Strategies for stereocontrol at C1 or C2 in syntheses of α-glucosaminides

Article abstract of DOI:10.1560/KDP7-D0BA-BN04-3H3A

The C1 and C2 stereocenters of α-glucosaminides can be prepared by establishing the stereocenters in either order. For the former, a C2-azido glucosyl donor is prepared first, and the restraining effect of a 4,6-O-benzylidene ring is used to induce α-coupling. For the latter, the C1 linkage is prepared first by use of an n-pentenyl-manno-1,2-orthoester donor which ensures (a) clean α-coupling and (b) a convenient C2-ester. The C2-ester is replaced with a triflate leaving group, and nucleophilic displacement is effected by use of a hypervalent silicon azide.

Full text of DOI:10.1560/KDP7-D0BA-BN04-3H3A

Strategies for Stereocontrol at C1 or C2 in Syntheses of α-Glucosaminides
BERT FRASER-REID,* G. ANILKUMAR,† LATHA G. NAIR, LARS OLSSON,‡ MERCEDES GARCIA MARTIN,§
AND JACQUITTA K. DANIELS
Natural Products and Glycotechnology Research Institute, Inc.,a 4118 Swarthmore Road, Durham, North Carolina 27707, USA
(Received 18 September 2000 and in revised form January 29 2001)
Abstract. The C1 and C2 stereocenters of α-glucosaminides can be prepared by
establishing the stereocenters in either order. For the former, a C2-azido glucosyl
donor is prepared first, and the restraining effect of a 4,6-O-benzylidene ring is used
to induce α-coupling. For the latter, the C1 linkage is prepared first by use of an n-
pentenyl-manno-1,2-orthoester donor which ensures (a) clean α-coupling and (b) a
convenient C2-ester. The C2-ester is replaced with a triflate leaving group, and
nucleophilic displacement is effected by use of a hypervalent silicon azide.
coworkers12 in order to avoid oxazoline formation, leads
INTRODUCTION
to excellent production of trans-1,2-glycosides.
In order to meet the challenge of cis-1,2-α-anomeric
selectivity, Paulsen and co-workers introduced the use
of donors with a C2 azido functionality, e.g., 4, as the
“latent amine”.13 Since neighboring group participation
is not a factor, α-glycosidation should be facilitated. On
the basis of this precedent, a ready route to 2-azido
hexopyranose donors was developed by Lemieux and
Ratcliffe14 as one of a series of preparative procedures
based on electrophilic addition to glycals,15 5→6
(Scheme 1).
Traditionally, the azide serves as a convenient latent
amine, 8→9,16 as indicated in Scheme 2. However, re-
cent work in Vasella’s laboratory has provided an el-
egant method for the reverse process, 9→8 by treating
an amine with trifluoromethanesulphonyl (triflyl) azide
(Scheme 2).17 The azido group can therefore now be
properly regarded as a “protecting group” for the amine,18
as well as a latent form thereof.
2-Amino-2-deoxy-α-D-glucopyranosides (α-glucosa-
minides), for example 1, are components of a wide
variety of biologically important oligosaccharides, in-
cluding the amino glycoside (aminocyclitol) antibiotics1
and glycosylphosphatidylinositols (GPIs).2
Members of the former class1 have been in clinical
use for over fifty years, while the latter have recently
entered into prominence following the first structure
assignment in 1988.2
The burgeoning interest3 in the latter class of oligo-
saccharides stems from their occurrence in a wide range
of health-related disorders including African sleeping
sickness,4 Chagas’ disease (or American sleeping sick-
ness),5 malaria,6 paroxysmal nocturnal hemoglobinuria,7
and transmissible spongiform encephalopathies8 such as
Mad Cow disease.
The ready availability of glucosamine, by acid hy-
drolysis of crustacean shells,9 provides what should be a
ready starting material for preparation of α-glucosa-
minides. The highly reactive amino group must be pro-
tected, but the nature of the amine protecting group is of
paramount importance. N-Acyl protection, e.g., 2, while
convenient, may cause problems during glycosidation,
owing to participation of the acyl group in the reaction
at the anomeric center. Thus, with primary alcohol ac-
ceptors, trans-1,2-glycosides may be obtained.10 How-
ever, with more hindered secondary alcohol acceptors,
neighboring group participation intervenes, leading to
oxazolines, 3, as major products.11 The use of phthal-
imide for amine protection, introduced by Lemieux and
*Authortowhomcorrespondenceshouldbeaddressed. E-mail:
dglucose@aol.com
†Present address: Schering-Plough Research Institute,
Kenilworth, NJ, USA.
‡Present address: Astra Zeneca, Stockholm, Sweden
§Present address: Insituto de Quimica Organica, Madrid,
Spain
aA non-profit organization at Centennial Campus (North
Carolina State University), Raleigh, NC, USA
A preliminary account of this work was published in Tetrahe-
dron Lett. 2000, 41, 7605–7608.
Israel Journal of Chemistry
Vol. 40
2000 pp. 255–262

256
tion of such donors from 1,6 anhydromannose has
served well, the strategy of Vasella et al. (Scheme 2)
opened the way for use of suitably protected amine
precursors, as first illustrated by Konradsson and co-
workers.25 Similarly, the readily cleaved pent-4-enoyl26
and tetrachlorophthaloyl (TCP)27 protecting groups de-
veloped in our laboratory, have greatly simplified routes
to azido donors such as 10a.28
However, the results in Table 1 make it clear that 2-
azido groups do not ensure α-glucoside formation.
Thus, our efforts using donor 10a28 with acceptor 11a29
failed to give either the desired pseudo-disaccharide
12a(α) or its anomer 12a(β) (Table 1, entry i). The
corresponding glycosyl bromide 10b and trichloro-
acetimidate 10c (prepared from 10a by standard proce-
dures)30 also failed to couple with 11a in ways that
combined good yields with good α-selectivity as (Table
1, entries ii to v).
