Rhamnosylation: Diastereoselectivity of conformationally armed donors

Article abstract of DOI:10.1021/jo300591k

The α/β-selectivity of super-armed rhamnosyl donors have been investigated in glycosylation reactions. The solvent was found to have a minor influence, whereas temperature was crucial for the diastereoselectivity. At very low temperature, a modest β-selectivity could be obtained, and increasing temperature gave excellent α-selectivity. The donors were highly reactive, and activation was observed at temperatures as low as -107 °C. Different promoter systems and leaving groups were investigated, and only activation with a heterogeneous catalyst increased the amount of the β-anomer significantly. By introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in β-product was observed.

Full text of DOI:10.1021/jo300591k

Article
pubs.acs.org/joc
Rhamnosylation: Diastereoselectivity of Conformationally Armed
Donors
Mads Heuckendorff, Christian Marcus Pedersen,* and Mikael Bols*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark
S
* Supporting Information
ABSTRACT: The α/β-selectivity of super-armed rhamnosyl donors have been investigated in glycosylation reactions. The
solvent was found to have a minor influence, whereas temperature was crucial for the diastereoselectivity. At very low
temperature, a modest β-selectivity could be obtained, and increasing temperature gave excellent α-selectivity. The donors were
highly reactive, and activation was observed at temperatures as low as −107 °C. Different promoter systems and leaving groups
were investigated, and only activation with a heterogeneous catalyst increased the amount of the β-anomer significantly. By
introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in β-product was observed.
particular problem. Yamada observed that the β-selectivity
could be increased by performing the reaction at low
temperature and by using hindered (slow) promoters; the
selectivity was however modest and limited to a single primary
acceptor. Earlier we observed the same selectivity trend using a
super-armed rhamnosyl donor when performing competition
experiments on either a 6-OH or 4-OH thioglucoside acceptor
(and donor).10 The yields were excellent, and only activation of
the super-armed donor was observed. A temperature depend-
ence of the diastereoselectivity was also noticed; i.e., increasing
α-selectivity when raising the temperature. The superior
reactivity of a “super-armed” rhamnosyl donor was underlined
by glycosylation of an N-acetylated glucosamine derivative in an
excellent yield with complete α-selectivity.11 From our own and
Yamada’s work in the area of “flipped”12 rhamnosyl donors
(Figure 1), a number of questions arose. To what extent does
the anomeric effect favor the β-anomer when the ring is
“flipped”?12 What is the effect of solvents and different
glycosylation methods on the selectivity? Would it be possible
to increase the β-selectivity by decreasing the flipped12 donor
reactivity? In this work we will try to answer these questions by
studying a range of different super-armed rhamnosyl donors
with different substitution pattern under various glycosylation
conditions, thereby illuminating the connection between
conformation, reactivity, and diastereoselectivity.
INTRODUCTION
■
Rhamnose is a common component of many natural
oligosaccharides and found in its free form in poison sumac
and buckthorn. L-Rhamnose is the most common enantiomer
and is found in many bacterial oligosaccharides especially in
Gram negative bacteria.1 Since rhamnosides are xenobiotic to
humans and are found in connection with several diseases,2
their chemistry is of general interest, and rhamnosides could
become important in drug discovery. Whereas α-rhamnosides
are easily synthesized, β-selective rhamnosylation is still a major
challenge in glycosylation chemistry, and new methods as well
as a fundamental understanding of the problem are important
in order to access this class of compounds.
β-L-Rhamnosides are found in pathogen bacteria, such as the
Salmonella serogroup,3 Shigella boydii type 18,4 and Vibrio
cholera,5 and consequently there is an increasing interest in
their synthesis. This is however challenging because of the 1,2-
cis relationship, which is disfavored by steric effects as well as
the anomeric effect both favoring the α-anomer. The problem
in the synthesis of the related β-mannosides has to a large
extent been solved by the elegant procedure developed by
Crich.6
This method is however not directly applicable to rhamno-
sides (6-deoxy mannosides), since the 4 and 6 positions cannot
easily be tethered together. Approaches to use other tethering
groups and glycosylation methods have been made, but a
general method for a direct highly diastereoselective L-
rhamnosylation is still not available.7 We have earlier
demonstrated the high stereoselectivity and reactivity of
conformationally (super8) armed glycosyl donors and became
interested in studying the effect of the rhamnosyl donor
conformation on the diastereoselectivity. Early papers by
Yamada and co-workers9 on β-selective rhamnosylation using
partly silyl-protected donors prompted our interest in this
The main conclusions from Yamada’s work was that a
modest β-selectivity could be obtained by performing the
glycosylation at very low temperature in apolar solvents with
bulky Lewis acid promoters all presumably leading to a SN2
type mechanism. The glycosylation was performed with
trichloroacetimidates, which were obtained as the thermody-
Received: March 29, 2012
© XXXX American Chemical Society
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Figure 1. Conformationally flipped12 rhamnosyl donors.
Scheme 1. Synthesis of the Super-Armed Donor 3
namic α-product.13 This is in contrast with what we would
expect from a flipped donor, where the β-anomer should be
favored by the anomeric effect and hence be the thermody-
namic product. An obvious place to start our investigation was
to synthesize a derivative of Yamada’s donor since it was clear
from our own results that a bulky 2-O protective group made
the β-face even less accessible.
CH2Cl2 at different temperatures; at room temperature, only
the α-product could be isolated in good yields, and at −78 and
−107 °C, the β-anomer was observed as the minor product (in
the ratios 1.8:1 and 4.3:1, respectively) (entries 16, 17, Table
1). It was noticed that the glycosylation took place at very low
temperature but with a significant prolonged reaction time
resulting in lower yields. In order to push the reaction toward a
SN2 type reaction, heptane was chosen as a nonpolar aprotic
solvent. Activation of the glycosyl donor was very slow at low
temperature. A change in reaction color, indicating formation of
iodine, was not observed until the temperature reached 25 °C.
The selectivity was again modest toward the α-product,
indicating that a SN2 type reaction (or “tight ion pair”) was
not favored with this kind of donor system. Similar result was
obtained when activating the thiorhamnoside 3 by methylation
using methyl triflate, where only the α-product was isolated
(entry 4, Table 1). Other promoter systems, such as NIS,
DMTST, or DPSO/Tf2O resulted in lower selectivity, lower
yields, and decomposition of the donor.
Participating solvents, such as nitriles and ether solvents, are
known to affect the outcome of glycosylation by forming
reactive intermediates favoring either the equatorial (β) or the
axial product (α). The effect of these solvent systems have not
earlier been observed when using “super-armed donors”. Since
our donor is predominantly in a flipped12 conformation, one
would expect the opposite selectivity as compared with the
“normal” chair conformation, here the 4C1 and 1C4, respectively.
Diethyl ether would therefore, according to the general
proposed participation mechanism,15 give the axial coupling,
i.e., the β-product. To our surprise the exact opposite
happened. Glycosylation in diethyl ether resulted in higher α-
selectivity (17:1) and lower reactivity of the donor (activation
at approximately −15 °C) (entry 8, Table 1). Nitrile solvents
were expected to give the equatorial product (α) because of the
nitrile effect,16 but as with the ether effect we were surprised.
