NaHCO3 solu-
tion (100 mL) and with brine (100 mL). After drying (MgSO4), the
solvent was evaporated and the residue purified by FC (1:1 EtOAc/
light petroleum); yield: 2.90 g (80%); colorless oil; [a]25589+5.7,
[a]25577+6.3, [a]25546+8.0, [a]25435+16.8, [a]25405+22.0 (c = 1.0,
CHCl3).
Because the iminosugar moiety of (–)-1 has the absolute
configuration of a b-D-manno-pyranoside we could ex-
pect some inhibition of a b-D-mannosidase. The fact the
b-D-mannosidase form Helix pomatia is not inhibited sug-
gests that this enzyme recognizes a different disaccharide
than b-D-Manp(1Æ3)-mannosides. It should be men-
tioned here that other C-linked imino disaccharides such
as b-D-azaManp-CH2-(1Æ6)-D-Gal, b-D-azaManp-CH2-
(1Æ6)-a-D-Man-OMe, b-D-azaManp-CH2-(1Æ6)-a-D-
UV (MeCN): lmax (e) = 191 nm (1000).
IR (film): n = 2935, 1765, 1555, 1470, 1405, 1215, 1045, 785, 705
cm–1.
1H NMR (CDCl3): d = 4.79–4.77 (m, H-6), 4.78, 4.74 (2 d, AB,
JAB = 7.0 Hz, CH3 OCH2O), 4.68, 4.64 (2 d, AB, JAB = 6.8 Hz,
CH3OCH2O), 4.38 (br d, J1,6 = 5.6 Hz, H-1), 4.16 (ddd, J3exo,4 = 6.5
Hz, J4,5 = 1.2 Hz, J1,4 = 1.2 Hz, H-4), 3.94 (d, J4,5 = 1.2 Hz, H-5),
3.43, 3.39 (2 s, CH3O), 2.52 (ddd, J = 17.7 Hz, J3exo,4 = 6.5 Hz,
Glcp-OMe,
b-D-azaManp-CH2-(1Æ4)-a-D-Talp-OMe
and b-D-azaManp-CH2-(1Æ1)-b-D-Glcp are not inhibi-
tors of mannosidases.8 It is also known that simple alkyl
substitution of 1-deoxymannonojirimycin at C-1 renders
this iminoalditol ignorant of mannosidases.28 The inhibi-
tion observed with the a-L-fucosidases is not a surprise
since the iminosugar moiety of (–)-1 has the same config-
uration as L-fuco-pyranose.
J1,3exo = 1.8 Hz, Hexo-3), 2.10 (d, J = 17.7 Hz, Hendo-3).
13C NMR (CDCl3): d = 207.1 (s, C-2), 96.6, 95.6 (2 t, J = 163 Hz, 2
CH3OCH2O), 83.1 (d, J = 150 Hz, C-1), 81.0, 80.6, 80.2 (3 d,
J = 157, 164, 167 Hz, C-4, C-5, C-6), 56.0, 55.6 (2 q, J = 143 Hz, 2
CH3O), 39.1 (t, J = 135 Hz, C-3).
CI-MS (NH3): m/z = 250 (15, [M+NH3]+), 232 (100, M+), 210 (22),
173 (32), 141 (42), 129 (83), 98 (24), 97 (73), 81 (42), 71 (27).
Anal. Calc. for C10H16O6 (232.2): C, 51,72; H, 6.94. Found C,
51.80; H, 6.92.
Conclusion
A new approach to the total synthesis of C-glycosides,
C-disaccharides and imino-C-linked disaccharide using
the "naked sugar" methodology has been developed. It ex-
ploits the high stereoselectivity of the Michael addition of
the lithium enolate of a 1,4-anhydro-5-dideoxyhexou-
(–)-(1S,5R,6R,7S)-6-exo,7-endo-Bis(methoxymethoxy)-2,8-diox-
abicyclo[3.2.1]octan-3-one [(–)-15]
A mixture of (+)-14 (2.22 g, 9.6 mmol), CHCl3 (96 mL), NaHCO3
(1.93 g, 23.0 mmol) and metachloroperbenzoic acid (Fluka, 80%,
2.33 g, 10.6 mmol) was stirred at 20 °C for 16 h. The precipitate was
filtered off and the solution concentrated in vacuo. EtOAc (300 mL)
was added and the solution washed successively with H2O (50 mL),
aq 5% Na2CO3 solution (50 mL) and brine (30 mL). After drying
(MgSO4), the solvent was evaporated and the residue purified by FC
(1:1 EtOAc/light petroleum); yield: 2.3 g (90%); colorless oil which
crystallized from 10:1:40 CH2Cl2/EtOAc/light petroleum; mp 36–
rono-1,6-lactone to
a
3-methylidene-7-oxabicyc-
lo[2.2.1]heptan-2-one derivative. The uronic moiety can
be converted into an amino group with retention of con-
figuration via a Curtius rearrangement. The branched
chain amino sugar so-obtained can be converted into a C-
linked imino disaccharide, i.e.: methyl 3-deoxy-3-(1',2',6'-
trideoxy-2',6'-imino-D-galactitol-1-yl)-a-D-manno-pyra-
noside. Its "imino sugar" part has the absolute configura-
tion of L-fuco-pyranose thus making this compound an
inhibitor of a-L-fucosidases. It has also the same configu-
ration of b-D-manno-pyranosides but this does not make
37 °C; [a]589 –65.0, [a]577 –67.0, [a]546 –76.0, [a]435 –134.0, [a]405
163.0 (c = 1.0, CHCl3).
–
UV (MeCN): lmax (e) = 202 (1000), 193 nm (600).
IR (film): n = 2935, 2835, 1745, 1480, 1370, 1330, 1210, 1155,
1110, 1090, 1040, 1005, 975, 915, 860, 790, 745, 685, 610, 590, 555
cm–1.
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conformational Analysis and Glycosidase Inhibition
1447
1H NMR (CDCl3): d = 5.85 (dd, J1,7 = 4.2 Hz, J = 0.7 Hz, H-1),
4.71, 4.69, 4.64, 4.63 (4 d, 2 AB, JAB = 6.9, 6.8 Hz, 2 CH3OCH2O),
4.55 (dd, J4exo,5 = 6.9 Hz, J5.7 = 1.1 Hz, H-5), 4.26 (ddd, J1.7 = 4.2 Hz,
J6.7 = 1.9 Hz, J5,7 = 1.1 Hz, H-7), 4.00 (d, J6.7 = 1.9 Hz, H-6), 3.39,
3.36 (2 s, 2 CH2OCH2O), 3.07 (dd, J = 18.3 Hz, J4exo,5 = 6.9 Hz,
Hexo-4), 2.58 (d, J = 18.3 Hz, Hendo-4).
13C NMR (CDCl3): d = 165.0 (s, C-3), 100.1 (d, J = 185 Hz, C-1),
96.8, 96.1 (2 t, J = 165 Hz, 2 CH2OCH2O), 85.7 (d, J = 150 Hz, C-
5), 83.6 (d, J = 150 Hz, C-7), 78.3 (d, J = 160 Hz, C-6), 56.3, 55.8
(2 q, J = 143 Hz, 2 CH3O), 36.1 (t, J = 132 Hz, C-4).
Anal. Calc. for C23H27ClO9Se (561.9): C, 49.17; H, 4.84; Cl, 6.31;
Se 14.05. Found C, 40.02; H, 4.65; Cl 6.30; Se, 13.98
Mixture of (–)-18 and 5-Deoxy-5-{(1''S,2''S,4''R,5''S,6''S)-[5''-
endo-chloro-6''-exo-phenylseleno-3''-oxo-7''-oxabicyc-
lo[2.2.1]hept-2''-endo-yl]methyl}-2,3-di-O-methoxymethyl-D-
gulo-furanurono-6,1-lactone (20)
Same procedure as for the preparation of (–)-18 was used starting
from ( )-15, obtained from ( )-(1RS, 4RS, 5RS, 6SR)-6-endo-ace-
toxy-5-exo-methoxymethoxy-7-oxabicyclo[2.2.1]heptan-2-one,19
instead of (–)-15. FC (2:3 EtOAc/light petroleum); yield:1.57 g
(85%); 1:1 mixture of (–)-18 and 20 that could not separated by fur-
ther FC; colorless foam.
CI-MS (NH3): m/z = 267 (100, [M+19]+), 266 (100, [M+NH3]+),
250 (13, (M+2]+), 249 (14, [M+1]+), 248 (3, M+, 223 (2), 222 (3),
186 (3), 187 (10).
Compound 20
Anal. Calc. for C10H16O7 (248.2): C, 48.39; H, 6.50. Found C,
48.46; H, 6.47.