Scheme 1
By contrast, good results were obtained with the
benzylidenated derivative 10d (Table 1, entry vi). This
is of mechanistic significance in view of the poor results
obtained with the related donor 10a (See Table 1, entry i
vs entry vi). It is clear that the conformational restraint
imposed by the benzylidene ring of 10d leads to accept-
able coupling, in contrast to the conformationally mo-
bile analogue 10a. On the basis of trasition state model-
Scheme 2
The glucosamine/inositol domain may be regarded ing in our laboratory, we have advanced the use of
as the “warhead”19 of GPIs in view of the fact that cyclic acetal protecting groups for torsional control of
several key biological20 and biosynthetic21 events are coupling reactions.31 Recently, elegant studies by Crich
controlled from this pseudo-disaccharide motif. For and coworkers32 have validated our findings.
synthetic approaches, 2-azido-2-deoxy glucosyl donors
However, slower reaction times for many acetalated
have been the preferred choice, in our22 and other23 donors have been predicted theoretically,31 and ob-
laboratories, for coupling to inositol acceptors. Al- served experimentally,33 in our model studies, and this
though the classic route of Paulsen et al.24 for prepara- was borne out by the experiment summarized in entry
Table 1. Coupling of different 2-azido glycosyl donors with myo-inositol derivatives
entry
donor
acceptor
reaction conditions
yield
product ratio (12a/12b)
i
ii
iii
iv
v
10a
10b
10b
10c
10c
10d
11a
11a
11a
11a
11a
11b
NIS/TESOTf/CH2Cl2
AgOTf/Et2O
AgCIO4/Et2O
TESOTf/CH2Cl2
TfOH/CH2Cl2
poor yield and selectivity
60
50
74
80
59
(1:2.5)
(1:1)
(1:9)
(1:1)
(1:0)
vi
NBS/CH2Cl2/7 days
Israel Journal of Chemistry
40
2000

257
vi. Thus, the good yield notwithstanding, the 7-day pling of NPOE 17 and the acetonide 18 afforded the
reaction time was a strong disincentive.
pseudo-disaccharide 19. The material was saponified to
The sequence in the traditional strategy outlined in give 20, which was subjected to a variety of Mitsunobu
Scheme 1 is (a) to prepare the C2-azido donor (e.g., 4), displacement conditions.39 The results were uniformly
and then (b) carry out the (hopefully) α-coupling to give unavailing. Binkley and coworkers have demonstrated
1. The alternative of carrying out the α-coupling before the advantage of C2-triflates in displacement reac-
azide installation, could be advantageous in view of the tions;40 but with the triflate from 20, β-elimination to
ease of obtaining α-mannosides. In this context, we give hex-2-enopyranosides such as 21 (Scheme 3b) was
have found that n-pentenyl-1,2-orthoesters (NPOEs) are the major reaction.
excellent donors; and the fact that the products are con-
In light of the last result, we were struck by a report
veniently acylated at C2 enhances their attractiveness.34 from DeShong’s laboratory on the use of hypervalent
Indeed coupling NPOE 1335 with acceptor 11a af- silicon derivatives in nucleophilic displacements41
forded disaccharide 14a in good yield. Conversion into (Scheme 4a). Particularly impressive was the virtually
ketone 15 proceeded smoothly (Scheme 3a); however, quantitative azide displacement of phenethyl bromide
attempts to apply the Lemieux–Gunner strategy for α- with reagent 22 (Scheme 4b) in a setting where β-
glucosaminide formation involving oximation followed elimination was highly favored. The result in Scheme 4c
by borane reduction36 led to decomposition. On the enhanced our enthusiasm even though, being a β-
other hand, reductive amination of 15 under standard mannoside, substrate 23 would be a better candidate38
conditions37 proceeded in excellent yield, but gave the for the observed displacement to 24 than the α-anomers
manno-product 16 rather than the desired gluco-isomer. of interest to us.
Nucleophilic displacement at C2 of sugars is tradi-
The two examples in Scheme 5 show that success
tionally problematic;38 but it was hoped that modern with this strategy is possible. Thus the α-linked pseudo-
methods might facilitate the process. Accordingly, cou- disaccharides 26 (a, b, and c) have been prepared in
Scheme 3
Fraser-Reid et al. / Strategies for Stereocontrol at C1 or C2 in Syntheses of α-Glucosaminides

258
Scheme 4
Scheme 5
Acknowledgments. We are grateful to the Research in Tropical
Diseases (TDR) program of the World Health Organization
and the National Institutes of Health (GM 40171) for support.
MGM thanks the CSIC of Spain for a fellowship.
very good yields, and saponification led to alcohols 27
(a, b, and c, respectively). The corresponding triflates
were stable enough to withstand column chromatogra-
phy; however, normally the crude materials were di-
rectly subjected to the displacement. Scheme 5 shows
that the yields for the two steps were moderate to good.
In summary, the C2 and C1 stereocenters of α-
glucosaminides can be cleanly established by first in-
stalling either the C1 or C2 functionality. For the
former, the restraining effect of a 4,6-O-benzylidene
ring operating in a C2-azido donor, can be used to
induce α-coupling. For the latter, a manno-1,2-ortho-
ester donor (a) ensures clean α-coupling and (b) pro-
vides a convenient C2-ester, ready to be replaced with a
triflate leaving group for displacement with DeShong’s
hypervalent silicon azide.
EXPERIMENTAL
General Methods
Solvents of commercial anhydrous grade have been used.
All reactions were conducted under an inert argon atmosphere.