There was hardly any effect of having nitrile solvents compared
with CH2Cl2. Activation was observed promptly at −42 °C in
MeCN (the melting point), when moving to EtCN and PrCN
as solvents the temperature could be lowered to −78 and −107
°C, respectively, but the reaction was essentially unselective
under these conditions (α:β ratio 1:1 and 1:1.4, respectively)
RESULTS AND DISCUSSION
■
The donor 3 was synthesized from the triol 1 using Ley’s
protective group14 followed by 2-O-benzylation, acidic
deprotection to give 2, and finally triisopropylsilylation
(Scheme 1). The conformation of the donor 3 was confirmed
to be “flipped”12 from the H NMR J coupling constants
showing a 1,2-trans-diaxial relationship (3J1−2 = 8.7 Hz) and
small coupling constants between H2−H3 (2.2 Hz), H3−H4
(2.8 Hz), and H4−H5 (3.0 Hz). With the donor in hand, the
influence of acceptor bulkiness was studied. Methoxyethanol,
cyclohexanol, and 1-adamantanol were used using the standard
activation of a super-armed glycosyl donor, i.e., NIS, TfOH at
−78 °C followed by slow heating to room temperature. Good
and similar yields were obtained, and the selectivity was
between 2/1 and 3/1 in favor of α. Bulkiness did not appear to
be important (entries 1−3, Table 1). When a competition
experiment with the armed 4-OH thioglucoside 4 was
performed, a good yield and excellent α-selectivity was
obtained, demonstrating the superior reactivity of the super-
armed donor 3.
1
3
Solvents are known to influence reactivity and selectivity in
glycosylations; therefore, a range of common, but in terms of
polarity very different, solvents were investigated.
The simple achiral acceptor, cyclohexanol, was again chosen,
and the glycosylations were carried out following a standard
procedure starting at low temperature (−78 °C) except in the
cases where the solvent has a higher melting point (MeCN and
MeNO2). Aprotic, nonparticipating solvents such as CH2Cl2,
MeNO2 were α-selective with MeNO2 giving a ratio of 4.7:1
and CH2Cl2 1.8:1 (entries 13−17, Table 1). The higher α-
selectivity can to a large extent be explained with the higher
starting temperature due to the melting point of −29 °C for
MeNO2. This could be confirmed by performing the reaction in
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Table 1. Rhamnosylation with the Super-Armed Rhamnosyl Donors 3, 5 and 6
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Table 1. continued
*
TIPS groups were lost.
Scheme 2. Synthesis of Conformational Armed Donors Having a Nonparticipating Strongly Electron-Withdrawing Group on 2-
O
(entries 10−12, Table 1). A fast activation was observed around
−60 °C in these nitrile solvents. It has recently been
demonstrated that DMF addition to glycosylation gives imidate
intermediates,17 which upon addition of the acceptor reacts in a
SN2 fashion to give the axial product (normally the α).
Applying the preactivation conditions with DMF on the super-
armed rhamnosyl donor 3 at low temperature resulted in a
2.3:1 selectivity (entry 14, Table 1), virtually no change in
selectivity, and hence no effect of the imidate intermediate.
Another more classic way to synthesize axial glycosidic
linkages was developed by Lemieux and co-workers.18 The
halide-ion-catalyzed glycosylation takes advantage of the higher
reactivity of equatorial halides over axial and the in situ
anomerisation when having excess of halide ions present in the
reaction mixture. With the flipped12 super-armed donor, we
expected to observe a faster reaction of the α-bromide
(equatorial) giving the β-anomer as the major product. The
rhamnosyl chloride was made in situ by reaction of 3 with
iodine monochloride. From 1H NMR a clean conversion of the
thio-glycoside into the L-rhamnosyl chloride was observed. An
attempt to isolate this chloride failed, presumably because of
the inherent high reactivity of such a super-armed glycosyl
halide. To the rhamnosyl chloride in CH2Cl2 was added 1 equiv
of tetrabutylammonium chloride (TBAC) as the ion source,
and the reaction was cooled to −78 °C, where the acceptor was
added after approximately 30 min. The reaction was allowed to
warm up slowly to room temperature. At low temperature, no
reaction took place; however, at room temperature slow
conversion could be observed by TLC. Surprisingly, only the α-
anomer was isolated in a decent yield of 68%. Performing the
entire reaction at 25 °C improved the yield to 88%, but the α-
selectivity was still high (entries 18, 19, Table 1). Changing to
the more reactive bromide, which was obtained from the
reaction of Br2 with the thioglycoside 3 and tetraethylammo-
nium bromide as the ion-source, gave essentially the same
result; starting from −78 °C with slow heating to rt gave the α-
product in 72% yield (entry 20, Table 1).
The use of solid promoters is known to lead to increased
formation of equatorial products. Indeed, this method is classic
in carbohydrate chemistry.19 This would give the equatorial α-
anomer, but since the donor seemed unpredictable, the reaction
was tried out using silver carbonate as the solid catalyst and the
glycosyl chloride donor at −78 °C to rt. Surprisingly, it turned
out to be slightly β-selective (1:1.4) (entry 21, Table 1).
Glycosyl triflates have had an amazing impact on
glycosylation chemistry during the past decades, where α-
triflates have made β-mannosides easily accessible.6 However,
rhamnosyl triflates have so far found little use as donors for
accessing β-L-rhamnosides.7 From the work, especially on
mannosides, it is clear that the reactivity of the triflate is crucial
for the outcome of the glycosylation.20 Nevertheless, super-
armed rhamnosyl triflates were investigated. The triflate was
obtained from the chloride by treating it with silver triflate at
low temperature or by Kahne’s sulfoxide method.21 In both
cases the α-anomer was obtained in excellent selectivity, with
the silver triflate giving the best result in terms of yield.
Performing the reaction on a primary alcohol, 4-penten-1-ol,
resulted in a dramatic decrease in α-selectivity to 2.8:1 with a
modest yield of 28% (entry 23, Table 1).
Finally, another widely used glycosylation method in form of
the n-pentenyl donor22 5 was tested. However, only the α-
product was formed in a modest yield (entry 25, Table 1).
From the above study, it appeared that the superior reactivity
of the super-armed rhamnosyl donor favored the α-product and
that the bulky group at 3-O, together with methyl group, to
some extent hampered the β-attack because of 1,3-diaxial
interactions;23 these steric and stereoelectronic effects seem to
overrule the “flipped” anomeric effect, which we expected to
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Table 2. Rhamnosylation with 2-O-Sulfonylated Donors 7−8, 11−12
a
Donor decomposed under the activation conditions.
increase the amount of the axial β-anomer. Too high reactivity
of a glycosyl donor has earlier been argued to give low
selectivity and especially, in the cases with manno-stereo-
chemistry, α-selectivity.24 One way to deal with this is to lower
the reactivity by installing an electron-withdrawing group on
the donor. This approach was originally developed by
Schuerch25 and later taken up by Schmidt26 and Crich,27 who
all focused on the 2-position and showed an effect of this
deactivation. Kim and co-workers have recently expanded this
concept to cover all positions on the donor ring and thereby
obtaining excellent results in terms of β-selectivity in
mannosylations.28 We speculated how a super-armed donor
would respond to a strongly electron-withdrawing group close
to the anomeric center and decided to introduce a
benzylsulfonyl group on 2-O.29
group on C2 must be a good leaving group) and is precluded in
14. The β-thioglycoside was synthesized from the peracetylated
rhamnosyl bromide 13, followed by treatment with thiophe-
nolate, deacetylation, and BDA protection of 3-O and 4-O
(Scheme 2). The unprotected 2-O was then benzylsulfonylated
using the sulfonyl chloride. Acid-mediated removal of the BDA
liberated the 3OH and 4OH to give 15, ready for
triisopropylsilylation, which surprisingly caused problems. The
3-OH 12 was very unreactive under the standard conditions,
and only small amounts of the desired disilylated donor 7 could
be obtained. This could to some extent be solved by using the
less bulky TBS-group to protect the 3-OH giving 8 under
forced conditions. Using the even smaller TMS group
proceeded smoothly to give the rhamnosyl donor 11 having
the standard 1C4 conformation, whereas the 3-O-TIPS and 3-O-
TBS both were in axial rich conformations.30
The donor was synthesized inspired by the synthesis
performed by Crich and co-workers.27 Crich prepared the β-
thiorhamnoside 14 as a way to avoid decomposition of the
donor by a 1,2 migration of the thiophenyl group. This
migration can only take place with 1,2-trans diaxial groups (the
Glycosylation with the new set of donors was again
performed with cyclohexanol as the acceptor. The reaction
mixture was cooled to −78 °C before activating the donor, and
the activation temperature was estimated from the change in
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color from transparent to purple. All the donors activated at ca.
