Constrained 3,6-anhydro-heptosides: Synthesis by a dast-induced debenzylative reaction, and reactivity profile

Article abstract of DOI:10.1002/ejoc.201301071

We report the first synthesis of a conformationally constrained 3,6-anhydroheptoside analogue of D-glycero-D-manno-heptopyranose 7-phosphate by a DAST (diethylaminosulfur trifluoride)-induced intramolecular cycloetherification. The reactivity of a series

Full text of DOI:10.1002/ejoc.201301071

FULL PAPER
DOI: 10.1002/ejoc.201301071
Constrained 3,6-Anhydro-Heptosides: Synthesis by a DAST-Induced
Debenzylative Reaction, and Reactivity Profile
Abdellatif Tikad[a] and Stéphane P. Vincent*[a]
Keywords: Carbohydrates / Glycosylation / Phosphorylation / Cyclization / Conformation analysis
We report the first synthesis of a conformationally con-
strained 3,6-anhydroheptoside analogue of -glycero-
manno-heptopyranose 7-phosphate by a DAST (diethyl-
aminosulfur trifluoride)-induced intramolecular cycloetherifi- heptose series, a reversal of chair conformation leads to an
in glycosylation reactions and compared with the reactivities
of related unconstrained mannose and heptose scaffolds.
Competition experiments confirmed that in the -manno-
D
D-
D
cation. The reactivity of a series of constrained bicyclic 3,6-
anhydro-thioheptosides as glycosyl donors was also studied
enhancement of the anomeric reactivity.
(IC50 = 34 μm) and HldE (IC50 = 9.4 μm) in the low micro-
molar range (Figure 1). In this paper, we report the first
synthesis of conformationally constrained 3,6-anhydro-
heptoside 1 (Figure 1), an analogue of d-glycero-d-manno-
heptopyranose 7-phosphate (H7P), by a DAST (diethyl-
aminosulfur trifluoride)-induced debenzylative reaction.
The synthesis of 3,6-anhydrosugars is rarely described in
the literature, despite their natural occurrence in algal poly-
saccharides.[3] Due to their perfectly defined and con-
strained conformations, polycyclic glycosides are also con-
stitute useful substrates for investigating the fundamental
parameters dictating the kinetics and the stereoselectivities
of glycosylation reactions (stereoelectronic effects, arming/
disarming effects, etc.).[4]
Introduction
The main polysaccharide present on the surface of
Gram-negative bacteria is the lipopolysaccharide (LPS).
This molecule plays key roles in the mortality of many in-
fectious diseases as well as in the virulence of many human
pathogens, and l-heptose (l-glycero-d-manno-heptopyr-
anose) is a constituent of its inner core (Figure 1).[1]
Therefore, we not only describe the synthesis of a new
constrained analogue of H7P, but we also compare the reac-
tivity profile of 3,6-anhydro-heptosides with those of the
corresponding heptose and mannose building blocks.
Figure 1. Target molecule.
We recently reported the synthesis of a series of d-
glycero-d-manno-heptopyranose 7-phosphate (H7P) ana-
logues and also the results of testing their inhibition proper-
ties against the isomerase GmhA and the kinase HldE, the
two first enzymes of the bacterial heptose biosynthetic
pathway.[2] The isomerase GmhA is a keto–aldose iso-
merase, and it is responsible for the transformation of se-
doheptulose-7-phosphate into d-glycero-d-manno-heptose
7-phosphate. The epimeric analogue 2 of H7P with the d-
gluco configuration in the pyranose ring moiety was found
to be the best inhibitor of both enzymes. It inhibited GmhA
Results and Discussion
For the synthesis of d-glycero-d-manno-heptose scaffolds
1
with a locked C4 conformation, we followed the general
synthetic pathway shown in Scheme 1. This strategy relies
on the known pathway described in the literature for the
construction of d-heptosides.[5] Starting alkene 5 was ob-
tained by Swern oxidation of alcohol 4, prepared from d-
mannose by the general procedure described by Martin-
Lomas et al.,[6] directly followed by a Wittig olefination
(Scheme 1). The subsequent dihydroxylation gave 6(d,l) in
74% yield as a mixture of diastereomers (d/l = 2:1).[2a] Pure
l-glycero diol 6(l) could be separated at this stage by careful
silica gel chromatography, and it was transformed into the
desired 7-silylated heptoside [i.e., 8(l)] under standard con-
[a] Chemistry Department, University of Namur,
Rue de Bruxelles 61, 5000 Namur, Belgium
E-mail: stephane.vincent@unamur.be
https://www.unamur.be/sciences/chimie/uco
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301071.
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Scheme 1. Reagents and conditions. i) K2OsO4(H2O)2, K3Fe(CN)6, K2CO3, tBuOH/H2O (1:1), 0 °C to room temp., 4 d; ii) BnBr, NaH,
DMF, 0 °C to r.t., 20 h; iii) TIPSCl (triisopropylsilyl chloride), imidazole, THF, 0 °C to r.t., 16 h; iv) a) p-NO2C6H4CO2H, PPh3, DIAD
(diisopropyl azodicarboxylate), room temp., 44 h, b) K2CO3, MeOH, room temp., 4 h; v) DAST (1.5 equiv.), CH2Cl2, –78 °C to r.t., 2 h.
ditions in good yield. Treatment of diol 6(l) with benzyl
bromide and sodium hydride in dry DMF gave donor 7 in
84% yield.
Next, to obtain a significant amount of l-heptoside 8(l),
the minor product of the dihydroxylation step, the absolute
configuration at C-6 of 8(d) was inverted under standard
Mitsunobu conditions in the presence of p-nitrobenzoic
acid. Hydrolysis of the resulting ester gave 8(l) in 70%
yield[7] over two steps, with just a single purification
(Scheme 1).
Treatment of compound 8(l) with DAST in dichloro-
methane at –78 °C gave 10 as the major product in 63%
isolated yield (Scheme 1).[8] A small amount of by-product
11 (11%), fluorinated at C-1, was isolated after purification
by flash chromatography. No trace of fluorinated com-
pound 9 was observed, which indicates that the cycloether-
ification reaction to give constrained 3,6-anhydroheptoside
10 was highly selective (Scheme 1). It should be noted that
8(d) did not undergo 3,6-anhydrosugar formation upon
treatment with DAST, but rather it gave rise to a complex
mixture of undefined products.
Figure 2. Schematic representation of cross-peaks observed in 2D
NMR experiments with compounds 10 [2-H–CH2Bn (HMBC); 4-
H–CH2Bn (HMBC); 3-H–C-6 (HMBC); 1-H–6-H (NOESY)] and
11 [2-H–CH2Bn (HMBC); 4-H–CH2Bn (HMBC); 3-H–C-6
(HMBC); 1-H–2-H (NOESY)] on which the assignment of peaks
was based.
The structures of 10 and 11 were fully ascertained by
NMR spectroscopy, using 1H, 13C, 19F, 1H,1H COSY,
1
1H,1H NOESY, and H,13C (HSQC, HMBC) spectra (Fig-
ure 2). The conformation of 10 was confirmed by its 3J cou-
pling constants. The trans-diaxial relationship between 1-H
The formation of 10 is clearly the result of a cycloether-
and 2-H (3J1,2 = 8.7 Hz), and the small coupling constant ification reaction, and its plausible mechanistic pathway is
between 4-H and 5-H (3J4,5 = 2.8 Hz) indicated that this shown in Figure 3. Activation of the hydroxy group at C-6
pyranoside ring was in the inverted (1C4) chair conforma- of 8(l) in the presence of DAST provides intermediate 8a,
tion.
which can be transformed into benzyloxonium 8b by attack
In addition, the 1H NMR spectrum showed only 4 benz- by the favourably positioned benzyloxy group at C-3 of the
ylic protons and 10 aryl protons, which strongly suggested pyranoside in its 1C4 conformation. The Newman represen-
that the molecule had rearranged to form the anhydrosugar tation nicely illustrates that the conformation necessary to
ring. Further confirmation of the structure was obtained establish the inversion of configuration at C-6 is favourable
from two-dimensional NMR experiments and high-resolu- (Figure 3). Finally, cleavage of the benzyl group at C-3 is
tion mass spectrometry (Figure 2). A survey of the litera- probably carried out by the fluoride anion present in the
ture informed us that the formation of 3,6-anhydrosugars medium, to give 3,6-anhydroheptoside 10 (Figure 3).
by a debenzylative reaction in the presence of diethyl-
Next, we decided to explore the reactivity profile of this
aminosulfur trifluoride had been already observed.[9] How- heptosidic scaffold. In particular, we were interested in es-
ever, the reaction has not yet been reported for a heptosidic tablishing whether such a constrained molecule could be
structure.
further modified at the 7-position, for potential biochemical
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Constrained 3,6-Anhydro-Heptosides
Scheme 2. Reagents and conditions: i) TBAF (tetrabutylammonium
fluoride), THF, 0 °C to room temp., 1.5 h; ii) BnBr, NaH, DMF,
0 °C to r.t., overnight; iii) HOPO(OBn)2, PPh3, DEAD (diethyl
azodicarboxylate), Et3N, THF, room temp., 16 h; iv) N-chlorosuc-
cinimide, MeOH, room temp., 40 min.
Figure 3. Plausible mechanism for DAST-induced formation of 3,6-
anhydrosugar 10 from 8(l).
applications. Furthermore, with this 3,6-anhydro structure,
1
we could address the effect of the C4 conformational re-
striction on the reactivity at the anomeric position. For
both studies, we decided to synthesize thioglycosides 12 and
13 and to explore their reactivities.
Derivatization of 3,6-Anhydro-Heptosides at the 7-Position
Figure 4. Mechanism of the six-membered-ring-opening reaction.
