On the Gluco/Manno Paradox: Practical α-Glucosylations by NIS/TfOH Activation of 4,6-O-Tethered Thioglucoside Donors

Article abstract of DOI:10.1002/ejoc.201600899

A practical protocol for obtaining α-glucosides was established. It was found that 4,6-O-benzylidene or 4,6-O-(di-tert-butylsilylene) tethering of glucosyl donors of the thioglycoside type enables highly α-selective glucosylation under conditions of N-iodosuccinimide (NIS)/triflic acid (TfOH) activation. The α-glucosylations were further found to be largely independent of promoter system, temperature, leaving group and anomeric configuration. The results are discussed in the context of the Glucose/Mannose paradox in glycosylation chemistry.

Full text of DOI:10.1002/ejoc.201600899

DOI: 10.1002/ejoc.201600899
Full Paper
Glycosylation
On the Gluco/Manno Paradox: Practical α-Glucosylations by NIS/
TfOH Activation of 4,6-O-Tethered Thioglucoside Donors
Mads Heuckendorff*[a] and Henrik H. Jensen*[a]
Abstract: A practical protocol for obtaining α-glucosides was The α-glucosylations were further found to be largely inde-
established. It was found that 4,6-O-benzylidene or 4,6-O-(di- pendent of promoter system, temperature, leaving group and
tert-butylsilylene) tethering of glucosyl donors of the thioglyc- anomeric configuration. The results are discussed in the context
oside type enables highly α-selective glucosylation under con- of the Glucose/Mannose paradox in glycosylation chemistry.
ditions of N-iodosuccinimide (NIS)/triflic acid (TfOH) activation.
Introduction
through SN2 reaction of the α-mannosyl triflate/ion pair with
the acceptor alcohol.[13] Recent studies by Crich have provided
further evidence for this mechanism by measuring kinetic
isotope effects under preactivation conditions[14] and using
cationic clock reactions.[15] Analogously, an α-glucosyl triflate is
observed by low temperature NMR in the Crich α-glucosylation
under preactivation conditions, although the α-glucosyl triflate
intermediate cannot explain the high α-selectivity in this reac-
tion.[16] The reversed selectivity in these glucosylations has
been suggested to originate from in-situ anomerization of α
and ꢀ-glucosyl triflates in a fashion analogous that noted for
bromide ions in the Lemieux method.[9] Furthermore, solvent
separated ion pairs,[17] and more recently, ꢀ-contact ion pairs
have been suggested as important intermediates in an SN2-like
reaction leading to α-selectivity although the ꢀ-glucosyl triflate
or its ions have never been observed (Scheme 1).[14]
α-Glucosides are ubiquitous motifs in Nature's glycospace and,
consequently, their synthetic availabilities are very important.[1]
In spite of the anomeric effect, highly α-selective glucosylations
are not easy to achieve. Contrary to Fischer glycosylation condi-
tions with simple alcohols like methanol, glycosylation reactions
leading to oligosaccharides are often conducted under kinetic
control; the kinetic products of glucosylation are typically the
equatorial product.[2,3] Several methods for selective synthesis
of α-glucosides have been developed over the years. Among
the most famous of these approaches are: i) in-situ anomeriza-
tion by Lemieux[4] & Gervay-Hague,[5] ii) intermolecular aglycon
delivery by Hindsgaul, Stork and Bols,[6] iii) the use of auxiliaries
by Boons, Fairbanks and Turnbull,[7] iv) hydrogen bond-medi-
ated aglycon delivery by Demchenko,[8] and v) the Crich α-glu-
cosylation reaction.[9]
In the original procedure by Crich for synthesizing ꢀ-manno-
sides[10] several measures had to be taken. Most importantly,
the reaction had to be conducted at low temperature under
pre-activation conditions to form the crucial α-triflate before
subsequent addition of the nucleophile. Lately, these original
reaction conditions have been further investigated and ex-
panded upon. It was shown that the original Crich ꢀ-mannosyl-
ation conditions are not pivotal. In fact, it has been noted that
high ꢀ-selectivity can actually be obtained using other condi-
tions not dependent on the mode of activation (normal or in-
verse), leaving group, type of tethering group, promoter system
and temperature.[18] From these results it was suggested that ꢀ-
mannosylation under conditions other than the original Crich-
The Crich approach for selective α-glucosylation was discov-
ered shortly after the more famous Crich ꢀ-mannosylation reac-
tion and was an outcome of conditions which, in the mannose
system, gave highly ꢀ-selective reactions.[10] The reversed se-
lectivity in the two cases has been called the Glucose/Mannose
paradox.[11]
Mechanistic studies of the Crich ꢀ-mannosylation reaction by
low temperature NMR revealed the importance of a transient
α-mannosyl triflate under pre-activation conditions from the
mannosyl sulfoxide/trifluoromethanesulfonic anhydride (Tf2O)
or 1-benzenesulfinyl piperidine (BSP)/Tf2O activation of thio-
mannosides.[12] This α-mannosyl triflate or the α-contact ion
pair is suggested to be a key intermediate in the reaction since
the high ꢀ-selectivity can be explained by Walden inversion
preactivation conditions proceeds through
a mechanism
wherein selectivity arises from the acceptor addition to a boat-
type oxacarbenium ion conformer of the intermediate. This
process leads to the glycosylation product irrespective of the
formerly generated α-mannosyl triflate.[18b,18c] Inspired by this
work, we investigated the Crich α-glucosylation system for simi-
lar effects in order to hopefully optimize and streamline the
Crich α-glucosylation protocol. Our results and progress in this
arena are described in this paper.
[a] Department of Chemistry, Aarhus University,
Langelandsgade 140, 8000 Aarhus C, Denmark
E-mail: heuckendorff@chem.au.dk
hhj@chem.au.dk
http://chem.au.dk/en/research/research-areas/organicchemistry/
bioorganic-chemistry/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600899.
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Scheme 1. ꢀ-Mannosylation and α-glucosylation by Crich and co-workers.
Results and Discussion
was possible to reduce the amount of NIS used without reduc-
ing the α-selectivity.[21] In addition, this order of reactivity corre-
lates to the C-1 NMR chemical shift of the different donors (i.e.
the more reactive donor the lower the δC(C-1)).
The importance of locking the 4,6-O is generally agreed upon
as an important motif for obtaining ꢀ-mannosides. However,
this process also disarms the thioglycoside donor,[19] which, in
turn, necessitates more forcing conditions or additional activat-
ing features for donor activation. Reactions can be tuned by
changing the promoter system and/or the aglycon. It was de-
cided to investigate the selectivity of a Crich-type α-glucosyl-
ation reaction with the often-used NIS/TfOH(cat) promoter sys-
tem[20] with different 4,6-O-locking groups as different thio-
glucosides under non-preactivation conditions.
Table 1. Glycosylation results with 1-adamantanol in CH2Cl2.
In more detail, we chose to synthesize donors with varying
aglycons (thiophenyl, thioethyl and thioadamantyl)[21] and to
investigate the 4,6-O-benzylidene and 4,6-di-O-(tert-butylsilyl-
ene)[22] as tethering groups.[23] The NIS/TfOH(cat) promoter sys-
tem was chosen due to its easy handling and because it is
fundamentally different from the BSP/Tf2O promoter system as
the former only forms another activating reagent upon a glyc-
osylation event, whereas the latter activates the whole pool of
glycosyl donors at low temperature. Finally, the 4,6-tethered
glucosyl donor type was chosen because it has never been ex-
plored systematically with the NIS/TfOH promoter system.
As seen from Table 1 reactions involving all six of the synthe-
sized donors (1–6) gave excellent α-selectivity in glucosylations
using 1-adamantanol as the acceptor and the NIS/TfOH pro-
moter system; the selectivities were independent of tempera-
ture and, importantly, resulting glucosides 7 and 8 were ob-
tained in good to excellent yields. The selectivities are compara-
ble to values previously reported by Crich and co-workers using
[a] Ref.[10c] BSP, Tf2O, TTBP, CH2Cl2, –60 to –40 °C, α/ꢀ > 9.1, 72 %.
From the screening in Table 1 we chose to continue our
investigations with donors 3 and 6 since they could be acti-
vated using only 1.1 equiv. of NIS even at low temperature.[24]
Having established a convenient protocol for glycosylation
BSP/Tf2O/2,4,6-tri-tert-butylpyrimidine (TTBP) pre-activation with donors 3 and 6 of 1-adamantanol we moved on to investi-
conditions at low temperature followed by acceptor addi- gate carbohydrate acceptors in the α-glucosylation reaction.
tion.[10c] The 4,6-O-silylene donor types (1, 3 and 5) that had Acceptors 9 and 10[25] were chosen for comparative reasons,
never been explored in glycosylation reactions could be acti- since they had earlier been used in glucosylations with the BSP/
vated fully at lower temperature with less NIS than the corre- Tf2O promoter system. Acceptors 11 and 12[26] were chosen
sponding 4,6-O-benzylidene donors (2, 4 and 6) but still gave since the oligosaccharide motifs that would be produced fol-
the same amount of α-product. The 4,6-O-silylene protective lowing deprotection and reduction are found in nature.[27] From
group is therefore a good alternative to the benzylidene protec- Table 2 it is apparent that donors 3 and 6 enable high α-select-
tive group. Furthermore, as a result of a more electron rich alkyl ivity in glycosylations with sugar acceptors using NIS/TfOH acti-
aglycon, the two thioadamantyl donors were found to be more vation. Unfortunately, the yields were diminished relative to
reactive than the corresponding thioethyl, and, in turn, thio- those obtained for glycosylation of 1-adamantanol.[28] Further-
phenyl donors, as expected from previous reports; thereby, it more we chose to investigate donors 1 and 2 using the BSP/
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Table 2. Glycosylation yields (isolated) and α/ꢀ-selectivity in CH2Cl2. Reaction conditions A: 1.1 equiv. NIS, 0.1 equiv. TfOH, –30 °C to 0 °C (no pre-activation,
2 h). Reaction conditions B: 1.0 equiv. BSP, 1.1 equiv. Tf2O, 1.1 equiv. TTBP, –60 °C to –40 °C (with pre-activation).