−40 °C, i.e., comparable reactivity to an armed donor
(perbenzylated). The relative high reactivity, despite the
strongly electron-withdrawing (disarming) sulfonyl group, can
be explained by the easier ring flip and thereby lower TS
together with the 6-deoxy functionality, which is not electron-
withdrawing and thereby arming. The donors are both
stereoelectronically armed, because of the conformation, and
disarmed by the sulfonyl group on O2. In glycosylation the
lower reactivity has a positive influence on the amount of β-
product formed, where 7 and 8 gives an α:β ratio of 1:1 and
1:1.5, respectively (entry 1−2, Table 2). When using the
smaller TMS group on 3-O (11), an even better ratio is
observed illustrating the steric effect from the protective group
on the glycosylation outcome, which also suggests a common
activated conformation for the 3 donors. Because of the
extremely low reactivity of the 3-OH in 12, it could easily be
used as the donor in a glycosylation without any self-coupling
observed; again, the glycosylation was slightly β-selective
(1:1.5) (entry 3, Table 2).
Figure 2. Proposed scenario of rhamnosyl halides. The α−β
equilibrium is catalyzed by excess of halide ions (Lemieux conditions).
The equatorial halides are more reactive than their axial counter parts,
and an axial rich conformation is more reactive.
After establishing that the 2-O-sulfonylated donor, despite its
relative high reactivity, was β-selective when using a simple
secondary achiral acceptor, more demanding glycosylations
were investigated. Cross coupling to a 6-OH acceptor 9 gave
virtually no selectivity, and a more “difficult” acceptor, 10, gave
exclusively the α-anomer (55%) (entry 5, Table 1). Attempts to
use Lemieux’s in situ anomerization glycosylation failed, and
only donor decomposition was observed.
reactive and halide ions are in excess. If the equatorial halide
(α) was much more reactive, the axial product (β) would be the
major (due to the Curtin−Hammett principle); this suggests
that the oxocarbenium ion is the common reactive species.
Only when using a solid promoter, silver carbonate, a difference
in selectivity toward the β-anomer was observed. Since the β-
halide predominates in the starting material, one would expect
the α-product to form preferentially. However, the result can be
explained by an easier activation of the equatorial and less
hindered α-halide giving rise to a modest β-selectivity. Attempts
to push the reaction toward a SN2 type mechanism by using
apolar nonprotic solvents such as heptanes had no influence on
the product ratio. This is in line with the donor being “super-
armed” by stabilizing the oxocarbenium intermediate, which has
been underlined by these results, where different solvents had
very little effect. Participating solvents, diethyl ether and nitriles,
performed as would be expected in glycosylation with a donor
in the low energy chair conformation (1C4 for a L-rhamnosyl
donor) and not as expected for donors with a flipped
conformation. This also points at a common intermediate as
the reactive species, regardless of the starting conformation.
From the experiments performed in this work, some new
pieces for the β-rhamnosyl donor puzzle have been added. It
has been shown that it is possible to get some β-selectivity
when having a very reactive donor. The protective groups do
have an influence on the stereochemical outcome, and a smaller
group is giving more β-product. However, if the group gets too
small a ring flip cost more energy and reactivity might be lost,
and the conformation of the reactive intermediate changed. It is
therefore not necessary to lock the ring in order to get
selectivity. Despite the resemblance between the flipped12 β-
rhamnoside and α-glucoside, both having preference for cis-1,2-
vicinal groups (according to the anomeric effect), no
connection could be found. The β-product was not significantly
4
favored when having a C1 L-rhamnoside donor. The anomeric
effect was however observable with halides, which anomerized
into the thermodynamic β-product. Hence, when a thiorham-
noside was treated with iodine chloride or bromine, only the β-
anomeric (axial) halide was observed. Anomerization of the
glycosylation products (α−β mixtures) into β-rhamnosides in a
related fashion did however not occur, which means that the
products were stable under the various glycosylation con-
ditions. When anomerisation was attempted with Lewis acids
such as TiCl4, SnCl4, BF3·OEt2, or AlCl3, only decomposition
was observed. AuCl3 and TMSOTf resulted in a slow
desilylation but no change in anomeric ratio.
The use of rhamnosyl halides as the donors afforded
products with high α-selectivity. This could be due to the
reaction taking place through an oxocarbenium intermediate
(red in Figure 2) or direct attack on the β-halide, which was
thermodynamically preferred because of the anomeric effect
(see Figure 2). If the latter is the case, the difference in
reactivity between the α- and β-halide is minimal since in situ
anomerization following Lemieux’s procedure essentially gave
the same selectivities. It is expected that the equilibration
between anomers is fast, since the rhamnosyl donor is highly
CONCLUSION
■
In conclusion, we have showed that super-armed rhamnosyl
donors have excellent reactivity and high α-selectivity.
Reactions can be performed at very low temperature in many
solvents. β-Selectivity can be obtained at low temperatures
using the in situ generated halide and a solid promoter or, even
better, a conformational armed 2-O-sulfonylated donor, which
in reactivity is comparable to an armed glycosyl donor. The
scope, in terms of β-selectivity, of the current donor is however
limited to relative simple acceptors, and more research into the
optimal reactive β-selective rhamnosyl donor is needed.
EXPERIMENTAL SECTION
General Methods. NMR assignments were based on COSY NMR
experiments throughout. The mass spectra were performed on an
electrospray mass spectrometer analyzing time-of-flight.
■
Phenyl 2-O-Benzyl-3,4-di-O-TIPS-1-thio-α-L-rhamnopyrano-
side (3). Phenyl 2-O-benzyl-1-thio-α-L-rhamnopyranoside (100 mg,
0.289 mmol) was dissolved in 3 mL of dry 2,6-lutidine. Then
TIPSOTf (0.24 mL, 0.865 mmol) was added, and the mixture was
F
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stirred at 80 °C overnight. The mixture was cooled, ethyl acetate was
added, and then it was extracted 2 times with 1 M HCl and one time
with brine. The organic layer was dried with Na2SO4 and evaporated
to dryness. The crude compound was purified by flash column
chromatography (petroleum ether, CH2Cl2, 5:1) giving the product as
by flash column chromatography (petroleum ether, EtOAc, 1:1) giving
the product as white foam. Yield: 0.484 g (88%); 1H NMR (500 MHz,
CDCl3) δ 7.55−7.50 (m, 4H, Ar.), 7.44−7.40 (m, 3H, Ar.), 7.36−7.30
(m, 3H, Ar.), 5.29 (dd, J = 3.1, 1.0 Hz, 1H, H2), 4.91 (d, J = 1.0 Hz,
1H, H1), 4.69 (d, J = 13.9 Hz, 1H, benzyl), 4.59 (d, J = 13.9, 1 H,
benzyl), 3.65 (dd, J = 9.0, 3.1 Hz, 1H, H3), 3.43−3.35 (m, 2H, H4,
H5), 1.40 (d, J = 5.7 Hz, 3H, H6); 13C NMR (126 MHz, CDCl3) δ
133.5(Ar.), 131.9(Ar.), 131.2(Ar.), 129.4(Ar.), 129.4(Ar.), 129.1(Ar.),
128.2(Ar.), 127.4(Ar.), 85.3(C1), 81.4(C2), 76.8(C5), 73.7(C3),
1
colorless syrup. Yield: 0.174 g, 92%; H NMR (500 MHz, CDCl3) δ
7.68−7.54 (m, 2H, Ar.), 7.42−7.15 (m, 8H, Ar.), 5.47 (d, J = 8.7 Hz,
1H, H1), 4.69 (d, J = 11.2 Hz, 1 H, benzyl), 4.58 (d, J = 11.2 Hz, 1H,
benzyl), 4.24 (t, J = 2.8 Hz, 1H, H3), 4.05 (qd, J = 6.9, 3.0 Hz, 1H,
H5), 3.90 (t, J = 3.0 Hz, 1H, H4), 3.83 (dd, J = 8.7, 2.2 Hz, 1H, H2),
1.44 (d, J = 7.0 Hz, 3H, H6), 1.16−0.96 (m, 42H, TIPSO); 13C NMR
(126 MHz, CDCl3) δ 138.15(Ar, ipso), 135.4(Ar, ipso), 131.2(Ar.),
128.9(Ar.), 128.4(Ar.), 128.2(Ar.), 127.6(Ar.), 126.7(Ar.), 82.1(C1),
75.7(C2,C4), 75.1(C5), 74.2(C3), 73.1(CH2-benzyl), 18.4−18.3(C6,
72.8(C4), 57.7(CH2-benzyl), 18.0(C6); [α]RT 32.2° (c 1.0,
D
CHCl3); HRMS calculated C19H22O6S2Na = 433.0755, found
433.0778
Phenyl 2-O-Sulfonylbenzyl-4-O-TIPS-1-thio-β-L-rhamnopyr-
anoside (12). Phenyl 2-O-sulfonylbenzyl-1-thio-β-L-rhamnopyrano-
side (2.87 g, 7.0 mmol) was dissolved in 20 mL of 2,6-lutidine, and
then TIPSOTf (10.5 mmol, 2.8 mL) was added. The mixture was
heated in an oil bath at 80 °C for 4 h. The mixture was cooled, and
ethyl acetate was added. Extraction was performed 3 times with 1 M
HCl, once with saturated bicarbonate solution and once with brine.