Desilylation of 10 in the presence of tetrabutylammo-
nium fluoride gave 12, and subsequent benzylation under
classical conditions led to tribenzylated heptoside 13 in
good yield (Scheme 2). Mitsunobu phosphorylation of
alcohol 12 gave the product in only 25% isolated yield Thus, compound 8(l) was treated under the same meth-
(Scheme 2). Once the phosphate group was installed at the anolysis conditions previously described for 14. After 3 h,
7-position, the removal of the anomeric thiophenyl group the desired heptosides (i.e., 18 and 19) were isolated in 52
had to be addressed. Therefore, we carried out methanolysis and 40% yields, respectively (Scheme 3). To study the effect
of thioglycoside 14 in the presence of N-chlorosuccinimide of the C-1 substituent on the debenzylative 3,6-an-
(NCS) and 4 Å molecular sieves in dry methanol. Surpris- hydrosugar formation, we prepared the 1-deoxy-heptoside
ingly, this apparently straightforward transformation gave derivative 20 from 8(l) by ready cleavage of the phenylsulf-
C-ribofuranoside derivative 15 as the major product in 72% anyl group in the presence of Raney nickel (Scheme 3).[12]
yield, along with the desired heptosides (i.e., 16 and 17) in The target 3,6-anhydroheptosides (i.e., 21–23) were formed
10 and 6% yields, respectively (Scheme 2).
in few hours in good to excellent yields, irrespective of the
As shown in Figure 4, the formation of by-product 15 nature of the substrate (i.e., 18–20).
can be explained as coming from heptosides 16 and 17,
Classical desilylation of compounds 21 and 22 followed
which can undergo endo ring-opening reactions[10] catalysed by hydrogenolysis gave unprotected 3,6-anhydro-l-heptos-
by hydrochloric acid generated in situ. Similar ring-opening ides 25 and 27 in 64 and 53% yields, respectively, over two
reactions were observed by Haworth et al. during the hy- steps (Scheme 3). Finally, the synthesis of compound 1 was
drolysis of various 3,6-anhydrosugars.[11]
carried out starting from 24, using the Mitsunobu phos-
To avoid this ring opening, we decided to carry out the phorylation procedure to give 16, followed by hydrogen-
methanolysis before the formation of the 3,6-anhydrosugar. ation. The hydrogenolysis of compound 16 proceeded
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A. Tikad, S. P. Vincent
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ditions, the 1C4 locked donor favoured the formation of the
axial β-anomer, a result that can probably be explained by
the anomeric effect.
It should be mentioned that the methanolysis of donor
14 (Table 1, entry 4, and Scheme 2) proceeded very dif-
ferently from that of TIPS-protected donor 10. As de-
scribed above, the phosphate group at C-7 favours the side-
reaction detailed in Figure 4. Due to this side-reaction, we
consider that the α/β ratio measured based on the isolated
product (Table 1, entry 4) cannot be compared with the pre-
ceding example (Table 1, entry 3).
The second series of comparative reactions were per-
formed under more classical glycosylation conditions, i.e.,
with a slight excess of a secondary alcohol. Thus, cyclo-
hexanol, a model acceptor, and perbenzylated thioglycoside
donors 29, 7, and 13 were combined with N-iodosuccin-
imide (NIS) and triflic acid (TfOH) as an activating system
in dry dichloromethane at 0 °C.[14] The reactions of mannos-
ide 29[15] and heptoside 7 gave the desired compounds [i.e.,
30 (α/β = 1.2:1) and 31 (α/β = 1.4:1)] in 90 and 88% yields,
respectively, with almost the same α-selectivity (Table 1, en-
tries 5–6). As shown in Table 1, entry 7, under the same
conditions, the O-glycosylation of 3,6-anhydroheptose 13
provided only α-linked product 32 in 75% yield. This α
stereoselectivity can be explained by the formation of an
anomeric axial triflate intermediate which can be displaced
in an SN2-like process to give the coupled product with in-
version of configuration at the anomeric centre.[16] Alterna-
tively, the α stereoselectivity may be simply due to the steric
hindrance of the β-face by the anhydro bridge. This result
demonstrates that the conformational restriction of glycosyl
donors has a significant impact on the stereoselectivity. In
the recent literature, it has been shown that conformational
Scheme 3. Reagents and conditions: i) Raney Ni, EtOH, room
temp., 2 h; ii) NCS, MeOH/CH2Cl2 (4:1), room temp., 3 h;
iii) DAST (1.5 equiv.), CH2Cl2, –78 °C to room temp., (2 h for 21,
22 and 6 h for 23); iv) TBAF, THF, room temp., 2 h; v) Pd/C, H2,
MeOH/THF 2:1, room temp., 24 h; iii) HOPO(OBn)2, PPh3,
DEAD, Et3N, THF, room temp., 24 h.
smoothly, but under the same conditions after 24 h, its β-
configured anomer (i.e., 17; see above, Scheme 2) unfortu-
nately gave only degradation products.
Reactivity of Constrained Heptosides at the Anomeric
Position
We decided to use our new ring-constrained 3,6-anhydro- restriction can lead to dramatic effects on relative reactivi-
heptosides to compare the reactivity of related donors with ties: some conformations enhance the reactivity (also
4
1
either a C1 or a C4 conformation in O-glycosylation reac- known as an “arming” effect[17]), or others slow down the
tions. This could shed light on the influence of the 3,6- glycosylation rates (a “disarming” effect).[3a,18]
bridge on the stereoselectivity (Table 1).
To address the question of the impact of conformation
As shown in Table 1, the first experiments were carried on reactivity with our donors, we performed a competition
out using a large excess of methanol as an acceptor, and experiment between donor 7 (4C1 conformation) and 13
with thiomannoside 4,[13] heptoside 8(l), and 3,6-heptoside (1C4 conformation). The glycosylation was performed using
10 as donors (Table 1, entries 1–3). Using N-chlorosuc- NIS (1 equiv.)/TfOH (0.17 equiv.) as a promoter, thiosugars
cinimide as a promoter and 4 Å molecular sieves in a mix- 7 and 13 (1 equiv. of each), and cyclohexanol (1 equiv.) in
1
ture of MeOH and CH2Cl2, the expected products were ob- dry CH2Cl2 at 0 °C. After 10 min, analysis of the crude H
tained in good yields, irrespective of the nature of starting NMR spectrum showed that donor 13 had completely dis-
glycoside.
appeared and that 32 had been formed as a major product.
The α,β ratio varied from α/β = 1.5:1 for mannoside 4, The second donor (i.e., 7) had hardly been consumed, and
through α/β = 1:1 for heptoside 8(l), to α/β = 1:2 for 3,6- only traces of product 31 were observed. We can conclude
anhydroheptoside 10 (Table 1, entries 1–3). This series of from this experiment that 3,6-anhydrothioheptoside donor
glycosylations carried out under solvolytic conditions 13 is more reactive than perbenzylated thioheptoside 7.
showed that the heptose scaffold itself 8(l) had a slight ef- Thus, restriction to a 1C4 chair conformation exerts an acti-
fect on the glycosylation reaction compared to its parent vating (arming) effect on the glycosylation reaction.
mannoside 4. Indeed, increasing the steric hindrance at the
These results obtained with 3,6-anhydro-d-manno-hept-
6-position by the addition of a CH2-OTIPS group raises the osides are consistent with previous studies on the glycosyl-
proportion of the disfavoured β-anomer formed (Table 1, ation behaviour of 3,6-anhydrogalactosyl orthoester donors
entries 1 and 2). The comparison of the two heptosides 8(l) compared to the corresponding galactosyl orthoesters,[19]
and 10 showed that the conformational restriction had a and also with the behaviour of 3,6-anhydro-glucopyran-
significant effect on the α/β ratio. Indeed, under these con- osides[4a] and galacturonic acid 3,6-lactone.[16a]
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Constrained 3,6-Anhydro-Heptosides
4
1
Table 1. O-Glycosylation of conformational C1 and C4 carbohydrates.
[a] Reagents and Conditions. PG: protecting group. Conditions A: NCS (2 equiv.), MeOH/CH2Cl2 (4:1), room temperature. Conditions
B: Cyclohexanol (1.5 equiv.), NIS (1.5 equiv.), TfOH (0.17 equiv.), CH2Cl2, 0 °C. [b] Yields of isolated products. [c] Reaction carried out
in MeOH.
4
ylative reaction starting from heptosides in the C1 confor-
Conclusions
mation gave ring-constrained 3,6-anhydroheptosides, irre-
We have described the first access to and a reactivity profile spective of the substituent at the anomeric position. The
of 3,6-anhydrothioheptosides. A DAST-induced debenz- presence of the phosphate group at C-7 has a significant
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A. Tikad, S. P. Vincent
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(94 mL) at 0 °C. The reaction mixture was then allowed to warm
to room temperature. After 48 h, further K2OsO4·2H2O (0.083 g,
0.23 mmol), K3Fe(CN)6 (2.54 g, 7.72 mmol), and K2CO3 (1.18 g,
8.49 mmol) were added, and the mixture was stirred for a further
2 d. The reaction was then quenched by the addition of Na2SO3
(32.2 g), and the mixture was stirred for 1.5 h. The mixture was
extracted with ethyl acetate (4ϫ 100 mL). The organic phase was
washed with KOH (1 m aq.; 100 mL), dried with MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (cyclohexane/ethyl acetate, 1:0 to 4:6) to give a
effect on the reactivity of the anomeric position, and fa-
voured a six-membered-ring-opening reaction under acidic
conditions. Based on this debenzylative reaction starting
from l-heptosides, the synthesis of methyl 3,6-anhydro-l-
glycero-α-d-manno-heptopyranoside 7-phosphate (1), an an-
alogue of d-glycero-d-manno-heptopyranose 7-phosphate,
was achieved. This molecule will be a useful tool as a con-
formational probe of enzymatic reactions.[2a,20] Glycosyl-
ations of thiomannoside 29 and thioheptoside (4C1) 7 pro-
moted by N-iodosuccinimide/triflic acid gave α,β mixtures mixture (d/l = 2:1) of the corresponding diol isomers (7.74 g, 74%)
as a colourless oil. For 6(d), see ref.[2a] Data for 6(l): [α]2D0 = +89.0
of products, whereas 3,6-anhydrothioheptoside 13 provided
the α-anomer as the sole product, probably via an axial β-
1
(c = 0.6, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.44–7.25 (m,
20 H, Harom), 5.55 (d, J1,2 = 1.6 Hz, 1 H, 1-H), 4.98 (AB, JAB
=
triflate intermediate. The O-glycosylation competition ex-
periment between (4C1)-7 and (1C4)-13 heptosides revealed
that the 3,6-anhydrothioheptoside donor is more reactive
10.8 Hz, 1 H, CH2Bn), 4.74–4.71 (m, 3 H, CH2Bn), 4.67 (AB, JAB
= 11.7 Hz, 1 H, CH2Bn), 4.63 (AB, JAB = 11.9 Hz, 1 H, CH2Bn),
4.22 (dd, J3,4 = 9.2, J4,5 = 9.6 Hz, 1 H, 4-H), 4.02 (dd, J5,6 = 1.4,
J4,5 = 9.6 Hz, 1 H, 5-H), 3.99–3.95 (m, 2 H, 2-H, 6-H), 3.90 (dd,
4
than the thioheptoside donor in a normal C1 conforma-
tion, thus confirming that in the manno-heptose series, flip-
ping the chair conformation leads to an increase of the an-
omeric reactivity.
J2,3 = 3.0, J3,4 = 9.2 Hz, 1 H, 3-H), 3.54 (dd, J6,7a = 6.2, J7a,7b
=
11.4 Hz, 1 H, 7a-H), 3.50 (m, 1 H, 7b-H), 2.40 (br., 1 H, OH), 1.87
(br., 1 H, OH) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.3
(Cqarom), 138.2 (Cqarom), 137.9 (Cqarom), 133.3 (Cqarom), 131.9 (2
CHarom), 129.4 (2 CHarom), 128.6 (6 CHarom), 128.2–127.9 (10
CHarom), 85.9 (C-1), 80.1 (C-3), 76.1 (C-2), 75.5 (CH2Bn), 74.4 (C-
4), 73.9 (C-5), 72.6 (CH2Bn), 72.4 (CH2Bn), 69.3 (C-6), 65.1 (C-7)
ppm. HRMS (ESI+): calcd. for C34H36O6SNa [M + Na]+ 595.2125;
found 595.2137.