Tf2O promoter system, under the original pre-activation condi- reaction involving donor 13 is highly α-selective, indicating that
tions.[10] In each reaction a mixture of donor, BSP and TTBP in SN2 substitution of the aglycon is unlikely. This result is in ac-
CH2Cl2 was cooled to –60 °C, Tf2O was then added, and the cordance with previous observations by Crich and Cai, who
reaction stirred for 30 min before acceptor addition. As antici-
pated, these glucosylations were α-selective although some of
the glycosylations were somewhat less α-selective, but instead
higher yielding compared to the NIS/TfOH activation condi-
tions. The yields and selectivities with NIS/TfOH and BSP/Tf2O
are comparable with literature examples (Table 2, Entry 5) sug-
gesting that the NIS/TfOH promoter is an easily handled activa-
tion protocol constituting a good alternative to the BSP/Tf2O
promoter system.
found that PhSOTf activation of either 2 or 13 or Tf2O activation
of their corresponding glycosyl sulfoxides gave high propor-
tions of α-glucoside product.[9a] All of the reactions conducted
or referred to until this point have been conducted in the pres-
ence of triflate ions, which could participate in the reaction
scheme as suggested by Crich and co-workers.[10] To investigate
the importance of triflate ions in the glucosylation reaction, a
non-triflate promoter system was chosen for study. NIS with a
catalytic amount (10 mol-%) of AgB(C6F5)4 easily activated do-
As seen from Tables 1 and 2, the 4,6-tethered thiogluc- nor 6 giving the glycosylation product with good α-selectivity,
oside donors are highly α-selective when using the NIS/TfOH but still somewhat smaller yield and selectivity (5:1) compared
promoter system, although the reactions are conducted at to the one observed with NIS/TfOH activation (Table 1, Entry 6).
higher temperature, with a catalytic amount of triflate ions and
without preactivation compared to the BSP/Tf2O promoter sys-
tem.
The high α-selectivities obtained from ꢀ-thioglucoside do-
nors may be explained by an SN2 reaction on the activated
thioaglycon. To investigate this possibility, α-thio glucoside 13
These data suggest that triflate ions are not crucial for good α-
selectivity using NIS activation. Since the α-glucosylation reac-
tion is independent of preactivation, triflate ions, temperature,
leaving group and tethering group, we propose analogously to
the ꢀ-mannosylation investigations[18b,18c] that the α-selectivity
obtained in the α-glucosylations with NIS/TfOH activation is in-
was used in a glycosylation reaction under the same conditions duced by a conformational effect from the 4,6-tethering. We
as with donor 2 in Table 1. As seen from Entry 1 in Table 3, the have previously shown[2] that glucosylation of tetra-O-benzyl
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in dry pyridine (5 mL). The solution was cooled to 0 °C and di-tert-
butylsilyl ditriflate (1.2 mL, 3.68 mmol) was then added drop wise
to the solution. The reaction mixture was stirred for 1 h at 0 °C
before the reaction was quenched by addition of methanol. The
protected counterpart (15) provides ꢀ-selectivity in the range
of 1:3 (α/ꢀ), (Table 3, Entry 3), whereas locking of the 4,6-O
moieties with either benzylidene or silylene affords the inverse
selectivity favoring the α-anomer. We suggest that 4,6-tethering
narrows the space of possible oxocarbenium ion[29] conforma-
tions and could favor a conformation in which α-attack from a
sterically demanding acceptor is advantageous as suggested in
several theoretic studies.[30]
solution was diluted with EtOAc and washed thrice with aq. 1
M
HCl solution, then a saturated hydrogen carbonate solution and
brine. The organic layer was dried with MgSO4, filtered and the
solvents evaporated to dryness. The crude product was purified by
flash column chromatography with pentane as eluent with a gradi-
ent of EtOAc, giving the product as a white foam, yield 1.34 g, 88 %.
Rf = 0.21 (pentane/EtOAc, 3:1). [α]Dr.t. = –41.8 (c = 1, CHCl3). 1H NMR
(400 MHz, CDCl3): δH = 7.54–7.49 (m, 2 H, ArH), 7.34–7.29 (m, 3 H,
ArH), 4.60 (d, J = 9.7 Hz, 1 H, H1), 4.21 (dd, J = 10.2, 5.1 Hz, 1 H,
H6a), 3.90 (t, J = 10.2 Hz, 1 H, H6b), 3.68 (t, J = 9.1 Hz, 1 H, H4), 3.60
(t, J = 8.7 Hz, 1 H, H3), 3.50–3.41 (m, 2 H, H2, H5), 2.86 (s, 2 H, OH),
1.04 [s, 9 H, C(CH3)3], 0.98 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δC = 133.0, 131.8, 129.2, 128.4 (Ar), 88.6 (C1), 77.9 (C3), 76.5
(C4), 74.6 (C5), 71.9 (C2), 66.2 (C6), 27.5 [C(CH3)3], 27.1 [C(CH3)3], 22.8
[C(CH3)3], 20.0 [C(CH3)3] ppm. HRMS (ES): calcd. for C20H32O5SSiNa+
435.1632, found 435.1636.
Table 3. Glucosylation with an α-thioglucoside and glucosylation using a non-
triflate promoter system.
Phenyl 2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-1-thio-ꢀ-
glucopyranoside (1): Phenyl 4,6-O-(di-tert-butylsilylene)-1-thio-ꢀ-
-glucopyranoside (1.29 g, 3.12 mmol) was dissolved in dry THF
D-
D
(20 mL) together with BnBr (3.7 mL, 31.2 mmol) and TBAI (2.31 g,
6.25 mmol). The solution was cooled 0 °C and added NaH (60 % in
mineral oil, 0.5 g, 12.5 mmol). The reaction mixture was stirred over-
night and quenched by addition of aq. satd. ammonium chloride
solution. The solution was diluted with EtOAc and washed with
water, with aqueous 20 % Na2S2O3 solution then brine. The organic
layer was dried with MgSO4, filtered and the solvents evaporated
to dryness. The crude product was purified by flash column chroma-
tography with pentane as eluent with a gradient of CH2Cl2, giving
the product as a clear syrup, yield 1.85 g, 57 %. Rf = 0.43 (pentane/
[a] Entry 3 is taken from ref.[2]
Conclusions
In conclusion, we have explored the 4,6-benzylidene and 4,6-
di-tert-butylsilylene tethered glucosyl donor types. These donor
types enable practical glucosylation reactions with a consistent
high level of α-selectivity with the NIS/TfOH promoter system.
Furthermore we have shown that the α-selectivity in the
glucosylation reactions is induced primarily by 4,6-tethering;
this feature appears to drive selectivity to a far greater extent
than the promoter system, temperature, leaving group or its
orientation. These results suggest that the 4,6-O-tethering indu-
ces α-selectivity due to conformational restriction of intermedi-
ates which favors α-attack from the nucleophile.
CH2Cl2, 1:1). [α]D –1.2 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3):
r.t.
δH = 7.61–7.56 (m, 2 H, ArH), 7.51–7.32 (m, 13 H, ArH), 5.10 (d, J =
10.9 Hz, 1 H, CHHPh), 4.92 (d, J = 10.3 Hz, 1 H, CHHPh), 4.88 (d, J =
10.9 Hz, 1 H, CHHPh), 4.87 (d, J = 10.3 Hz, 1 H, CHHPh), 4.78 (d, J =
9.8 Hz, 1 H, H1), 4.29 (dd, J = 10.2, 5.0 Hz, 1 H, H6a), 4.03 (t, J =
9.2 Hz, 1 H, H4), 4.02 (t, J = 10.2 Hz, 1 H, H6b), 3.71 (t, J = 8.7 Hz, 1
H, H3), 3.55–3.47 (m, 2 H, H2, H5), 1.17 [s, 9 H, C(CH3)3], 1.08 [s, 9
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 138.6, 138.3, 133.3,
132.4, 129.0, 128.5, 128.4, 128.3, 128.2, 127.9, 127.8 (Ar), 88.3 (C1),
86.3 (C3), 80.0 (C2), 77.9 (C4), 75.8 (CH2Ph), 75.8 (CH2Ph), 74.5 (C5),
66.4 (C6), 27.5 [C(CH3)3], 27.1 [C(CH3)3], 22.8 [C(CH3)3], 20.0
[C(CH3)3] ppm. HRMS (ES): calcd. for C34H44O5SSiNa+ 615.2571,
found 615.2574.
Experimental Section
Ethyl 4,6-O-(Di-tert-butylsilylene)-1-thio-ꢀ-
D-glucopyranoside:
Ethyl 1-thio-ꢀ-
D
-glucopyranoside[31] (0.9 g, 4.0 mmol) was dissolved
General Methods: All reagents were used as purchased without
further purification. Dry solvents were taken from an MBraun SPS-
800 solvent purification system. Glassware used for water-free reac-
tions were dried for 12 h at 120 °C before use. Columns were packed
with silica gel 60 (230–400 mesh) as the stationary phase. TLC plates
(Merck, 60, F254) were visualized by 10 % H2SO4 in EtOH and heat-
ing until spots appeared. 1H-NMR and 13C-NMR spectra were re-
corded with a 400 MHz spectrometer. Chemical shifts (δ) are re-
ported in ppm relative to the residual solvent signal. High-resolu-
tion mass spectral (HRMS) data were obtained using an electrospray
(ES) mass spectrometer analyzing time-of-flight. NMR assignments
were based on COSY and HSQC NMR experiments.
in dry pyridine (5 mL). The solution was cooled to 0 °C and di-tert-
butylsilyl ditriflate (1.3 mL, 4.0 mmol) was then added drop wise to
the solution. The reaction mixture was stirred for 1 h at 0 °C before
the reaction was quenched by addition of methanol. The resulting
solution was diluted with EtOAc and washed thrice with aq. 1
M
HCl solution, once with aq. satd. hydrogen carbonate solution and
brine. The organic layer was dried with MgSO4, filtered and the
solvents evaporated to dryness. The crude product was crystallized
from CH2Cl2/pentane giving white needles and the mother liquor
purified by flash column chromatography with pentane as eluent
with a gradient of EtOAc to give the product as a white solid, yield
r.t.
1.00 g, 68 %. Rf = 0.26 (pentane/EtOAc, 3:1). [α]D = –54 (c = 1,
Synthesis of Donors
CHCl3), m.p. 125–126 °C 1H NMR (400 MHz, CDCl3): δH = 4.42 (d, J =
9.7 Hz, 1 H, H1), 4.18 (dd, J = 10.2, 5.1 Hz, 1 H, H6a), 3.89 (t, J =
10.2 Hz, 1 H, H6b), 3.72 (t, J = 9.1 Hz, 1 H, H4), 3.59 (t, J = 8.7 Hz, 1
Phenyl 4,6-O-(Di-tert-butylsilylene)-1-thio-ꢀ-
D-glucopyranoside:
Phenyl 1-thio-ꢀ- -glucopyranoside (1.0 g, 3.68 mmol) was dissolved
D
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H, H3), 3.50–3.42 (m, 2 H, H2, H5), 2.73 (qd, J = 7.4, 1.1 Hz, 2 H,
SCH2), 1.31 (t, J = 7.4 Hz, 3 H, CH3), 1.05 [s, 9 H, C(CH3)3], 0.99 [s, 9
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 86.5 (C1), 77.9
solution was diluted with EtOAc and washed once with water, once
with aq. 20 % Na2S2O3 solution and then brine. The organic layer
was dried with MgSO4, filtered and the solvents evaporated to dry-
(C3), 76.7 (C4), 74.7 (C5), 72.4 (C2), 66.2 (C6), 27.6 [C(CH3)3], 27.1 ness. The crude product was purified by flash column chromatogra-
[C(CH3)3], 24.8 (SCH2), 22.8 [C(CH3)3], 20.1 [C(CH3)3], 15.4 (CH3) ppm.
phy with pentane as eluent with a gradient of CH2Cl2, giving the
HRMS (ES): calcd. for C16H32O5SSiNa+ 387.1632, found 387.1632.
product as a clear syrup, yield 0.90 g, 58 %. Rf = 0.22 (pentane/
EtOAc, 50:1). [α]D 13.4 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3):
r.t.