TLC plates (Riedel-de Haen, coated with silica gel 60 F 254)
were detected by UV. Silica gel (Spectrum SIL 58, 230-400
mesh, grade 60) was used for column chromatography. All
NMR spectra were recorded at 25 °C at 400/300 MHz (1H) or
100/75 MHz (13C), and chemical shifts are reported relative to
internal TMS. Accurate mass measurements were made using
FAB at 10 K resolution.
Israel Journal of Chemistry
40
2000

259
1-O-Allyl-2,3,4,5-tetra-O-benzyl-6-O-(2-O-benzoyl-3,4,6- of water. The solvent was evaporated off and the residue on
tri-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol (14a). A flash column chromatography (4:1 EtOAc–Hexane) afforded
mixture of donor 13 (208 mg, 0.335 mmol) and acceptor 11a the amine. It was redissolved in MeOH (2.5 mL) and added
(150 mg, 0.258 mmol) was dried by azeotropic distillation Ac2O (0.5 mL). After stirring for 14 h the solvent was evapo-
with toluene, kept under vacuum overnight, and then dis- rated off and the residue on flash column chromatography (2:3
solved in dry CH2Cl2 (3 mL). N-Iodosuccinimide (76 mg, EtOAc–Hexane) afforded the mannosamino derivative 16 (24
0.335 mmol) was added to the solution; after stirring for 3 min, mg, 0.023 mmol, 47% [overall yield]) as the major product.
TBDMSOTf (18 mL, 0.077 mmol) was added. The reaction
1H NMR (400 MHz, CDCl3): δ 7.42 - 7.03 (m, ArH), 5.97–
was quenched after 20 min with 10% aq sodium thiosulfate 5.88 (m, 2H), 5.46 (bs, 1H), 5.25–5.15 (m, 2H), 4.96–4.31 (m,
and saturated sodium bicarbonate (1:1), and extracted with 14H), 4.21–3.96 (m, 8H), 3.71–3.66 (t, J=9.6 Hz, 1H), 3.38–
CH2Cl2. The organic layer was separated, dried, and the sol- 3.35 (dd, J=10, 2 Hz, 1H), 3.34–3.29 (t, J=9.6 Hz, 1H), 3.24–
vent was removed under reduced pressure. The crude residue 3.20 (m, 3H), 1.96 (s, 3H).
on flash column chromatography (1:4 EtOAc–Hexane) af-
forded 14a (225 mg, 0.20 mmol, 78%) as colorless semisolid.
1H NMR (400 MHz, CDCl3): δ 8.07–8.04 (d, 2H, Ar-H),
7.52–7.06 (m, 38H, Ar-H), 5.95–5.85 (m, 1H), 5.71–5.70 (dd,
J=2, 2.4 Hz, 1H), 5.64–5.63 (d, J=1.6 Hz, 1H), 5.24–5.09 (m,
2H), 4.97–4.46 (m, 14H), 4.31–4.25 (m, 2H), 4.15–3.98 (m,
7H), 3.45–3.33 (m, 3H), 3.27–3.24 (dd, J=9.6, 2 Hz, 1H).
13C NMR: δ 165.52, 138.94, 138.74, 138.60, 138.18,
134.29, 132.86, 130.02, 129.91, 128.34, 128.25, 128.18,
128.12, 128.06, 128.02, 127.94, 127.83, 127.68, 127.60,
127.41, 127.34, 127.17, 117.55, 98.20, 81.90, 81.60, 81.39,
80.79, 78.15, 75.81, 75.56, 74.99, 74.34, 73.87, 73.17, 73.05,
72.63, 71.36, 71.23, 69.02, 68.49.
FABMS: m/z 1054.4 (MH+)
1,2-O-Isopropylidine-3,4,5-tri-O-benzyl-6-O-(2-O-ben-
zoyl-3,4-di-O-benzyl-6-O-[t-butyldiphenylsilyl]-α-D-
mannopyranosyl)-D-myo-inositol (19). A mixture of donor 17
(142 mg, 0.18 mmol) and acceptor 18 (70 mg, 0.14 mmol) was
dried by azeotropic distillation with toluene, kept under
vaccuum overnight, and then dissolved in dry CH2Cl2 (3 mL).
N-Iodosuccinimide (42 mg, 0.18 mmol) was added to the
solution; after stirring for 3 min, BF3OEt2 (5 µL, 0.04 mmol)
was added. The reaction was quenched after 30 min with 10%
aq sodium thiosulfate and saturated sodium bicarbonate (1:1),
and extracted with CH2Cl2. The organic layer was separated,
dried, and the solvent removed under reduced pressure. The
crude residue on flash column chromatography (1:4 EtOAc–
Hexane) afforded 19 (70 mg, 0.06 mmol, 43%) [89% yield
based on recovered acceptor 18 (36 mg, 0.073 mmol)].
1H NMR (400 MHz, CDCl3): δ 8.17–8.14 (m, Ar-H, 2H),
7.75–6.86 (m, Ar-H, 38H), 5.75–5.73 (dd, J=3.2, 2 Hz, 1H),
5.563–5.559 (d, J=1.6 Hz, 1H), 4.96–4.51 (m, 10H), 4.33–
4.28 (t, J=9.6 Hz, 1H), 4.20–3.75 (m, 8H), 3.67–3.64 (dd,
J=3.6, 8.8 Hz, 1H), 3.28–3.23 (t, J=9.6 Hz, 1H), 1.51 (s, 3H),
1.32 (s, 3H), 1.098 (s, 9H).
1-O-Allyl-2,3,4,5-tetra-O-benzyl-6-O-(3,4,6-tri-O-benzyl-
α-D-mannopyranosyl)-D-myo-inositol (14b). The benzoate
14a (210 mg, 0.187 mmol) was dissolved in CH2Cl2/MeOH
(1 mL/4mL) solvent mixture and NaOMe (4.5 mg, 0.187
mmol) was added. The reaction mixture was stirred for 14 h
and the solvent was evaporated off. The residue on flash
column chromatography (1:3 EtOAc–Hexane) afforded the
alcohol 14b (180 mg, 0.18 mmol, 95%).