The organic layer was dried with MgSO4 and evaporated. The crude
residue was purified by flash column chromatography with CH2Cl2 as
eluent giving the product 8 as white foam. Yield: 2.2 g, 55%; 1H NMR
(500 MHz, CDCl3) δ 7.54−7.48 (m, 4H, Ar.), 7.42−7.38 (m, 3H,
Ar.), 7.36−7.28 (m, 3H, Ar.), 5.29 (dd, J = 3.2, 0.8 Hz, 1H, H2), 4.91
(d, J = 0.8 Hz, 1H, H1), 4.69 (d, J = 13.9 Hz, 1H, CH2-benzyl), 4.56
(d, J = 13.9 Hz, 1H CH2-benzyl), 3.64 (ddd, J = 9.0, 7.7, 3.2 Hz, 1H,
H3), 3.56 (t, J = 8.9 Hz, 1H, H4), 3.36 (dq, J = 8.7, 6.2 Hz, 1H, H5),
2.57 (d, J = 7.6 Hz, 1H,OH3), 1.41 (d, J = 6.1 Hz, 3H, H6), 1.18−1.09
(m, 3H TIPS), 1.06−0.99 (m, 18H, TIPS); 13C NMR (126 MHz,
CDCl3) δ 133.8(Ar.), 131.6(Ar.), 131.2(Ar.), 129.3(Ar.), 129.0(Ar.),
128.0(Ar.), 127.6(Ar.), 85.1(C1), 82.2(C2), 78.0(C5), 74.8(C4),
74.3(C3), 57.7(CH2-benzyl), 18.5(C6), 18.41−18.40(TIPS), 13.2-
CH3-TIPS), 12.8(CH-TIPS), 12.6(CH-TIPS); [α]RT −62.8° (c 1.0,
D
CH2Cl2); HRMS calculated C37H62O4SSi2Na = 681.3805, found
681.3817
Phenyl 2-O-Benzyl-3,4-di-O-TIPS-1-thio-α-L-rhamnopyrano-
side Sulfoxide (6). Phenyl 2-O-benzyl-3,4-di-O-TIPS-1-thio-α-L-
rhamnopyranoside (114 mg, 0.173 mmol) was dissolved in 5 mL
CH2Cl2. The solution was cooled to −78 °C, and m-CPBA was added
(0.04 g, 0.173 mmol). The solution was slowly warmed up to room
temperature and then washed with saturated bicarbonate solution and
brine. The organic layer was dried with Na2SO4 and evaporated to
dryness. The crude compound was purified by flash column
chromatography (petroleum ether, CH2Cl2, 5:1) giving the product
as colorless syrup. Yield: 0.091 g, 78%; 1H NMR (500 MHz, CDCl3) δ
7.65−7.17 (m, 7 H), 5.02 (d, J = 8.7 Hz, 1H), 4.82 (d, J = 11.0 Hz, 0.4
H, benzyl), 4.73 (d, J = 11.0 Hz, 0.4H), 4.60 (d, J = 11.5 Hz, 1 H),
4.50 (d, J = 9.3 Hz, 0.4H), 4.50 (d, J = 11.6 Hz, 1H), 4.41 (dd, J = 9.5,
2.2 Hz, 0.4H), 4.35 (t, J = 2.4 Hz, 0.4H), 4.28 (t, J = 2.6 Hz, 1H),
4.13−4.07 (m, 0.4H), 3.95 (dd, J = 8.7, 2.3 Hz, 1H), 3.83−3.79 (m,
1H), 3.79−3.76 (m, 0.4H), 3.62 (qd, J = 6.7, 4.0 Hz, 3H), 1.33 (d, J =
6.8 Hz, 1.2H), 1.12 (d, J = 6.9 Hz, 1H), 1.09−0.92 (m, 54H); 13C
NMR (126 MHz, CDCl3) δ 141.1, 140.7, 137.4, 137.3, 130.6, 130.2,
129.5, 129.1, 128.5, 128.2, 128.1, 128.0, 127.7, 127.7, 127.4, 125.3,
124.9, 92.6, 89.6, 76.7, 76.6, 76.0, 75.6, 73.9, 73.1, 72.8, 72.5, 72.3,
71.0, 18.7, 18.1, 18.0, 18.0, 18.0, 18.0, 17.9, 12.5, 12.5, 12.4, 12.3;
HRMS calculated C37H62O5SSi2Na = 697.3754, found 697.3795
Phenyl 3,4-Di-O-(2,3-dimethoxybutane-2,3-diyl)-2-O-sulfo-
nylbenzyl-1-thio-β-L-rhamnopyranoside. Phenyl 3,4-di-O-(2,3-
dimethoxybutane-2,3-diyl)-1-thio-β-L-rhamnopyranoside (0.511 g.