Experimental Section
General Techniques: All reactions were carried out under an argon
atmosphere, yields refer to chromatographically and spectroscopi-
cally homogeneous materials. Reagents and chemicals were pur-
chased from Sigma–Aldrich and Acros as ACS grade, and were
used without purification. All reactions were performed using puri-
fied and dried solvents: tetrahydrofuran (THF) was heated at reflux
over sodium/benzophenone, dichloromethane (CH2Cl2), triethyl-
amine (NEt3), and pyridine were heated at reflux over calcium
hydride (CaH2). All reactions were monitored by thin-layer
chromatography (TLC) carried out on Merck aluminum-backed
silica gel 60-F254 plates, using UV light and a molybdate/sufuric
acid solution as staining reagent. 1H, 13C, and 31P NMR spectra
were recorded with a JEOL (JNM EX-400) instrument. All com-
pounds were characterized by 1H, 13C, and 31P NMR spectroscopy,
as well as by 1H,1H and 1H,13C correlation experiments where nec-
essary. The following abbreviations have been used to describe the
multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet,
br. = broad. The numbering of the protons and carbons is analo-
gous to the proton numbers in the name of the compound. Aro-
matic, benzyl, acetyl, and methyl (carbons and protons) are respec-
tively labeled with “arom”, “Bn”, “Ac”, and “Me” superscripts,
quaternary carbon atoms are indicated with a “q” subscript. Chem-
ical shifts (δ) are reported in ppm relative to tetramethylsilane, and
spectra were calibrated using the solvent (or residual solvent) sig-
nals. Merck silica gel (60, particle size 0.040–0.063 mm) was used
for flash column chromatography and preparative thin layer
chromatography; technical grade solvents were used as eluting sol-
vents and were distilled prior to use. LC–MS measurements were
performed on an Agilent 6200 series TOF mass spectrometer using
an Agilent 1200 series LC system. Purifications of final molecules
were carried out by semi-preparative HPLC using a Waters Delta
prep 4000 chromatography system equipped with a RP-C18 col-
umn (Agilent). Compounds 4[6] and 29[15] were prepared following
known procedures.
Phenyl 2,3,4,6,7-Penta-O-benzyl-1-thio-L-glycero-α-D-manno-hepto-
pyranoside (7): NaH (60% in oil; 56 mg, 4 equiv., 1.396 mmol) was
added to a solution of 6(l) (200 mg, 1 equiv., 0.349 mmol) in dry
DMF (4 mL) under argon. After 20 min, benzyl bromide (167 μL,
4 equiv., 1.396 mmol) was added at 0 °C. Then the mixture was
allowed to warm to room temperature, and it was stirred for 20 h.
The mixture was then diluted with diethyl ether and successively
washed with HCl (1 n), NaHCO3 (saturated aq.), and water. The
organic phase was dried with MgSO4 and filtered, and the solvents
were removed in vacuo. The residue was purified by flash
chromatography (dichloromethane/methanol, 95:5) to give thio-
heptoside 7 (220 mg, 84%) as a colourless oil. [α]2D0 = +78.9 (c =
1
0.72, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.39–7.20 (m, 30
H, Harom), 5.77 (d, J1,2 = 1.4 Hz, 1 H, 1-H), 4.90–4.85 (m, 3 H,
CH2Bn), 4.77 (AB, JAB = 12.4 Hz, 1 H, CH2Bn), 4.63 (AB, JAB
12.4 Hz, 1 H, CH2Bn), 4.57 (m, 2 H, CH2Bn), 4.53 (AB, JAB
11.7 Hz, 1 H, CH2Bn), 4.40–4.32 (m, 3 H, CH2Bn), 4.26 (dd, J3,4
=
=
=
J4,5 = 9.4 Hz, 1 H, 4-H), 4.15–4.12 (m, 2 H, 5-H, 6-H), 3.99 (dd,
J2,1 = 1.4, J2,3 = 3.0 Hz, 1 H, 2-H), 3.88 (dd, J3,2 = 3.0, J3,4
=
9.4 Hz, 1 H, 3-H), 3.69 (dd, J7b,6 = 6.9, J7b,7a = 9.9 Hz, 1 H, 7b-
H), 3.45 (dd, J7a,6 = 5.3, J7a,7b = 9.9 Hz, 1 H, 7a-H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 138.8 (Cqarom), 138.7 (Cqarom), 138.3
(Cqarom), 138.2 (Cqarom), 138.0 (Cqarom), 134.5 (Cqarom), 130.8 (2
CHarom), 129.1 (2 CHarom), 129.1–127.1 (26 CHarom), 85.2 (C-1),
80.7 (C-3), 75.9 (C-2), 75.4 (C-5), 74.9 (CH2Bn), 74.4 (C-4), 73.4
(CH2Bn), 73.1 (C-6), 73.0 (CH2Bn), 72.1 (CH2Bn), 72.0 (CH2Bn), 71.1
(C-7) ppm. HRMS (ESI+): calcd. for C48H48O6SNa [M + Na]+
775.3064; found 775.3025.
Phenyl 2,3,4-Tri-O-benzyl-7-O-triisopropylsilyl-1-thio-
-manno-heptopyranoside [8( )] and Phenyl 2,3,4-Tri-O-benzyl-7-O-
triisopropylsilyl-1-thio- -glycero-α- -manno-heptopyranoside [8( )]:
D-glycero-α-
D
D
L
D
L
Phenyl
anoside [6(
2,3,4-Tri-O-benzyl-1-thio-
L)]: A solution of alkene 5 (9.9 g, 18.38 mmol) in toluene
L
-glycero-α-
D
-manno-heptopyr-
TIPSCl (2.3 mL, 1.5 equiv. 10.256 mmol) was added dropwise at
0 °C to a solution of diol 6(d,l) (4.145 g, 1 equiv., 7.237 mmol),
imidazole (1.478 g, 3 equiv., 21.712 mmol), and a catalytic amount
(37 mL) was added dropwise to a solution of K2OsO4·2H2O
(0.20 g, 0.55 mmol), K3Fe(CN)6 (16.94 g, 51.46 mmol), and K2CO3 of DMAP in dry THF (30 mL). The reaction mixture was stirred at
(7.92 g, 56.94 mmol) in a mixture of water (94 mL) and tBuOH room temperature for 16 h. The mixture was then concentrated in
7598
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7593–7603

Constrained 3,6-Anhydro-Heptosides
vacuo, and the resulting syrup was diluted with CH2Cl2 (150 mL).
The organic phase was washed with NH4Cl (saturated aq.; 2ϫ
70 mL) and water (80 mL), dried with MgSO4, and filtered, and the
solvents were removed in vacuo. The residue was purified by flash
chromatography (hexane/ethyl acetate, 9:1) to give separable di-
asteroisomers 8(d) and 8(l) (3.904 g, 74%) as colourless oils.
hexane/ethyl acetate, 9:1) to give 10 (427 mg, 63%) and 11 (64 mg,
11%).
Data for 10: [α]2D0 = +29.5 (c = 0.41, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.62–7.58 (m, 2 H, Harom), 7.37–7.14 (m, 13 H, Harom),
5.12 (d, J1,2 = 8.7 Hz, 1 H, 1-H), 4.68 (AB, JAB = 11.7 Hz, 1 H,
CH2Bn), 4.60 (AB, JAB = 11.7 Hz, 1 H, CH2Bn), 4.53 (AB, JAB
=
Data for 8(d): [α]2D0 = +72.3 (c = 0.56, CHCl3). 1H NMR
11.7 Hz, 1 H, CH2Bn), 4.48 (d, J5,4 = 2.8 Hz, 1 H, 5-H), 4.36 (AB,
(400 MHz, CDCl3): δ = 7.44–7.41 (m, 2 H, Harom), 7.35–7.24 (m, JAB = 11.7 Hz, 1 H, CH2Bn), 4.32 (dd, J6,7b = 3.4, J6,7a = 5.5 Hz,
18 H, Harom), 5.53 (d, J1,2 = 2.5 Hz, 1 H, 1-H), 4.92 (AB, JAB
=
=
1 H, 6-H), 4.24 (dd, J2,3 = 1.4, J3,4 = 6.0 Hz, 1 H, 3-H), 4.19 (dd,
J4,5 = 2.8, J4,3 = 6.0 Hz, 1 H, 4-H), 3.79 (dd, J7b,6 = 3.4, J7a,7b
10.8 Hz, 1 H, CH2Bn), 4.71–4.53 (m, 5 H, CH2Bn), 4.15 (dd, J5,6
=
3.4, J5,4 = 9.2 Hz, 1 H, 5-H), 4.10 (dd, J4,3 = 8.0, J4,5 = 9.2 Hz, 1
H, 4-H), 4.02–3.98 (m, 1 H, 6-H), 3.94 (dd, J2,1 = 2.5, J2,3 = 3.0 Hz,
1 H, 2-H), 3.86 (dd, J3,2 = 3.0, J3,4 = 8.0 Hz, 1 H, 3-H), 3.79 (dd,
J7b,6 = 3.7, J7a,7b = 10.3 Hz, 1 H, 7b-H), 3.71 (dd, J7a,6 = 7.8, J7a,7b
= 10.3 Hz, 1 H, 7a-H), 2.69 (br., 1 H, OH), 0.97–1.07 (m, 21 H,
HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.5 (Cqarom),
11.0 Hz, 1 H, 7b-H), 3.75 (dd, J2,1 = 8.7, J2,3 = 1.4 Hz, 1 H, 2-H),
3.63 (dd, J7a,6 = 5.5, J7a,7b = 11.0 Hz, 1 H, 7a-H), 1.08–0.99 (m, 21
H, HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.1 (Cqarom),
137.6 (Cqarom), 133.7 (Cqarom), 132.2 (2 CHarom), 128.8–127.4 (m,
13 CHarom), 83.8 (C-1), 80.6 (C-6), 76.4 (C-4), 75.9 (C-5), 75.6 (C-
3), 74.7 (C-2), 72.9 (CH2Bn), 71.9 (CH2Bn), 64.0 (C-7), 18.0
138.2 (Cqarom), 138.0 (Cqarom), 134.4 (Cqarom), 131.7 (2 CHarom), (CH3TIPS), 11.9 (CHTIPS
)
ppm. HRMS (ESI+): calcd. for
129.1 (2 CHarom), 128.6–127.5 (16 CHarom), 85.6 (C-1), 80.0 (C-3),
76.2 (C-2), 75.6 (C-4), 74.5 (CH2Bn), 73.4 (C-6), 72.8 (C-5), 72.3
C36H48O5SSiNa [M + Na]+ 643.2884; found 643.2855.