1H NMR (400 MHz, CDCl3): δ 7.42–7.06 (m, 35H, ArH),
5.89–5.79 (m, 1H), 5.505–5.501 (d, J=1.6Hz, 1H), 5.29–5.16
(m, 2H), 4.94–4.39 (m, 14H), 4.25–4.21 (m, 2H), 4.12–3.83
(m, 8H), 3.37–3.24 (m, 3H), 3.18–3.15 (dd, J=10, 2 Hz, 1H),
2.40 (d, 1H, -OH).
13C NMR: δ 138.86, 138.74, 138.59, 138.24, 134.24, 128.37,
128.27, 128.16, 128.07, 127.98, 127.87, 127.70, 127.63, 127.49,
127.41, 127.33, 127.27, 127.16, 117.15, 100.11, 81.97, 81.72,
81.35, 80.83, 80.12, 76.30, 75.79, 75.46, 74.78, 74.17, 73.90,
73.25, 72.90, 72.67, 71.83, 70.90, 70.83, 68.65, 68.15.
FABMS m/z: 1013 (MH+), 1145 (M+CS+).
FABMS: m/z 1173.4 (M+-1).
1,2-O-Isopropylidine-3,4,5-tri-O-benzyl-6-O-(3,4-di-O-
benzyl-6-O-[t-butyldiphenylsilyl]-α-D-mannopyranosyl)-D-
myo-inositol (20). The benzoate 19 (30 mg, 0.025 mmol) was
dissolved in CH2Cl2/MeOH (1 mL/2mL) solvent mixture and
NaOMe (2 mg, 0.025 mmol) was added. The reaction mixture
was stirred for 4 days and the solvent was removed. The
residue on flash column chromatography (1:4 EtOAc–Hex-
ane) afforded the alcohol 20 (26 mg, 0.024 mmol, 97%).
1H NMR (400 MHz, CDCl3): δ 7.69–6.91 (m, ArH, 35H),
5.563–5.559 (d, J=1.6 Hz, 1H), 4.90–4.59 (m, 10H), 4.19–
4.17 (dd, J=4.8, 4.4 Hz, 1H), 4.08–3.95 (m, 5H), 3.90–3.83
(m, 2H), 3.748–3.743 (d, J=2 Hz, 2H), 3.66–3.63 (dd, J=3.6,
8.8 Hz, 1H), 3.26–3.21 (t, J=8.8 Hz, 1H), 2.354–2.344 (d, 1H,
-OH), 1.56 (s, 3H), 1.33 (s, 3H), 1.02 (s, 9H).
13C NMR: δ 138.82, 138.53, 138.13, 137.97, 137.82,
135.85, 135.60, 133.75, 133.26, 129.42, 128.44, 128.38,
128.31, 128.13, 128.03, 127.92, 127.88, 127.82, 127.72,
127.58, 127.48, 127.34, 127.29, 110.06, 97.25, 80.91, 80.65,
79.67, 79.46, 76.87, 76.49, 75.65, 75.31, 75.03, 74.60, 74.03,
73.22, 72.17, 71.81, 68.65, 62.91, 27.85, 26.84, 25.96, 19.26.
FABMS: m/z 1069.5 (M+-1).
1-O-Allyl-2,3,4,5-tetra-O-benzyl-6-O-(2-Acetamido-
3,4,6-tri-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol
(16). The alcohol 14b (50 mg, 0.048 mmol) was dissolved in 5
mL solvent mixture DMSO/Ac2O (2:1) and stirred for 16 h
(complete conversion, by TLC). The reaction mixture was
diluted with CH2Cl2 (25 mL), washed with H2O (3 × 10 mL).
The aq layer was extracted with CH2Cl2 (3 × 10 mL). The
organic layer was separated, dried, and the solvent evaporated
off. The ketone 15 was dried under high vaccuum. NaBH3CN
(3 mg, 0.048 mmol) and NH4OAc (37 mg, 0.48 mmol) were
added and the mixture dissolved in methanol (2 mL). After
stirring for 3 h the reaction mixture was quenched with drops
Fraser-Reid et al. / Strategies for Stereocontrol at C1 or C2 in Syntheses of α-Glucosaminides

260
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(2-O-ben-
1H NMR (300 MHz, CDCl3): δ 7.39–7.02 (m, 30H, Ar-H),
zoyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol 5.617–5.604 (d, J=3.9Hz, 1H), 4.89–4.318 (m, 12H), 4.29–
(26a). A mixture of donor 13 (305 mg, 0.49 mmol) and accep- 4.27 (t, J=5.1, 3.6 Hz, 1H), 4.20–4.16 (t, J=6.6 Hz, 1H), 4.12–
tor 11b (200 mg, 0.377 mmol) was dried by azeotropic distilla- 3.90 (m, 4H), 3.80–3.70 (m, 2H), 3.49–3.36 (m, 4H), 1.77–
tion with toluene, kept under vaccuum overnight, and then 1.24 (m, 10H).
dissolved in dry CH2Cl2 (3 mL). N-Iodosuccinimide (110 mg,
0.049 mmol) was added to the solution; after stirring for 3 min,
BF3OEt2 (14.1 µL, 0.113 mmol) was added. The reaction was
quenched after 20 min with 10% aq sodium thiosulfate and
saturated sodium bicarbonate (1:1), and extracted with
CH2Cl2. The organic layer was separated, dried, and the sol-
vent removed under reduced pressure. The crude residue on
flash column chromatography (1:5 EtOAc–Hexane) afforded
26a (289 mg, 0.27 mmol, 72%).