1H NMR (CDCl3): d = 7.71–7.65 (m, 2Harom), 7.37–7.25 (m,
3Harom), 5.81 (dd, J1,2 = 3.8 Hz, J1,4 = 0.9 Hz, H-1), 5.00 (br. d,
J
1’’,2’’ = 5.9 Hz, H-1''), 4.73, 4.72, 4.70, 4.68 (4 d, 2 AB, JAB = 7.0, 6.9
Hz, 2 CH3OCH2O), 4.47 (d, J4’’,5’’ = 5.9 Hz, H-4''), 4.32 (dd,
4’’,5’’ = 5.9 Hz, J5’’,6’’ = 3.1 Hz, H-5''), 4.27 (br s, H-4), 4.22 (ddd,
(–)-5-Deoxy-5-{(1''S,2''S,4''R,5''S,6''S)-[5''-endo-chloro-6''-
exo-phenylseleno-3''-oxo-7''-oxabicyclo[2.2.1]hept-2''-endo-
yl]methyl}-2,3-di-O-methoxymethyl-L-gulo-furanurono-6,1-
lactone [(–)-18]
J
J1,2 = 3.8 Hz, J2,3 = 2.1 Hz, J2,4 = 0.9 Hz, H-2), 3.88 (d, J2,3 = 2.1 Hz,
H-3), 3.57 (d, J5’’,6’’ = 3.1 Hz, H-6''), 3.43, 3.40 (2 s, 2 CH3O), 2.88
(ddd, J1’a,2’= 6.4 Hz, J1’b,2’’ = 6.4 Hz, J1’’,2’’ = 5.9 Hz, H-2''), 2.31 (m,
H-5, Ha-1'), 1.81 (m, Hb-1').
13C NMR (CDCl3): d = 206.3 (s, C-3''), 167.0 (s, C-6), 135.3, 129.5,
128.1 (3 d, J = 167, 161, 159 Hz, Carom), 128.0 (s, Carom), 100.5 (d,
J = 186 Hz, C-1), 96.9, 96.6 (2 t, J = 165 Hz, 2 CH3OCH2O), 85.7
(d, J = 155 Hz, C-2), 85.5 (d, J = 180 Hz, C-1''), 85.3 (d, J = 161 Hz,
C-4''), 83.4 (d, J = 165 Hz, C-3), 82.5 (d, J = 160 Hz, C-4), 58.3 (d,
J = 147 Hz, C-5''), 56.4, 55.9 (2 q, J = 143 Hz, 2 CH3O), 50.6 (d,
J = 134 Hz, C-2''), 46.5 (d, J = 153 Hz, C-6''), 44.3 (d, J = 133 Hz,
C-5), 28.6 (t, J = 130, C-1').
BuLi (1.5 M in hexane, 3.08 mL, 4.6 mmol) was added dropwise to
a stirred solution of anhyd hexamethyldisilazane (1.24 mL, 7.2
mmol, freshly distilled from CaH2) in anhyd THF (7 mL) at –10 °C
under Ar. After stirring at –10 °C for 15 min the mixture was cooled
to –78 °C and a solution of (–)-15 (1.04 g, 4.20 mmol) in anhyd
THF (7 mL) was added slowly in 30 min. After stirring at –78 °C
for 40 min, a solution of (+)-8,18 (1.30 g, 4.20 mmol) in anhyd THF
(7 mL) was added slowly over 40 min at –78 °C under Ar. After stir-
ring at –78 °C for 30 more min, the mixture was cannulated into a
solution of AcOH (2.38 mL, 42 mmol) in MeOH (20 mL) at –78 °C.
After slow warming to 20 °C, CH2Cl2 (100 mL) was added and the
solution was washed with aq satd NaHCO3 solution (40 mL) and
brine (20 mL). After drying (MgSO4), the solvent was evaporated
and the residue purified by FC (2:3 EtOAc/light petroleum);
(–)-5-Deoxy-5-{(1''S,2''S,3''S,4''R)-[5''-chloro-3''-endo-hy-
droxy-7-oxabicyclo[2.2.1]hept-5''-en-2''-endo-yl]methyl}-2,3-
di-O-methoxymethyl-L-gulo-furanurono-6,1-lactone [(–)-22]
NaBH4 (263 mg, 6.95 mmol) was added portionwise to a stirred so-
lution of (–)-18 (1.3 g, 2.32 mmol) in THF (11.6 mL) and MeOH
(11.6 mL) at 0 °C. After stirring at 0 °C for 15 min, CH2Cl2 (100
mL), then actone (2 mL) were added together with ice (20 g), then
brine (22 mL) and 1 N HCl (3 mL) were added. After shaking for
10 min, the organic phase was collected, the aq layer extracted with
CH2Cl2 (3 ´ 100 mL) and the combined org. extracts were washed
with brine (40 mL). After drying (MgSO4), the solvent was evapo-
rated; the residue was taken in anhyd CH2Cl2 (46 mL) and anhyd
THF (24 mL). After cooling to –78 °C, a solution of metachloro-
perbenzoic acid (80%, 595 mg) in anhyd CH2Cl2 (24 mL) was add-
ed dropwise over 20 min under stirring. After stirring at –78 °C for
80 min and at 20 °C for 2 h, CH2Cl2 (60 mL) was added. The organ-
ic phase was washed with aq satd NaHCO3 solution (50 mL) and
brine (40 mL). After drying (MgSO4), the solvent was evaporated in
vacuo and the residue purified by FC (3:2 EtOAc/light petroleum);
yield:851 mg (86%); colorless oil which was used as such in the
next step; [a]589 –58.0, [a]577 –61.0, [a]546 –70.0, [a]435 –124.0,
[a]405 –151.0 (c = 0.6, CHCl3).
yield:2.08 g (90%); white foam; [a]589 –32.0, [a]577 –33.0, [a]546
38.0, [a]435 –68.0, [a]405 –84.0 (c = 2.4, CHCl3).
–
UV (MeCN): lmax (e) = 217 (8800), 207 nm (9100).
IR (KBr): n = 2950, 1765, 1440, 1370, 1205, 1115, 1110, 1045,
740, 695 cm–1.
1H NMR (CDCl3): d = 7.67–7.65 (m, 2Harom), 7.37–7.32 (m,
3Harom), 5.74 (dd, J1,2 = 3.4 Hz, J1,4 = 0.5 Hz, H-1), 4.68 (d,
J1’’,2’’ = 6.0 Hz, H-1''), 4.72, 4.69 (2 d, AB, JAB = 6.1 Hz,
CH3OCH2O), 4.68 (s, 2H, CH3OCH2O), 4.51 (d, J4’’,5’’ = 5.9 Hz, H-
4''), 4.29 (dd, J4’’,5’’ = 5.9 Hz, J5’’,6’’ = 3.3 Hz, H-5''), 4.27 (br s, H-4),
4.18 (dd, J1,2 = 3.4 Hz, J2,3 = 2.5 Hz, H-2), 3.78 (d, J2,3 = 2.5 Hz, H-
3), 3.61 (d, J5’’,6’’ = 3.3 Hz, H-6''), 3.44, 3.38 (2 s, 2 CH3O), 2.92 (br.
ddd, J1’a,2’’ = 7.2 Hz, J1’b,2’’ = 7.2 Hz, J1’’,2’’ = 6.0, H-2''), 2.54 (t,
J1’a,5 = 7.3 Hz, J1’b,5 = 7.3 Hz, H-5), 2.14 (ddd, J = 14.4 Hz,
J1’a,5 = 7.3 Hz, J1’a,2’’ = 7.2 Hz, Ha-1'), 1.87 (ddd, J = 14.4 Hz,
J1’b,5 = 7.3 Hz, J1’b,2’’ = 7.2 Hz, Hb-1).
13C NMR (CDCl3): d = 207.1 (s, C-3''), 168.1 (s, C-6), 135.6, 130.3,
129.3 (3 d, J = 162, 162, 165 Hz, 5 Carom), 128.7 (s, Carom), 101.1 (d,
J = 194 Hz, C-1), 97.6, 97.2 (2 t, J = 164 Hz, 2 CH3OCH2O), 86.3
(d, J = 153 Hz, C-2), 86.0 (d, J = 177 Hz, C-1''), 84.1 (d, J = 160 Hz,
C-4''), 84.0 (d, J = 164 Hz, C-3), 83.0 (d, J = 159 Hz, C-4), 58.7 (d,
J = 166 Hz, C-5''), 57.0, 56.6 (2 q, J = 142, 143 Hz, 2 CH3O), 51.2
(d, J = 134 Hz, C-2''), 47.0 (d, J = 151 Hz, C-6''), 46.0 (d, J = 132
Hz, C-5), 29.5 (t, J = 131 Hz, C-1').