Data for 11: [α]2D0 = –14.0 (c = 1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.24 (m, 10 H, Harom), 5.77 (dd, J1,2 = 4.6, J1,F
= 58.2 Hz, 1 H, 1-H), 4.68 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.64–
4.59 (m, 3 H, 6-H, CH2Bn), 4.45 (AB, JAB = 11.7 Hz, 1 H, CH2Bn),
4.39–4.36 (m, 2 H, 4-H, 5-H), 4.31–4.29 (m, 1 H, 3-H), 3.92 (ddd,
(CH2Bn), 72.2 (CH2Bn), 64.6 (C-7), 18.1 (CH3TIPS), 12.0 (CHTIPS
)
ppm. HRMS (ESI+): calcd. for C43H56O6SSi [M + Na]+ 751.3459;
found 751.3446.
Data for 8(l): [α]2D0 = +98.3 (c = 0.36, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.22 (m, 20 H, Harom), 5.60 (d, J1,2 = 1.6 Hz, 1
H, 1-H), 4.98 (AB, JAB = 10.8 Hz, 1 H, CH2Bn), 4.76–4.55 (m, 5
H, CH2Bn), 4.26 (dd, J4,3 = 9.4, J4,5 = 9.6 Hz, 1 H, 4-H), 4.12–4.09
J2,1 = 4.6, J2,3 = 1.6, J2,F = 21.3 Hz, 1 H, 2-H), 3.78 (dd, J7b,6
3.2, J7a,7b = 11.2 Hz, 1 H, 7b-H), 3.63 (dd, J7a,6 = 5.3, J7a,7b
=
=
11.2 Hz, 1 H, 7a-H), 1.07–0.98 (m, 21 H, HTIPS) ppm. 13C NMR
(m, 1 H, 5-H), 4.07–4.02 (m, 1 H, 6-H), 3.99 (dd, J2,1 = 1.6, J2,3
=
(101 MHz, CDCl3): δ = 137.6 (Cqarom), 137.3 (Cqarom), 128.7–127.8
3.2 Hz, 1 H, 2-H), 3.87 (dd, J3,2 = 3.2, J3,4 = 9.4 Hz, 1 H, 3-H), (m, 10 CHarom), 106.0 (d, JC,F = 231.9 Hz, C-1), 81.1 (d, JC,F
=
3.67 (dd, J7b,6 = 7.9, J7a,7b = 10.1 Hz, 1 H, 7b-H), 3.51 (dd, J7a,OH
= 6.2, J7a,7b = 10.1 Hz, 1 H, 7a-H), 3.32 (d, J = 6.2 Hz, 1 H, OH),
1.08–0.94 (m, 21 H, HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ
2.9 Hz, C-6), 77.0 (C-5), 74.9 (d, JC,F = 2.9 Hz, C-4), 74.2 (C-3),
72.3 (CH2Bn), 72.1 (d, JC,F = 20.1 Hz, C-2), 71.7 (CH2Bn), 64.0
(C-7), 18.0 (CH3TIPS), 11.9 (CHTIPS) ppm. 19F NMR (400 MHz,
= 138.7 (Cqarom), 138.4 (Cqarom), 138.0 (Cqarom), 134.2 (Cqarom), CDCl3): δ = –133.3 (dd, JH1,F = 58.2, JH2,F = 21.3 Hz) ppm.
131.5 (2 CHarom), 129.0 (2 CHarom), 128.5–127.5 (16 CHarom), 85.8 HRMS (ESI+): calcd. for C30H43FO5SiNa [M + Na]+ 553.2756;
(C-1), 80.5 (C-3), 76.1 (C-2), 75.5 (CH2Bn), 74.6 (C-4), 72.4 found 553.2747.
(CH2Bn), 72.3 (CH2Bn), 71.6 (C-5), 69.8 (C-6), 64.4 (C-7), 18.1
Phenyl 3,6-Anhydro-2,4-di-O-benzyl-1-thio-L-glycero-α-D-manno-
heptopyranoside (12): TBAF·3H2O (372 mg, 2 equiv., 1.179 mmol)
was added to a solution of derivative 10 (366 mg, 1 equiv.,
(CH3TIPS), 12.0 (CHTIPS
)
ppm. HRMS (ESI+): calcd. for
C43H56O6SSi [M + Na]+ 751.3459; found 751.3425.
Synthesis of 8( ) from 8(D) Following the Mitsunobu Procedure: 0.589 mmol) in dry THF (8 mL) under an argon atmosphere. The
L
PPh3 (870 mg, 2 equiv., 3.316 mmol) and p-nitrobenzoic acid
(554 mg, 2 equiv., 3.316 mmol) were added to a solution of silyl
ether 8(d) (1.209 g, 1 equiv., 1.658 mmol) in dry THF (20 mL). Af-
ter 5 min, DIAD (687 μL, 2 equiv., 3.316 mmol) was added at room
temperature, and the mixture was stirred for 44 h. Then the reac-
tion mixture was concentrated in vacuo. The residue was dissolved
reaction mixture was stirred for 1.5 h at room temperature, then it
was diluted with NH4Cl (saturated aq.; 10 mL), and the mixture
was extracted with CH2Cl2 (3ϫ 10 mL). The organic phase was
washed with water (10 mL) and brine (10 mL), dried with MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (dichloromethane/methanol,
in CH2Cl2/MeOH (1:5, 12 mL), and K2CO3 (252 mg, 1.1 equiv. 99:1) to give alcohol 12 (270 mg, 98%) as a colourless oil. [α]2D0
=
1.824 mol) was added in one portion. The mixture was stirred for
4 h at room temperature. Then the reaction mixture was concen-
trated, and the residue was dissolved in ethyl acetate. This solution
was washed with water and brine, dried, and concentrated. The
residue was purified by chromatography (hexane/ethyl acetate, 9:1)
to give isomer 8(l) (856 mg, 70%).
+37.6 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.60–7.56
(m, 2 H, Harom), 7.37–7.15 (m, 13 H, Harom), 5.10 (d, J1,2 = 8.7 Hz,
1 H, 1-H), 4.69 (AB, JAB = 11.4 Hz, 1 H, CH2Bn), 4.59 (AB, JAB
= 11.7 Hz, 1 H, CH2Bn), 4.52 (AB, JAB = 11.4 Hz, 1 H, CH2Bn),
4.36–4.32 (m, 3 H, 5-H, 6-H, CH2Bn), 4.26 (dd, J3,2 = 1.6, J3,4
=
6.0 Hz, 1 H, 3-H), 4.05 (dd, J4,5 = 3.0, J3,4 = 6.0 Hz, 1 H, 4-H),
3.74 (dd, J2,1 = 8.7, J2,3 = 1.6 Hz, 1 H, 2-H), 3.64 (ddd, J7b,6 = 4.6,
J7b,OH = 6.2, J7a,7b = 11.2 Hz, 1 H, 7b-H), 3.57–3.51 (m, 1 H, 7a-
H), 1.75 (t, J = 6.2 Hz, 1 H, OH) ppm. 13C NMR (101 MHz,
CDCl3): δ = 137.9 (Cqarom), 137.4 (Cqarom), 133.5 (Cqarom), 132.2
(2 CHarom), 128.8–127.5 (m, 13 CHarom), 83.9 (C-1), 80.3 (C-6),
76.6 (C-4), 76.0 (C-3), 75.7 (C-5), 74.7 (C-2), 73.1 (CH2Bn), 72.0
(CH2Bn), 63.4 (C-7) ppm. HRMS (APCI+): calcd. for
C27H28O5SNa [M + Na]+ 487.1550; found 487.1539.
Phenyl 3,6-Anhydro-2,4-di-O-benzyl-7-O-triisopropylsilyl-1-thio-
glycero-α- -manno-heptopyranoside (10) and 3,6-Anhydro-2,4-di-O-
benzyl-7-O-triisopropylsilyl- -glycero-β- -manno-heptopyranosyl
L-
D
L
D
Fluoride (11): DAST (269 μL, 2 equiv., 2.194 mmol) was added
dropwise to a solution of 8(l) (800 mg, 1 equiv., 1.097 mmol) in
CH2Cl2 (15 mL) at –78 °C under argon. The reaction mixture was
allowed to warm to room temperature over 2 h. Then H2O (25 mL)
was added. The aqueous phase was extracted with CH2Cl2 (3ϫ
25 mL). The combined organic extracts were washed with brine
(25 mL) and dried (MgSO4). The solvents were evaporated, and the
residue was purified by flash chromatography on silica gel (cyclo-
Phenyl 3,6-Anhydro-2,4,7-tri-O-benzyl-1-thio-L-glycero-α-D-manno-
heptopyranoside (13): NaH (60% in oil; 43 mg, 2 equiv.,
1.067 mmol) was added to a solution of 12 (248 mg, 1 equiv.,
Eur. J. Org. Chem. 2013, 7593–7603
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7599

A. Tikad, S. P. Vincent
FULL PAPER
1
0.533 mmol) in dry DMF (4 mL) under argon. After 20 min, benzyl
bromide (128 μL, 2 equiv., 1.067 mmol) was added at 0 °C, and the
mixture was warmed to room temperature and stirred overnight.