1.40 mmol) was dissolved in 5 mL of dry pyridine. Then
benzylsulfonylchloride (0.790 g, 4.14 mmol) was added to the
mixture, and it was stirred for 1 h. To the mixture was then added
ethyl acetate, and it was extracted 3 times with 1 M HCl, one time with
saturated sodium bicarbonate, and one time with brine. The organic
layer was dried with Na2SO4 and evaporated to dryness. The crude
compound was purified by flash column chromatography (petroleum
ether, EtOAc, 3:1) giving the product as a white foam. Yield: 0.700 g,
(TIPS); [α]RT 25.8° (c 1.0, CH2Cl2); HRMS calculated
D
C28H42O6S2SiNa = 589.2090, found 589.2083
Phenyl 2-O-Sulfonylbenzyl-3,4-di-O-TIPS-1-thio-β-L-rhamno-
pyranoside (7). Phenyl 2-O-sulfonylbenzyl-1-thio-β-L-rhamnopyra-
noside (2.60 g, 6.32 mmol) was dissolved in 20 mL of 2,6-lutidine, and
then TIPSOTf (15.8 mmol, 4.3 mL) was added. The mixture was
heated in an oil bath at 80 °C for 24 h. The mixture was cooled, ethyl
acetate was added, and it was extracted 3 times with 1 M HCl, once
with saturated bicarbonate solution and finally on time with brine. The
organic layer was dried with MgSO4 and evaporated. The crude
compound was purified by flash column chromatography with CH2Cl2
1
as eluent giving the product as clear syrup. Yield: 0.193 g, 4%; H
NMR (500 MHz, CDCl3) δ 7.53−7.48 (m, 2H, Ar.), 7.39 (d, J = 7.2
Hz, 2H,Ar.), 7.35−7.20 (m, 6H, Ar.), 5.44 (d, J = 5.6 Hz, 1H, H1),
5.38 (dd, J = 5.7, 2.7 Hz, 1H, H2), 4.41 (d, J = 1.9 Hz, 2H, CH2-
benzyl), 4.35−4.31 (m, 1H, H3), 4.08 (d, J = 4.3 Hz, 1H, H4), 4.02 (q,
J = 7.6 Hz, 1H, H5), 1.75 (d, J = 7.5 Hz, 3H, H6), 1.19−1.03 (m, 42H,
TIPS); 13C NMR (126 MHz, CDCl3) δ 138.3(Ar.), 130.9(Ar.),
129.1(Ar), 129.02(Ar.), 128.96(Ar.), 127.5(Ar.), 126.8(Ar.), 84.3(C1),
76.5(C5), 75.2(C2), 74.8(C4), 73.1(C3), 57.9(CH2-benzyl),
20.5(C6), 18.44(TIPS), 18.43(TIPS), 18.23(TIPS), 18.17(TIPS),
1
97%; H NMR (500 MHz, CDCl3) δ 7.60−7.51 (m, 4H, Ar.), 7.44−
7.37 (m, 4H, Ar.), 7.34−7.27 (m, 4H, Ar.), 5.28 (dd, J = 3.1, 1.0 Hz,
1H, H2), 4.92 (d, J = 1.0 Hz, 1H, H1), 4.67 (q, J = 13.9 Hz, 2H, CH2-
benzyl), 3.90 (dd, J = 10.3, 3.1 Hz, 1H, H3), 3.81−3.74 (m, 1H, H4),
3.55 (dq, J = 9.4, 6.1 Hz, 1H, H5), 3.32 (d, J = 1.1 Hz, 6H), 1.39 (s,
3H, Me), 1.37 (d, J = 6.1 Hz, 3H, H6), 1.32 (s, 3H, Me); 13C NMR
(126 MHz, CDCl3) δ 134.0(Ar.), 132.0(Ar.), 131.2(Ar.), 129.2(Ar.),
128.94(Ar.), 128.90(Ar.), 128.6(Ar.), 127.9(Ar.), 86.0(C1), 80.5(C2),
75.1(C5), 70.2 (C3), 68.3(C4), 57.9(CH2-benzyl), 48.6(CH3O),
17.9(TIPS), 12.8(TIPS), 12.6(TIPS), 12.4(TIPS); [α]RT 49.7° (c
D
1.0, CHCl3); HRMS calculated C37H62O6S2Si2Na = 745.3424, found
745.3409
Phenyl 2-O-Sulfonylbenzyl-3-O-TBS-4-O-TIPS-1-thio-β-L-
rhamnopyranoside (8). Phenyl 2-O-sulfonylbenzyl-4-O-TIPS-1-
thio-β-L-rhamnopyranoside (0.5 g, 0.882 mmol) was dissolved in 5
mL of 2,6-lutidine, and then TBSOTf (1.76 mmol, 0.41 mL) was
added. The mixture was heated in an oil bath at 80 °C for 24 h. The
mixture was cooled, ethyl acetate was added, and the mixture was
extracted 3 times with 1 M HCl, once with saturated bicarbonate
solution and finally once with brine. The organic layer was dried with
MgSO4 and evaporated. The crude compound was purified by flash
column chromatography with petroleum ether as eluent with a
gradient of CH2Cl2 giving the product 8 as clear syrup. Yield: 0.5 g,
78%; 1H NMR (500 MHz, CDCl3) δ 7.54−7.49 (m, 2H), 7.40 (m, J =
7.4 Hz, 2H), 7.31 (q, J = 7.6 Hz, 3H), 7.28−7.22 (m, 3H), 5.27 (dd, J
= 4.9, 2.6 Hz, 1H, H2), 5.24 (d, J = 4.9 Hz, 1H, H1), 4.48−4.40 (m,
48.1(CH3O), 17.9(CH3), 17.9(CH3), 17.0(C6); [α]RT −32.8° (c
D
1.0, CHCl3); HRMS calculated C25H32O8S2Na = 547.1436, found
547.1458
Phenyl 2-O-Sulfonylbenzyl-1-thio-β-L-rhamnopyranoside
(15). Phenyl 3,4-di-O-(2,3-dimethoxybutane-2,3-diyl)-2-O-sulfonyl-
benzyl-1-thio-β-L-rhamnopyranoside (0.700 g, 1.33 mmol) was
dissolved in 10 mL of CH2Cl2, and then 2 mL of TFA and 0.2 mL
of water were added. The mixture was stirred for 1 h and quenched
with saturated sodium bicarbonate solution, and ethyl acetate was
added. The organic layer was separated, washed with brine, dried with
Na2SO4, and evaporated to dryness. The crude compound was purified
G
dx.doi.org/10.1021/jo300591k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2H, CH2-benzyl), 4.12−4.07 (m, 1H, H3), 3.96−3.88 (m, 2H, H4,
H5), 1.68 (d, J = 7.3 Hz, 3H, H6), 1.06 (d, 18H, TIPS), 0.98 (s, 9H,
CH3-TBS), 0.21 (s, 3H, Me-TBS), 0.12 (s, 3H, Me-TBS); 13C NMR
(126 MHz, CDCl3) δ 137.8(Ar.), 130.90(Ar.), 130.87(Ar.),
129.1(Ar.), 129.03(Ar.), 128.97(Ar.), 127.72(Ar.), 126.96(Ar.),
84.3(C1), 77.0, 76.4(C2), 74.6, 73.3(C3), 57.9(CH2-benzyl),
26.1(CH3-TBS), 20.2(C6), 18.33(TBS), 18.27(TIPS), 18.2(TIPS),
12.7, −4.3(CH3-TBS), −4.7(CH3-TBS); [α]RTD 67.2° (c 1.0, CHCl3);
HRMS calculated C34H56O6S2Si2Na = 703.2955, found 703.2949
Phenyl 2-O-Sulfonylbenzyl-4-O-TIPS-3-O-TMS-1-thio-β-L-
rhamnopyranoside (11). Phenyl 2-O-sulfonylbenzyl-4-O-TIPS-1-
thio-β-L-rhamnopyranoside (0.200 g, 0.353 mmol) was dissolved in 3
mL of 2,6-lutidine, and then TMSOTf (0.706 mmol, 0.13 mL) was
added. The mixture was stirred for 2 h, then ethyl acetate was added,