Ethyl
2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-1-thio-ꢀ-
D
-
δH = 7.44–7.27 (m, 10 H, ArH), 5.01 (d, J = 11.0 Hz, 1 H, CHHPh),
4.92 (d, J = 10.1 Hz, 1 H, CHHPh), 4.81 (d, J = 11.0 Hz, 1 H, CHHPh),
4.74 (d, J = 10.1 Hz, 1 H, CHHPh), 4.69 (d, J = 10.0 Hz, 1 H, H1), 4.14
(dd, J = 10.3, 5.0 Hz, 1 H, H6a), 3.95 (t, J = 9.2 Hz, 1 H, H4), 3.95 (t,
J = 10.3 Hz, 1 H, H6b), 3.61 (t, J = 8.7 Hz, 1 H, H3), 3.41 (ddd, J =
10.0, 5.0 Hz, 1 H, H5), 3.32 (dd, J = 10.0, 8.7 Hz, 1 H, H2), 2.07 (s, 3
H), 1.99 (d, J = 12.1 Hz, 3 H), 1.91 (d, J = 12.1 Hz, 3 H), 1.71 (s, 6 H),
1.09 [s, 9 H, C(CH3)3], 1.03 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δC = 138.9, 138.5, 128.4, 128.4, 128.3, 128.3, 127.8 (Ar), 86.5
(C3), 82.0 (C1), 80.9 (C2), 77.9 (C4), 76.0 (CH2Ph), 75.9 (CH2Ph), 74.2
(C5), 66.5 (C6), 46.6 (CS), 44.3, 36.3, 29.9, 27.6 [C(CH3)3], 27.2
[C(CH3)3], 22.8 [C(CH3)3], 20.0 [C(CH3)3] ppm. HRMS (ES): calcd. for
glucopyranoside (3): Ethyl 4,6-O-(di-tert-butylsilylene)-1-thio-ꢀ-
D
-
glucopyranoside (1.0 g, 2.73 mmol) was dissolved in dry THF
(20 mL) together with BnBr (3.3 mL, 27.3 mmol) and TBAI (2.02 g,
5.46 mmol). The solution was cooled 0 °C and added NaH (0.44 g,
10.9 mmol). The reaction mixture was stirred overnight and
quenched by addition of aq. satd. ammonium chloride solution. The
solution was diluted with EtOAc and washed with water, aq. 20 %
Na2S2O3 and then brine. The organic layer was dried with MgSO4,
filtered and the solvents evaporated to dryness. The crude product
was purified by flash column chromatography with pentane as elu-
ent with a gradient of CH2Cl2, giving the product as a clear syrup,
r.t.
yield 1.20 g, 81 % Rf = 0.22 (pentane/EtOAc, 30:1). [α]D = –23 (c =
C
38H54O5SSiNa+ 673.3353, found 673.3360.
1
1, CHCl3). H NMR (400 MHz, CDCl3): δH = 7.44–7.29 (m, 10 H, ArH),
5.04 (d, J = 11.0 Hz, 1 H, CHHPh), 4.87 (d, J = 10.2 Hz, 1 H, CHHPh),
4.84 (d, J = 11.0 Hz, 1 H, CHHPh), 4.80 (d, J = 10.2 Hz, 1 H, CHHPh),
4.53 (d, J = 9.8 Hz, 1 H, H1), 4.21 (dd, J = 10.2, 5.0 Hz, 1 H, H6a),
3.98 (t, J = 9.2 Hz, 1 H, H4), 3.94 (t, J = 10.2 Hz, 1 H, H6b), 3.62 (t,
J = 8.7 Hz, 1 H, H3), 3.44 (ddd, J = 10.0, 5.0 Hz, 1 H, H5), 3.39 (dd,
J = 9.8, 8.7 Hz, H2), 2.82–2.67 (m, 2 H, SCH2), 1.32 (t, J = 7.4 Hz, 3
H, CH3), 1.11 [s, 9 H, C(CH3)3], 1.03 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δC = 138.8, 138.2, 128.5, 128.4, 128.4, 128.3, 127.9,
127.8 (Ar), 86.2 (C3), 85.7 (C1), 80.8 (C2), 78.1 (C3), 75.9 (CH2Ph), 75.8
(CH2Ph), 74.5 (C5), 66.4 (C6), 27.6 [C(CH3)3], 27.1 [C(CH3)3], 25.1
(CH2S), 22.8 [C(CH3)3], 20.1 [C(CH3)3], 15.3 (CH3) ppm. HRMS (ES):
1-Adamantyl
2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-ꢀ-
D
-
-
glucopyranoside (6): 1-Adamantyl 4,6-O-benzylidene-1-thio-ꢀ-
D
glucopyranoside[21c] (2.05 g, 4.9 mmol) was dissolved in dry DMF
(20 mL). The solution was cooled 0 °C and added NaH (0.78 g,
19.6 mmol). The reaction mixture was stirred for 5 min before
benzyl bromide was added (2.33 mL, 19.6 mmol). The reaction mix-
ture was stirred overnight and quenched by addition of aq. satd.
ammonium chloride. The solution was diluted with EtOAc and
washed four times with water and then brine. The organic layer was
dried with MgSO4, filtered and the solvents evaporated to dryness.
The crude product was purified by flash column chromatography
with pentane as eluent with a gradient of EtOAc, giving the product
as a white solid, yield 2.93 g, 100 %. Rf = 0.44 (pentane/EtOAc, 20:1).
+
calcd. for C30H44O5SSiNH4 562.3017, found 562.3024.
1-Adamantyl 4,6-O-(Di-tert-butylsilylene)-1-thio-ꢀ-
D-glucopyr-
r.t.
1
-glucopyranoside[21c] (1.00 g,
[α]D 8 (c = 1, CHCl3), m.p. 128–130 °C, H NMR (400 MHz, CDCl3):
δH = 7.52–7.47 (m, 2 H, ArH), 7.43–7.24 (m, 13 H, ArH), 5.58 (s, 1 H,
CHPh), 4.94 (d, J = 11.6 Hz, 1 H, CHHPh), 4.93 (d, J = 9.5 Hz, 1 H,
CHHPh), 4.79 (d, J = 11.0 Hz, 1 H, CHHPh), 4.77 (d, J = 11.0 Hz, 1 H,
CHHPh), 4.74 (d, J = 10.1 Hz, 1 H, H1), 4.32 (dd, J = 10.5, 5.0 Hz, 1
H, H6a), 3.81 (dd, J = 9.8, 6.7 Hz, 1 H, H3), 3.79 (t, J = 10 Hz, 1 H,
H6b), 3.71 (t, J = 9.3 Hz, 1 H, H4), 3.47 (ddd, J = 9.5, 4.9 Hz, 1 H,
H5), 3.41 (dd, J = 9.9, 8.4 Hz, 1 H, H2), 2.07 (s, 3 H), 2.00 (d, J =
12.2 Hz, 3 H), 1.91 (d, J = 12.1 Hz, 3 H), 1.71 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δC = 138.6, 138.3, 137.5, 129.1, 128.5, 128.4, 128.4,
128.4, 128.2, 127.9, 127.8, 126.1 (Ar), 101.2 (CHPh), 83.3 (C3), 82.2
(C1), 81.6 (C2), 81.4 (C4), 76.2 (CH2Ph), 75.4 (CH2Ph), 70.0 (C5), 69.0
(C6), 46.8 (CS), 44.3, 36.3, 29.9 ppm. HRMS (ES): calcd. for
C37H43O5SH+ 599.2826, found 599.2830.
anoside: 1-Adamantyl 1-thio-ꢀ-
D
3.03 mmol) was dissolved in dry pyridine (5 mL). The solution was
cooled to 0 °C and di-tert-butylsilyl ditriflate (1 mL, 3.03 mmol) was
then added drop wise to the solution. The reaction mixture was
stirred for 1 h at 0 °C. The reaction was quenched by addition of
methanol and the solution was diluted with EtOAc and washed
thrice with aq. 1
M HCl, satd. aq. hydrogen carbonate and then
brine. The organic layer was dried with MgSO4, filtered and the
solvents evaporated to dryness. The crude product was purified by
flash column chromatography with pentane as eluent with a gradi-
ent of EtOAc, giving the product as a white foam, yield 1.13 g, 79 %.
r.t.
1
Rf = 0.31 (pentane/EtOAc, 3:1). [α]D –33.6 (c = 1, CHCl3). H NMR
(400 MHz, CDCl3): δH = 4.55 (d, J = 9.8 Hz, 1 H, H1), 4.09 (dd, J =
10.2, 5.1 Hz, 1 H, H6a), 3.86 (t, J = 10.2 Hz, 1 H, H6b), 3.69 (t, J =
9.1 Hz, 1 H, H4), 3.58 (t, J = 8.7 Hz, 1 H, H3), 3.39 (ddd, J = 14.7,
5.2 Hz, 1 H, H5), 3.35 (dd, J = 9.8, 8.7 Hz, 1 H, H2), 2.89 (s, 2 H, OH),
2.04 (s, 3 H), 1.93 (d, J = 12.1 Hz, 3 H), 1.84 (d, J = 12.1 Hz, 3 H),
1.67 (s, 6 H), 1.02 [s, 9 H, C(CH3)3], 0.98 [s, 9 H, C(CH3)3] ppm. 13C
NMR (100 MHz, CDCl3): δC = 82.4 (C1), 77.7 (C3), 76.5 (C4), 74.3 (C5),
72.4 (C2), 66.2 (C6), 46.6 (CH2S), 44.1, 36.1, 29.8, 27.5 [C(CH3)3], 27.1
[C(CH3)3], 22.8 [C(CH3)3], 20.0 [C(CH3)3] ppm. HRMS (ES): calcd. for
C24H42O5SSiNa+ 493.2414, found 493.2418.
4-Chlorophenyl 3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-
pyranoside: 1,3,4,6-Tetra-O-acetyl-2-azido-2-deoxy-α/ꢀ-
D
-gluco-
-gluco-
D
pyranose (0.50 g, 1.34 mmol) was dissolved in dry CH2Cl2 (5 mL).