The mixture was then diluted with diethyl ether and successively
washed with HCl (1 n), NaHCO3 (saturated aq.), and water. The
organic phase was dried with MgSO4 and filtered, and the solvents
were removed in vacuo. The residue was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate, 8:2) to give
thioheptoside 13 (249 mg, 84%) as a colourless oil. [α]2D0 = +37.8
Data for 15: [α]2D0 = –8.4 (c = 0.45, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.37–7.24 (m, 20 H, Harom), 5.06–4.98 (m, 4 H,
CH2Bn), 4.94 (AB, JAB = 11.0 Hz, 1 H, CH2Bn), 4.68 (d, J2Ј,1Ј
=
5.5 Hz, 1 H, 2Ј-H), 4.65 (AB, JAB = 11.2 Hz, 1 H, CH2Bn), 4.60
(AB, JAB = 11.0 Hz, 1 H, CH2Bn), 4.40 (AB, JAB = 11.2 Hz, 1 H,
CH2Bn), 4.35 (dd, J1,1Ј = 5.0, J1,2 = 6.4 Hz, 1 H, 1-H), 4.16 (dd,
J2,3 = 5.0, J2,1 = 6.4 Hz, 1 H, 2-H), 4.09–4.00 (m, 3 H, 4-H, 5a-H,
3-H), 3.99–3.93 (m, 1 H, 5a-H), 3.88 (d, J = 11.0 Hz, 1 H, OH),
3.80 (dd, J1Ј,2Ј = 5.5, J1,1Ј = 5.0 Hz, 1 H, 1Ј-H), 3.42 (s, 3 H, OMe),
(c = 0.58, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.61–7.54 (m, 3.34 (s, 3 H, OMe) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.0
2 H, Harom), 7.37–7.14 (m, 18 H, Harom), 5.08 (d, J1,2 = 8.7 Hz, 1 (Cqarom), 137.9 (Cqarom), 135.8 (d, JC,P = 1.9 Hz, Cqarom), 135.7 (d,
H, 1-H), 4.67 (AB, JAB = 11.7 Hz, 1 H, CH2Bn), 4.58 (AB, JAB
=
JC,P = 1.9 Hz, Cqarom), 128.7–127.7 (m, 20 CHarom), 105.4 (C-2Ј),
11.7 Hz, 1 H, CH2Bn), 4.53–4.44 (m, 3 H, CH2Bn), 4.41–4.38 (m, 1 83.7 (d, JC,P = 6.7 Hz, C-4), 80.9 (C-1Ј), 79.3 (C-2), 79.0 (C-1), 75.3
H, 6-H), 4.37 (d, J5,4 = 2.8 Hz, 1 H, 5-H), 4.32 (AB, JAB = 11.9 Hz,
1 H, CH2Bn), 4.25 (d, J3,4 = 6.0 Hz, 1 H, 3-H), 4.13 (dd, J4,5 = 2.8,
J3,4 = 6.0 Hz, 1 H, 4-H), 3.72 (d, J2,1 = 8.7 Hz, 1 H, 2-H), 3.52
(dd, J7b,6 = 3.9, J7a,7b = 10.5 Hz, 1 H, 7b-H), 3.43 (dd, J7a,6 = 5.0,
J7a,7b = 10.5 Hz, 1 H, 7a-H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 138.0 (Cqarom), 137.8 (Cqarom), 137.5 (Cqarom), 133.7 (Cqarom),
132.3 (2 CHarom), 128.8 (2 CHarom), 128.5–127.4 (m, 16 CHarom),
83.9 (C-1), 79.1 (C-6), 76.4 (C-4), 76.0 (C-5), 75.7 (C-3), 74.7 (C-2),
73.5 (CH2Bn), 72.9 (CH2Bn), 72.0 (CH2Bn), 70.4 (C-7) ppm. HRMS
(APCI+): calcd. for C34H34O5SNa [M + Na]+ 577.2019; found
577.2037.
(CH2Bn), 72.9 (CH2Bn), 71.3 (C-3), 69.4 (CH2Bn), 69.3 (CH2Bn), 67.9
(d, JC,P = 5.7 Hz, C-5), 56.5 (OMe), 55.4 (OMe) ppm. 31P NMR
(101 MHz, CDCl3): δ = –0.15 ppm. HRMS (ESI+): calcd. for
C37H43O10PNa [M + Na]+ 701.2486; found 701.2475.
1
Data for 16: [α]2D0 = +20.5 (c = 0.2, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.38–7.23 (m, 20 H, Harom), 5.05–4.95 (m, 4 H,
CH2Bn), 4.78 (d, J1,2 = 6.4 Hz, 1 H, 1-H), 4.69 (AB, JAB = 11.9 Hz,
1 H, CH2Bn), 4.57 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.53 (AB, JAB
= 11.9 Hz, 1 H, CH2Bn), 4.33 (AB, JAB = 11.9 Hz, 1 H, CH2Bn),
4.26 (d, J5,4 = 3.0 Hz, 1 H, 5-H), 4.25–4.23 (m, 1 H, 6-H), 4.13 (dd,
J3,2 = 1.1, J3,4 = 6.0 Hz, 1 H, 3-H), 3.94–3.88 (m, 1 H, 7b-H), 3.87
(dd, J4,5 = 3.0, J3,4 = 6.0 Hz, 1 H, 4-H), 3.84–3.78 (m, 1 H, 7a-H),
3.65 (dd, J2,1 = 6.4, J2,3 = 1.1 Hz, 1 H, 2-H), 3.54 (s, 3 H, OMe)
ppm. 13C NMR (101 MHz, CDCl3): δ = 138.4 (Cqarom), 137.4
(Cqarom), 135.7 (Cqarom), 135.6 (Cqarom), 128.8–127.7 (m, 20
CHarom), 103.1 (C-1), 78.5 (d, JC,P = 8.6 Hz, C-6), 76.1 (C-2), 76.0
(C-3, C-4), 74.2 (C-5), 72.8 (CH2Bn), 72.3 (CH2Bn), 69.7 (CH2Bn),
69.6 (CH2Bn), 66.9 (d, JC,P = 5.8 Hz, C-7), 57.1 (OMe) ppm. 31P
NMR (101 MHz, CDCl3): δ = –0.45 ppm. HRMS (ESI+): calcd.
for C36H39O9PNa [M + Na]+ 669.2424; found 669.2249.
Phenyl 3,6-Anhydro-7-O-dibenzyloxyphosphoryl-2,4-di-O-benzyl-1-
thio-L-glycero-α-D-manno-heptopyranoside (14): DEAD (593 μL,
5 equiv., 3.766 mmol) was slowly added to alcohol 12 (350 mg,
1 equiv., 0.753 mmol), PPh3 (988 mg, 5 equiv., 3.766 mmol), (Bn)
2PO2H (1.048 g, 5 equiv., 3.766 mmol), and NEt3 (1.047 mL,
5 equiv., 7.533 mmol) in dry THF (5 mL) at room temperature. Af-
ter 16 h, the solvents were removed in vacuo, and the residue was
purified by flash chromatography on silica gel (dichloromethane/
diethyl ether, 9:1) to give phosphate 14 (137 mg, 25%). [α]2D0
=
1
+29.6 (c = 0.48, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.57–
7.54 (m, 2 H, Harom), 7.37–7.13 (m, 23 H, Harom), 5.05–4.95 (m, 5
H, 1-H, CH2Bn), 4.65 (AB, JAB = 11.7 Hz, 1 H, CH2Bn), 4.50 (AB,
JAB = 10.1 Hz, 1 H, CH2Bn), 4.48 (AB, JAB = 10.1 Hz, 1 H, CH2Bn),
4.32 (d, J5,4 = 3.0 Hz, 1 H, 5-H), 4.31–4.28 (m, 1 H, 6-H), 4.22
(AB, JAB = 11.7 Hz, 1 H, CH2Bn), 4.17 (dd, J3,2 = 1.6, J3,4 = 6.0 Hz,
1 H, 3-H), 3.94–3.89 (m, 2 H, 4-H, 7b-H), 3.87–3.81 (m, 1 H, 7a-
H), 3.68 (dd, J2,1 = 8.7, J2,3 = 1.6 Hz, 1 H, 2-H) ppm. 13C NMR
1
Data for 17: [α]2D0 = –32.2 (c = 0.6, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.36–7.27 (m, 18 H, Harom), 7.22–7.20 (m, 2 H, Harom),
5.03–4.99 (m, 4 H, CH2Bn), 4.90 (d, J1,2 = 5.7 Hz, 1 H, 1-H), 4.69–
4.66 (m, 1 H, 6-H), 4.59 (AB, JAB = 12.1 Hz, 1 H, CH2Bn), 4.53
(AB, JAB = 11.5 Hz, 1 H, CH2Bn), 4.49 (AB, JAB = 12.1 Hz, 1 H,
CH2Bn), 4.31 (AB, JAB = 11.5 Hz, 1 H, CH2Bn), 4.22 (dd, J3,2
1.6, J3,4 = 6.2 Hz, 1 H, 3-H), 4.17 (d, J5,4 = 3.0 Hz, 1 H, 5-H), 4.01
(dd, J4,5 = 3.0, J3,4 = 6.2 Hz, 1 H, 4-H), 3.95 (ddd, J7b,6 = 3.9, J7b,P
=
a-
(101 MHz, CDCl3): δ = 137.8 (Cqarom), 137.3 (Cqarom), 135.6 (Cq
rom), 135.5 (Cqarom), 133.3 (Cqarom), 132.3 (2 CHarom), 128.8–127.5
(m, 23 CHarom), 83.9 (C-1), 78.1 (d, JC,P = 8.6 Hz, C-6), 76.1 (C-
4), 75.8 (C-3), 75.1 (C-5), 74.5 (C-2), 72.9 (CH2Bn), 72.0 (CH2Bn),
69.6 (d, JC,P = 1.9 Hz, CH2Bn), 69.5 (CH2Bn), 66.8 (d, JC,P = 5.8 Hz,
C-7) ppm. 31P NMR (101 MHz, CDCl3): δ = –0.44 ppm. HRMS
(APCI+): calcd. for C41H41O8PSNa [M + Na]+ 747.2152; found
747.2130.
= 6.4, J7b,7a = 11.0 Hz, 1 H, 7b-H), 3.90 (dd, J2,1 = 5.7, J2,3
=
1.6 Hz, 1 H, 2-H), 3.81 (dt, J7a,P = 6.4, J7b,7a = 11.0 Hz, 1 H, 7a-
H), 3.44 (s, 3 H, OMe) ppm. 13C NMR (101 MHz, CDCl3): δ =
137.9 (Cqarom), 137.3 (Cqarom), 135.7 (Cqarom), 135.6 (Cqarom),
128.8–127.9 (m, 20 CHarom), 99.8 (C-1), 78.9 (d, JC,P = 7.7 Hz, C-
6), 77.0 (C-4), 75.1 (C-3), 73.4 (C-5), 72.3 (C-2), 72.2 (CH2Bn), 71.7
(CH2Bn), 69.6 (d, JC,P = 2.9 Hz, CH2Bn), 69.5 (d, JC,P = 3.8 Hz,
CH2Bn), 67.2 (d, JC,P = 5.7 Hz, C-7), 56.3 (OMe) ppm. 31P NMR
(101 MHz, CDCl3): δ = –0.45 ppm. HRMS (APCI+): calcd. for
C36H39O9PNa [M + Na]+ 669.2424; found 669.2253.
(1ЈS)-1Ј,2-Di-O-benzyl-1-deoxy-2Ј,2Ј-di-O-methyl-5-O-dibenzyloxy-
phosphoryl-α-
benzyloxyphosphoryl-2,4-di-O-benzyl-
pyranoside (16), and Methyl 3,6-Anhydro-7-O-dibenzyloxyphos-
phoryl-2,4-di-O-benzyl- -glycero-β- -manno-heptopyranoside (17):
NCS (48 mg, 2 equiv., 353 μmol) was added to a solution of 14
(128 mg, 1 equiv., 176 μmol) in methanol (2 mL) at room tempera- (177 mg, 2 equiv., 1.325 mmol) was added to a solution of 8(l)
D-ribofuranoside (15), Methyl 3,6-Anhydro-7-O-di-
L
-glycero-α- -manno-hepto-
D
Methyl
manno-heptopyranoside (18) and Methyl 2,3,4-tri-O-Benzyl-7-O-tri-
isopropylsilyl- -glycero-β- -manno-heptopyranoside (19): NCS
2,3,4-Tri-O-benzyl-7-O-triisopropylsilyl-L-glycero-α-D-
L
D
L
D
ture. After 40 min, the mixture was quenched by the addition of a
saturated solution of NaHCO3, and then it was diluted with ethyl
acetate. The aqueous phase was extracted with ethyl acetate (10 mL).
