Cooperative Br?nsted Acid-Type Organocatalysis for the Stereoselective Synthesis of Deoxyglycosides

Article abstract of DOI:10.1021/acs.joc.6b02498

A practical approach for the α-stereoselective synthesis of deoxyglycosides using cooperative Br?nsted acid-type organocatalysis has been developed. The method is tolerant of a wide range of glycoside donors and acceptors, and its versatility is exemplified in the one-pot synthesis of a trisaccharide. Mechanistic studies suggest that thiourea-induced acid amplification of the chiral acid via H-bonding is key for the enhancement in reaction rate and yield, while stereocontrol is dependent on the chirality of the acid.

Full text of DOI:10.1021/acs.joc.6b02498

Article
pubs.acs.org/joc
Cooperative Brønsted Acid-Type Organocatalysis for the
Stereoselective Synthesis of Deoxyglycosides
Carlos Palo-Nieto, Abhijit Sau,‡ Ryan Williams,‡ and M. Carmen Galan*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
ABSTRACT: A practical approach for the α-stereoselective
synthesis of deoxyglycosides using cooperative Brønsted acid-
type organocatalysis has been developed. The method is
tolerant of a wide range of glycoside donors and acceptors,
and its versatility is exemplified in the one-pot synthesis of a
trisaccharide. Mechanistic studies suggest that thiourea-induced
acid amplification of the chiral acid via H-bonding is key for the
enhancement in reaction rate and yield, while stereocontrol is
dependent on the chirality of the acid.
Scheme 1. Proposed Cooperative Acid/Thiourea-Catalyzed
Synthesis of Deoxyglycosides
INTRODUCTION
■
Cooperative catalysis between thioureas and Brønsted acids,
whereby the enhanced catalytic activity of the thiourea acts as
an acid amplifier, has successfully been applied to asymmetric
catalysis,1 and more recently, reports have emerged from the
Schmidt group applying this type of synergistic catalysis to
glycosylation reactions involving O-glycosyl trichloroacetimi-
date donors to yield β-selective glycosides.2
Deoxy-hexoses are an important class of glycosides that occur
widely in many natural products ranging from antibiotics to
anticancer agents.3 The stereoselective formation of glycosidic
linkages employing 2-deoxyglycosides, where a substituent at
C-2 that can direct the coupling reaction is lacking, is a very
challenging endeavor and many efforts have been devoted to
achieve their stereoselective synthesis.4 Acid-catalyzed direct
nucleophilic substitution on a glycal is one of the most widely
used and efficient methods for their synthesis, however these
reactions often give anomeric mixtures and side products (e.g.,
To evaluate our hypothesis, thiourea 1 was chosen as the
organocatalyst based on previous successful work from our
group and others.1a,b,2,7,8 Moreover, BINOL-derived phosphor-
ic acids have been shown to be particularly effective in many
asymmetric transformations,9 including some success in
glycosylations involving trichloroacetimidate glycoside do-
nors.10 More recently, chiral phosphoric acids have also been
shown to catalyze the spiroketalization of cyclic enol ethers
bearing a pendant alcohol nucleophile in a highly diaster-
eoselective syn-selective concerted mechanism whereby the
phosphoric acid acts as a bifunctional catalyst activating both
the alkene and alcohol nucleophile.11
Ferrier rearrangement side-products).4e,4 5 As part of our
r,
ongoing interest in developing stereoselective glycosylation
methods,6 we decided to focus our attention on the synthesis of
deoxyglycosides. Recently, our team reported a mild organo-
catalytic method for the preparation of 2-deoxygalactosides
employing Schreiner’s thiourea with excellent yields and α-
selectivity.4e,7 Although the method worked well with galactals,
reactions needed to be refluxed over 24 h to reach completion,
and in general, the thiourea catalyst was unable to activate
glucal or rhamnal substrates. We postulated that synergistic
acid/thiourea activation could provide a more efficient and
practical glycosylation strategy for the preparation of
deoxyglycosides than current methods that use hydrogen-
bonding organocatalysts or acids as the sole promoters
(Scheme 1).