1H NMR (CDCl3): d = 6.31 (d, J1’’,6’’ = 1.9 Hz, H-6''), 5.81 (d,
J1,2 = 4.0 Hz, H-1), 4.91 (dd, J1’’,2’’ = 4.3 Hz, J1’’,6’’ = 1.9 Hz, H-1''),
4.76-4.68 (m, 5H, H-4'', 2 CH3OCH2O), 4.63 (m, H-3''), 4.37 (br s,
H-4), 4.22 (dd, J1,2 = 4.0 Hz, J2,3 = 2.3 Hz, H-2), 3.95 (d, J2,3 = 2.3
Hz, H-3), 3.44, 3.41 (2 s, 2 CH3O), 2.67 (t, J1’a,5 = J1’b,5 = 6.9 Hz, H-
5), 2.50–2.44 (m, H-2'), 1.97–1.55 (m, H2-1'), 1.76 (br s, HO-2'').
13C NMR (CDCl3): d = 168.7 (s, C-6), 138.2 (s, C-5''), 128.9 (d,
J = 179 Hz, C-6''), 100.4 (2 d, J = 185 Hz, C-1, C-1''), 96.9, 96.4 (2
t, J = 164 Hz, 2 CH3 OCH2O), 85.8, 83.7, 83.2, 82.8, 70.0 (5 d,
J = 149, 161, 160, 160, 156 Hz, C-2, C-3, C-4, C-3'', C-4''), 56.3,
CI-MS (NH3): m/z = 584 (36), 582 (46), 581 (21), 580 (56,
[M+NH3]+), 578 (32), 563 (12, [M+1]+), 562 (8, M+), 560 (28), 411
(15), 388 (66), 328 (10), 326 (20), 314 (8), 311 (9), 293 (11), 279
(8), 266 (19), 164 (20), 158 (17), 157 (27), 156 (15), 155 (29), 154
(23), 121 (22), 93 (24), 91 (30), 78 (100), 77 (20).
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

1448
C. Marquis et al.
PAPER
55.9 (2 q, J = 143, 142 Hz, 2 CH3O), 45.9, 40.2 (2 d, J = 131, 128
Hz, C-5, C-2’’), 29.5 (t, J = 132 Hz, C-1’).
CI-MS (NH3): m/z = 424 (37, [M+NH3]+), 407 (48, M+), 389 (22),
377 (12), 375 (31), 331 (11), 283 (6), 227 (19), 102 (100), 731 (22).
UV (MeCN): lmax (e) = 209 nm (950).
IR (film): n = 3475, 2995, 2955, 2935, 2855, 1750, 1685, 1655,
1635, 1465, 1445, 1380, 1310, 1255, 1210, 1185, 1160, 1120, 1105,
1080, 990, 970, 940, 920, 910, 880, 865, 825, 785, 770, 755, 725,
710, 620 cm–1.
1H NMR (CDCl3): d = 6.30 (d, J1'',6'' = 2.0 Hz, H-6’’), 5.80 (dd,
J1,2 = 4.0 Hz, J = 0.8 Hz, H-1), 4.95 (ddd, J1'',2'' = 4.3 Hz, J1'',6'' = 2.0
Hz, J = 0.9 Hz, H-1''), 4.77–4.61 (m, 7H, H-4'', 3 CH3CH2O), 4.35
(dd, J2’’,3’’ = 8.4 Hz, J3’’,4’’ = 4.4 Hz, H-3''), 4.31 (s, H-4), 4.22 (ddd,
Anal. Calc. for C17H23ClO9 (406.8): C, 50.19; H, 5.70; Cl 8.71.
Found C, 50.07; H, 5.70; Cl, 8.84.
(–)-5-Deoxy-5-{(1''S,2''S,3''S,4''R)-[5''-chloro-3''-endo-meth-
oxymethoxy-7-–oxabicyclo[2.2.1]hept-5''-en-2''-endo-yl]meth-
yl}-2,3-di-O-methoxymethyl-L-gulo-furanurono-6,1-lactone
[(–)-23]
J1,2 = 4.0 Hz, J2,3 = 2.3 Hz, J = 0.9 Hz, H-2), 3.94 (d, J2,3 = 2.3 Hz,
H-3), 3.44, 3.43, 3.41 (3 s, 3 CH3O), 2.62–2.51 (m, H-2'', H-5),
1.98–1.93 (m, Ha-1'), 1.62–1.53 (m, Hb-1').
CI-MS (NH3): m/z = 451 (8, M+), 391 (6), 389 (16), 271 (10), 240
(12), 227 (12), 197 (11), 148 (14), 104 (38), 103 (11), 102 (100), 75
(18), 73 (25).
(i-Pr)2NEt (4.2 mL, 24.6 mmol), then MeOCH2Cl (1.41 mL, 18.5
mmol) were added to a stirred solution of (–)-22 (500 mg, 1.23
mmol) in anhyd CH2Cl2 (4.2 mL) cooled to 0 °C under Ar. After
stirring at 20 °C for 48 h, an additional amount of MeOCH2Cl (0.47
mL, 6.15 mmol) was added and the mixture stirred for 4 h [TLC
control, 1:1 EtOAc/light petroleum, Rf 0.2]. CH2Cl2 (120 mL) was
added and the solution washed with aq satd NaHCO3 solution (20
mL) and brine (15 mL). After drying (MgSO4) the solvent was
evaporated in vacuo and the residue purified by FC (1:1 EtOAc/
light petroleum); yield:495 mg (89%); white solid; mp 113.5–
115 °C; [a]589 –86.0, [a]577 –90.0, [a]546–104.0, [a]435 –180.0, [a]405
–219.0 (c = 1, CHCl3).
Anal. Calc. for C19H27ClO (450.9): C, 50.62; H, 6.04; Cl, 7.86.
Found C, 50.70; H, 6.02; Cl, 7.90.
Mixture of Benzyl 5-Deoxy-5-{(1’’S,2’’S,3’’S,4’’R)-[5’’-chloro-
3’’-endo-methoxymethoxy-7-oxabicyclo[2.2.1]hept-5’’-en-2’’-
endo-yl]methyl}-[(tert-butyl)dimethylsilyl)-2,3-di-O-meth-
oxymethyl-a- and b-L-gulo-furanosiduronate [(–)-25]
BuLi (1.44 M in hexane, 0.91 mL, 1.31 mmol) was added dropwise
to a stirred solution of benzyl alcohol (freshly distilled from CaO,
0.226 mL, 2.18 mmol) in anhyd THF (13 mL) cooled to 0 °C under
Ar. After stirring at 0 °C, a solution of (–)-23 (494 mg, 1.09 mmol)
in anhyd THF (12 mL) was added over 10 min. After stirring at 0 °C
for 6.5 h the cooling bath was removed and the mixture stirred for
another 15 min. THF (12.7 mL) and AcOH (630 mL) were then add-
ed to the mixture. After dilution with CH2Cl2 (50 mL), the organic
phase was washed with aq satd NaHCO3 solution (20 mL) and with
brine (15 mL). After drying (MgSO4) the solvent was evaporated in
vacuo and the crude mixture of furanoses 24 was dissolved in anhyd
CH2Cl2 (12 mL) and cooled to –78 °C. 2,6-Lutidine (633 mL, 5.45
mmol) and t-BuMe2SiOTf (884 mL, 382 mmol) were added to the
mixture. After stirring at –78 °C for 1 h, the cooling bath was re-
moved and the mixture stirred for 15 min. CH2Cl2 (200 mL) was
added and the solution washed with brine (30 mL). After drying
(MgSO4) the solvent was evaporated in vacuo and the residue puri-
fied by FC (EtOAc/light petroleum); yield:505 mg (75%), colorless
oil; 3:1 mixture of a- and b-anomers that could not be separated;
[a]589 –5.9, [a]577 –6.1, [a]546 –7.5, [a]435 –14.3, [a]405 –18.9
(c = 1.2, CHCl3).
UV (MeCN): lmax (e) = 207 nm (1000).
IR (film): n = 3445, 3000, 2940, 2985, 2825, 2360, 2345, 1750,
1655, 1595, 1560, 1445, 1365, 1340, 1315, 1245, 1195, 1155, 1125,
1110, 1040, 1020, 995, 935, 915, 895, 845, 815, 795, 740, 705, 610
cm–1.