To the solution was 4-chlorophenol (0.35 g, 2.72 mmol) and TMSOTf
(0.05 mL, 0.27 mmol) added. The reaction mixture was stirred for
3 d and then quenched by addition of Et3N. The solvent was evapo-
rated and the crude product purified by flash column chromatogra-
phy with pentane as eluent with a gradient of EtOAc, giving the
product as a clear oil, yield 0.55 g, 93 %. Rf = 0.68 (pentane/EtOAc,
1:1). 1H NMR (400 MHz, CDCl3): δH = 7.08–7.01 (m, 10 H, ArH), 6.88–
6.81 (m, 8 H, ArH), 6.80–6.74 (m, 2 H, ArH), 5.44 (dd, J = 10.6, 9.3 Hz,
4 H, H3α), 5.34 (d, J = 3.5 Hz, 4 H, H1α), 4.94–4.87 (m, 4 H, H4α),
4.86–4.80 (m, 2 H), 4.66 (d, J = 8.1 Hz, 1 H, H1ꢀ), 4.10–3.99 (m, 5 H),
1-Adamantyl
thio-ꢀ- -glucopyranoside (5): 1-Adamantyl 4,6-O-(di-tert-butylsil-
ylene)-1-thio-ꢀ- -glucopyranoside (1.13 g, 2.4 mmol) was dissolved
2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-1-
D
D
in dry THF (20 mL) together with BnBr (2.9 mL, 24 mmol) and TBAI
(1.8 g, 4.8 mmol). The solution was cooled 0 °C and added NaH
(0.38 g, 9.6 mmol) before the reaction mixture was stirred overnight 4.95–4.85 (m, 4 H), 3.94–3.86 (m, 5 H), 3.82 (dd, J = 12.3, 2.2 Hz, 4
and quenched by addition of aq. satd. ammonium chloride. The
H), 3.63–3.52 (m, 2 H), 3.26 (dd, J = 10.6, 3.5 Hz, 4 H, H2α), 1.89 (s,
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12 H, CH3), 1.87 (s, 3 H, CH3), 1.85 (s, 3 H, CH3), 1.81 (s, 12 H, CH3),
1.81 (s, 12 H, CH3), 1.80 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
5 min Bu2BOTf (0.7 mL of 1
and the reaction stirred for additional 2 h before quenched by addi-
M
in DCM) was added to the mixture,
δC = 170.5, 170.4, 170.0, 169.9, 169.6, 169.6 (C=O), 155.2, 154.5, tion of Et3N (0.5 mL) and methanol. The reaction mixture was co-
129.7, 129.6, 128.8, 128.5, 118.5, 118.0 (Ar), 100.6 (C1ꢀ), 96.9 (C1α), distilled with methanol 3 times and then purified by flash column
72.2, 72.1, 70.2 (C4α), 68.5, 68.2, 68.2, 63.5, 61.9 (C6ꢀ), 61.6 (C6α),
60.7, 20.7 (CH3), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3), 20.6 (CH3) ppm.
chromatography with pentane as eluent with a gradient of EtOAc
giving the product as a white solid, yield 0.256 g, 73 %. Rf = 0.63
HRMS (ES): calcd. for C18H20N3O8Cl35NH4 459.1277, found
(pentane/EtOAc, 2:1). [α]D 172 (c = 1, CHCl3), m.p. 118–119 °C, H
NMR (400 MHz, CDCl3): δH = 8.14 (d, J = 7.2 Hz, 2 H, ArH), 7.65 (t,
J = 7.4 Hz, 1 H, ArH), 7.52 (t, J = 7.7 Hz, 2 H, ArH), 7.30 (d, J = 8.9 Hz,
2 H, ArH), 7.22 (s, 5 H, ArH), 7.11 (d, J = 8.9 Hz, 2 H, ArH), 6.09 (dd,
J = 10.6, 8.7 Hz, 1 H, H3), 5.66 (d, J = 3.4 Hz, 1 H, H1), 4.69 (s, 2 H,
CH2Ph), 4.14–3.94 (m, 2 H, H4, H5), 3.86 (s, 2 H, H6), 3.46 (dd, J =
10.7, 3.4 Hz, 1 H, H2), 1.95 (s, 1 H, OH) ppm. 13C NMR (100 MHz,
CDCl3): δC = 165.6 (C=O), 154.6, 137.2, 133.6, 129.9, 129.7, 129.4,
128.6, 128.5, 128.2, 128.1, 128.1, 118.0 (Ar), 97.4 (C1), 75.1 (C4), 75.0
(CH2Ph), 72.5 (C3), 72.1 (C5), 61.3 (C2), 61.0 (C6) ppm. HRMS (ES):
calcd. for C26H24N3O6Cl35Na+ 532.1246, found 532.1252.
+
r.t.
1
459.1282.
4-Chlorophenyl 2-Azido-4,6-O-benzylidene-2-deoxy-α-
pyranoside: To a stirred solution of chlorophenyl 3,4,6-tri-O-acetyl-
2-azido-2-deoxy-α- -glucopyranoside (0.5 g, 1.13 mmol) in MeOH a
D-gluco-
D
catalytic amount of NaOMe was added until a pH-value of 10 was
reached. The reaction mixture was stirred for 1 h at room temp.,
then neutralized with IR-120 resin in MeOH. The resin was filtered
off and the product mixture was concentrated in vacuo. The prod-
uct was dissolved in anhydrous DMF (5 mL) and to the solution was
added benzaldehyde dimethyl acetal (0.42 mL, 2.8 mmol) and
pTsOH (20 mg, 0.1 mmol). The solution was stirred on a rotary evap-
orator (50 °C, 200 mbar) for 4 h. The reaction mixture was then
neutralized with triethylamine and concentrated. The crude product
was purified by flash column chromatography with pentane as elu-
ent with a gradient of EtOAc, giving the product as a white solid,
General Procedure for Glycosylations
NIS/TfOH-Promoted Glycosylations: A mixture of glycosyl donor
(0.10 mmol), glycosyl acceptor (0.15 mmol), and freshly activated
molecular sieves (3 Å, 100 mg) in CH2Cl2 (2 mL) was stirred under
argon for 1 h. The solution was cooled to –30 °C using a dry ice/
acetone bath. NIS (0.11 mmol or 0.2 mmol) and TfOH (0.1 mL of a
r.t.
yield 0.343 g, 75 %. Rf = 0.61 (pentane/EtOAc, 3:1). [α]D 217 (c =
1, CHCl3), m.p. 159–160 °C, 1H NMR (400 MHz, CDCl3): δH = 7.52–
7.46 (m, 2 H, ArH), 7.42–7.36 (m, 3 H, ArH), 7.31–7.27 (m, 2 H, ArH),
7.08–6.98 (m, 2 H, ArH), 5.57 (s, 1 H, CHPh), 5.53 (d, J = 3.6 Hz, 1 H,
H1), 4.43 (td, J = 9.7, 2.6 Hz, 1 H, H3), 4.24 (dd, J = 10.3, 4.9 Hz, 1
H, H6a), 3.99 (td, J = 10.0, 4.9 Hz, 1 H, H5), 3.76 (t, J = 10.3 Hz, 1 H,
H6b), 3.63 (t, J = 9.4 Hz, 1 H, H4), 3.45 (dd, J = 10.0, 3.6 Hz, 1 H,
H2), 2.73 (d, J = 2.6 Hz, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3):
δC = 154.8 (Ar.), 136.8 (Ar.), 129.7 (Ar.), 129.6 (Ar.), 128.5 (Ar.), 128.3
(Ar.), 126.4 (Ar.), 118.2 (Ar.), 102.2 (CHPh), 97.6 (C1), 81.6 (C4), 68.7
(C3), 68.6 (C6), 63.3 (C5), 62.7 (C2) ppm. HRMS (ES): calcd. for
0.1
M solution of TfOH in CH2Cl2) were added. The reaction was
slowly allowed to reach 0 °C (approximately 2 h). Upon completion,
the solids were filtered off and the filtrate washed with aq. 10 %
Na2S2O3 solution. The organic layer was separated, dried with
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel to afford the correspond-
ing glycoside. Anomeric ratios were measured by comparison of
integral intensities of the signals of the anomeric protons and ano-
meric carbon atoms from 1H-NMR and 13C-NMR spectra of crude
reaction mixtures.
C
19H18N3O5Cl35H+ 404.1008, found 404.1012.
BSP/Tf2O-Promoted Glycosylations: A mixture of glycosyl donor
(0.10 mmol), TTBP (0.11 mmol), BSP(0.10 mmol) and freshly acti-
vated molecular sieves (3 Å, 100 mg) in CH2Cl2 (2 mL) was stirred
under argon for 1 h. The solution was cooled to –60 °C using a dry
ice/acetone bath before Tf2O (0.11 mmol) was added. The reaction
was stirred for 0.5 h at –60 °C before the acceptor (0.15 mmol)
dissolved in CH2Cl2 (0.5 mL) and added. The reaction was stirred for
0.5 h at –60 °C and then slowly allowed to reach –40 °C. Upon
completion, the reaction was quenched by addition of triethyl-
amine. The solids were filtered off and the filtrate was washed with
brine. The organic layer was separated, dried with MgSO4, and con-
centrated in vacuo. The residue was purified by flash column chro-
matography on silica gel to afford the corresponding glycoside.
Anomeric ratios were measured by comparing integral intensities
of the signals of the anomeric protons and anomeric carbon atoms
4-Chlorophenyl 2-Azido-3-O-benzoyl-4,6-O-benzylidene-2-de-
oxy-α- -glucopyranoside: To a stirred solution of 4-chlorophenyl
D
2-azido-4,6-O-benzylidene-2-deoxy-α- -glucopyranoside (0.343 g,
D
0.85 mmol) in CH2Cl2 (10 mL) was added Et3N (0.18 mL, 1.3 mmol),
DMAP (10 mg, 0.085 mmol) and finally BzCl (0.4 mL, 3.4 mmol)
The reaction mixture was stirred overnight before DMAPA (0.43 mL,
3.4 mmol) was added and the reaction mixture stirred for an addi-
tional 0.5 h. The mixture was transferred to a separation funnel and
the organic layer was washed twice with aq. 1
M HCl, aq. satd.
hydrogen carbonate and then brine. The organic layer was dried
with MgSO4, filtered and the solvents evaporated to dryness, giving
the product as a white solid.[32] Yield 0.430 g, 100 %. Rf = 0.57
r.t.