RESULTS AND DISCUSSION
■
Initial experiments began with the screening of a series of
commercial BINOL-derived phosphoric acids for their ability to
promote the stereoselective glycosylation of perbenzylated
galactal 2a with glucoside acceptor 312 in the absence and
presence of 1 in CH2Cl2 at room temperature. As summarized
in Table 1, coupling reactions employing 10 mol % of chiral
Received: October 13, 2016
© XXXX American Chemical Society
A
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The use of achiral p-toluenesulfonic acid (pTsOH, 5 mol %)
4e or bis(4-nirophenyl)hydrogen phosphate 4f or less acidic
phosphoric catalysts 4c and 4d (pKa = 3.86)13 in combination
with 1 proved to be detrimental to reaction rate, yield, and
stereocontrol, with reactions needing 6−20 h for completion
(entries 6−9). Next, we decided to explore the reaction
conditions using 4b and 1 as the cocatalyst. Increasing the acid
loading to 20 mol % in the presence of 10 mol % of 1 had no
effect on the outcome of the model reaction (entry 10), while
lowering the reaction temperature significantly slowed product
formation (entry 11). Changing the reaction solvent to either
MeCN or diethyl ether (Table 1, entries 12 and 13) had a
detrimental effect on the rate of the reaction. In the case of
MeCN, which is known to participate during the glycosylation
reaction involving oxocarbenium ions favoring β-glycoside
products,15 significant erosion of the α-selectivity was observed
with 5 being isolated as a 3:1 α:β mixture (entry 11 vs entry 5).
Having established the optimum reaction conditions, our
attention was then turned to exploring the scope of the
cooperative catalytic system on coupling reactions between 2a
and a range of OH nucleophiles 6a−6j (Table 2). In all cases,
reactions proceeded smoothly within 2−6 h and in excellent
yields and α-selectivity, as determined by the characteristic
anomeric signals in the 1H- and 13C NMR spectra,4i,6b,7
demonstrating that the catalytic system tolerates the presence
of common alcohol and amine protecting groups such as
acetals, ethers, esters, and carbamates. Glycosylations with
primary alcohols 6a−6d and Boc-protected serine 6h afforded
the corresponding glycoside products in 80−86% yield within
2−3 h and with a >30:1 α:β ratio (entries 1−4 and 8).
Reactions with secondary alcohols such as phenols 6e,
glycosides 6f and 6g, Boc-protected threonine 6i, or cholesterol
6j prove to be more challenging and required higher reaction
temperatures (45 °C) and the use of 20 mol % of 1 in
combination with 10 mol % of 4b in CH2Cl2, to drive reactions
to completion within 5−6 h. Under these optimized conditions,
the desired products were thus isolated with similar high α-
selectivity (>30:1 α:β ratio) and yields of 74−85% (Table 2,
entries 5−7, 9, and 10).