The organic phase was dried with MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography on silica
gel (hexane/EtOAc, 5:5) to give ribofuranoside 15 (86 mg, 72%), 16
(12 mg, 10%), and 17 (7 mg, 6%) as colourless oils.
(483 mg, 1 equiv., 662 μmol) in methanol/CH2Cl2 (4:1; 6 mL) at
room temperature. After 3 h, the mixture was quenched by the ad-
dition of NaHCO3 (saturated aq.; 10 mL), and then diluted with
ethyl acetate (20 mL). The aqueous phase was extracted with ethyl
acetate (3ϫ 10 mL). The combined organic extracts were dried
with MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (hexane/EtOAc,
7600
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7593–7603

Constrained 3,6-Anhydro-Heptosides
95:5) to give separable products 18 (224 mg, 52%) and 19 (172 mg,
40%) as oils.
ing from 18, using the same procedure described for compound 10.
Purification by flash chromatography on silica gel (cyclohexane/
ethyl acetate, 95:5) gave 21 (230 mg, 63%). [α]2D0 = +22.8 (c = 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.23 (m, 10 H,
Harom), 4.86 (d, J1,2 = 6.6 Hz, 1 H, 1-H), 4.72 (AB, JAB = 11.9 Hz,
1 H, CH2Bn), 4.65 (AB, JAB = 12.1 Hz, 1 H, CH2Bn), 4.58 (AB, JAB
= 11.9 Hz, 1 H, CH2Bn), 4.46 (AB, JAB = 12.1 Hz, 1 H, CH2Bn),
4.39 (d, J5,4 = 3.0 Hz, 5-H), 4.22 (dd, J6,7b = 3.4, J6,7a = 5.5 Hz, 1
H, 6-H), 4.19 (dd, J3,4 = 6.0, J2,3 = 1.4 Hz, 1 H, 3-H), 4.13 (dd,
Data for 18: [α]2D0 = +19.3 (c = 0.76, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.38–7.24 (m, 15 H, Harom), 4.97 (AB, JAB = 11.0 Hz,
1 H, CH2Bn), 4.77 (AB, JAB = 12.6 Hz, 1 H, CH2Bn), 4.74–4.69 (m,
3 H, 1-H, CH2Bn), 4.65 (AB, JAB = 11.7 Hz, 1 H, CH2Bn), 4.61
(AB, JAB = 11.7 Hz, 1 H, CH2Bn), 4.16 (dd, J4,5 = 9.4, J4,3 = 9.8 Hz,
1 H, 4-H), 4.00 (m, 1 H, 6-H), 3.90 (dd, J5,6 = 3.0, J5,4 = 9.4 Hz,
1 H, 5-H), 3.83 (dd, J7b,6 = 6.8, J7a,7b = 9.4 Hz, 1 H, 7b-H), 3.78
J3,4 = 6.0, J4,5 = 3.0 Hz, 1 H, 4-H), 3.75 (dd, J7b,6 = 3.4, J7a,7b
=
(dd, J2,1 = 3.0, J2,3 = 1.8 Hz, 1 H, 2-H), 3.74 (dd, J3,2 = 1.8, J3,4
=
10.8 Hz, 1 H, 7b-H), 3.70 (dd, J2,1 = 6.6, J2,3 = 1.4 Hz, 1 H, 2-H),
3.59 (dd, J7a,6 = 5.5, J7a,7b = 10.8 Hz, 1 H, 7a-H), 3.57 (s, 3 H,
OMe), 1.08–0.98 (m, 21 H, HTIPS) ppm. 13C NMR (101 MHz,
CDCl3): δ = 138.6 (Cqarom), 137.7 (Cqarom), 127.7–128.6 (10
CHarom), 103.2 (C-1), 81.0 (C-6), 76.4 (C-2), 76.2 (C-4), 75.6 (C-3),
74.8 (C-5), 72.8 (CH2Bn), 72.2 (CH2Bn), 64.1 (C-7), 57.0 (OMe),
18.0 (CH3TIPS), 11.9 (CHTIPS) ppm. HRMS (ESI+): calcd. for
C31H46O6SiNa [M + Na]+ 565.2956; found 565.2960.
9.8 Hz, 1 H, 3-H), 3.72 (dd, J7a,6 = 7.6, J7a,7b = 9.4 Hz, 1 H, 7a-
H), 3.29 (s, 3 H, OMe), 2.28 (d, J = 6.6 Hz, 1 H, OH), 1.06–1.02
(m, 21 H, HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.8
(Cqarom), 138.7 (Cqarom), 138.5 (Cqarom), 128.4–127.6 (m, 15
CHarom), 99.4 (C-1), 88.5 (C-5), 75.3 (CH2Bn), 74.7 (C-2), 74.5 (C-
4), 72.9 (CH2Bn), 72.4 (CH2Bn), 69.9 (C-3), 69.7 (C-6), 63.9 (C-7),
54.7 (OMe), 18.1 (CH3TIPS), 12.0 (CHTIPS) ppm. MS (ESI+): m/z
= 689.3 [M + K]+.
1
Data for 19: [α]2D0 = –54.1 (c = 0.12, CHCl3). H NMR (400 MHz,
Methyl 3,6-Anhydro-2,4-di-O-benzyl-7-O-triisopropylsilyl-
L-glycero-
CDCl3): δ = 7.45–7.43 (m, 2 H, Harom), 7.37–7.24 (m, 13 H, Harom),
4.98 (AB, JAB = 11.0 Hz, 1 H, CH2Bn), 4.94 (AB, JAB = 12.4 Hz,
1 H, CH2Bn), 4.83 (AB, JAB = 12.4 Hz, 1 H, CH2Bn), 4.75 (AB, JAB
= 11.0 Hz, 1 H, CH2Bn), 4.54 (AB, JAB = 12.4 Hz, 1 H, CH2Bn),
4.51 (AB, JAB = 12.4 Hz, 1 H, CH2Bn), 4.32 (br., 1 h, 1-H), 4.17
(dd, J4,5 = J4,3 = 9.6 Hz, 1 H, 4-H), 4.00–3.97 (m, 1 H, 6-H), 3.89
(dd, J2,1 = 6.0, J2,3 = 3.0 Hz, 1 H, 2-H), 3.84 (dd, J7b,OH = 6.0,
J7a,7b = 9.2 Hz, 1 H, 7b-H), 3.77 (dd, J7a,OH = 8.5, J7a,7b = 9.2 Hz,
1 H, 7a-H), 3.54 (dd, J3,2 = 3.0, J3,4 = 9.6 Hz, 1 H, 3-H), 3.50 (s,
3 H, OMe), 3.48 (dd, J5,6 = 1.1, J5,4 = 9.6 Hz, 1 H, 5-H), 1.07–1.01
(m, 21 H, HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.8
(Cqarom), 138.7 (Cqarom), 138.4 (Cqarom), 128.5–127.5 (m, 15
CHarom), 102.9 (C-1), 82.6 (C-3), 75.4 (CH2Bn), 74.3 (C-4), 74.2 (C-
2), 74.1 (CH2Bn), 73.7 (C-5), 71.8 (CH2Bn), 69.9 (C-6), 63.7 (C-7),
57.4 (OMe), 18.1 (CH3TIPS), 12.0 (CHTIPS) ppm. MS (ESI+): m/z
= 673.3 [M + Na]+.
β- -manno-heptopyranoside (22): Compound 22 was obtained start-
D
ing from 19, using the same procedure described for compound
10., Purification by flash chromatography on silica gel (cyclohex-
ane/ethyl acetate, 95:5) gave 22 (170 mg, 69%). [α]2D0 = –53.4 (c =
0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.23 (m, 10 H,
Harom), 4.94 (d, J1,2 = 5.5 Hz, 1 H, 1-H), 4.63 (AB, JAB = 12.4 Hz, 1
H, CH2Bn), 4.62 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.58 (dd, J6,7b
= 3.7, J6,7a = 6.6 Hz, 1 H, 6-H), 4.52 (AB, JAB = 12.4 Hz, 1 H,
CH2Bn), 4.45 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.29–4.21 (m, 3 H,
3-H, 4-H, 5-H), 3.95 (dd, J2,1 = 5.5, J2,3 = 1.4 Hz, 1 H, 2-H), 3.75
(dd, J7b,6 = 3.7, J7a,7b = 11.0 Hz, 1 H, 7b-H), 3.54 (dd, J7a,6 = 6.6,
J7a,7b = 11.0 Hz, 1 H, 7a-H), 3.48 (s, 3 H, OMe), 1.07–0.92 (m, 21
H, HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.2 (Cqarom),
137.6 (Cqarom), 127.8–128.6 (m, 10 CHarom), 99.8 (C-1), 81.3 (C-6),
77.2 (C-5), 74.8 (C-4), 74.0 (C-3), 72.6 (C-2), 72.1 (CH2Bn), 71.6
(CH2Bn), 64.2 (C-7), 56.1 (OMe), 18.0 (CH3TIPS), 11.9 (CHTIPS
)
1,5-Anhydro-2,3,4-tri-O-benzyl-7-O-triisopropylsilyl-
L
-glycero-
D
-
ppm. HRMS (ESI+): calcd. for C31H46O6SiNa [M
565.2956; found 565.2965.
+
Na]+
manno-heptitol (20): Raney nickel (1 g) was added to a solution of
thioheptoside 8(l) (320 mg, 439 μmol) in absolute EtOH (5 mL).