and extraction was performed 3 times with 1 M HCl, once with
saturated bicarbonate solution and once with brine. The organic layer
was dried with MgSO4 and evaporated. The crude compound was
purified by flash column chromatography with petroleum ether and
CH2Cl2 (2:1) as eluent giving the product as white foam. Yield: 0.162
g, 73%; 1H NMR (500 MHz, CDCl3) δ 7.55−7.47 (m, 4H, Ar.) 7.39−
7.35 (m, 3H)., 7.30 (dddd, J = 13.7, 7.0, 4.6, 2.1 Hz, 3H), 5.19 (dd, J =
2.6, 1.3 Hz, 1H, H2), 4.95 (d, J = 1.2 Hz, 1H, H1), 4.65 (d, J = 13.7
Hz, 1H, CH2-benzyl), 4.52 (d, J = 13.7 Hz, 1H, CH2-benzyl)), 3.84 (t,
J = 8.2 Hz, 1H, H4), 3.70 (dd, J = 8.4, 2.7 Hz, 1H, H3), 3.47−3.40 (m,
1H, H5), 1.45 (d, J = 6.4 Hz, 3H, H6), 1.16−1.04 (m, 21H, TIPS),
0.21 (s, 9H, TMS); 13C NMR (126 MHz, CDCl3) δ 134.6(Ar.),
131.4(Ar.), 131.1(Ar.), 129.2(Ar.), 129.0(Ar.), 128.9(Ar.), 128.2(Ar.),
127.7(Ar.), 85.1(C1), 82.5(C2), 78.1(C5), 75.1(C3), 74.2(C4),
58.1(CH2-benzyl), 18.8(C6), 18.6(TIPS), 18.3(TIPS), 13.9(TIPS),
11.7 Hz, 1H), 4.77 (d, J = 12.0 Hz, 0.3H), 4.66 (d, J = 11.7 Hz, 1H),
4.58 (d, J = 12.0 Hz, 0.3H), 4.16 (d, J = 2.6 Hz, 1H), 4.14−4.10 (m,
0.3H), 4.03−3.94 (m, 1.6H), 3.92−3.86 (m, 1H), 3.83 (t, J = 3.3 Hz,
0.3H), 3.82−3.77 (m, 1.3H), 3.76−3.70 (m, 1H), 3.67 (dd, J = 6.7, 2.4
Hz, 1H), 3.63 (t, J = 5.0 Hz, 2H), 3.61−3.55 (m, 1H), 3.42 (s, 3H),
3.39 (s, 1H), 1.55 (d, J = 7.2 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.17−
0.98 (m, 56H); 13C NMR (126 MHz, CDCl3) δ 138.99, 138.96, 128.3,
128.1, 127.9, 127.4, 99.6, 98.67, 98.65, 76.6, 75.3, 74.8, 74.4, 74.0, 73.5,
72.9, 72.1, 72.0, 71.5, 67.9, 59.1, 20.0, 19.0, 18.5, 18.4, 18.32, 18.28,
13.0, 12.9, 12.8, 12.7; HRMS calculated C34H64O6Si2Na = 647.4139,
found 647.4199
Adamantyl 2-O-Benzyl-3,4-di-O-TIPS-α,β-L-rhamnopyrano-
side. Data: 1H NMR (500 MHz, CDCl3) δ 7.44−7.22 (m, 7.5),
5.40 (d, J = 7.1 Hz, 1H), 5.09 (d, J = 2.6 Hz, 0.3H), 4.98 (d, J = 12.1
Hz, 0.3H), 4.89 (d, J = 11.5 Hz, 1H), 4.68 (d, J = 11.7 Hz, 1H), 4.55
(d, J = 12.1 Hz, 0.3H), 4.18 (s, 1H), 4.07−3.91 (m, 1.6 H), 3.78 (s,
1H), 3.75 (t, J = 2.6 Hz, 0.3 H), 3.60 (dd, J = 7.2, 2.5 Hz, 1.6 H), 2.18
(s, 5H), 2.02−1.77 (m, 10H), 1.73−1.60 (m, 10H), 1.52 (d, J = 6.9
Hz, 1.3H), 1.43 (d, J = 6.3 Hz, 3.7H), 1.23−0.95 (m, 78H); 13C NMR
(126 MHz, CDCl3) δ 139.3, 139.0, 128.3, 128.0, 127.9, 127.4, 127.2,
126.9, 91.7, 90.0, 75.9, 74.9, 74.4, 74.3, 74.11, 74.08, 73.3, 72.3, 42.9,
42.5, 36.5, 30.7, 30.7, 20.3, 18.43, 18.39, 18.33, 18.28, 18.25, 18.22,
18.17, 13.3, 12.6, 12.5; HRMS calculated C41H72O5Si2Na = 723.4816,
found 723.4816
1-Pentenyl 2-O-Benzyl-3,4-di-O-TIPS-α,β-L-rhamnopyrano-
side (5). Data: 1H NMR (500 MHz, CDCl3) δ 7.45−7.22 (m,
7.7H), 6.00−5.65 (m, 1.3H), 5.07 (dd, J = 3.5, 1.6 Hz, 1H), 5.06 (dd, J
= 3.6, 1.7 Hz, 0.3H), 5.04 (dd, J = 3.5, 1.6 Hz, 1H), 5.03 (dd, J = 3.6,
1.7 Hz, 0.3H), 5.00 (dt, J = 2.2, 1.2 Hz, 1H), 5.00−4.99 (m, 0.3H),
4.98 (dt, J = 2.2, 1.2 Hz, 1H), 4.98−4.97 (m, 0.3H), 4.96 (d, J = 6.7
Hz, 1H), 4.83 (d, J = 1.8 Hz, 0.3H), 4.81 (d, J = 6.1 Hz, 1H), 4.73 (d, J
= 12.0 Hz, 0.3H), 4.67 (d, J = 11.7 Hz, 1H), 4.58 (d, J = 12.0 Hz,
0.3H), 4.16 (t, J = 2.7 Hz, 1H), 4.15−4.12 (m, 0.3H), 4.00 (dd, J = 4.6,
2.5 Hz, 0.3H), 3.96−3.75 (m, 4.3H), 3.64 (dd, J = 6.7, 2.3 Hz, 1H),
3.53 (dt, J = 9.7, 6.6 Hz, 1H), 3.32 (dt, J = 9.4, 6.7 Hz, 0.3H), 2.29−
2.14 (m, 2.8H), 1.83−1.67 (m, 2.8H), 1.55 (d, J = 7.3 Hz, 1.2H), 1.40
(d, J = 6.9 Hz, 3H), 1.19−0.98 (m, 66H); 13C NMR (126 MHz,
CDCl3) δ 138.95, 138.90, 138.8, 138.5, 128.2, 127.9, 127.4, 114.9,
114.6, 98.8, 98.5, 76.4, 75.3, 74.9, 74.4, 74.1, 73.7, 73.0, 72.8, 71.6,
68.5, 68.1, 30.7, 30.5, 29.2, 29.1, 20.0, 19.0, 18.5, 18.4, 18.34, 18.32,
18.29, 18.25, 13.0, 12.84, 12.79, 12.7; HRMS calculated
C36H66O5Si2Na = 657.4346, found 657.4327
0.5(TMS); [α]RT 39.8° (c 1.0, CH2Cl2); HRMS calculated
D
C31H50O6S2Si2Na = 661.2485, found 661.2481
General Procedure for Glycosylations. Equivalent amounts of
donor and acceptor31 were dried under a vacuum. Then solvent (1 mL
per 1 mmol donor) and 4 Å molecular sieves were added, and the
solution was stirred for an hour. The solution was cooled to the
desired temperature, and the promoter32 was added. The reaction
mixture was slowly warmed up to room temperature and quenched
with Et3N. The solution was washed with 1 M HCl, saturated
bicarbonate solution, NaS2O5 solution, and brine. The organic layer
was dried with Na2SO4 and evaporated to dryness. NMR measure-
ments of the crude product were done to check the α/β selectivity,
and the crude compound was purified by flash column chromatog-
raphy.
General Procedure for Desilylation. The compound was
dissolved in a small amount of THF, and 4 equiv of 1 M TBAF(THF)
was added.
The mixture was stirred until the deprotection was finished. To the
mixture was added ethyl acetate, and the organic layer was extracted
with 1 M HCl, saturated bicarbonate solution, and brine. The organic
layer was dried with MgSO4 and evaporated to dryness. NMR
measurements of the crude product were done to check the α/β
selectivity, and the crude compound was purified by flash column
chromatography.