Our attention then turned to exploring the scope of the
glycal donor. To that end, a series of differentially protected
galactals 2b−2f, glucals 8a−8c, and L-rhamnal 9 bearing
methyl, acetate, benzyl, allyl, silyl ether, and siloxane protecting
groups were prepared and subjected to the reaction conditions
with 3 or 6k, which bears a secondary OH, as the acceptor
(Table 3). Pleasingly, high yields and excellent selectivities for
α-linked glycosides were obtained in most examples (entries 1,
3−5, and 7). Although substrate 2d, which bears an acetate
group at C-6, shows that ester groups can be tolerated (entry
3), in the case of acetyl-protected galactal 2c (entry 2), an
inseparable mixture of glycosides including Ferrier side-
products16 was observed after 20 h under the more forcing
conditions (20 mol % of 4b and reflux in CH2Cl2). This lack of
reactivity has been previously noted for glycals bearing a
deactivating group (e.g., ester) at C-3, which is in close
proximity to the reacting double bond.7,17 Encouragingly, the
reaction was also amenable to glycosylations with glucal
substrates, and both benzyl-derivative 8a and 3,4-O-siloxane
protected 8b6b or 8c6b afforded the corresponding glycosides
with high α-stereocontrol within 2 h, albeit 11a was isolated in
a lower yield (40%) than 11b (81% yield) or 11c (82%). This is
not completely unexpected, as 8b has been shown to be a more
Table 1. Initial Catalyst Screen in the Glycosylation of
Galactal 2a
c
c
entry
acid
time (h) yield (%)
α:β
N/A
9:1
1
−
4a
24
20
3
0
55
82
70
89
82
78
76
65
89
79
74
75
a
a
2
3
4a
7:1
>30:1
>30:1
8:1
4
4b
4b
4c
4d
20
3
5
6
20
20
16
6
7
12:1
b
8
pTsOH 4e
20:1
b
9
(O2NC6H4O)2P(O)OH 4f
9:1
d
10
11
12
13
4b
3
>30:1
>30:1
3:1
e
4b
20
20
20
f
4b
g
4b
>30:1
a
b
Reactions in the absence of 1. 5 mol %, as reactions at 10 mol % lead
c
d
to rapid hydrolysis of 2a. From 1H NMR; N/A = not applicable. 20
e
f
mol % of 1. Reaction at −40 °C-10 °C. Reaction in MeCN.
g
Reaction in diethyl ether.
phosphoric acids (S)-4a and (R)-4b (pKa = 2.63 in DMSO)13
proceeded cleanly to give product 57 in 55 and 70% yields,
albeit after 20 h (entries 2 and 4) and with different degrees of
α:β stereocontrol 9:1 and >30:1, respectively. When 10 mol %
of 1 was added as the cocatalyst (entries 3 and 5), reactions
were complete within 3 h, and glycoside 5 was obtained in
improved yields of 82% and 89%, respectively, and with an α:β
ratio of 7:1 for the (S)-acid and >30:1 for the (R)-acid catalyst.
These results demonstrate the strong influence of thiourea 1, as
a cocatalyst, on reaction rate and yield, while the stereo-
chemistry of the acid catalyst has the biggest effect on the α:β
selectivity of the glycosylation reaction. This observation is not
completely surprising, as Bennett and co-workers had already
reported that the stereo-outcome of acid-catalyzed glycosyla-
tion reactions involving trichloroacetimidate donors was
dependent on the chirality of the catalyst, the configuration
of the leaving group in the glycoside donor, and the nature of
the nucleophile acceptor.14 It is important to note that
glycosylation reactions with 10 mol % of thiourea 1 in
CH2Cl2 (in the absence of acid) yielded only starting material
(entry 1) as previously observed by our team,7 likely due to
catalyst inactivation via self-association at high catalyst
loading,1c further demonstrating the importance of the synergy
between both cocatalysts.
B
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optimized conditions. Following disaccharide formation,
acceptor 6c was added to the same pot along with NIS and
catalytic TMSOTf and trisaccharide 13 was obtained in 58%
yield with complete stereoselectivity.
Table 2. Acceptor Scope in Glycosylation Reactions with
Galactal 2a
To probe the mechanism of our reaction, a 3:1 α/β-anomeric
mixture of 5 was subjected to the reaction conditions and gave
no change in the anomeric ratio, indicating that the high α-
selectivity is not the result of anomerization. Moreover, reaction
with deuterated galactal 14 yielded disaccharide 15 with the
1
newly formed bonds cis to each other, as evidenced by the H
NMR shifts associated with H-1 (δ 4.62 ppm, d, 1H, J = 2.7
Hz) and H-2 (δ 2.03−1.99, m, 1H, H-2′) of the deuterated 2-
deoxygalactoside7 (Scheme 3), which suggest that both the C−
H and the C−O bond formation steps are syn-diastereose-
lective. 1H NMR spectroscopy studies in CD2Cl2 of mixtures of
thiourea 1 and acid 4b showed proton shifts associated with the
aromatic signals from both acid and thiourea, indicating that an
interaction between both catalysts occurs in solution.