(pentane/EtOAc, 5:1). [α]D 170 (c = 1, CHCl3), m.p. 168.5–169.5 °C,
1H NMR (400 MHz, CDCl3): δH = 8.14–8.06 (m, 2 H, ArH), 7.59 (t, J =
7.4 Hz, 1 H, ArH), 7.47 (t, J = 7.7 Hz, 2 H, ArH), 7.43–7.36 (m, 2 H,
ArH), 7.34–7.28 (m, 4 H, ArH), 7.13–7.06 (m, 2 H, ArH), 6.06 (t, J =
9.9 Hz, 1 H, H3), 5.66 (d, J = 3.5 Hz, 1 H, H1), 5.55 (s, 1 H, CHPh),
4.29 (dd, J = 10.3, 4.9 Hz, 1 H, H6a), 4.17 (td, J = 9.9, 4.9 Hz, 1 H,
H5), 3.91 (t, J = 9.5 Hz, 1 H, H4), 3.81 (t, J = 10.2 Hz, 1 H, H6b), 3.54
(dd, J = 10.4, 3.5 Hz, 1 H, H2) ppm. 13C NMR (100 MHz, CDCl3): δC =
165.6 (C=O), 154.7, 136.8, 133.5, 130.1, 129.9, 129.5, 129.3, 128.6,
128.6, 128.3, 126.3, 118.2 (Ar), 101.9 (CHPh), 98.1 (C1), 79.5 (C4),
69.4 (C3), 68.7 (C6), 63.9 (C5), 61.8 (C2) ppm. HRMS (ES): calcd. for
C26H22N3O6Cl35H+ 508.1270, found 508.1257.
1
from H-NMR and 13C-NMR spectra of crude reaction mixtures.
1-Adamantantyl 2,3-Di-O-benzyl-4,6-O-benzylidene-α-D-gluco-
r.t.
pyranoside: Clear syrup. Rf = 0.63 (pentane/EtOAc, 9:1). [α]D 28
1
(c = 1, CHCl3), ref.[9a] 2.6 (1.7 g, 100 mL, CHCl3). H NMR (400 MHz,
CDCl3): δH = 7.56–7.51 (m, 2 H, ArH), 7.44–7.27 (m, 13 H, ArH), 5.58
(s, 1 H, CHPh), 5.25 (d, J = 3.8 Hz, 1 H, H1), 4.95 (d, J = 11.1 Hz, 1 H,
CHHPh), 4.85 (d, J = 11.1 Hz, 1 H CHHPh), 4.79 (d, J = 12.0 Hz, 1 H,
CHHPh), 4.72 (d, J = 12.0 Hz, 1 H, CHHPh), 4.25 (dd, J = 10.2, 4.9 Hz,
1 H, H6a), 4.14–4.05 (m, 2 H, H4, H5), 3.69 (t, J = 10.3 Hz, 1 H, H6b),
3.62 (t, J = 9.4 Hz, 1 H, H3), 3.54 (dd, J = 9.4, 3.8 Hz, 1 H, H2), 2.18
(s, 3 H), 1.89 (d, J = 11.5 Hz, 3 H), 1.83 (d, J = 11.6 Hz, 3 H), 1.71–
1.59 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δC = 139.1, 138.4,
137.7, 128.9, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.6, 126.1
(Ar), 101.2 (CHPh), 91.2 (C1), 82.8 (C3), 79.5 (C2), 78.8 (C4), 75.4
4-Chlorophenyl 2-Azido-3-O-benzoyl-4-O-benzyl-2-deoxy-α-
glucopyranoside (11): 4-Chlorophenyl 2-azido-3-O-benzoyl-4,6-O-
benzylidene-2-deoxy-α- -glucopyranoside (351 mg, 0.69 mmol)
, 7.0 mL) at 0 °C. After stirring for
D-
D
was dissolved in BH3·THF (1
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(CH2Ph), 75.0 [(CH2)3CO], 73.4 (CH2Ph), 69.3 (C6), 62.2 (C5), 42.6, 36.4, 105.3 (C1), 101.3 (CHPh), 98.9 (C1′), 84.2 (C2), 82.4 (C4′), 81.3 (C4),
30.8 ppm. HRMS (ES): calcd. for C37H42O6Na+ 605.2874, found
605.2871. Spectral values were in accordance with those re-
ported.[9a]
80.4 (C3), 79.3 (C2′), 78.3 (C3′), 75.4 (CH2Ph), 73.8 (CH2Ph), 72.2 (C5),
69.1 (C6′), 67.3 (C6), 63.5 (C5′), 27.2 (CH3), 27.0 (CH3), 26.5 (CH3), 25.6
(CH3) ppm. HRMS (ES): calcd. for C39H46O11NH4 708.3378, found
+
708.3389. Spectral values were in accordance with those re-
1-Adamantyl 2,3-Di-O-benzyl-4,6-O-benzylidene-ꢀ-D-glucopyr-
ported.[9a]
anoside: Clear syrup. Rf = 0.60 (pentane/EtOAc, 9:1). [α]Dr.t. –4.4 (c =
1
1, CHCl3). H NMR (400 MHz, CDCl3): δH = 7.52–7.46 (m, 2 H, ArH),
3-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α/ꢀ-
D-glucopyranosyl)-
7.40–7.26 (m, 13 H, ArH), 5.55 (s, 1 H, CHPh), 4.95 (d, J = 10.9 Hz, 1
H, CHHPh), 4.89 (d, J = 11.4 Hz, 1 H, CHHPh), 4.81 (d, J = 7.8 Hz, 1
H, H1), 4.78 (d, J = 11.4 Hz, 1 H, CHHPh), 4.76 (d, J = 10.9 Hz, 1 H,
CHHPh), 4.29 (dd, J = 10.5, 5.0 Hz, 1 H, H6a), 3.79 (t, J = 10.5 Hz, 1
H, H6b), 3.76–3.71 (m, 1 H), 3.68 (t, J = 9.1 Hz, 1 H), 3.45 (t, J =
8.3 Hz, 1 H, H2), 3.42–3.36 (m, 1 H, H5), 2.17 (s, 3 H), 1.91 (d, J =
11.5 Hz, 3 H), 1.80 (d, J = 11.6 Hz, 3 H), 1.63 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δC = 138.8, 138.6, 137.6, 129.0, 128.5, 128.4, 128.4,
128.3, 128.2, 127.8, 127.7, 126.2 (Ar), 101.2 (CHPh), 96.8 (C1), 82.4
(C2), 81.7, 81.5, 75.8, 75.6, 75.3, 69.1 (C6), 66.1 (C5), 42.9, 36.4,
30.8 ppm. HRMS (ES): calcd. for C37H42O6Na+ 605.2874, found
605.2880.
1,2;5,6-di-O-isopropylidene-α-
D
-glucofuranose: 1H NMR
(400 MHz, CDCl3): δH = 7.54–7.46 (m, ArH), 7.42–7.27 (m, ArH), 5.93
(d, J = 3.6 Hz), 5.75 (d, J = 3.8 Hz), 5.59 (s), 5.58 (s), 5.25 (d, J =
3.7 Hz), 4.94 (d, J = 11.3 Hz), 4.87–4.78 (m), 4.69 (d, J = 11.2 Hz),
4.61–4.57 (m), 4.57–4.48 (m), 4.35 (4.41–4.31) (m), 4.25 (d, J =
2.7 Hz), 4.10 (dd, J = 8.6, 2.7 Hz), 4.08–3.98 (m), 3.91–3.81 (m), 3.79–
3.71 (m), 3.66 (t, J = 9.3 Hz), 3.59 (dd, J = 9.4, 3.7 Hz), 3.40 (t, J =
7.9 Hz), 1.59 (s), 1.51 (s), 1.48 (s), 1.45 (s), 1.42 (s), 1.38 (s), 1.32 (s),
1.27 (s), 1.23 (s) ppm. 13C NMR (100 MHz, CDCl3): δC = 138.7, 138.4,
138.4, 138.2, 138.1, 137.3, 129.1, 128.6, 128.5, 128.5, 128.4, 128.4,
128.2, 128.1, 127.9, 127.8, 127.8, 126.1, 126.0, 112.1, 112.0, 109.3,
108.8, 105.3, 105.2, 101.8, 101.3, 98.9, 84.2, 82.6, 82.4, 81.9, 81.5,
81.3, 81.0, 80.9, 80.4, 80.3, 79.4, 78.3, 75.6, 75.4, 75.2, 73.9, 73.4, 72.2,
69.1, 68.8, 67.3, 66.4, 66.2, 63.5, 27.3, 27.0, 26.8, 26.7, 26.5, 26.2, 25.7,
1-Adamantyl 2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-α-D-
r.t.
glucopyranoside: Clear syrup. Rf = 0.57 (CH2Cl2). [α]D 41 (c = 1,
CHCl3). 1H NMR (400 MHz, CDCl3): δH = 7.46–7.42 (m, 2 H, ArH),
7.39–7.27 (m, 8 H, ArH), 5.17 (d, J = 3.9 Hz, 1 H, H1), 5.01 (d, J =
11.0 Hz, 1 H, CHHPh), 4.84 (d, J = 11.0 Hz, 1 H CHHPh), 4.78 (d, J =
11.9 Hz, 1 H CHHPh), 4.68 (d, J = 11.9 Hz, 1 H, CHHPh), 4.09–3.98
(m, 2 H), 3.91–3.81 (m, 2 H), 3.80 (t, J = 11.5 Hz, 1 H, H6a), 3.44 (dd,
J = 9.3, 3.9 Hz, 1 H, H2), 2.17 (s, 3 H), 1.88 (d, J = 11.5 Hz, 3 H), 1.80
(d, J = 11.5 Hz, 3 H), 1.65 (s, 6 H), 1.09 [s, 9 H, C(CH3)3], 1.04 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 139.5, 138.7, 128.4,
128.4, 128.2, 128.1, 127.8, 127.6 (Ar), 90.7 (C1), 82.1, 79.0, 79.0, 75.7
(CH2Ph), 74.7 [(CH2)3CO], 73.4 (CH2Ph), 67.0 (C6), 65.9, 42.6, 36.4,
30.8, 27.6 [C(CH3)3], 27.2 [C(CH3)3], 22.8 [C(CH3)3], 20.2
[C(CH3)3] ppm. HRMS (ES): calcd. for C38H54O6SiNa+ 657.3582, found
657.3587.
+
25.6 ppm. HRMS (ES): calcd. for C39H46O11NH4 708.3378, found
708.3380.
3-O-[2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-α-
D-gluco-
pyranosyl]-1,2;5,6-di-O-isopropylidene-α- -glucofuranose:
D
r.t.