The mixture was stirred for 2 h at room temperature, then the cata-
lyst was removed by filtration through a Celite pad. The catalyst
was washed with absolute EtOH (30 mL), and the filtrate was con-
centrated under reduced pressure. The residue was purifued by
chromatography on silica gel (cyclohexane/ethyl acetate, 9:1) to give
20 (226 mg, 83%) as a colourless oil. [α]2D0 = –28.9 (c = 0.54,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.41–7.27 (m, 15 H,
1,5:3,6-Dianhydro-2,4-di-O-benzyl-7-O-triisopropylsilyl-L-glycero-D-
manno-heptitol (23): Compound 23 was obtained starting from 20,
using the same procedure described for compound 10. Purification
by flash chromatography on silica gel (cyclohexane/ethyl acetate,
9:1) gave 23 (62 mg, 98%). [α]2D0 = +31.5 (c = 0.46, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.40–7.24 (m, 10 H, Harom), 4.68
(AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.54 (AB, JAB = 12.1 Hz, 1 H,
CH2Bn), 4.48 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.45 (AB, JAB
12.1 Hz, 1 H, CH2Bn), 4.32–4.26 (m, 3 H, 2-H, 3-H, 5-H), 4.21 (dd,
J4,5 = 3.2, J4,3 = 6.2 Hz, 1 H, 4-H), 4.06 (dd, J7b,6 = 6.9, J7a,7b
=
Harom), 5.00 (AB, JAB = 10.8 Hz, 1 H, CH2Bn), 4.78 (AB, JAB
=
12.8 Hz, 1 H, CH2Bn), 4.76 (AB, JAB = 10.8 Hz, 1 H, CH2Bn), 4.69
(AB, JAB = 12.8 Hz, 1 H, CH2Bn), 4.64 (AB, JAB = 11.9 Hz, 1 H,
=
10.8 Hz, 1 H, 7b-H), 3.98–3.94 (m, 1 H, 6-H), 3.79 (dd, J1b,2 = 3.4,
J1a,1b = 11.0 Hz, 1 H, 1b-H), 3.73 (dd, J7a,6 = 9.4, J7a,7b = 10.8 Hz,
1 H, 7a-H), 3.65 (dd, J1a,2 = 5.5, J1a,1b = 11.0 Hz, 1 H, 1a-H), 1.09–
1.01 (m, 21 H, HTIPS) ppm. 13C NMR (101 MHz, CDCl3): δ =
138.2 (Cqarom), 137.7 (Cqarom), 128.6–127.7 (m, 10 CHarom), 80.2
(C-2), 76.9 (C-4), 74.5 (C-5), 74.2 (C-3), 72.3 (CH2Bn), 71.7 (C-6),
CH2Bn), 4.60 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.17 (dd, J3,4
=
9.4, J4,5 = 9.6 Hz, 1 H, 4-H), 4.08 (dd, J1b,2 = 1.8, J1b,1a = 12.6 Hz,
1 H, 1b-H), 4.00–3.96 (m, 1 H, 6-H), 3.80 (dd, J7b,6 = 6.9, J7b,7a
=
9.4 Hz, 1 H, 7b-H), 3.76–3.74 (m, 1 H, 2-H), 3.70 (dd, J7a,6 = 7.3,
J7a,7b = 9.4 Hz, 1 H, 7a-H), 3.59 (dd, J3,2 = 3.0, J3,4 = 9.4 Hz, 1 H,
3-H), 3.33 (d, J5,4 = 9.6 Hz, 1 H, 5-H), 3.27 (d, J1a,1b = 12.6 Hz, 1
H, 1a-H), 2.27 (br., 1 H, OH), 1.09–0.99 (m, 21 H, HTIPS) ppm.
13C NMR (101 MHz, CDCl3): δ = 138.7 (Cqarom), 138.4 (Cqarom),
138.3 (Cqarom), 127.6–128.4 (15 CHarom), 83.2 (C-3), 78.0 (C-5),
75.4 (CH2Bn), 74.6 (C-4), 72.6 (C-2), 71.7 (CH2Bn), 71.3 (CH2Bn),
71.4 (CH2Bn), 64.1 (C-1), 64.0 (C-7), 18.0 (CH3TIPS), 11.9 (CHTIPS
)
ppm. HRMS (ESI+): calcd. for C30H44O5SiNa [M
535.2850; found 535.2820.
+
Na]+
Methyl 3,6-Anhydro-2,4-di-O-benzyl-L-glycero-α-D-manno-hepto-
pyranoside (24): Compound 24 was obtained starting from 21,
using the same procedure described for compound 12. Purification
69.7 (C-6), 67.1 (C-1), 64.0 (C-7), 18.1 (CH3TIPS), 12.0 (CHTIPS
)
ppm. HRMS (APCI+): calcd. for C37H52O6SiNa [M + Na]+
643.3425; found 643.3429.
by flash chromatography on silica gel (dichloromethane/methanol,
1
Methyl 3,6-Anhydro-2,4-di-O-benzyl-7-O-triisopropylsilyl-
L
-glycero- 99:1) gave 24 (112 mg, 79%). [α]2D0 = +36.0 (c = 0.66, CHCl3). H
α-D-manno-heptopyranoside (21): Compound 21 was obtained start-
NMR (400 MHz, CDCl3): δ = 7.37–7.23 (m, 10 H, Harom), 4.86 (d,
Eur. J. Org. Chem. 2013, 7593–7603
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7601

A. Tikad, S. P. Vincent
FULL PAPER
J1,2 = 6.4 Hz, 1 H, 1-H), 4.73 (AB, JAB = 12.1 Hz, 1 H, CH2Bn),
29 (50 mg, 1 equiv., 79 μmol) and cyclohexanol (12 μL, 1.5 equiv.,
118 μmol) in CH2Cl2 (2 mL) containing molecular sieves 4 Å
4.65 (AB, JAB = 12.1 Hz, 1 H, CH2Bn), 4.57 (AB, JAB = 11.9 Hz,
1 H, CH2Bn), 4.44 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.30–4.28 (m, (100 mg) at 0 °C under argon. The mixture was stirred for 10 min,
1 H, 6-H), 4.27 (d, J5,4 = 3.0 Hz, 1 H, 5-H), 4.21 (dd, J3,2 = 1.6, then it was filtered through Celite, and the filtrate was quenched
J3,4 = 5.9 Hz, 1 H, 3-H), 4.00 (dd, J4,5 = 3.0, J3,4 = 5.9 Hz, 1 H, 4-
H), 3.70 (dd, J2,1 = 6.4, J2,3 = 1.6 Hz, 1 H, 2-H), 3.63–3.57 (m, 1
with Na2S2O3 (5% aq.). The aqueous phase was extracted with
CH2Cl2, and the combined organic extracts were washed with
H, 7b-H), 3.56 (s, 3 H, OMe), 3.55–3.49 (m, 1 H, 7a-H) ppm. 13C brine, dried with MgSO4, filtered, concentrated, and purified by
NMR (101 MHz, CDCl3): δ = 138.3 (Cqarom), 137.4 (Cqarom),
128.6–127.7 (m, 10 CHarom), 103.2 (C-1), 80.7 (C-6), 76.4 (C-4),
76.2 (C-2), 76.0 (C-3), 74.6 (C-5), 72.9 (CH2Bn), 72.2 (CH2Bn), 63.4
(C-7), 57.1 (OMe) ppm. HRMS (ESI+): calcd. for C22H26O6Na [M
+ Na]+ 409.1622; found 409.1603.
silica gel chromatography (cyclohexane/ethyl acetate, 95:5) to give
30 (44 mg, 90%) as an inseparable mixture, α/β = 54:46. [α]2D0
=
–2.6 (c = 0.7, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.52–7.17
(m, 20 H, Harom), 5.06–4.43 (m, 10 H, 1α-H, 1β-H, CH2Bn), 4.01
(dd, J3α,4α = 9.2, J4α,5α = 9.4 Hz, 1 H, 4α-H), 3.96 (dd, J3α,2α = 3.0,
J3α,4α = 9.2 Hz, 1 H, 3α-H), 3.89–3.80 (m, 5 H, 2β-H, 4β-H, 5α-H,
6bα-H, 6bβ-H), 3.77–3.71 (m, 4 H, 1Јβ-H, 2α-H, 6aα-H, 6aβ-H),
3.62–3.56 (m, 1 H, 1Јα-H), 3.53 (dd, J3β,2β = 3.0, J3β,4β = 9.4 Hz,
1 H, 3β-H), 3.47 (ddd, J5β,6βb = 1.6, J5β,6βa = 6.2, J5β,4β = 9.4 Hz,
1 H, 5β-H), 2.02–1.15 (m, 10 H, HCy) ppm. 13C NMR (101 MHz,
CDCl3): δ = 139.0 (Cqarom), 138.7 (Cqarom), 138.6 (Cqarom), 138.5
(3 Cqarom), 138.4 (Cqarom), 138.3 (Cqarom), 128.8–127.4 (20 CHarom),
99.6 (C-1β), 95.8 (C-1α), 82.7 (C-3β), 80.4 (C-3α), 76.7 (C-1Јβ),
75.9 (C-5β), 75.4 (C-2α), 75.3 (C-4α), 75.2 (2 CH2Bn), 75.1 (C-4β),
74.8 (C-1Јα), 74.1 (C-2β), 73.8 (CH2Bn), 73.5 (CH2Bn), 73.4
(CH2Bn), 72.7 (CH2Bn), 72.3 (CH2Bn), 71.8 (C-5α), 71.4 (CH2Bn),
69.9 (C-6β), 69.4 (C-6α), 33.6 (CH2Cyβ), 33.3 (CH2Cyα), 31.7
(CH2Cyβ), 31.3 (CH2Cyα), 25.8 (CH2Cyβ), 25.7 (CH2Cyα), 24.1
(CH2Cyβ), 24.0 (CH2Cyα), 23.9 (CH2Cyβ), 23.8 (CH2Cyα) ppm.
HRMS (ESI+): calcd. for C40H46O6Na [M + Na]+ 645.3187; found
645.3171.
Methyl 3,6-Anhydro-L-glycero-α-D-manno-heptopyranoside (25): A
solution of 24 (40 mg, 0.1 mmol) in THF/MeOH (1:2; 3 mL) was
hydrogenolysed in the presence of Pd/C (10%; 40 mg) at room tem-
perature. After 24 h, the reaction mixture was filtered through a
pad of Celite, and the filtrate was concentrated in vacuo to give
heptoside 25 (17 mg, 81%) as a white foam. [α]2D0 = +90.0 (c = 0.4,
MeOH). 1H NMR (400 MHz, CD3OD): δ = 4.67 (d, J1,2 = 6.6 Hz,
1 H, 1-H), 4.27 (dd, J4,5 = 3.0, J3,4 = 6.0 Hz, 1 H, 4-H), 4.17 (dd,
J6,7b = 5.0, J6,7a = 6.0 Hz, 1 H, 6-H), 4.12 (d, J5,4 = 3.0 Hz, 1 H,
5-H), 4.07 (dd, J3,2 = 1.6, J3,4 = 6.0 Hz, 1 H, 3-H), 3.75 (dd, J2,1
6.6, J2,3 = 1.6 Hz, 1 H, 2-H), 3.56 (dd, J7b,6 = 5.0, J7a,7b = 11.7 Hz,
1 H, 7b-H), 3.52 (s, 3 H, OMe), 3.47 (dd, J7a,6 = 6.0, J7a,7b
=
=
11.7 Hz, 1 H, 7a-H) ppm. 13C NMR (101 MHz, CD3OD): δ =
105.0 (C-1), 82.2 (C-6), 79.9 (C-3), 78.2 (C-5), 70.5 (C-4), 70.3 (C-
2), 63.9 (C-7), 57.4 (OMe) ppm. HRMS (ESI+): calcd. for
C8H14O6Na [M + Na]+ 229.0683; found 229.0681.