IR (KBr, film): 2104.7 cm-1.
FABMS: m/z 988 (MH+).
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(2-O-ben-
zoyl-3,4-di-O-benzyl-6-O[t-butyldiphenylsilyl]-α-D-manno-
pyranosyl)-D-myo-inositol (26b). The acceptor 11b (100 mg,
0.18 mmol) and glycosyl donor 17 (200 mg, 0.25 mmol) were
together taken up in a small quantity of toluene, azeotroped to
remove traces of water and then placed under high vaccuum
overnight. The mixture was dissolved in dry CH2Cl2 (3 mL)
under argon atmosphere. N-Iodosuccinimide (58.5mg, 0.26
mmol) was added to the solution; after stirring for 3 min,
BF3OEt2 (7.5 µL, 0.06mmol) was added. The reaction was
quenched after 40 min with 10% aq sodium thiosulphate and
saturated sodium bicarbonate (1:1), and extracted with
CH2Cl2. The organic layer was separated, dried, and the sol-
1H NMR (400 MHz, CDCl3): δ 8.09–8.07 (m, 2H, ArH),
7.53–7.01 (m, 33H, Ar-H), 5.72–5.70 (dd, J=2, 2.4 Hz, 1H),
5.536–5.531 (d, J=2 Hz, 1H), 4.89–4.39 (m, 12H), 4.27–4.06
(m, 6H), 3.91–3.87 (t, J=8 Hz, 1H), 3.76–3.69 (m, 2H), 3.59–3.56
(m, 1H), 3.35–3.30 (dd, J=8.4, 8 Hz, 1H), 1.77–1.33 (m, 10H).
FABMS: m/z 1065.4 (M+-1).
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(3,4,6-tri- vent removed under reduced pressure. The crude residue on
O-benzyl-α-D-mannopyranosyl)-D-myo-inositol (27a). The flash column chromatography (1:10 EtOAc–Hexane) afforded
benzoate 26a (289 mg, 0.27 mmol) was dissolved in CH2Cl2 / 26b (118 mg, 70 %) as a colorless paste [yield is based on
MeOH (2mL/6mL) solvent mixture, and NaOMe (150 mg, recovered acceptor 11b (25 mg, 0.047 mmol)].
excess) was added. The reaction mixture was stirred for 24 h
and the solvent was evaporated off. The residue on flash 74–7.72 (d, ArH, 2H), 7.67–7.64 (d, ArH, 2H), 7.53–7.50 (t,
1H NMR (300 MHz, CDCl3): δ 8.17–8.14 (d, ArH, 2H), 7.
column chromatography (1:4 EtOAc–Hexane) afforded 27a 1H, ArH), 7.41–6.85 (m, 33H, ArH), 5.75–5.73 (t, J=2.1 Hz,
(195 mg, 0.20 mmol, 75%).
1H), 5.60 (bs, 1H), 4.95–4.50 (m, 10H), 4.31–4.24 (t, J=9.6
1H NMR (300 MHz, CDCl3): δ 7.38–7.20 (m, 30H, ArH), Hz, 1H), 4.22–4.19 (t, J=4.5 Hz, 1H), 4.11–3.96 (m, 3H),
5.53 (bs, 1H), 4.84–4.33 (m, 12H), 4.25–4.21 (m, 1H), 4.11– 3.87–3.73 (m, 3H), 3.68–3.64 (dd, J1, J2=4.2, 9.3 Hz), 3.28–
3.85 (m, 7H), 3.69–3.44 (m, 3H), 3.30–3.24(dd, J=8.1 Hz, 3.22 (t, J=9.6 Hz, 1H), 1.76–1.72 (m, 2H), 1.60–1.55 (m, 6H),
10.2 Hz, 1H). 2.30 (bs, 1H, OH), 1.78–1.26 (m, 10H).
1.35–1.33 (m, 2H), 1.08 (s, 9H).
13C NMR: d 138.75, 138.43, 138.33, 138.17, 138.88,
13C NMR (75 MHz, CDCl3): δ 165.77(OCOPh), 139.00,
128.38, 128.28, 128.12, 127.89, 127.83, 127.54, 127.41, 138.59, 138.20, 138.08, 137.74, 135.87, 135.63, 133.69,
127.31, 110.77, 97.42, 80.88, 80.75, 79.59, 78.71, 77.23, 133.29, 133.00, 130.07, 129.52, 129.42, 128.39, 128.36,
76.81, 75.38, 74.84, 74.16, 73.99, 73.06, 72.96, 71.70, 70.76, 128.32, 128.11, 127.98, 127.88, 127.82, 127.73, 127.64,
68.53, 37.13, 35.06, 24.91, 23.85, 23.56.
127.55, 127.48, 127.36, 127.20, 110.82, 96.20, 80.82, 80.70,
78.81, 77.89, 77.20, 75.71, 75.27, 75.15, 74.09, 74.03, 73.07,
72.38, 71.33, 69.21, 62.85, 37.42, 35.10, 26.85, 24.95, 23.82,
23.66, 19.37.
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(2-azido-
3,4,6-tri-O-benzyl-α-D-glucopyranosyl)-D-myo-inositol
(28a). The alcohol 27a (45 mg, 0.046 mmol) was dissolved in
3 mL CH2Cl2 and cooled to –78 °C. Pyridine (0.3 mL) and
DMAP (catalytic) was added to the reaction mixture followed
by Tf2O (79 mL, 0.46 mmol). The temperature was allowed to
rise gradually to room temperature and the reaction mixture
was stirred for 24 h. The solvent was evaporated off and the
residue on flash column chromatography (1:4 EtOAc–Hex-
ane) afforded the triflate (51 mg, 0.046 mmol) in almost
quantitative yield. The triflate (24 mg, 0.022 mmol) was dis-
solved in dry THF (2 mL), and TMSN3 (7.4 mL, 0.055 mmol)
and TBAF (44 mL of 1M solution in THF) were added. The
reaction mixture was stirred at 70 °C for 24 h. The solvent was
evaporated off and the residue on flash column chromatogra-
phy (1:5 EtOAc–Hexane) afforded the azide 28a (16 mg,
0.016 mmol, 74%) as the major product. [The Rf value of the
azide was the same as the triflate.] The side product due to
elimination was not characterized due to the decomposition
after isolation.