Clear syrup. Rf = 0.5 (pentane/EtOAc, 9:1). [α]D 24 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δH = 7.43–7.38 (m, 2 H, ArH), 7.36–7.27
(m, 8 H, ArH), 5.91 (d, J = 3.6 Hz, 1 H, H1), 5.14 (d, J = 3.7 Hz, 1 H,
H1′), 4.99 (d, J = 11.0 Hz, 1 H, CHHPh), 4.82 (d, J = 11.0 Hz, 1 H
CHHPh), 4.78 (d, J = 11.7 Hz, 1 H, CHHPh), 4.72 (d, J = 11.7 Hz, 1 H,
CHHPh), 4.54–4.46 (m, 2 H), 4.22 (d, J = 2.7 Hz, 1 H), 4.15–4.10 (m,
2 H), 4.07–3.99 (m, 2 H), 3.92–3.83 (m, 2 H), 3.84–3.76 (m, 2 H), 3.47
(dd, J = 9.5, 3.7 Hz, 1 H, H2′), 1.51 (s, 3 H, CH3), 1.42 (s, 3 H, CH3),
1.31 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 1.08 [s, 9 H, C(CH3)3], 1.03 [s, 9
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 139.1, 138.4, 128.5,
128.4, 128.2, 127.8, 127.7, 127.7 (Ar), 112.1 [C(CH3)2], 109.2 [C(CH3)2],
105.3 (C1), 98.6 (C1′), 84.1, 81.5, 81.3, 80.5, 78.8 (C2′), 78.6, 75.8
(CH2Ph), 73.8 (CH2Ph), 72.4, 67.4, 67.1, 27.5 [C(CH3)3], 27.2 (CH3),
27.1 [C(CH3)3], 27.0 (CH3), 26.2 (CH3), 25.5 (CH3), 22.8 [C(CH3)3], 20.2
1-Adamantyl 2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-ꢀ-D-
r.t.
glucopyranoside: Clear syrup. Rf = 0.33 (CH2Cl2). [α]D 4.4 (c = 1,
CHCl3). 1H NMR (400 MHz, CDCl3): δH = 7.40–7.27 (m, 10 H, ArH),
4.94 (t, J = 11.0 Hz, 2 H, CHHPh, CHHPh), 4.79 (d, J = 11.0 Hz, 1 H,
CHHPh), 4.75 (d, J = 7.8 Hz, 1 H, H1), 4.72 (d, J = 11.0 Hz, 1 H,
CHHPh), 4.10 (dd, J = 10.2, 5.0 Hz, 1 H, H6a), 3.96–3.89 (m, 2 H), 3.52
(t, J = 9.0 Hz, 1 H), 3.39–3.31 (m, 2 H), 2.15 (s, 3 H), 1.88 (d, J =
11.3 Hz, 3 H), 1.77 (d, J = 11.5 Hz, 3 H), 1.63 (s, 6 H), 1.07 [s, 9 H,
C(CH3)3], 1.00 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC =
139.1, 138.8, 128.4, 128.4, 128.3, 128.2, 128.1, 127.7, 127.7 (Ar), 96.6
(C1), 84.7, 81.8, 78.0, 75.7, 75.6, 75.5, 70.3, 66.7, 42.8, 36.4, 30.8, 27.6
[C(CH3)3], 27.2 [C(CH3)3], 22.8 [C(CH3)3], 20.1 [C(CH3)3] ppm. HRMS
(ES): calcd. for C38H54O6SiNa+ 657.3582, found 657.3589.
+
[C(CH3)3] ppm. HRMS (ES): calcd. for C40H58O11SiNH4 760.4087,
found 760.4090.
3-O-[2,3-Di-O-benzyl-4,6-O-(di-tert-butylsilylene)-α/ꢀ-
D-gluco-
pyranosyl]-1,2;5,6-di-O-isopropylidene-α- -glucofuranose:
D
Clear syrup. Rf = 0.49 (pentane/EtOAc, 9:1), 1H NMR (400 MHz,
CDCl3): δH = 7.43–7.38 (m, 2 H, ArH), 7.36–7.27 (m, 13 H, ArH), 5.91
(d, J = 3.6 Hz, 1 H, H1α), 5.75 (d, J = 3.8 Hz, 0.2 H, H1ꢀ), 5.14 (d, J =
3.7 Hz, 1 H, H1′α), 5.03–4.95 (m, 1.2 H), 4.87–4.64 (m, 4 H), 4.55–
4.44 (m, 2.4 H), 4.37–4.32 (m, 0.2 H), 4.28–4.26 (m, 0.2 H), 4.22 (d,
J = 2.7 Hz, 1 H), 4.17–4.10 (m, 2.4 H), 4.08–3.98 (m, 2.4 H), 3.95–3.75
(m, 5 H), 3.55 (t, J = 8.9 Hz, 0.2 H), 3.47 (dd, J = 9.5, 3.7 Hz, 1 H),
3-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl)-
1,2;5,6-di-O-isopropylidene-α-D-glucofuranose: Clear syrup. Rf =
0.62 (pentane/EtOAc, 8:1). [α]D 27 (c = 1, CHCl3). ref[33]. 5.9 (c = 1,
CHCl3). 1H NMR (400 MHz, CDCl3): δH = 7.54–7.49 (m, 2 H, ArH),
r.t.
7.42–7.27 (m, 13 H, ArH), 5.93 (d, J = 3.6 Hz, 1 H, H1), 5.59 (s, 1 H, 3.38 (td, J = 10.0, 5.1 Hz, 0.2 H), 3.33–3.26 (m, 0.2 H), 1.51 (s, 3 H),
CHPh), 5.25 (d, J = 3.7 Hz, 1 H H1′), 4.94 (d, J = 11.2 Hz, 1 H, CHHPh),
4.83 (d, J = 11.2 Hz, 1 H, CHHPh), 4.80 (s, 2 H, CH2Ph), 4.59 (d, J =
3.6 Hz, 1 H, H2), 4.52 (ddd, J = 8.6, 6.2, 4.3 Hz, 1 H, H5), 4.35 (dd,
J = 10.1, 4.6 Hz, 1 H, H6a′), 4.25 (d, J = 2.7 Hz, 1 H, H3), 4.10 (dd,
J = 8.6, 2.7 Hz, 1 H H4), 4.09–3.98 (m, 3 H, H6a, H6b, H3′), 3.87 (ddd,
1.47 (s, 0.6 H), 1.43–1.41 (m, 3 H), 1.35 (s, 0.6 H), 1.31 (s, 3 H), 1.26
(s, 3 H), 1.22 (s, 0.6 H), 1.08 (s, 12 H), 1.03 (s, 9 H), 1.00 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δC = 139.1, 138.8, 138.5, 138.3, 128.6,
128.5, 128.4, 128.2, 128.2, 127.9, 127.9, 127.8, 127.8, 127.8, 127.7,
127.7, 112.1, 111.9, 109.2, 108.7, 105.3, 105.2, 101.8 (C1′ꢀ), 98.6 (C1′
J = 9.9, 4.6 Hz, 1 H, H5′), 3.76 (t, J = 10.2 Hz, 1 H, H6b′), 3.66 (t, J = α), 84.3, 84.1, 82.7, 81.5, 81.4, 80.9, 80.5, 80.3, 78.8, 78.6, 78.0, 75.8,
9.3 Hz, 1 H, H4′), 3.59 (dd, J = 9.4, 3.7 Hz, 1 H, H2′), 1.51 (s, 3 H, 75.6, 75.5, 73.8, 73.5, 72.4, 70.7, 67.4, 67.1, 66.8, 66.4, 66.0, 27.6, 27.6,
CH3), 1.43 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.27 (s, 3 H, CH3) ppm. 13
NMR (100 MHz, CDCl3): δC = 138.7, 138.2, 137.3, 129.1, 128.5, 128.5,
C
27.5, 27.3, 27.2, 27.1, 27.1, 27.0, 26.8, 26.7, 26.2, 25.6, 25.5, 22.8, 20.2,
20.1 ppm. HRMS (ES): calcd. for C40H58O11SiNH4 760.4087, found
+
128.4, 128.1, 127.9, 127.8, 126.0 (Ar), 112.1 [C(CH3)2], 109.3 [C(CH3)2], 760.4094.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Methyl 4-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-
D
-gluco-
(s, 3 H, CH3), 1.25 (d, J = 5.3 Hz, 3 H, H6), 1.08 [s, 9 H, C(CH3)3], 0.99
[s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 139.1, 138.9,
128.4, 128.4, 128.2, 128.1, 127.7, 127.6 (Ar), 109.4 [C(CH3)2], 101.8
(C1′), 98.2 (C1), 84.5 (C3′), 81.9, 78.5, 78.2, 78.2, 76.1, 75.6 (CH2Ph),
75.2 (CH2Ph), 70.3, 66.6 (C6′), 64.2, 55.0 (OCH3), 28.0 (CH3), 27.6
pyranosyl)-2,3-O-isopropylidene-α-
L-rhamnopyranoside: Clear
syrup. Rf = 0.34 (pentane/EtOAc, 8:1). [α]Dr.t. 10 (c = 1, CHCl3), ref.[18d]
4.4 (5.2 g, 100 mL, CHCl3). 1H NMR (400 MHz, CDCl3): δH = 7.51 (dd,
J = 7.6, 1.8 Hz, 2 H, ArH), 7.42–7.27 (m, 13 H, ArH), 5.57 (s, 1 H,
CHPh), 4.97 (d, J = 11.1 Hz, 1 H, CHHPh), 4.91 (d, J = 3.8 Hz, 1 H,
[C(CH3)3], 27.2 [C(CH3)3], 26.4 (CH3), 22.8 [C(CH3)3], 20.1 [C(CH3)3],
+
H1′), 4.87 (d, J = 11.7 Hz, 1 H, CHHPh), 4.85 (s, 1 H, H1), 4.82 (d, J = 17.8 (C6) ppm. HRMS (ES): calcd. for C38H56O10SiNH4 718.3981,
11.1 Hz, 1 H, CHHPh), 4.74 (d, J = 11.7 Hz, 1 H, CHHPh), 4.29 (dd,
J = 9.9, 5.0 Hz, 1 H, H6a′), 4.20–4.03 (m, 4 H), 3.81–3.73 (m, 1 H, H5),
3.70 (t, J = 10.1 Hz, 1 H, H6b′), 3.64 (t, J = 9.5 Hz, 1 H), 3.59 (dd, J =
9.4, 3.8 Hz, 1 H, H2′), 3.38–3.29 (m, 4 H, OCH3, H4), 1.50 (s, 3 H, CH3),
found 718.3985.