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2-O-benzyl-3,4-di-O-TIPS-α-
L-rhamnopyranosyl)-1-thio-β-D-glucopyranoside. Data: 1H
NMR (500 MHz, CDCl3) δ 7.64−7.59 (m, 2H), 7.44−7.18 (m,
23H), 5.17 (d, J = 10.8 Hz, 1H), 5.13 (d, J = 7.6 Hz, 1H), 4.83−4.65
(m, 6H), 4.56 (q, J = 11.8 Hz, 2H), 4.20 (t, J = 2.5 Hz, 1H), 4.01 (m,
2H), 3.95 (t, J = 9.5 Hz, 1H), 3.86 (dd, J = 10.8, 5.8 Hz, 1H), 3.81 (s,
broad, 1H), 3.71−3.64 (m, 2H), 3.58−3.48 (m, 2H), 1.28 (d, J = 7.1
Hz, 3H), 1.05 (dd, J = 32.6, 3.6 Hz, 42H); 13C NMR (126 MHz,
CDCl3) δ 139.0, 138.9, 138.5, 138.4, 133.9, 132.1, 129.0, 128.6,
128.44, 128.39, 128.34, 128.27, 128.2, 127.8, 127.7, 127.5, 127.43,
127.36, 97.6, 87.3, 85.1, 80.4, 80.1, 76.3, 75.8, 75.6, 75.0, 74.9, 73.7,
73.3, 69.1, 18.37, 18.35, 18.2, 18.0, 12.7, 12.5; [α]RT −26.1° (c 1.0,
Cyclohexyl 2-O-Benzyl-3,4-di-O-TIPS-α,β-L-rhamnopyrano-
D
1
side. Data: H NMR (500 MHz, CDCl3) δ 7.43−7.22 (m, 10H),
CH2Cl2); HRMS calculated C64H90O9SSi2Na = 1113.5742, found
1113.5828
5.12 (d, J = 6.7 Hz, 1H), 5.01 (d, J = 3.3 Hz, 1H), 4.86 (d, J = 11.6 Hz,
1H), 4.83 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 11.6 Hz, 1H), 4.54 (d, J =
11.9 Hz, 1H), 4.16 (s, 1H), 4.10 (dd, J = 4.9, 3.2 Hz, 1H), 4.01 (dd, J
= 5.1, 3.1 Hz, 1H), 3.90 (s, 1H), 3.81 (t, J = 3.3 Hz, 1H), 3.79 (s, 1H),
3.76−3.72 (m, 1H), 3.72−3.65 (m, 2H), 3.63 (dd, J = 6.7, 2.3 Hz,
1H), 1.97 (s, 4H), 1.78 (d, J = 8.2 Hz, 4H), 1.55 (d, J = 7.2 Hz, 3H),
1.40 (d, J = 6.9 Hz, 3H), 1.36−1.20 (m, 8H), 1.18−0.98 (m, 84H);
13C NMR (126 MHz, CDCl3) δ 139.1, 139.0, 128.2, 128.12, 128.10,
Cyclohexyl 2-O-Sulfonylbenzyl-3,4-di-O-TIPS-α,β-L-rhamno-
1
pyranoside. Data: H NMR (500 MHz, CDCl3) δ 7.50−7.09 (m,
Ar.), 5.37 (d, J = 5.6 Hz, 1H,), 5.31 (dd, J = 5.7, 2.7 Hz, 1H), 5.16 (d, J
= 6.9 Hz, 1H), 4.94 (dt, J = 6.7, 3.5 Hz), 4.73 (dd, J = 7.4, 2.6 Hz),
4.54 (d, J = 13.7 Hz), 4.42−4.22 (m), 4.19−4.12 (m), 4.03−3.91 (m),
3.89 (dd, J = 4.9, 2.9 Hz), 3.81 (s), 3.70 (qd, J = 7.1, 2.9 Hz), 3.60 (s),
3.54 (tt, J = 9.0, 3.7 Hz), 1.98−1.78 (m), 1.67 (t, J = 10.3 Hz), 1.47 (d,
J = 7.2 Hz), 1.43−1.32 (m), 1.32−0.92 (m,); 13C NMR (126 MHz,
CDCl3) δ 138.2, 130.92, 130.90, 130.87, 129.1, 129.0, 128.94, 128.89,
128.1, 128.0, 127.5, 126.8, 94.9, 92.1, 84.3, 80.3, 76.7, 76.6, 76.54,
76.47, 75.8, 75.16, 75.12, 74.8, 74.2, 73.1, 72.8, 57.9, 57.3, 34.0, 33.6,
32.2, 31.6, 31.4, 30.4, 30.3, 29.8, 25.8, 25.7, 24.6, 24.5, 24.3, 20.5, 20.4,
18.42, 18.41, 18.36, 18.3, 18.21, 18.15, 13.0, 12.9, 12.8, 12.6; HRMS
calculated C37H68O7SSi2Na = 735.4122, found 735.4175
127.8, 127.34, 127.27, 96.7, 95.5, 76.6, 76.1, 75.6, 75.0, 74.7, 74.3, 73.2,
73.0, 71.6, 34.0, 33.6, 32.2, 31.5, 29.9, 26.0, 25.9, 24.6, 24.4, 24.3, 24.2,
20.5, 19.0, 18.5, 18.41, 18.39, 18.36, 18.34, 18.30, 13.1, 13.0; HRMS
calculated C37H68O5Si2Na = 671.4503, found 671.4488
Methoxyethyl 2-O-Benzyl-3,4-di-O-TIPS-α,β-L-rhamnopyra-
noside. Data: 1H NMR (500 MHz, CDCl3) δ 7.42−7.20 (m,
7.5H), 5.00 (d, J = 6.7 Hz, 1H), 4.89 (d, J = 3.4 Hz, 0.3H), 4.84 (d, J =
H
dx.doi.org/10.1021/jo300591k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Cyclohexyl 2-O-Sulfonylbenzyl-α,β-L-rhamnopyranoside.