FABMS m/z: 1213 (M+-1).
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(3,4-di-O-
benzyl-6-O-[t-butyldiphenylsilyl]-α-D-mannopyranosyl)-D-
myo-inositol (27b). The disaccharide 26b (75 mg, 0.06 mmol)
was dissolved in CH2Cl2/MeOH ( 1 mL/3 mL) solvent mixture
and NaOMe (9.7 mg, 0.18 mmol) was added to it and stirred at
RT under argon atmosphere. The solvent was evaporated off
after 24 h and the residue on flash column chromatography
[1:4 EtOAc–Hexane] afforded 27b (50 mg, 0.045 mmol, 74%)
as a colorless paste.
1H NMR (300 MHz, CDCl3): δ 7.68–7.62 (m, 4H, ArH),
7.41–6.90 (m, 31H, ArH), 5.60 (bs, 1H, H-1), 4.89–4.55 (m,
10H), 4.21–4.18 (t, 1H, J=3.6 Hz), 4.09–3.83 (m, 8H), 3.74
(bs, 1H), 3.67–3.62 (dd, J1, J2=3.9, 9.0 Hz, 1H), 3.26–3.19 (t,
1H, J=9.6 Hz), 2.36–2.35 (d, 1H, J=3.6 Hz), 1.82–1.78 (m,
2H), 1.64–1.54 (m, 6H), 1.39–1.36 (m, 2H), 1.01 (s, 9H).
FABMS m/z: 1109 (M+-1).
Israel Journal of Chemistry
40
2000

261
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(2-azido- 5.87–5.76 (m, 1H), 5.49 (s, 1H), 5.20–5.06 (m, 2H), 4.80–4.34
3,4-di-O-benzyl-6-O-[t-butyldiphenylsilyl]-α-D-gluco- (m, 10H), 4.30–4.42 (m, 2H), 4.09–3.65 (m, 9H), 3.55–3.42
pyranosyl)-D-myo-inositol (28b). The alcohol 27b (35 mg, (m, 2H), 3.31–3.25 (t, J=8.7 Hz, 1H), 2.39 (s, 1H, -OH), 1.78–
0.031 mmol) was dissolved in 2 mL CH2Cl2 and cooled to 1.25 (m, 10H).
–78 °C. Pyridine (0.5 mL) and DMAP (catalytic) was added to
the reaction mixture, followed by Tf2O (53 µL, 0.315 mmol).
The temperature was allowed to rise gradually to room tem-
perature and the reaction mixture was stirred for 24 h. The
solvent was evaporated off and the residue on flash column
chromatography [1:4 EtOAc–Hexane] afforded the triflate (38
mg) in almost quantitative yield. The triflate (20 mg, 0.016
mmol) was dissolved in dry THF (2 mL) and was added
TMSN3 (3.37 µL, 0.025 mmol) and TBAF (25 µL of 1M
solution in THF). The reaction mixture was stirred at 70 °C for
16 h. The solvent was evaporated off, and the residue on flash
column chromatography (1:10 EtOAc–Hexane) afforded the
azide 28b (12 mg, 0.01 mmol, 63%) as the major product.
[The Rf value of the azide was the same as the triflate.] The
side product due to elimination was not characterized due to
the decomposition after isolation.
FABMS: m/z 911.4 (M+-1).
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(2-azido-
4-O-allyl-3,6-di-O-benzyl-a-D-glucopyranosyl)-D-myo-inosi-
tol (28c). The alcohol 27c (500 mg, 0.55 mmol) was dissolved
in 9 mL CH2Cl2 and cooled to –78 °C. Pyridine (3 mL) and
DMAP (34 mg, 0.27 mmol) were added to the reaction mix-
ture, followed by Tf2O (599 µL, 2.75 mmol). The temperature
was allowed to rise gradually to room temperature, and the
reaction mixture was stirred for 24 h. The solvent was evapo-
rated off and the residue on flash column chromatography [1:4
EtOAc–Hexane] afforded the triflate (570 mg, 0.55 mmol) in
almost quantitative yield. The triflate (526 mg, 0.5 mmol) was
dissolved in dry THF (2 mL) and was added TMSN3 (101.2 µL,
0.75 mmol) and TBAF (750 µL of 1M solution in THF). The
reaction mixture was stirred at 70 °C for 24 h. The solvent was
evaporated off and the residue on flash column chromatogra-
phy (1:5 EtOAc–Hexane) afforded the azide 28c (235 mg,
0.25 mmol, 50%) as the major product. [The Rf value of the
azide was the same as the triflate.] The side product due to
elimination was not characterized due to the decomposition
after isolation.
1H NMR (300 MHz, CDCl3): δ 7.65–7.59 (m, 5H, ArH)
7.42–7.26 (m, 28H, ArH), 7.20–7.17 (d, 2H, ArH), 7.12–7.01
(m, 3H, ArH), 6.93–6.88 (t, 2H, ArH), 5.68–5.67 (d, 1H, J=3.6
Hz), 4.88–4.61 (m, 10H), 4.23–4.20 (t, 1H, J=4.5 Hz), 4.16–
4.12 (t, 1H, 5.1 Hz), 4.05–3.94 (m, 3H), 3.89–3.79 (m, 2H),
3.69–3.58 (m, 3H), 3.41–3.31 (m, 2H), 1.78–1.58 (m, 3H),
1.55–1.09 (7H), 1.01 (s, 9H).