4-Chlorophenyl 6-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α/ꢀ-
glucopyranosyl)-2-azido-3-O-benzoyl-4-O-benzyl-2-deoxy-α-
D
D
-
-
glucopyranoside: Clear syrup. Rf = 0.29 (pentane/EtOAc, 5:1). 1H
NMR (400 MHz, CDCl3): δH = 8.03–7.95 (m, 3 H, ArH), 7.62–7.54 (m,
2 H, ArH), 7.50–7.41 (m, 6 H, ArH), 7.40–7.17 (m, 23 H, ArH), 7.11 (s,
6 H, ArH), 7.09–6.98 (m, 10 H, ArH), 6.98–6.92 (m, 1 H, ArH), 5.98
(dd, J = 10.7, 9.0 Hz, 0.3 H, H3ꢀ), 5.89 (dd, J = 10.6, 9.0 Hz, 1 H,
H3α), 5.61 (d, J = 3.4 Hz, 0.3 H, H1ꢀ), 5.56 (s, 1 H, CHPh), 5.52 (s, 0.3
H, CHPh), 5.43 (d, J = 3.5 Hz, 1 H, H1α), 4.98 (d, J = 3.6 Hz, 1 H, H1′
α), 4.95–4.88 (m, 2 H), 4.85–4.80 (m, 2 H), 4.77 (d, J = 11.4 Hz, 0.3
H, CHHPh), 4.70 (d, J = 11.9 Hz, 1 H, CHHPh), 4.58 (d, J = 11.1 Hz, 1
H, CHHPh), 4.54 (d, J = 11.1 Hz, 1 H, CHHPh), 4.40 (d, J = 5.9 Hz, 0.3
H), 4.37 (d, J = 7.7 Hz, 0.3 H, H1′ꢀ), 4.29–4.19 (m, 1.3 H), 4.08 (dd,
J = 11.1, 1.8 Hz, 0.3 H), 4.04–3.95 (m, 2.3 H), 3.95–3.82 (m, 3.6 H),
3.78–3.57 (m, 6 H), 3.53 (t, J = 8.2 Hz, 0.3 H), 3.39–3.24 (m, 1 H),
2.98 (dd, J = 10.7, 3.5 Hz, 1 H, H2α) ppm. 13C NMR (100 MHz, CDCl3):
1.36–1.31 (m, 6 H, CH3, H6) ppm. 13C NMR (100 MHz, CDCl3): δC
=
138.8, 138.0, 137.6, 129.0, 128.6, 128.5, 128.4, 128.4, 128.1, 128.1,
127.7, 126.2 (Ar), 109.2 [C(CH3)2], 101.3 (CHPh), 99.3 (C1′), 98.0 (C1),
82.6, 81.5 (C4), 79.3, 79.1, 77.0, 76.1, 75.4 (CH2Ph), 74.8 (CH2Ph), 69.3
(C1′), 64.8 (C5), 62.6, 54.8 (OCH3), 28.3 (CH3), 26.6 (CH3), 17.5
+
(C6) ppm. HRMS (ES): calcd. for C37H44O10NH4 666.3273, found
666.3275. Spectral values were in accordance with those re-
ported.[18d]
Methyl 4-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-ꢀ-
D
-gluco-
pyranosyl)-2,3-O-isopropylidene-α-
L-rhamnopyranoside: Clear
syrup. Rf = 0.43 (pentane/EtOAc, 8:1). [α]Dr.t. 24 (c = 1, CHCl3), ref.[18d]
–24.5 (4.8 g, 100 mL, CHCl3). 1H NMR (400 MHz, CDCl3): δH = 7.48
(dd, J = 7.4, 2.1 Hz, 2 H, ArH), 7.42–7.27 (m, 13 H, ArH), 5.56 (s, 1 H,
CHPh), 5.05 (d, J = 7.8 Hz, 1 H, H1′), 4.93–4.89 (d, J = 0.9 Hz, 1 H, δC = 165.6, 165.6 (C=O), 154.8, 154.7, 138.7, 138.6, 138.4, 138.4,
H1), 4.87 (d, J = 6.5 Hz, 2 H, CH2Ph), 4.78 (d, J = 11.4 Hz, 1 H,
CHHPh), 4.74 (d, J = 11.1 Hz, 1 H, CHHPh), 4.31 (dd, J = 10.4, 5.0 Hz,
1 H, H6a′), 4.21 (t, J = 6.2 Hz, 1 H), 4.09 (d, J = 5.7 Hz, 1 H), 3.83–
3.74 (m, 2 H), 3.70–3.57 (m, 3 H), 3.43–3.34 (m, 5 H), 1.51 (s, 3 H,
CH3), 1.34 (s, 3 H, CH3), 1.29 (d, J = 5.7 Hz, 3 H, H6) ppm. 13C NMR
(100 MHz, CDCl3): δC = 138.8, 138.7, 137.5, 129.1, 128.4, 128.4, 128.2,
128.1, 127.7, 127.7, 126.1 (Ar), 109.4 [C(CH3)2], 101.8 (C1′), 101.3
137.4, 137.4, 137.3, 133.6, 133.5, 130.0, 130.0, 129.8, 129.7, 129.5,
129.4, 129.1, 129.1, 128.6, 128.6, 128.5, 128.5, 128.4, 128.4, 128.2,
128.1, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6, 127.6, 127.4,
126.1, 118.2, 118.1 (Ar), 104.1 (C1′ꢀ), 101.4 (CHPh), 101.3 (CHPh),
98.6 (C1′α), 97.5 (C1ꢀ), 97.2 (C1α), 82.4, 81.8, 81.6, 81.1, 79.9, 78.1,
76.2, 75.7, 75.5, 75.3, 75.2, 75.0, 74.9, 73.4, 72.7, 72.5, 72.0, 70.9, 69.2,
68.7, 68.1, 66.3, 65.6, 62.8, 61.2 (C2ꢀ), 61.1 (C2α) ppm. HRMS (ES):
(CHPh), 98.2 (C1), 82.4, 81.8, 81.2, 78.4, 78.2, 76.1, 75.3 (CH2Ph), 75.2 calcd. for C53H50O11N3Cl35NH4 957.3472, found 957.3478.
+
(CH2Ph), 69.0 (C6′), 66.1, 64.2, 55.0 (OCH3), 28.0 (CH3), 26.5 (CH3),
4-Chlorophenyl 6-O-[2,3-Di-O-benzyl-(di-tert-butylsilylene)-α-
17.8 (C6) ppm. HRMS (ES): calcd. for C37H44O10NH4+ 666.3273, found
glucopyranosyl]-2-azido-3-O-benzoyl-4-O-benzyl-2-deoxy-α-
666.3276. Spectral values were in accordance with those re-
D
D
-
-
glucopyranoside: Clear syrup. Rf = 0.23 (pentane/EtOAc, 20:1).
ported.[18d]
r.t.
1
[α]D 134 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δH = 8.02–7.97
(m, 2 H, ArH), 7.59 (t, J = 7.4 Hz, 1 H, ArH), 7.50–7.18 (m, 14 H, ArH),
7.14–7.06 (m, 5 H, ArH), 7.04–6.98 (m, 2 H, ArH), 5.93–5.79 (m, 1 H,
H3), 5.35 (d, J = 3.5 Hz, 1 H, H1), 5.01 (d, J = 11.3 Hz, 1 H, CHHPh),
4.97 (d, J = 3.7 Hz, 1 H, H1′), 4.87 (d, J = 11.3 Hz, 1 H, CHHPh), 4.84
(d, J = 11.9 Hz, 1 H, CHHPh), 4.68 (d, J = 11.9 Hz, 1 H, CHHPh), 4.53
(s, 1 H, CH2Ph), 4.10–4.03 (m, 1 H), 3.97–3.79 (m, 7 H), 3.69 (d, J =
12.3 Hz, 1 H), 3.50 (dd, J = 9.0, 3.6 Hz, 1 H, H2′), 2.88 (dd, J = 10.6,
3.5 Hz, 1 H, H2), 1.06 [s, 1 H, C(CH3)3], 0.95 [s, 1 H, C(CH3)3] ppm.
13C NMR (100 MHz, CDCl3): δC = 165.6 (C=O), 154.9, 139.0, 138.9,
Methyl 4-O-[2,3-Di-O-benzyl-(di-tert-butylsilylene)-α-D-gluco-
pyranosyl]-2,3-O-isopropylidene-α-L-rhamnopyranoside: Clear
r.t.
syrup. Rf = 0.33 (pentane/EtOAc, 20:1). [α]D = –19 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δH = 7.45–7.41 (m, 2 H, ArH), 7.37–7.27
(m, 8 H, ArH), 5.04 (d, J = 10.9 Hz, 1 H, CHHPh), 4.90–4.80 (m, 4 H,
CH2Ph, H1, H1′), 4.70 (d, J = 11.7 Hz, 1 H, CHHPh), 4.23–4.10 (m, 4
H), 3.92–3.85 (m, 2 H), 3.83–3.73 (m, 2 H), 3.48 (ddd, J = 6.6, 3.5 Hz,
1 H), 3.37–3.29 (m, 4 H), 1.51 (s, 3 H, CH3), 1.36–1.29 (m, 6 H, CH3),
1.08 [s, 9 H, C(CH3)3], 1.02 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δC = 139.1, 138.1, 128.4, 128.3, 128.3, 128.2, 128.1, 127.8, 137.4, 133.5, 130.0, 129.8, 129.6, 128.6, 128.6, 128.5, 128.4, 128.3,
127.6 (Ar), 109.0 [C(CH3)2], 98.4, 97.9, 82.0, 80.4, 78.7, 78.6, 76.9, 76.0, 128.3, 128.2, 128.0, 127.9, 127.7, 127.2, 118.4 (Ar), 98.5 (C1′), 97.6
75.7 (CH2Ph), 74.5 (CH2Ph), 67.0, 66.3, 64.8, 54.7 (OCH3), 28.1 (CH3), (C1), 81.0, 79.4 (C2′), 78.7, 75.7, 75.5 (CH2Ph), 75.1 (CH2Ph), 73.3
27.4 [C(CH3)3], 27.1 [C(CH3)3], 26.2 (CH3), 22.6 [C(CH3)3], 20.1
[C(CH3)3], 17.4 (C6) ppm. HRMS (ES): calcd. for C38H56O10SiNH4
718.3981, found 718.3984.
(CH2Ph), 72.4 (C3), 72.2, 67.0, 66.7, 65.6, 61.1 (C2), 27.6 [C(CH3)3],
27.2 [C(CH3)3], 22.8 [C(CH3)3], 20.1 [C(CH3)3] ppm. HRMS (ES): calcd.
+
for C54H62O11N3Cl35SiNH4 1009.4180, found 1009.4196.
+
Methyl 4-O-[2,3-Di-O-benzyl-(di-tert-butylsilylene)-ꢀ-
D
-gluco-
4-Chlorophenyl 6-O-[2,3-Di-O-benzyl-(di-tert-butylsilylene)-α/ꢀ-
pyranosyl]-2,3-O-isopropylidene-α- -rhamnopyranoside: Clear
L
D
-glucopyranosyl]-2-azido-3-O-benzoyl-4-O-benzyl-2-deoxy-α-
-glucopyranoside: Clear syrup. Rf = 0.2 (pentane/EtOAc, 20:1). H
syrup. Rf = 0.46 (pentane/EtOAc, 20:1). [α]D 37 (c = 1, CHCl3). 1H
NMR (400 MHz, CDCl3): δH = 7.40–7.35 (m, 4 H, ArH), 7.35–7.27 (m,
6 H, ArH), 4.96 (d, J = 7.3 Hz, 1 H, H1′), 4.95 (d, J = 12.0 Hz, 1 H,
CHPh), 4.86 (d, J = 11.2 Hz, 1 H, CHPh), 4.85 (s, H1), 4.79 (d, J =
11.2 Hz, 1 H, CHHPh), 4.71 (d, J = 11.1 Hz, 1 H, CHHPh), 4.19 (t, J =
6.2 Hz, 1 H), 4.12 (dd, J = 10.2, 5.0 Hz, 1 H), 4.09 (d, J = 5.7 Hz, 1 H,
H2′), 3.94–3.87 (m, 2 H), 3.62–3.58 (m, 2 H), 3.55 (t, J = 8.9 Hz, 1 H,
H3′), 3.38 (s, 3 H, OCH3), 3.36–3.27 (m, 2 H), 1.51 (s, 3 H, CH3), 1.34
D
r.t.