1H NMR (CDCl3): d = 6.33 (d, J1'',6'' = 2.0 Hz, H-6’’), 5.77 (dd,
J1,2 = 4.0 Hz, J = 0.8 Hz, H-1), 4.86 (ddd, J1'',2'' = 4.3 Hz, J1'',6'' = 2.0
Hz, J = 0.9 Hz, H-1''), 4.76–4.63 (m, 7H, H-4'', 3 CH3OCH2O), 4.43
(dd, J2’’,3’’ = 8.2 Hz, J3’’,4’’ = 4.3 Hz, H-3''), 4.29 (s, H-4), 4.24 (ddd,
J1,2 = 4.0 Hz, J2,3 = 2.5 Hz, J = 0.9 Hz, H-2), 3.93 (d, J2,3 = 2.5 Hz,
H-3), 3.44, 3.43, 3.41 (3 s, 3 CH3O), 2.62–2.50 (m, H-2'', H-5),
1.95–1.66 (m, H2-1').
13C NMR (CDCl3): d = 168.8 (s, C-6), 138.9 (s, C-5''), 129.3 (d,
J = 175 Hz, C-6''), 100.1 (d, J = 185 Hz, C-1), 97.8, 97.7, 97.5 (3 t,
J = 163, 163, 165 Hz, 3 CH3OCH2O), 86.5 (d, J = 149 Hz, C-2),
84.0 (d, J = 143 Hz, C-3), 83.6 (d, J = 159 Hz, C-4), 83.5 (d, J = 157
Hz, C-4''), 83.2 (d, J = 165 Hz, C-1''), 75.6 (d, J = 207 Hz, C-3''),
57.0, 56.9, 56.5 (3 q, J = 142, 140, 142 Hz, 3 CH3O), 46.5 (d,
J = 132 Hz, C-5), 40.7 (d, J = 136 Hz, C-2''), 30.4 (t, J = 131 Hz, C-
1').
CI-MS (NH3): m/z = 468 (37, [M+NH3]+), 419 (9), 389 (15), 375
(11), 345 (6), 271 (7), 227 (14), 197 (14), 181 (14), 154 (12), 151
(18), 148 (19), 141 (17), 129 (13), 128 (13), 125 (15), 124 (11), 123
(14), 115 (13), 111 (10), 105 (15), 104 (38), 103 (18), 102 (100), 97
(10), 96 (11), 85 (15), 83 (11), 77 (19), 75 (19), 73 (23), 71 (14).
UV (MeCN): lmax (e) = 257 (1531), 199 (16600), 196 (18300), 194
nm (13000).
IR (film): n = 2930, 2890, 2855, 2825, 2065, 2065, 1735, 1595,
1500, 1470, 1465, 1455, 1360, 1030, 985, 915, 895, 840, 780, 735,
700 cm–1.
1H NMR (CDCl3): d, a-anomer = 7.39–7.31 (m, 5Harom), 6.16 (d,
Anal. Calc. for C19H27ClO10 (450.9): C, 50.62; H, 6.04; Cl, 7.86.
Found C, 50.64; H, 6.10; Cl, 7.94.
J1’’,6’’ = 2.0 Hz, H-6'), 5.28 (br s, H-1), 5.23, 5.15 (2 d, AB, JAB = 12.4
Hz, C6H5CH2), 4.72–4.58 (m, 8 H, H-1'', H-4'', 3 CH3OCH2O), 4.33
(dd, J2’’,3’’ = 8.2 Hz, J3’’,4’’ = 4.2 Hz, H-3''), 4.17, (dd, J4,5 = 8.9 Hz,
(–)-5-Deoxy-5-{(1''S,2''S,3''S,4''R)-[5''-chloro-3''-endo-meth-
oxymethoxy-7-oxabicyclo[2.2.1]hept-5''-en-2''-endo-yl]meth-
yl}-2,3-di-O-methoxymethyl-D-gulo-furanurono-6,1-lactone
[(–)-23b]
Same procedure as for the preparation of (–)-23 was used, starting
from a 1:1 mixture of (–)-18 and 20 (1.52 g, 2.69 mmol). The mix-
ture of (–)-23 and (–)-23b obtained by FC was crystallized from
CH2Cl2/light petroleum, and recrystallized twice from CH2Cl2/light
petroleum; yield: 191 mg [16%, based on 1:1 mixture of (–)-18 and
20]. The mother-liquors were combined and the solvent evaporated.
The residue was recrystallized three times from CH2Cl2/light petro-
leum to give (–)-23b; yield:119 mg (10%); colorless solid; mp
139.5–141.0 °C; [a]589 –38.0 (c = 1.0, CHCl3).
J3,4 = 5.4 Hz, H-4), 4.02 (d, J2,3 = 1.2 Hz, H-2), 3.87 (br. d, J3,4 = 5.4
Hz, H-3), 3.41, 3.38, 3.36 (3 s, CH3O), 2.76–2.70 (m, H-5), 2.24–
2.18 (m H-2''), 1.55–1.48 (m, H2-1'), 0.88 [s, (CH3)3CSi], 0.09, 0.08
[2 s, (CH3)3Si]. b-anomer = 6.14 (d, J1’’,6’’ = 2.0 Hz, H-6''), 5.27
(J1,2 = 10.1 Hz, H-1), 5.25, 5.11 (2 d, AB JAB = 12.3 Hz, C6H5CH2),
4.27 (dd, J3,4 = 8.3 Hz, J2,3 = 4.3 Hz, H-3), 4.06 (dd, J4,5 = 6.3 Hz,
J3,4 = 3.9 Hz, H-4), 3.97 (dd, J1,2 = 10.2 Hz, J2,3 = 5.8 Hz, H-2).
13C NMR (CDCl3): d = a-anomer = 174.0 (s, C-6), 138.5 (s, C-5''),
136.5 (s, Carom), 129.6–129.0 (C-6''+Carom), 101.9 (d, J = 171 Hz, C-
1), 97.5, 96.7, 96.4 (3 t, J = 162, 160, 162 Hz, 3 CH3OCH2O), 87.3
(d, J = 157 Hz, C-2), 84.4 (d, J = 170 Hz, C-3), 83.6, 83.5, 83.3 (3
d, J = 169, 152, 170 Hz, C-4, C-1'', C-4''), 75.1 (d, J = 161 Hz, C-
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conformational Analysis and Glycosidase Inhibition
1449
3’’), 67.2 (t, J = 148 Hz, C6H5CH2O), 56.9, 56.4, 56.2 (3 q, J = 142,
142, 141 Hz, 3 CH3O), 49.7 (d, J = 133 Hz, C-5), 41.3 (d, J = 135
Hz, C-2’’), 26.6 (t, J = 131 Hz, C-1’), 26.3 [q, J = 125 Hz,
(H3C)3CSi], 18.5 [s, (H3C)3CSi], –3.8, –4.7 [ 2 q, J = 120 Hz,
(H3C)2Si].
CI-MS (NH3): m/z = 691 (2, [M+NH3]+), 465 (3), 389 (2), 387 (3),
315 (2), 161 (7), 141 (2), 132 (3), 131 (5), 130 (3), 102 (21), 92 (41),
91 (100), 75 (16).
L-gulo-furanosiduronate [(–)-27]
A mixture of (–)-26 (251 mg, 0.35 mmol), CHCl3 (3.5 mL),
NaHCO3 (71 mg, 0.84 mmol) and metachloroperbenzoic acid (70%,
96 mg, 0.39 mmol) was stirred at 20 °C for 16 h. CH2Cl2 (20 mL)
was added and the organic phasewas washed with aq 5% Na2CO3
solution and brine (10 mL). After drying (MgSO4) the solvent was
evaporated and the residue purified by FC (3:7 EtOAc/light petro-
leum); yield:202 mg (80%); colorless foam; 3:1 mixture of a- and
b-anomer; [a]25 –35.0, [a]25 –37.0, [a]25 –42.0, [a]25
–
435
589
577
546
75.0, [a]25405 –92.0 (c = 1.07, CHCl3).
Anal. Calc. for C32H49ClO11 (673.3): C, 57.09; H, 7.34. Found C,
56.98; H, 7.17.
UV (MeCN): lmax (e) = 204 (15700), 200 nm (15300).
IR (film): n = 2950, 2895, 2855, 1770, 1470, 1375, 1250, 1205,
Mixture of Benzyl (5-Deoxy-5-{(1’’S,2’’S,3’’S,4’’R,6’’S)-[6’’-
exo-acetoxy-3’’-endo-methoxymethoxy-5’’-oxo-7-oxabicyc-
lo[2.2.1]hept-2’’-endo-yl]methyl}-2-[(tert-butyl)dimethylsilyl]-
2,3-di-O-methoxymethyl-a- and b-L-gulo-furanosiduronate
[(–)-26]
1155, 1110, 1035, 915, 840, 780, 700 cm–1.