Data: 1H NMR (500 MHz, CDCl3) δ 7.51−7.47 (m), 7.45−7.40
(m), 7.39−7.33 (m), 4.97 (d, J = 3.0 Hz), 4.78 (d, J = 1.5 Hz), 4.76−
4.69 (m), 4.67 (s), 4.52−4.40 (m), 3.91 (dd, J = 9.6, 3.1 Hz), 3.76 (tt,
J = 9.2, 3.7 Hz), 3.67 (ddd, J = 12.0, 9.2, 4.7 Hz), 3.49 (dt, J = 8.6, 4.8
Hz), 3.36 (t, J = 9.5 Hz,), 3.33−3.22 (m), 2.00−1.85 (m), 1.83−1.63
(m), 1.58−1.46 (m), 1.43 (s), 1.34−1.16 (m); 13C NMR (126 MHz,
CDCl3) δ 131.1, 131.0, 129.2, 129.0, 128.9, 128.8, 128.4, 127.8, 95.9,
95.7, 82.2, 80.1, 77.3, 76.0, 73.2, 72.8, 72.4, 72.1, 69.8, 68.3, 57.5, 57.4,
33.5, 33.3, 31.7, 31.5, 25.6, 24.14, 24.09, 24.0, 23.8, 17.8, 17.6; HRMS
calculated C19H28O7SNa = 423.1453, found 423.1463
Methyl 2,3,4-Tri-O-benzyl-6- O-(2-O-sulfonylbenzyl-α,β-L-
rhamnopyranosyl)-α-D-glucopyranoside. Data: 1H NMR (500
MHz, chloroform-d) δ 7.48−7.20 (m), 5.04 (d, J = 2.9 Hz), 4.99 (d, J
= 10.8 Hz), 4.94 (d, J = 11.0 Hz), 4.92−4.87 (m), 4.84−4.76 (m), 4.73
(d, J = 10.9 Hz), 4.70 (d, J = 1.5 Hz), 4.69−4.63 (m), 4.61 (d, J = 3.4
Hz), 4.57 (d, J = 3.2 Hz), 4.55 (d, J = 4.3 Hz), 4.53 (d, J = 2.5 Hz),
4.51 (d, J = 3.0 Hz), 4.46−4.40 (m), 4.18 (dd, J = 11.0, 3.7 Hz), 3.97
(dt, J = 15.6, 9.3 Hz), 3.86 (dd, J = 9.6, 3.2 Hz), 3.80 (d, J = 11.0 Hz),
3.74 (ddd, J = 16.1, 11.3, 3.7 Hz), 3.68−3.56 (m), 3.53−3.46 (m),
3.41−3.27 (m), 1.31 (d, J = 5.4 Hz), 1.26 (d, J = 6.3 Hz); 13C NMR
(126 MHz, CDCl3) δ 138.9, 138.7, 138.5, 138.18, 138.16, 131.1, 130.9,
129.3, 129.1, 129.0, 128.9, 128.61, 128.58, 128.54, 128.50, 128.46,
128.2, 128.13, 128.07, 127.98, 127.96, 127.94, 127.85, 127.8, 127.67,
127.65, 98.4, 98.2, 97.93, 97.85, 82.1, 81.8, 80.5, 80.1, 78.8, 77.9, 77.6,
75.9, 75.7, 75.1, 73.51, 73.46, 73.2, 72.9, 72.5, 72.3, 70.1, 69.8, 68.3,
68.0, 66.7, 57.6, 57.5, 55.5, 55.4, 17.6, 17.5; HRMS calculated
C41H48O12SNa = 787.2764, found 787.2415
ACKNOWLEDGMENTS
■
We thank the Danish technical research council (FTP) for
financial support.
REFERENCES
■
(1) Merck Index, 11th ed.; Merck & Company: Whitehouse Station,
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Methyl 2,3,6-Tri-O-benzyl-4- O-(2-O-sulfonylbenzyl-α,β-L-
rhamnopyranosyl)-α-D-glucopyranoside. Data: 1H NMR (500
MHz, chloroform-d) δ 7.41−7.20 (m, 20H), 5.12−5.04 (m, 2H, H1R,
benzyl), 4.80 (dd, J = 3.1, 1.7 Hz, 1H, H2R), 4.74 (d, J = 12.0 Hz, 1H),
4.69 (d, J = 10.9 Hz, 1H), 4.65−4.56 (m, 3H), 4.48 (d, J = 12.0 Hz,
1H), 4.32 (s, 2H), 3.91−3.76 (m, 4H), 3.72−3.56 (m, 4H), 3.36 (s,
3H), 3.23 (td, J = 9.6, 4.0 Hz, 1H, H4R), 2.63 (d, J = 6.3 Hz, 1H,
OH3), 2.05 (d, J = 4.0 Hz, 1H, OH4), 0.96 (d, J = 6.2 Hz, 3H, H6R);
13C NMR (126 MHz, CDCl3) δ 138.9, 138.0, 130.9, 129.2, 129.0,
(8) For a different type of super-armed glycosyl donor, see:
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128.6, 128.4, 128.3, 128.1, 128.0, 127.9, 127.6, 127.61, 127.57, 98.0
(C1G), 97.4 (C1R), 80.5, 80.0, 79.0 (C2R), 75.6, 74.7, 73.4, 73.3,
73.2(C4R), 69.9, 69.8, 68.8, 68.5, 57.5, 55.4, 55.4, 17.2 (C6R); [α]RT
D
(11) Pedersen, C. M.; Marinescu, L. G.; Bols, M. Chem. Commun.
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27.8° (c 1.0, CH2Cl2); HRMS calculated C41H48O12SNa = 787.2764,
found 787.2809
(12) By “flipped” or “ring-flipped” is meant the forced change from a
Cyclohexyl 2-O-Sulfonylbenzyl-4-O-TIPS-α,β-L-rhamnopyra-
1
4
normally more stable C4 conformation to a C1 conformation.
(13) According to the authors in ref 5.
1
noside. Data: H NMR (500 MHz, CDCl3) δ 7.72 (dd, J = 5.3, 2.1
Hz), 7.58−7.34 (m), 5.01−4.95 (m), 4.83 (d, J = 1.8 Hz), 4.77 (dd, J =
3.1, 1.9 Hz), 4.76−4.72 (m,), 4.66 (d, J = 13.9 Hz), 4.54−4.47 (m),
4.43 (d, J = 14.1 Hz), 3.89 (dd, J = 9.0, 3.2 Hz), 3.77 (td, J = 9.2, 4.6
Hz), 3.71−3.60 (m), 3.58−3.47 (m), 3.40−3.29 (m), 2.00−1.62 (m),
1.60−1.47 (m), 1.42−1.18 (m), 1.18−0.99 (m); 13C NMR (126 MHz,
CDCl3) δ 132.0, 131.1, 130.9, 129.2, 129.1, 129.00, 128.97, 128.9,
128.3, 127.9, 125.2, 95.9, 95.7, 81.4, 80.6, 77.0, 76.2, 75.4, 75.3, 73.6,
73.0, 70.7, 69.3, 57.6, 57.5, 33.83, 33.76, 33.5, 33.4, 31.6, 25.7, 25.3,
24.2, 24.1, 24.0, 23.9, 18.5, 18.44, 18.40, 18.1, 13.2, 13.1; HRMS
calculated C28H48O7SSiNa = 579.2788, found 579.2787
(14) Reviewed in: Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(20) Crich, D. Acc. Chem. Res. 2010, 43, 1144−11−53.
(21) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc.
1989, 111, 6881−6882.
1
13C and H NMR spectra of all prepared compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(22) Fraser-Reid, B.; Konradsson, P.; Mootoo, D. R.; Udodong, U. J.
Chem. Soc. Commun. 1988, 823−825.
1
(23) Also observed in C4: Crich, D.; Dudkin, V. Tetrahedron Lett.
AUTHOR INFORMATION
■
2000, 5643−5646.
(24) Especially in cases where a triflate intermediate is crucial for the
selectivity.
(25) (a) Srivastava, V. K.; Schuerch, C. Carbohydr. Res. 1980, 79,
C13−C16. (b) El Ashry, E. S. H.; Schuerch, C. Carbohydr. Res. 1982,
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Corresponding Author
*E-mail: cmp@chem.ku.dk; bols@chem.ku.dk.
Notes
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/jo300591k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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(29) The benzylsulfonyl group can be removed by relatively mild
methods in contrast to many other sulfonyl groups. See ref 19d.
(30) The conformation is analyzed from 1H NMR data. See the
Supporting Information.
(31) When cyclohexanol was used as donor, it was added at same
time as the molecular sieves.
(32) The promoters used were NIS (1.2 equiv), TfOH (10 mol%);
MeOTf (1.2 equiv); DMTST (1.2 equiv); Ph2SO (2.8 equiv); Tf2O
(1.4 equiv); DTBMP (2 equiv); (1) ICl (1 equiv) (2) TBAC (1
equiv), Hunigs base (1 equiv); (1) Br (1 equiv) (2) TEAB (1 equiv),
̈
2
Hunigs base (1 equiv); (1) ICl (1 equiv) (2) Ag CO (3 equiv); (1)
̈
2
3
ICl (1 equiv) (2) AgOTf (3 equiv), DTBMP (3 equiv); NIS (1.3
equiv), TESOTf (0.25 equiv) or Tf2O (1.2 equiv), TTBP (2 equiv).
J
dx.doi.org/10.1021/jo300591k | J. Org. Chem. XXXX, XXX, XXX−XXX