1
NMR (400 MHz, CDCl3): δH = 8.08–7.96 (m, 1.6 H, ArH), 7.63–7.57
(m, 1.6 H, ArH), 7.52–7.41 (m, 6 H, ArH), 7.40–7.18 (m, 22 H, ArH),
7.17–6.93 (m, 12 H, ArH), 5.98 (dd, J = 10.7, 9.0 Hz, 1 H, H3ꢀ), 5.92–
5.83 (m, 0.6 H), 5.61 (d, J = 3.4 Hz, 1 H, H1ꢀ), 5.37 (d, J = 3.5 Hz, 0.6
H), 5.05–4.97 (m, 3 H), 4.94–4.86 (m, 3 H), 4.85–4.79 (m, 1.6 H), 4.70
(d, J = 11.9 Hz, 1 H, CHHPh), 4.55 (s, 1.2 H, CH2Ph), 4.44 (d, J =
11.0 Hz, 1 H, CHHPh), 4.38 (d, J = 11.0 Hz, 1 H, CHHPh), 4.32 (d, J =
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7.7 Hz, 1 H, H1′ꢀ), 4.13–3.81 (m, 13 H), 3.72 (dd, J = 11.4, 3.2 Hz, 2 Supporting Information (see footnote on the first page of this
1
H), 3.57–3.49 (m, 1.6 H), 3.48–3.41 (m, 1 H), 3.35 (dd, J = 10.7, 3.4 Hz,
1 H), 3.29 (td, J = 9.9, 4.9 Hz, 1 H), 2.90 (dd, J = 10.6, 3.5 Hz, 0.6 H),
1.07 [s, 6 H, C(CH3)3], 1.06 [s, 9 H, C(CH3)3], 0.99 [s, 9 H, C(CH3)3],
0.97 [s, 6 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 165.6,
165.6, 154.9, 154.8, 139.1, 138.9, 138.7, 138.6, 137.5, 137.4, 133.6,
133.5, 130.0, 130.0, 129.8, 129.7, 129.6, 129.5, 128.6, 128.6, 128.6,
128.5, 128.5, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.1,
128.1, 128.0, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6, 127.3, 118.4,
118.1, 103.9 (C1′ꢀ), 98.5, 97.6, 97.5 (C1ꢀ), 84.3, 81.3, 81.0, 79.4, 78.7,
78.0, 76.2, 75.8, 75.6, 75.5, 75.4, 75.1, 75.0, 73.3, 72.7, 72.5, 72.2,
70.9, 70.5, 67.9, 67.0, 66.7, 66.4, 65.7, 61.3, 61.2, 27.6 [C(CH3)3], 27.6
[C(CH3)3], 27.2 [C(CH3)3], 22.8 [C(CH3)3], 20.1 [C(CH3)3] ppm. HRMS
article): H and 13C spectra of compounds.
The Authors declare no competing financial interest.
Acknowledgments
We are grateful for financial support from The Villum Founda-
tion (VKR023110).
Keywords: Synthetic methods · Carbohydrates ·
Glycosylation · Thioglucosides · Ion pairs · Conformational
control
(ES): calcd. for C54H62O11N3Cl35SiNH4 1009.4180, found 1009.4187.
+
Acetyl 2-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α,ꢀ-
D-gluco-
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pyranosyl)-3,4,6-tri-O-acetyl-ꢀ- -mannopyranoside: Clear syrup.
D
Rf = 0.4 (pentane/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δH = 7.47–
7.42 (m, 4 H, ArH), 7.42–7.35 (m, 5 H, ArH), 7.35–7.24 (m, 8 H, ArH),
5.83 (s, 1 H, H1α), 5.78 (s, 0.1 H, H1ꢀ), 5.58 (t, J = 9.8 Hz, 1 H), 5.57
(s, 0.1 H, CHPh), 5.54 (s, 1 H, CHPh), 5.49 (t, J = 10.1 Hz, 0.1 H), 5.22–
5.15 (m, 2 H), 4.95 (d, J = 12.1 Hz, 1 H, CHHPh), 4.89 (d, J = 11.2 Hz,
1 H, CHHPh), 4.80 (d, J = 11.2 Hz, 1 H, CHHPh), 4.75 (d, J = 12.1 Hz,
1 H, CHHPh), 4.69 (s, 0.1 H), 4.59 (d, J = 7.6 Hz, 0.1 H), 4.46–4.28 (m,
4 H), 4.27–4.24 (m, 0.1 H), 4.23–4.15 (m, 3 H), 3.83 (ddd, J = 9.7, 5.0,
2.3 Hz, 1 H), 3.70 (t, J = 10.4 Hz, 1 H), 3.67–3.59 (m, 2 H), 2.19 (s, 3
H, CH3), 2.08 (s, 0.3 H, CH3), 2.07 (s, 3 H, CH3), 2.02 (s, 3 H, CH3), 2.00
(s, 3 H, CH3), 1.93 (s, 0.3 H, CH3), 1.80 (s, 0.3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δC = 170.9 (C=O), 170.8 (C=O), 170.4 (C=O), 169.9
(C=O), 169.5 (C=O), 169.4 (C=O), 169.0 (C=O), 168.8 (C=O), 138.8
(Ar.), 138.8 (Ar.), 138.4 (Ar.), 137.5 (Ar.), 137.3 (Ar.), 129.1 (Ar.), 128.8
(Ar.), 128.7 (Ar.), 128.5 (Ar.), 128.4 (Ar.), 128.3 (Ar.), 128.3 (Ar.), 128.1
(Ar.), 127.9 (Ar.), 127.7 (Ar.), 127.6 (Ar.), 127.1 (Ar.), 126.2 (Ar.), 126.1
(Ar.), 105.0 (C1ꢀ′), 101.6 (CHPhα), 101.3 (CHPhꢀ), 97.9 (C1′α), 91.6
(C1ꢀ), 91.5 (C1α), 82.1, 81.8, 81.3, 80.8, 79.2, 78.3, 75.4, 75.2, 74.9,
73.6, 73.5, 73.0, 72.4, 72.0, 69.1, 68.8, 66.1, 66.0, 65.5, 65.0, 62.8, 62.1,
61.9, 21.2 (CH3), 21.1 (CH3), 21.0 (CH3), 20.9 (CH3), 20.9 (CH3), 20.8
(CH3), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3) ppm. HRMS (ES): calcd. for
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C41H46O15NH4 796.3175, found 796.3183.
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Acetyl 2-O-[2,3-Di-O-benzyl-(di-tert-butylsilylene)-α,ꢀ-
D-gluco-
pyranosyl]-3,4,6-tri-O-acetyl-ꢀ- -mannopyranoside: Clear syrup.
D
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Rf = 0.38 (pentane/EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δH = 7.45–
7.36 (m, 5 H, ArH), 7.35–7.26 (m, 5 H, ArH), 5.80 (s, 1 H, H1α), 5.76
(s, 0.3 H, H1ꢀ), 5.51 (t, J = 9.5 Hz, 1 H), 5.45 (t, J = 10.1 Hz, 0.3 H),
5.14 (d, J = 10.4 Hz, 0.3 H, CHHPh), 5.10 (dd, J = 9.7, 2.6 Hz, 1 H),
5.01 (d, J = 3.8 Hz, 1 H, H1′α), 4.99 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.87
(d, J = 11.4 Hz, 0.3 H, CHHPh), 4.86–4.80 (m, 2 H, CH2Ph), 4.76 (d,
J = 12.4 Hz, 2 H, CH2Ph), 4.70 (d, J = 10.3 Hz, 0.3 H, CHHHPh), 4.50
(d, J = 7.3 Hz, 0.3 H, H1′ꢀ), 4.37 (d, J = 3.1 Hz, 0.3 H), 4.29–4.18 (m,
4 H), 4.15–4.03 (m, 3 H), 3.94–3.78 (m, 5 H), 3.77–3.72 (m, 1 H), 3.53–
3.47 (m, 2 H), 3.31 (td, J = 9.9, 4.9 Hz, 0.3 H), 2.16 (s, 3 H, CH3), 2.07
(s, 3 H, CH3), 2.06 (s, 1 H, CH3), 2.05 (s, 3 H, CH3), 2.03 (s, 1 H, CH3),
1.92 (s, 1 H, CH3), 1.90 (s, 3 H, CH3), 1.79 (s, 1 H, CH3), 1.09 [s, 9 H,
C(CH3)3], 1.08 [s, 3 H, C(CH3)3], 1.03 [s, 9 H, C(CH3)3], 0.99 [s, 3 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δC = 170.9, 170.8, 170.5,
170.1, 169.4, 169.4, 169.1, 169.0 (C=O), 139.2, 139.1, 139.0, 138.7,
128.7, 128.4, 128.4, 128.4, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6
(Ar), 105.0 (C1′ꢀ), 98.3 (C1′α), 91.6 (C1ꢀ), 91.5 (C1α), 84.1, 81.3, 81.1,
79.0, 78.6, 77.8, 75.8, 75.5, 74.7, 73.8, 73.7, 73.5, 73.2, 73.1, 73.0,
72.4, 70.3, 67.0, 66.8, 66.6, 66.2, 65.0, 62.5, 61.9, 27.7 [C(CH3)3], 27.5
[C(CH3)3], 27.3 [C(CH3)3], 27.2 [C(CH3)3], 22.9 [C(CH3)3], 22.8 [C(CH3)3],
21.2, 21.1, 20.9, 20.8, 20.8, 20.7, 20.6, 20.1 [C(CH3)3], 20.0
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see ref.[11]
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+
[C(CH3)3] ppm. HRMS (ES): calcd. for C42H58O15SiNH4 848.3883,
found 848.3884.
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For the synthesis of glucosyl donors see Exp. Section.
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Received: July 20, 2016
Published Online: ■
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Glycosylation
M. Heuckendorff,*
H. H. Jensen* .................................... 1–11
On the Gluco/Manno Paradox: Prac-
tical α-Glucosylations by NIS/TfOH
Activation of 4,6-O-Tethered Thio-
glucoside Donors
Highly α-selective glucosylations were activation conditions. The investiga-
achieved using 4,6-O-tethered thio- tion sheds new insights into the Gluc-
glucoside donors under NIS/TfOH ose/Mannose Paradox.
DOI: 10.1002/ejoc.201600899
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