1H NMR (CDCl3): d, a-anomer = 7.38–7.33 (m, 5Harom), 5.86 (dd,
J1’’,2’’ = 4.4 Hz, J = 0.4 Hz, H-1''), 5.28 (s, H-1), 5.26 (s, H-5''), 5.21,
5.14 (2 d, AB, JAB = 12.3 Hz, C6H5CH2), 4.72–4.60 (m, 6H, 3
CH3OCH2O), 4.28 (dd, J4,5 = 8.4 Hz, J3,4 = 5.3 Hz, H-4), 4.23 (d,
J3’’,4’’ = 7.2 Hz, H-4''), 4.21 (dd, J2’’,3’’ = 9.5 Hz, J1’’,2’’ = 4.4 Hz, H-2''),
4.04 (d, J = 1.2 Hz, H-2), 3.91 (br d, J3,4 = 5.3 Hz, H-3), 3.45, 3.39,
3.38 (3 s, 3 CH3O), 2.81–2.75 (m, H-5), 2.32–2.23 (m, H-3''), 2.15
(s, CH3COO), 1.92–1.86 (m, H2-1'), 0.88 [s, (CH3)3CSi], 0.11, 0.09
[2 s, (CH3)2Si].
13C NMR (CDCl3): d a-anomer = 173.2 (s, CH3COO), 169.8 (s, C-
6), 164.1 (s, C-6''), 136.4 (s, Carom), 129.2, 129.0 (2 d, J = 160, 163
Hz, Carom), 102.1 (d, J = 172 Hz, C-1''), 101.9 (d, J = 171 Hz, C-1),
98.7, 96.7, 96.6 (3 t, J = 163, 159, 160 Hz, 3 CH3OCH2O), 87.0 (d,
J = 154 Hz, C-2), 85.0 (d, J = 163 Hz, C-3), 83.1 (d, J = 189 Hz, C-
4), 82.3 (d, J = 177 Hz, C-4''), 75.8 (d, J = 155 Hz, C-2''), 68.0 (d,
J = 160, C-5''), 67.2 (t, J = 148 Hz, C6H5CH2O), 57.8, 56.5, 56.2 (3
q, J = 146, 146, 147 Hz, 3 CH3O), 48.6 (d, J = 135 Hz, C-5), 39.8
(d, J = 135 Hz, C-3''), 26.2 [q, J = 114 Hz, (H3C)3CSi], 22.9 (t,
J = 130 Hz, C-1'), 21.3 (q, J = 129 Hz, CH3COO), 18.5, [s,
(H3C)3CSi], –3.8, –4.7 [2 q, J = 127 Hz, (H3C)2Si].
A mixture of (–)-25 (300 mg, 0.44 mmol), THF/H2O (70 mL, 5:1),
NaHCO3 (145 mg, 1.78 mmoL), 0.1 M OsO4 in CCl4 (45 mL, 0.0178
mmol) and triethylamine-N-oxide dihydrate (99 mg, 0.89 mmol)
was stirred at 20 °C for 80 min. CH2Cl2 (200 mL) was added and the
organic phase washed with 1 N HCl (15 mL) and 5% Na2S2O4 (20
mL). After drying (MgSO4), the solution was concentrated by evap-
oration in vacuo. Ac2O (850 mL, 8.91 mmol), Et3N (1.55 mL, 11.14
mmoL) and 4-dimethylaminopyridine (2 mg) were added. After
stirring at 20 °C for 15 h, CH2Cl2 (250 mL) was added and the
CH2Cl2 phase was washed successively with 1 N HCl (15 mL), aq
satd NaHCO3 solution (20 mL) and brine (15 mL). After drying
(MgSO4), the solvent was evaporated and the residue purified by FC
(3:7 EtOAc/light petroleum); yield:303 mg (97%); colorless oil; 3:1
mixture of a- and b-anomer; [a]25589 –0.9, [a]25577 –1.2, [a]25546+3.0,
[a]25435+30.0, [a]25405+60.0 (c = 0.94, CHCl3).
UV (MeCN): lmax (e) = 257 (1700), 205 (12200), 196 nm (14800).
IR (film): n = 2935, 2895, 2855, 2825, 2255, 2065, 1785, 1500,
1470, 1465, 1455, 1375, 665, 650 cm–1.
CI-MS (NH3): m/z = 747 (6, [M+NH]+), 598 (1), 523 (1), 519 (1),
161 (63), 91 (100).
1H NMR (CDCl3): d, a-anomer = 7.38–7.31 (m, 5Harom), 5.28 (s, H-
1), 5.22, 5.14 (2 d, AB, JAB = 12.3 Hz, C6H5CH2), 4.93 (s, H-6''),
4.72–4.59 (m, 3 CH3<<<<<CH2O), 4.48 (d, J3’’,4’’ = 5.4 Hz, H-4''),
4.38 (d, J1’’,2’’ = 5.4 Hz, H-1''), 4.27 (dd, J4,5 = 8.4 Hz, J3,4 = 5.3 Hz,
H-4), 4.17 (dd, J2’’,3’’ = 9.1 Hz, J3’’,4’’ = 5.4 Hz, H-3''), 4.04 (s, H-2),
3.89 (d, J3,4 = 5.3 Hz, H-3), 3.37, 3.36, 3.35 (3 s, 3 CH3O), 2.77–
2.71 (m, H-5), 2.36–2.22 (m, H-2''), 2.13 (s, CH3COO), 1.90–1.85
(m, H2-1'), 0.86 [s, (CH3)3CSi], 0.09, 0.08 [2 s, (CH3)2Si].
Anal. Calc. for C34H52O15Si (728.9): C, 56.03; H, 7.19; Si 3.85.
Found C, 55.98; H, 7.19; Si 3.95.
Mixture of 5-O-Acetyl-3-[(tert-butyl)dimethylsilyl-5’-N-(benzy-
loxy)carbonyl-2’,3’-di-O-methoxymethyl-a and b-D-manno-
furanoside]-2-O-methoxymethyl-D-manno-furanurono-6,1-lac-
tone [(–)-30]
13C NMR (CDCl3): d a-anomer = 203.1 (s, CH3COO), 173.4 (s, C-
6), 170.7 (s, C-5''), 136.4 (s, Carom), 129.9, 129.2, 129.0 (3 d,
J = 157, 160, 158 Hz, Carom), 101.4 (d, J = 171 Hz, C-1), 98.1, 96.7,
96.3 (3 t, J = 162, 160, 162 Hz, 3 CH3OCH2O), 87.2 (d, J = 156 Hz,
C-2), 85.0 (d, J = 167 Hz, C-3), 84.0 (d, J = 165 Hz, C-1''), 83.3 (d,
J = 171 Hz, C-4), 83.1 (d, J = 168 Hz, C-4''), 74.7 (d, J = 157 Hz,
C-3''), 70.6 (d, J = 161 Hz, C-6''), 67.2 (t, J = 148 Hz, C6H5CH2O),
57.5, 56.5, 56.2 (3 q, J = 142 Hz, 3 CH3O), 48.7 (d, J = 132 Hz, C-
5), 41.4 (d, J = 137 Hz, C-2''), 26.3 (q, J = 126 Hz, (H3C)3CSi), 23.4
(t, J = 130 Hz, C-1'), 21.3 (q, J = 130, CH3COO), 18.5 [s,
(H3C)3CSi], –3.8, –4.7 [2 q, J = 119, 120 Hz, (H3C)2Si].
A mixture of (–)-27 (320 mg, 0.44 mmol), Pd(OH)2 (10% on char-
coal, 32 mg) and EtOAc (8 mL) was degassed and pressurized (1
atm) with H2. After shaking at 20 °C for 16 h the mixture was fil-
tered on Celite and the solution concentrated in vacuo. The residue
was taken in anhyd toluene (12 mL) under Ar. Diphenyloxyphos-
phoryl azide (143 mL, 0.66 mmol) and Et3N (307 mL, 2.2 mmol)
were added to the mixture. After stirring at 20 °C for 20 h, benzyl
alcohol (freshly distilled from CaO, 455 mL, 4.4 mmol) was added
and the mixture heated to 105 °C for 16 h. After cooling to 20 °C,
toluene (150 mL) was added. The organic phase was washed with 1
N HCl (7 mL) and brine (15 mL). After drying (MgSO4) the solvent
was evaporated and the residue purified by FC (3:7 EtOAc/light pe-
troleum); yield:274 mg (85%); colorless oil; 3:1 mixture of a- and
b-anomer. An analytical sample of the a-anomer could be obtained
pure by column chromatogrpahy on silica gel.