1H NMR (300 MHz, CDCl3): δ 7.38–7.24 (m, 25H, ArH),
5.86–5.74 (m, 1H), 5.587–5.575 (d, J=3.6Hz, 1H), 5.17–5.08
(m, 2H), 4.87–4.31 (m, 10H), 4.27–3.85 (m, 8H), 3.73–3.69
(dd, J=3.9, 8.1 Hz, 1H), 3.63–3.57 (t, J=9.6 Hz, 1H), 3.43–
3.32 (m, 4H), 1.74–1.25 (m, 10H).
IR ( KBr, film) : 2106 cm–1.
FABMS: m/z 1134 ( M+ –1).
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(4-O-allyl-
2-O-benzoyl-3,6-di-O-benzyl-α-D-mannopyranosyl)-D-myo-
inositol (26c). A mixture of donor 25 (543 mg, 0.79 mmol) and
acceptor 11b (322 mg, 0.609 mmol) was dried by azeotropic
distillation with toluene, kept under vaccuum overnight, and
then dissolved in dry CH2Cl2 (5 mL). N-iodosuccinimide (180
mg, 0.79 mmol) was added to the solution; after stirring for 3
min, BF3OEt2 (22.7 µL, 0.182 mmol) was added. The reaction
was quenched after 20 min with 10% aq sodium thiosulfate
and saturated sodium bicarbonate (1:1), and extracted with
CH2Cl2. The organic layer was separated, dried, and the sol-
vent removed under reduced pressure. The crude residue on
flash column chromatography (1:4 EtOAc–Hexane) afforded
26c (490 mg, 0.48 mmol, 79%).
IR (KBr, film): 2104 cm-1
FABMS: m/z 938 (MH+)
REFERENCES AND NOTES
(1) Reinhart, K.L., Jr.; Suami, T., Eds. Aminocyclitol Anti-
biotics. ACS Symposium Series 125; American Chemi-
cal Society: Washington, DC, 1980. Claes, P.J. In Ana-
lytical Profiles in Drug Substances; Florey, K. Ed.;
Academic Press New York, 1977, Vol 6, pp 259–271.
(2) Ferguson, M.A.J.; Homans, S.W.; Dwek, R.A.;
Rademacher, T.W. Science 1988, 239, 753–759.
(3) McConville, M.; Ferguson, M.J. Biochem. J. 1993, 294,
305–324. Ferguson, M.A.J.; Brimacombe, J.S.; Brown,
J.R.; Crossman, A.; Diz, A.; Field, R.A.; Guther,
M.L.S.; Milne, K.G.; Sharma, D.K.; Smith, T.K. Bio-
chim. Biophys. Acta 1999, 1455, 327–340. Low, M.G.;
Saltiel, A.R. Science 1988, 239, 268–275.
(4) Ralton, J.E., McConville, M.J. J. Biol. Chem. 1998,
273, 4245–4257.
(5) Couto, A.S.; De Lederkremer, R.M.; Colli, W.; Alves,
M.J.M. Eur. J. Biochem. 1993, 217, 597–602.
(6) Schofield, L.; Hackett, F. J. Exp. Med. 1993, 171, 145–
153. Schofield, L.; McConville, M.J.; Hansen, D.;
Campbell, A.S.; Fraser-Reid, B. Science 1999, 283,
225–229.
1H NMR (300 MHz, CDCl3): δ 8.07–8.04 (m, 2H, Ar-H),
7.55–7.13 (m, 28H, ArH), 5.92–5.78 (m, 1H), 5.673–5.658 (t,
J=2.4 Hz, 1H), 5.502–5.495 (d, J=2.1 Hz, 1H), 5.17–5.05 (m,
2H), 4.83–4.40 (m, 10H), 4.36–4.23 (m, 2H), 4.12–3.53 (m,
10H), 3.35–3.29 (t, J=8.7 Hz, 1H), 1.76–1.25 (m, 10H).
1,2-O-Cyclohexylidine-3,4,5-tri-O-benzyl-6-O-(4-O-allyl-
3,6-di-O-benzyl-a-D-mannopyranosyl)-D-myo-inositol (27c).
The benzoate 26c (400 mg, 0.39 mmol) was dissolved in
CH2Cl2/MeOH (3mL/9mL) solvent mixture and NaOMe (131
mg, 2.4 mmol) was added. The reaction mixture was stirred
for 14 h and the solvent was removed under reduced pressure.
The residue on flash column chromatography (1:3 EtOAc–
Hexane) afforded the alcohol 27c (260 mg, 0.28 mmol, 72%).
1H NMR (300 MHz, CDCl3): δ 7.38 –7.23 (m, 25H, ArH),
(7) Luzzatto, L. Blood 1999, 94, 2941–2944.
(8) Stahl, N.; Borchelt, D.R.; Haiao, K.; Prusiner, S.B. Cell
Fraser-Reid et al. / Strategies for Stereocontrol at C1 or C2 in Syntheses of α-Glucosaminides

262
1987, 51, 229–240.
1978, 64, 339–364.
(9) Stacey, M.; Webber, J.M. Methods Carbohydr. Chem.
1962, 1, 228–230.
(25) Buskas, T.; Garegg, P.J.; Konradsson, P.; Maloisel,
J.-L. Tetrahedron: Asymmetry 1994, 5, 2187–2194.
(26) Madsen, R., Roberts, C.; Fraser-Reid., B. J. Org. Chem.
1995, 60, 7920–7926.
(27) Debenham, J.S.; Fraser-Reid, B. J. Org. Chem. 1996,
61, 432–433.