Cyclohexyl 2,3,4,6,7-Penta-O-benzyl-L-glycero-D-manno-heptopyr-
Methyl
3,6-Anhydro-2,4-di-O-benzyl-L-glycero-β-D-manno-hepto-
anoside (31): Compound 31 was obtained starting from thioheptos-
ide 7, using the same procedure described for compound 30. Purifi-
cation by flash chromatography on silica gel (cyclohexane/ethyl
acetate, 95:5) gave 31 (43 mg, 88%) as an inseparable mixture, α/β
= 58:42. [α]2D0 = –1.8 (c = 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.50–7.18 (m, 25 H, Harom), 5.06 (d, J1α,2α = 1.6 Hz,
1 H, 1α-H), 5.04–4.73 (m, 4 H, CH2Bn), 4.63–4.32 (m, 7 H, 1β-H,
CH2Bn), 4.20 (dd, J3α,4α = 9.2, J4α,5α = 9.6 Hz, 1 H, 4α-H), 4.19
(dd, J3β,4β = 9.4, J4β,5β = 9.6 Hz, 1 H, 4β-H), 4.15–4.11 (m, 2 H,
6α-H, 6β-H), 3.95 (dd, J3α,2α = 3.0, J3α,4α = 9.2 Hz, 1 H, 3α-H),
pyranoside (26): Compound 26 was obtained starting from 22,
using the same procedure described for compound 12. Purification
by flash chromatography on silica gel (dichloromethane/methanol,
99:1) gave 26 (62%). [α]2D0 = –70.3 (c = 0.38, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.24 (m, 10 H, Harom), 4.93 (d, J1,2
=
5.7 Hz, 1 H, 1-H), 4.66–4.61 (m, 3 H, 6-H, CH2Bn), 4.52 (AB, JAB
= 12.1 Hz, 1 H, CH2Bn), 4.44 (AB, JAB = 11.7 Hz, 1 H, CH2Bn),
4.31 (dd, J3,2 = 1.4, J3,4 = 5.7 Hz, 1 H, 3-H), 4.17–4.13 (m, 2 H, 4-
H, 5-H), 3.95 (dd, J2,1 = 5.7, J2,3 = 1.4 Hz, 1 H, 2-H), 3.58 (dd,
J7b,6 = 4.8, J7a,7b = 11.9 Hz, 1 H, 7b-H), 3.52 (dd, J7a,6 = 5.3, J7a,7b
= 11.9 Hz, 1 H, 7a-H), 3.48 (s, 3 H, OMe) ppm. 13C NMR
(101 MHz, CDCl3): δ = 138.0 (Cqarom), 137.4 (Cqarom), 128.6–127.9
(m, 10 CHarom), 99.9 (C-1), 81.2 (C-6), 77.5 (C-5), 75.3 (C-3), 74.0
(C-4), 72.5 (C-2), 72.2 (CH2Bn), 71.7 (CH2Bn), 63.7 (C-7), 56.3
(OMe) ppm. HRMS (ESI+): calcd. for C22H26O6Na [M + Na]+
409.1622; found 409.1632.
3.87–3.80 (m, 4 H, 2β-H, 5α-H, 7bα-H, 7bβ-H), 3.76 (dd, J7βa,6β
6.4, J7βa,7βb = 9.6 Hz, 1 H, 7aβ-H), 3.73–3.69 (m, 2 H, 2α-H, 7aα-
=
H), 3.64–3.58 (m, 1 H, 1Јβ-H), 3.52 (dd, J3β,2β = 3.0, J3β,4β
9.4 Hz, 1 H, 3β-H), 3.51–3.47 (m, 1 H, 1Јα-H), 3.40 (dd, J5β,6β
=
=
2.1, J5β,4β = 9.6 Hz, 1 H, 5β-H), 1.92–1.63 (m, 4 H, HCy), 1.55–
1.10 (m, 6 H, HCy) ppm. 13C NMR (101 MHz, CDCl3): δ = 139.1
(Cqarom), 139.0 (Cqarom), 138.9 (Cqarom), 138.8 (2 Cqarom), 138.64
(Cqarom), 138.62 (Cqarom), 138.4 (Cqarom), 138.3 (Cqarom), 138.2
(Cqarom), 128.6–127.3 (25 CHarom), 100.4 (C-1β), 95.3 (C-1α), 83.2
(C-3β), 80.8 (C-3α), 77.0 (C-1Јβ), 75.5 (C-5β), 75.4 (C-6α), 75.1 (C-
2α), 75.0 (C-6β), 74.8 (CH2Bn), 74.7 (CH2Bn), 74.6 (C-4α), 74.3 (C-
4β), 74.2 (C-1Јα), 73.6 (C-2β), 73.5 (CH2Bn), 73.4 (CH2Bn), 72.8
(CH2Bn), 72.5 (CH2Bn), 72.4 (CH2Bn), 72.1 (CH2Bn), 71.9 (C-5α),
71.3 (CH2Bn), 70.9 (C-7α), 69.9 (C-7β), 33.5 (CH2Cyβ), 33.2
(CH2Cyα), 31.5 (CH2Cyβ), 31.0 (CH2Cyα), 25.8 (CH2Cyβ), 25.7
(CH2Cyα), 24.1 (CH2Cyβ), 24.0 (CH2Cyα), 23.9 (CH2Cyβ), 23.8
(CH2Cyα) ppm. HRMS (ESI+): calcd. for C48H54O7Na [M + Na]+
765.3762; found 765.3727.
Methyl 3,6-Anhydro-L-glycero-β-D-manno-heptopyranoside (27): A
solution of 26 (40 mg, 0.1 mmol) in THF/MeOH (1:2, 3 mL) was
hydrogenolysed in the presence of Pd/C 10% (40 mg) at room tem-
perature. After 24 h, the reaction mixture was filtered through a
pad of Celite, and the filtrate was concentrated in vacuo to give
heptoside 27 (18 mg, 86%). [α]2D0 = –93.3 (c = 0.6, MeOH). 1H
NMR (400 MHz, CD3OD): δ = 4.84–4.83 (m, 1 H, 1-H), 4.41 (dd,
J6,7b = 4.8, J6,7a = 6.6 Hz, 1 H, 6-H), 4.34 (dd, J4,5 = 6.2, J3,4
3.2 Hz, 1 H, 4-H), 4.04–4.00 (m, 2 H, 2-H, 3-H), 3.98 (d, J5,4
=
=
3.2 Hz, 1 H, 5-H), 3.51 (dd, J7b,6 = 4.8, J7a,7b = 11.7 Hz, 1 H, 7b-
H), 3.45 (s, 3 H, OMe), 3.40 (dd, J7a,6 = 6.6, J7a,7b = 11.7 Hz, 1 H,
7a-H) ppm. 13C NMR (101 MHz, CD3OD): δ = 101.6 (C-1), 82.8
(C-6), 79.3 (C-3), 77.2 (C-5), 71.3 (C-4), 67.1 (C-2), 64.0 (C-7), 56.4
(OMe) ppm. MS (ESI+): m/z = 229.0 [M + Na]+.
Cyclohexyl 3,6-Anhydro-2,4,7-tri-O-benzyl-L-glycero-α-D-manno-
heptopyranoside (32): Compound 32 was obtained starting from
3,6-anhydrothioheptoside 13, using the same procedure described
for compound 30. Purification by flash chromatography on silica
gel (cyclohexane/ethyl acetate, 9:1) gave 32 (37 mg, 75%) as the
pure α isomer. [α]2D0 = +26.8 (c = 0.66, CHCl3). 1H NMR
Cyclohexyl 2,3,4,6-Tetra-O-benzyl-D-mannopyranoside (30): NIS
(27 mg, 1.5 equiv., 118 μmol) and TfOH (1.2 μL, 0.17 equiv.,
13 μmol) were added successively to a solution of thiomannoside
7602
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7593–7603

Constrained 3,6-Anhydro-Heptosides
(400 MHz, CDCl3): δ = 7.36–7.24 (m, 15 H, Harom), 5.04 (d, J1,2
=
M. Yoshikawa, X. Wu, O. Muraoka, Bioorg. Med. Chem. 2011,
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6.6 Hz, 1 H, 1-H), 4.75 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.62
(AB, JAB = 12.1 Hz, 1 H, CH2Bn), 4.58 (AB, JAB = 11.9 Hz, 1 H,
CH2Bn), 4.50 (AB, JAB = 11.9 Hz, 1 H, CH2Bn), 4.45 (AB, JAB
=
12.1 Hz, 1 H, CH2Bn), 4.42 (AB, JAB = 12.1 Hz, 1 H, CH2Bn), 4.33
(dd, J6,7b = 3.9, J6,7a = 5.5 Hz, 1 H, 6-H), 4.28 (d, J5,4 = 2.8 Hz, 1
H, 5-H), 4.19 (dd, J3,2 = 1.1, J3,4 = 6.0 Hz, 1 H, 3-H), 4.05 (dd,
J4,5 = 2.8, J3,4 = 6.0 Hz, 1 H, 4-H), 3.72–3.69 (m, 1 H, 1Ј-H), 3.67
(dd, J2,3 = 1.1, J2,1 = 6.6 Hz, 1 H, 2-H), 3.49 (dd, J7b,6 = 3.9, J7a,7b
= 10.5 Hz, 1 H, 7b-H), 3.37 (dd, J7a,6 = 3.9, J7a,7b = 10.5 Hz, 1 H,
7a-H), 2.04–1.94 (m, 2 H, HCy), 1.80–1.71 (m, 2 H, HCy), 1.55–
1.19 (m, 6 H, HCy) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.7
(Cqarom), 137.9 (Cqarom), 137.8 (Cqarom), 128.6–127.6 (m, 15
CHarom), 100.1 (C-1), 79.5 (C-6), 77.7 (C-1Ј), 76.9 (C-2), 76.2 (C-
4), 76.1 (C-3), 74.7 (C-5), 73.6 (CH2Bn), 72.9 (CH2Bn), 72.1
(CH2Bn), 70.6 (C-7), 33.9 (CH2Cy), 32.2 (CH2Cy), 25.8 (CH2Cy), 24.4
(CH2Cy), 24.2 (CH2Cy) ppm. HRMS (ESI+): calcd. for C34H40O6Na
[M + Na]+ 567.2717; found 567.2699.
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1
to give 3,6-anhydroheptoside 1 (7 mg, 78%). H NMR (400 MHz,
CD3OD): δ = 4.67 (d, J1,2 = 6.4 Hz, 1 H, 1-H), 4.33 (m, 2 H, 4-H,
6-H), 4.23 (m, 1 H, 5-H), 4.10 (m, 1 H, 3-H), 3.94 (m, 1 H, 7b-H),
3.83 (m, 1 H, 7a-H), 3.76 (d, J2,1 = 6.4 Hz, 1 H, 2-H), 3.52 (s, 3 H,
OMe) ppm. 13C NMR (101 MHz, CD3OD): δ = 105.0 (C-1), 80.2
(C-3, C-6), 77.9 (C-5), 70.3 (C-4), 70.2 (C-2), 67.3 (C-7), 57.4
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(ESI–): calcd. for C8H15O9PNa [M – H]– 285.0381; found 285.0376.
[10]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra.
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Published Online: September 25, 2013
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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