CI-MS (NH3): m/z = 731 (15, [M+NH3]+), 697 (9), 581 (12), 505
(6), 457 (5), 385 (5), 161 (11), 108 (17), 106 (11), 92 (40), 91 (100),
75 (15), 74 (14), 73 (9).
Anal. Calc. for C34H52O14Si (712.9): C, 57.29; H, 7.35; Si, 3.94.
Found C, 57.34; H, 7.47; Si, 3.87.
a-Anomer of (–)-30
[a]589 –19.0, [a]577 –20.0, [a]546 –23.0, [a]435 –44.0, [a]405 –56.0
(c = 0.64, CHCl3).
Mixture of Benzyl 5-Deoxy-5-[5’’-O-acetyl-3’’-deoxy-2’’-O-
methoxymethyl-D-manno-furanurono-6,1-lactone-3’’-yl)meth-
yl]-(tert-butyl)dimethylsilyl)-2,3-di-O-methoxymethyl-a- and b-
UV (MeCN): lmax (e) = 204 (6600), 192 nm (15600).
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

1450
C. Marquis et al.
PAPER
IR (film): n = 3400, 2955, 2895, 2855, 2830, 2065, 1770, 1715,
1515, 1470, 1375, 1300, 1205, 1155, 1110, 1040, 920, 840, 780,
745, 700, 670 cm–1.
CI-MS (NH3): m/z = 647 (1, [M+NH3]+), 630 (1, [M+1]+), 612 (3),
568 (3), 378 (3), 346 (8), 259 (3), 145 (5), 144 (9), 126 (6), 125 (8),
120 (6), 110 (15), 109 (10), 108 (12), 92 (30), 91 (100), 78 (17), 73
(15), 72 (15).
1H NMR (CDCl3): d = 7.38–7.32 (m, 5Harom), 5.90 (d, J1,2 = 4.1 Hz,
H-1), 5.30 (s, H-1'), 5.28 (s, H-5), 5.16 (d, JH-N,H-5’= 9.8 Hz, NH),
5.12, 5.08 (2 d, AB, JAB = 12.3 Hz, C6H5CH2O), 4.76–4.54 (m, 6H,
3 CH3OCH2O), 4.40 (dd, J2,3 = 9.4 Hz, J1,2 = 4.1 Hz, H-2), 4.34 (d,
J3,4 = 6.9 Hz, H-4), 4.14–4.07 (m, 2H, H-4', H-5'), 4.03 (d, J2’,3’= 1.5
Hz, H-2'), 3.76 (dd, J3’,4’= 5.1 Hz, J2’,3’= 1.5, H-3'), 3.46, 3.36, 3.31
(3 s, 3 CH3O), 2.58–2.54 (m, H-3), 2.11 (s, CH3COO), 1.82–1.78
(m, H2-6'), 0.90 [s, (CH3)3CSi], 0.13, 0.12 [2 s, (CH3)2Si].
13C NMR (CDCl3): d = 169.4 (s, CH3COO), 163.8 (s, C-6), 157.0 (s,
BnOCONH), 136.3 (s, Carom), 128.5, 128.2, 127.9 (3 d, J = 160, 159
Hz, 5Car), 101.7 (d, J = 172 Hz, C-1, C-1'), 97.5, 96.6, 95.7 (3 x t,
J = 162 Hz, 3 CH3OCH2O), 86.8 (d, J = 152 Hz, C-2'), 83.9 (s,
J = 151 Hz, C-4'), 83.0 (d, J = 164 Hz, C-3'), 81.3 (d, J = 177 Hz,
C-4), 76.7 (d, J = 156 Hz, C-2), 67.8 (d, J = 146 Hz, C-5), 66.8 (t,
J = 147 Hz, C6H5CH2), 56.9, 55.6, 55.5 (3 q, J = 147, 146 Hz, 3
CH3O), 49.8 (d, J = 138 Hz, C-5'), 38.6 (d, J = 135 Hz, C-3), 28.5
(t, J = 130 Hz, C-6'), 25.5 [q, J = 122 Hz, (CH3)3CSi], 20.6 (q,
J = 129 Hz, CH3COO), 17.8 [s, (CH3)3CSi], –4.4, –5.3 [q, J = 126
Hz, (CH3)2Si].
Anal. Calc. for C28H39NO15 (629.6): C, 53.41; H, 6.24; N, 2.22.
Found C, 53.40; H, 6.37; N, 2.22.
5-O-Acetyl-3-deoxy-3-(1’,2’,6’-trideoxy-2’,6’-imino-4’,5’-di-O-
methoxymethyl-D-galactitol-1’-yl)-2-O-methoxymethyl-D-man-
no-furanurono-6,1-lactone [(–)-34]
A mixture of (–)-31 (33 mg, 0.05 mmol) and 10% Pd(OH)2 on char-
coal (3.3 mg) and EtOAc (5 mL) was degassed and pressurized with
H2 (1 atm). After shaking at 20 °C for 24 h the mixture was filtered
through Celite and the solvent evaporated in vacuo. The residue was
purified by FC (4:1:1 EtOAc/light petroleum/MeOH); yield:19.4
mg (80%); colorless oil; [a]589 –68.0, [a]577 –75.0, [a]546 –67.0,
[a]435 –80.0, [a]405 –106.0 (c = 0.49, CHCl3).
UV (MeCN): lmax (e) = 208 nm (900).
IR (film): n = 3495, 2945, 2895, 2825, 1765, 1745, 1650, 1440,
1375, 1300, 1205, 1150, 1105, 1035, 850 cm–1.
1H NMR (CDCl3): d = 5.92 (dd, J1,2 = 4.2 Hz, J = 0.6 Hz, H-1), 5.38
(s, H-5), 4.64, 4.61 (2 d, AB, JAB = 6.8 Hz, CH3OCH2O), 4.73, 4.67
(2 d, AB, JAB = 6.7 Hz, CH3OCH2O), 4.81, 4.77 (2 d, AB, JAB = 6.9
Hz, CH3OCH2O), 4.49 (d, J3,4 = 6.8 Hz, H-4), 4.33 (dd, J2,3 = 9.3
Hz, J1,2 = 4.2 Hz, H-2), 3.86 (dd, J3',4' = 3.0 Hz, J2',3' = 1.1 Hz, H-3’),
3.71 (ddd, J5',6' = 10.7 Hz, J4',5' = 9.3 Hz, J5',6'a = 5.5 Hz, H-5’), 3.50
(dd, J4',5' = 9.3 Hz, J3',4' = 3.0 Hz, H-4’), 3.46, 3.42, 3.37 (3 s, 3
CH3O), 3.23 (dd, J = 13.4 Hz, J5',6'a = 5.5 Hz, Ha-6'), 2.73–2.66 (m,
H-3), 2.58 (ddd, J1’a,2’= 9.0, J1’b,2’= 4.8 Hz, J2’,3’= 1.1 Hz, H-2'), 2.39
(dd, J = 13.4 Hz, J4’,6’b = 10.7 Hz, Hb-6'), 2.18 (s, CH3COO), 1.81–
1.68 (m, H2-1').
CI-MS (NH3): m/z = 762 (3, [M+NH3]+), 612 (4), 610 (6), 536 (3),
161 (13), 129 (8), 117 (7), 108 (6), 103 (8), 92 (26), 90 (7), 89 (13),
85 (10), 83 (9), 75 (21), 74 (11), 73 (13).
Anal. Calc. for C34H53NO15Si (743.9): C, 54.90; H, 7.18; N, 1.88;
Si, 3.78. Found C, 54.86; H, 7.04; N, 1.80; Si 3.74.
Mixture of 5-O-Acetyl-3-[5’-N-(benzyloxy)carbonyl-2’,3’-di-O-
methoxymethyl-a and b-D-manno-furanose]-2-O-methoxyme-
thyl-D-manno-furanurono-6,1-lactone [(–)-31]
A mixture of (–)-30 (321 mg, 0.43 mmol), THF (9 mL) and HF•py-
ridine (524 mL, 0.53 mmol) was stirred at 0 °C for 10 min, then at
20 °C for 1 h. The mixture was poured into aq satd NaHCO3 solu-
tion (2 mL). The org. phase was collected and the aqueous layer ex-
tracted with EtOAc (3 x 10 mL). The combined organic extracts
were dried (MgSO4) and the solvent was evaporated in vacuo. The
residue was purified by FC (4:1 EtOAc/light petroleum); yield:245
13C NMR (CDCl3): d = 170.2 (s, CH3COO), 164.6 (s, C-6), 101.4
(d, J = 185 Hz, C-1), 97.0, 96.8, 96.2 (3 t, J = 164, 164, 163 Hz, 3
CH3OCH2O), 81.6 (d, J = 162 Hz, C-4), 80.8 (d, J = 141 Hz, C-4'),
76.0 (d, J = 154 Hz, C-2), 74.6 (d, J = 144 Hz, C-2'), 70.9 (d,
J = 146 Hz, C-3'), 67.7 (d, J = 149 Hz, C-5), 57.2, 55.7, 55.4 (3 q,
J = 146 Hz, 3 CH3O), 56.8 (d, J = 146 Hz, C-5'), 49.3 (t, J = 137 Hz,
C-6'), 39.7 (d, J = 135 Hz, C-3), 26.4 (t, J = 126 Hz, C-1'), 20.7 (q,
J = 130 Hz, CH3COO).