(28) Olsson, L.; Jia, Z.J.; Fraser-Reid. B. J. Org. Chem.
1998, 63, 3790–3792
(29) Madsen, R.; Udodong, U.E.; Roberts, C.; Mootoo, D.
R.; Konradsson, P.; Fraser-Reid, B. J. Am. Chem.
Soc.1995, 117, 1554–1565.
(30) Fraser-Reid, B.; Udodong, U.E.; Wu, Z.; Ottosson, H.;
Merritt, J.R.; Rao, C.S.; Roberts, C.; Madsen, R. Synlett
1992, 927–942.
(31) Andrews, C.W.; Rodebaugh, R. and Fraser-Reid, B. J.
Org. Chem. 1996, 61, 5280–5289. Fraser-Reid, B.; Wu,
Z.; Andrews, C.W.; Skowronski, E.; Bowen, J.P. J. Am.
Chem. Soc. 1991, 113, 1434–1435.
(32) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem., 2000, 65,
1291–1297. Chich, D.; Sun, S. J. Am. Chem. Soc. 1998,
120, 435–436.
(10) Weidmann, H.; Tartler, D.; Stockl, P.; Binder, L.;
Honig, U.H. Carbohydr. Res. 1973, 29, 135-140.
Micheel, F.; Van der Kamp, F.P.; Petersen, H. Chem.
Ber. 1957, 90, 521. Michael, F.; Kochlug, Chem. Ber.
1957, 90, 1597.
(11) Banoub, J.; Boullanger, P.; Lafont, D. Chem. Rev.
1992, 92, 1165–1195.
(12) Lemieux, R.; Takeda, T.; Chung, B. In Synthetic Meth-
ods for Carbohydrates; El Khadem, H.S., Ed.; ACS
Symposium Series 39; American Chemical Society:
Washington, DC, 1976; pp 90–115.
(13) Paulsen, H.; Stenzel, W.; Kolar, C. Tetrahedron Lett.
1977, 2785-2788.
(14) Lemieux, R.U.; Ratcliffe, R.M. Can. J. Chem., 1979,
57, 1244–1251.
(15) See for example, Lemieux, R.U.; Fraser-Reid, B.; Can.
J. Chem. 1964, 42, 532-538. Lemieux, R.U.;
Nagabhuskan, T.L.; O’Neill, I.K.; Can. J. Chem. 1968,
46, 413–418.
(16) See for example, Smith, P.A.S.; Rolc, J.H.H. J. Am.
Chem Soc. 1962, 84, 485–493.
(33) Wilson, B.G.; Fraser-Reid, B. J. Org. Chem. 1995, 60,
317–320
(17) Vasella, A.; Witzig, C.; Chiara, J.L.; Martin-Lomas, M.
Helv. Chim. Acta 1991, 74, 2073–2077.
(34) Allen, J.G.; Fraser-Reid, B. J. Am. Chem. Soc. 1999,
121, 468–469.
(18) Alper, P.B.; Hung S.-C.; Wong, C.-H. Tetrahedron
Lett. 1996, 37, 6029–6932.
(35) Roberts, C.; May, C.L.; Fraser-Reid, B. Carbohydr.
Lett. 1994, 1, 89–93. Roberts, C.; Madsen, R.; Fraser-
Reid, B. J. Am. Chem. Soc. 1995, 117, 1546–1553.
(36) Lemieux, R.U.; Gunner, S.W. Can. J. Chem. 1968, 46,
405–411.
(37) See for example, Balogh, E.R.; Zsadon, B.; Csampai,
A.; Pal, R. Synth. Commun. 1994, 24, 701–707.
(38) Richardson, A.C. Carbohydr. Res. 1969, 10, 395–402.
(39) Mitsunobu, O. Synthesis 1981, 1. Simon, C.; Hosztafi,
S.; Makleit, S. J. Heterocyclic Chem. 1997, 34, 349–
365.
(19) Anilkumar, G.; Gilbert, M.R.; Fraser-Reid, B. Tetrahe-
dron 2000, 56, 1993–1997 and references therein.
(20) Low, M.G.; Saltiel, A.R. Science 1988, 239, 268–275.
(21) Hrafnsdottir, S.; Nichols, J.W.; Menon, A.K. Biochem-
istry 1997, 36, 4969–4978).
(22) Campbell, A.S.; Fraser-Reid, B. J. Am. Chem. Soc.
1995, 117, 10387–10388. Mootoo, D.R.; Konradsson,
P.; Fraser-Reid, B. J. Am. Chem. Soc. 1989, 111, 8540–
8542.
(23) Baeschlin, D.K.; Chaperson, A.R.; Charbonneau, V.;
Green, L.G.; Ley, S.V.; Lucking, U.; Walther, E.
Angew. Chem., Int. Ed. Engl. 1998, 37, 3423–3428.
Baeschlin, D.K.; Chaperon, A.R.; Green, L.G.; Hahn,
M.G.; Ince, S.J.; Ley, S.V. Chem.—Eur. J. 2000, 6, 172–
186. Tailler, D.; Ferrieres, V.; Pekari, K., Schmidt, R.R.
Tetrahedron Lett. 1999, 40, 679–682.
(40) Binkley, R.; Binkley. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker, New
York, 1997.
(41) Soli, E.D.; Manoso, A.S.; Patterson, M.C.; DeShong,
P.; Favor, D.A.; Hirschmann, R.; Smith, A.B.III. J.
Org. Chem. 1999, 64, 3171–3177.
(42) Anilkumar, G.; Nair, L G.; Olsson, L.; Daniels, J.K.;
Fraser-Reid, B. Tetrahedron Lett. 2000, 41, 7605–7608.
(24) Paulsen, H.; Richter, A.; Stenzel, W. Carbohydr. Res.,
Israel Journal of Chemistry
40
2000