CI-MS (NH3): m/z = 480 (28, M+.), 448 (22), 418 (20), 377 (17),
376 (55), 358 (40), 356 (29), 334 (18), 302 (15), 300 (15), 291 (17),
290 (43), 276 (21), 273 (20), 272 (41), 262 (27), 259 (25), 256 (25),
248 (30), 242 (14), 220 (55), 219 (23), 125 (50), 112 (22), 111 (35),
110 (33), 109 (20), 99 (21), 98 (51), 85 (57), 83 (62), 71 (100), 70
(50).
mg (90%); colorless oil; 3:1 mixture of a- and b-anomer; [a]589
–
30.0, [a]25 –29.0, [a]25 –33.0, [a]25 –60.0, [a]25 –75.0
577
546
435
405
(c = 0.87, CHCl3).
UV (MeCN): lmax (e) = 208 (9800), 194 nm (11100).
IR (film): n = 3390, 2955, 2850, 2830, 2065, 1770, 1745, 1720,
1715, 1695, 1680, 1650, 1635, 1585, 1470, 1455, 1445, 1380, 1335,
1205, 875, 850, 805, 755, 700, 665 cm–1.
1H NMR (CDCl3): d, major anomer = 7.36–7.32 (m, 5 Harom), 5.90
(d, J1,2 = 4.2 Hz, H-1), 5.35 (s, H-1'), 5.32 (s, H-5), 5.24 (d, JH-N,H-
5’= 9.7 Hz, NH), 5.12, 5.07 (2 d, AB, JAB = 12.2 Hz, C6H5CH2O),
4.75–4.53 (m, 6H, 3 CH3OCH2O), 4,39 (dd, J2,3 = 9.5 Hz, J1,2 = 4.2
Hz, H-2), 4.35 (d, J3,4 = 7.1 Hz, H-4), 4.23 (dd, J3’,4’= 4.7 Hz,
Anal. Calc. for C20H33NO12 (479.5): C, 50.10; H, 6.94. Found C,
50.09; H, 7.06.
Methyl 3-Deoxy-3-(1’,2’,6’-trideoxy-2’,6’-imino-D-galactitol-1’-
yl)-a-D-manno-pyranoside Uronate [(+)-35]
J4’,5’= 1.8 Hz, H-4'), 4.09 (s, H-2'), 4.09 (m, H-5'), 3.88 (d, J3’,4’= 4.7
Freshly distilled SOCl2 (60 mL, 0.81 mmol) was added slowly (sy-
ringe) to a stirred solution of (–)-34 (26 mg, 0.05 mmol) in anhyd
MeOH (2 mL) cooled to 0 °C under Ar. After stirring at 0 °C for 24
h, the solvent was evaporated to dryness under high vacuum (0.001
Torr, 12 h, 20 °C): 20 mg of (–)-35 (ca 100%) sufficiently pure for
the next step. An analytical sample was obtained by FC (2:1:1
CHCl3/MeOH/AcOH) or by column chromatography on Florisil
(8:2:1 CHCl3/MeOH/Et3N).
Hz, H-3'), 3.44, 3.36, 3.29 (3 s, 3 CH3O), 2.62–2.54 (m, H-3), 2.12
(s, CH3COO), 1.82–1.78 (m, H2-6').
13C NMR (CDCl3): d major anomer = 169.6 (s, CH3COO), 163.6 (s,
C-6), 157.0 (s, BnOCONH), 136.3 (s, Carom), 129.3, 128.7, 127.7 (3
d, J = 160, 160, 158 Hz, Carom), 102.3 (d, J = 186 Hz, C-1), 102.1 (d,
J = 162 Hz, C-1'), 98.2, 97.2, 96.3 (3 t, J = 163, 163, 160 Hz, 3
CH3OCH2O), 85.8 (d, J = 154 Hz, C-2'), 85.1 (d, J = 150 Hz, C-4'),
82.9 (d, J = 165 Hz, C-3'), 82.1 (d, J = 177 Hz, C-4), 77.0 (d,
J = 157 Hz, C-2), 68.6 (d, J = 147 Hz, C-5), 67.6 (t, J = 146 Hz,
C6H5CH2), 57.7, 56.4, 56.4 (3 q, J = 143, 142, 142 Hz, 3 CH3O),
50.9 (d, J = 138 Hz, C-5'), 39.2 (d, J = 133 Hz, C-3), 29.0 (t, J = 130
Hz, C-6'), 21.3 (q, J = 126 Hz, CH3COO).
(+)-35•AcOH
1H NMR (D2O): d = 4.53 (d, J1,2 = 1.2 Hz, H-1), 3.99 (d, J4,5 = 9.8
Hz, H-5), 3.94 (br. d, J3’,4’= 2.9 Hz, H-3’), 3.85 (ddd, J5’,6’b = 11.6 Hz,
J
4’,5’= 9.7 Hz, J5’,6’a = 5.4 Hz, H-5’), 3.62 (br s, H-2), CH3OCO), 3.57
(dd, J3,4 = 10.0 Hz, J4,5 = 9.8 Hz, H-4), 3.43 (dd, J4’,5’= 9.7 Hz,
3’,4’= 2.9 Hz, H-4'), 3.34–3.28 (m, H-2'), 3.26 (dd, J = 12.2 Hz,
J
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conformational Analysis and Glycosidase Inhibition
1451
J5’,6’a = 5.4 Hz, Ha-6), 3.24 (s, H3CO), 2.66 (dd, J = 12.2 Hz,
Acknowledgement
J5’,6’b = 11.6, Hb-6'), 1.90–1.53 (m, 6H, H-3, H2-1', CH3COO).
We are grateful to the Swiss National Science Foundation and the
Fonds Herbette (Lausanne) for financial support. We thank Mr.
Maurizio Maio, Mr. Martial Rey and Mr. Francisco Sepúlveda for
their technical assistance. We also thank Dr. Eric Frérot who carried
out the first exploratory synthetic experiments.1
(+)-35
Colorless oil; [a]25589+11.1, [a]25577+7.8, [a]25546 –8.0, [a]25435 –30,
[a]25405 –6.3 (c = 1.0, CHCl3).
IR (film): n = 3405, 2930, 2360, 2340, 1735, 1595, 1560, 1445,
1260, 1230, 1140, 1055, 670, 615, 465, 415 cm–1.
1H NMR (CD3OD): d = 4.60 (d, J1,2 = 1.2 Hz, H-1), 4.05 (d, References
4,5 = 9.7 Hz, H-5), 3.87 (dd, J3,4 = 10.6 Hz, J4,5 = 9.7 Hz, H-4), 3.86
(d, J3,4 = 3.0 Hz, H-3’), 3.82 (ddd, J5',6'b = 11.0 Hz, J4',5' = 9.1 Hz,
J
(1) Frérot, E.; Marquis, C.; Vogel, P. Tetrahedron Lett. 1996, 37,
2023.
(2) See, e.g.:
J
J
5',6'a = 5.4 Hz, H-5’), 3.81 (s, CH3OCO), 3.68 (dd, J2,3 = 2.6 Hz,
1,2 = 1.2 Hz, H-2), 3.44 (s, H3CO), 3.40 (dd, J4',5' = 9.1 Hz,
a) Varki, A. Glycobiology 1993, 3, 97.
b) Morenem, K. W.; Trimble, R. B.; Herscovics, A.
Glycobiology 1994, 4, 113.
c) Varki, A. Proc. Natl. Acad. Sci. USA 1994, 91, 7390.
d) Crocker, P. R.; Feizi, T. Curr. Opin. Struct. Bio. 1996, 6,
679.
J3',4' = 3.0 Hz, H-4’), 3.12 (dd, J = 13.3 Hz, J5',6'a = 5.4 Hz, Ha-6’),
2.82 (br. dd, J1'a,2' = 7.7 Hz, J1'b,2' = 4.8 Hz, H-2’), 2.41 (dd, J = 13.3
Hz, J5',6'b = 11.0 Hz, Hb-6'), 2.17–1.91 (m, 1H, H-3), 1.87–1.83 (m,
H2-1').
13C NMR (CD3OD): d = 172.6 (s, CH3OCO), 102.5 (d, J = 167 Hz,
C-1), 76.9 (d, J = 133 Hz, C-5'), 74.5 (d, J = 150 Hz, C-5), 73.7 (d,
J = 144 Hz, C-3'), 71.5 (d, J = 148 Hz, C-2), 69.0 (d, J = 144 Hz, C-
4), 68.0 (d, J = 144 Hz, C-4'), 58.2 (d, J = 128 Hz, C-2'), 55.4 (q,
J = 143 Hz, H3CO), 52.7 (q, J = 147 Hz, CH3COO), 50.2 (CD3OD,
C-6'), 41.7 (d, J = 123 Hz, C-3), 33.8 (t, J = 124 Hz, C-1').
(3) a) Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985, 54,
631.
b) Lal, A.; Pang, P.; Kalelkar, S.; Romero, P. A.; Herscovics,
A.; Moremen, K. W. Glycobiology 1998, 8, 981 and ref. cited
therein.
CI-MS (NH3): m/z = 352 (10, M+), 320 (13), 228 (7), 200 (7), 167
(8), 160 (10), 148 (11), 147 (33), 146 (81), 145 (22), 133 (35), 132
(100), 129 (44), 108 (55).
(4) a) Marshall, J. J. Adv. Carbohydr. Chem. Biochem. 1974, 30,
257.
b) Schmidt, D. D.; Frommer, W.; Junge, B.; Müller, L.;
Wingender, W.; Truscheit, E.; Schefer, D.
Naturwissenschaften 1977, 64, 535.
Methyl 3-Deoxy-3-(1’,2’,6’-trideoxy-2’,6’-imino-D-galactitol-1’-
yl)-a-D-manno-pyranoside [(–)-1]
(5) See, e.g.:
a) Mulligan, M. S.; Paulson, J. C.; DeFrees, S.; Zheng, Z. I.;
Lowe, J. B.; Ward, P. A. Nature 1993, 364, 149.
b) Hendrix, M.; Wong, C.-H. Pure & Appl. Chem. 1996, 68,
2081.
c) Ganem, B. Acc. Chem. Res. 1996, 29, 340.
d) Platt, F. M.; Reinkensmeier, G.; Dwek, R. A.; Butters, T. D.
J. Biol. Chem. 1997, 272, 19365.
e) Lapierre, F.; Holme, K.; Lam, L.; Tressler, R. J.; Storm, N.;
Wee, J.; Stack, R. J.; Castellot, J.; Tyrrell, D. J. Glycobiology
1996, 6, 355.
f) Kolter, T. Angew. Chem. 1997, 109, 2044; Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1955.
g) Fenouillet, E.; Papandreou, M. J.; Jones, I. M. Virology
1997, 231, 89.
h) Bols, M. Acc. Chem. Res. 1998, 31, 1.
i) Izumi, M.; Suhara, Y.; Ichikawa, Y. J. Org. Chem. 1998, 63,
4811.
A mixture of (–)-35 (30 mg, 0.1 mmol), EtOH (4 mL) and NaBH4
(15 mg, 0.42 mmol) was stirred at 0 °C for 15 min, then at r.t. for 2
h. After cooling to 0 °C, 1 N aq HCl (1 mL) was added under vi-
gourous stirring. After 15 min at 0 °C, the solvents were evaporated
to dryness and the residue purified by FC (1% Et3N in 2:1 CHCl3/
MeOH). A second purification on Dowex 1 ¥ 8 (OH–) (elution with
H2O) gave 17 mg (61%) of (–)-1; hygroscopic oil; [a]25 –6.3,
589
[a]25 –7.4, [a]25 –7.6, [a]25 –10.5, [a]25 –12.9 (c = 0.8,
577
546
435
405
H2O).
UV (MeCN): lmax (e) = 193 nm (460).
IR (KBr): n = 3420, 1665, 1570, 1450, 1305, 1140, 1070, 880 cm–1.
1H NMR (D2O+0.5% CD3OD, 62 °C): d = 4.69 (d, J1,2 = 1.4 Hz, H-
1), 3.91 (dd, J = 12.0 Hz, J6a,5 = 2.3 Hz, Ha-6), 3.91 (dd, J3’,4’= 3.2
Hz, J2’,3’= 1.3 Hz, H-3'), 3.78 (dd, J2,3 = 2.9 Hz, J1,2 = 1.4 Hz, H-2),
3.78–3.75 (m, H-5'), 3.75 (dd, J = 12.0 Hz, J5,6b = 5.9 Hz, Hb-6),
3.62 (ddd, J4,5 = 8.4 Hz, J5,6b = 5.9 Hz, J5,6a = 2.3 Hz, H-5), 3.56 (dd,
J4,5 = 8.4 Hz, J3,4 = 11.3 Hz, H-4), 3.53 (dd, J4’,5’= 9.7 Hz, J3’,4’= 3.2
Hz, H-4'), 3.47 (s, CH3O), 3.13 (dd, J = 13.1 Hz, J5’,6’a = 5.4 Hz, Ha-
6'), 2.75 (ddd, J1’,2’= 9.7 Hz, J1’b,2’= 3.5 Hz, J2’,3’= 1.3 Hz, H-2'), 2.38
(dd, J = 13.1 Hz, J5’,6’b = 10.8 Hz, Hb-6'), 1.94 (dddd, J3,4 = 11.3 Hz,
k) Granier, T.; Vasella, A. Helv. Chim. Acta 1998, 81, 865.
(6) a) Van de Broek, L. A. G. M.; Vermaas, D. J.; Heskamp, B.
M.; Van Boeckel, C. A. A.; Tan, M. C. A. A.; Bolscher, J. G.
M.; Ploegh, H. L.; Van Kemenade, F. J.; De Goede, R. E. Y.;
Miedema, F. Rec. Trav. Chim. Pays-Bas 1993, 112, 82.
b) Pal, R.; Hoke, G. M.; Sarngadharan, M. G. Proc. Natl.
Acad. Sci. USA 1989, 86, 3384.
J
1’b,3 = 6.6 Hz, J1’a,3 = 6.0 Hz, J2,3 = 2.9 Hz, H-3), 1.80 (ddd, J = 14.7
Hz, J1’a,2’= 9.7 Hz, J1’a,3 = 6.0 Hz, Ha-1'), 1.73 (ddd, J = 14.7 Hz,
1’b,3 = 6.6 Hz, J1’b,2’= 3.5 Hz, Hb-1').
J
c) Johnson, V. A.; Walker, B. D.; Barlow, M. A.; Paradis, T.
J.; Chou, T. C. Hirsch, M. S. Antimicrob. Agents Chemother.
1989, 33, 53.
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A. Proc. Natl. Acad. Sci. USA 1997, 94, 1822.
e) Goss, P. E.; Baptiste, J.; Fernandes, B.; Baker, M.; Dennis,
J. W. Cancer Res. 1994, 54, 1450.
13C NMR (D2O+0.5% CD3OD): d = 101.0 (d, J = 170 Hz, C-1),
76.0 (d, J = 136 Hz, C-5'), 74.2 (d, J = 144 Hz, C-5), 73.6 (d,
J = 146 Hz, C-3'), 70.2 (d, J = 127 Hz, C-2), 68.8 (d, J = 126 Hz, C-
4), 66.5 (d, J = 146 Hz, C-4'), 62.3 (d, J = 143 Hz, C-6), 56.4 (d,
J = 130, C-2'), 55.5 (q, J = 144 Hz, CH3O), 49.6 (CD3OD, C-6'),
40.3 (d, J = 128 Hz, C-3), 32.1 (t, J = 125 Hz, C-1').
CI-MS (NH3): m/z = 324 (4, M+), 261 (14), 189 (15), 177 (11), 169
(17), 135 (22), 123 (35), 97 (45), 95 (100), 81 (97), 79 (48), 71 (61),
70 (60).
f) Zheng, Y.; Pau. Y. T.; Asano, N.; Nash, R. J.; Elbein, A. D.
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B.; Tai, C. Y.; Laver, N. G.; Stevens, R. C. J. Am. Chem. Soc.
1997, 119, 681.
MS (electrospray): m/z = 324.4 (100): C13H25O8N (323.34).
Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York

1452
C. Marquis et al.
PAPER
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Synthesis 1999, No. SI, 1441–1452 ISSN 0039-7881 © Thieme Stuttgart · New York