Furthermore, NMR mixtures of thiourea 1, acid 4b, and
glycoside donor 2a showed additional downfield H-shifts
associated with the anomeric protons in 2a (δ 6.33 ppm),
while shifts for the OH signal from acceptor 3 (from δ 1.84
ppm to δ 2.54 ppm) were detected in mixtures of 1, 4b, and 3
(see Supporting Information for details). Thiourea 1 and chiral
phosphoric acid 4b have been shown to individually hydrogen
bond with OH nucleophiles.1b,11 Thus, as expected, mixtures of
3 and 10 mol % of thiourea 1 or 3 mixed with 10 mol % of acid
4b also showed shifts associated with the OH protons of
glycosyl acceptor 3, although the magnitude of those shifts was
different to that of mixtures of 3 and both cocatalysts (1 and
4b). These results further demonstrate that the combination of
1 and chiral acid (R)-4b leads to a cooperative catalytic system
that can activate both enol ether and OH nucleophiles in a
synergistic fashion, leading to an enhancement in reaction rate
and α-stereocontrol of the glycosylation reaction. As proposed
in Scheme 3, our findings suggest that a hydrogen-bond-
mediated complex between thiourea 1 and acid 4b leads to a
urea-induced acid amplification, and proton addition from this
complex to the less hindered face of the enol ether (I) forms a
short-lived oxocarbenium intermediate (II) that is rapidly
trapped by the OH nucleophile which is in turn activated by the
phosphate intermediate that is generated in situ, to give 15.
This might help to explain the effect the chirality of the
phosphoric acid has on the stereo outcome of the glycosylation
reaction.
a
b
Yield of isolated product. Reaction performed at 45 °C, 1.5 equiv of
c
donor and thiourea 1 (20 mol %) (5−6 h). Product was isolated as
the desilylated disaccharide for purification purposes.
CONCLUSIONS
effective glycosylation donor than its benzylated counterpart
(Table 3, entries 6−8).
■
In summary, we have described a practical, highly stereo-
selective, and efficient direct glycosylation method for glycals
using a cooperative Brønsted acid-organocatalytic promoter
system. The reaction is widely applicable to a range of glycosyl
donors and nucleophile acceptors, proceeds with excellent
yields and high selectivity for the α-anomer, and is tolerant of
most common protecting groups. We note that the stereo-
selectivity of the reaction is highly dependent on the chirality of
the acid, with (R)-4b leading to the formation of α-glycosides
preferentially, while both yield and rate of reaction are greatly
enhanced by the synergistic interaction between thiourea and
acid. Moreover, we exemplify the generality of the approach in
the stereoselective synthesis of a series of disaccharides,
glycosyl-amino acids, and other glycoconjugates and also in
the one-pot chemo- and stereoselective synthesis of a
trisaccharide. Further work from our lab is underway to exploit
2,6-Dideoxyglycosides are also an important class of
compounds, and their stereoselective synthesis is further
complicated by the lack of oxygen substituents at both C-2
and C-6.18 Excitingly, activation of 3,4-O-siloxane protected L-
rhamnal 9 afforded 12 in 74% yield within 3 h and with an 8:1
α:β ratio (entry 9). It is important to highlight that thiourea 1
alone was not able to activate any of the glucal and rhamnal
substrates. These results further emphasize that the synergistic
catalytic system works well across a range of reactivity profiles
for both glycal donors and nucleophile acceptors.
Having found that thioglycosides are inert under the
cooperative organocatalytic glycosylation conditions (Table 2,
entry 4), we decided to evaluate the methodology in a three-
component, one-pot synthesis of trisaccharide 13 (Scheme 2).
Thus, galactal 2a was reacted with thioglycoside 6d under the
C
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a
Table 3. Reaction of Glycals 2b−2f, 8a, 8b, and 9 with Model Acceptor 3 or 6k
a
b
entry
R1
R2
R3
Me
time (h)
2
product
yield (%)
α:β
1
2
2b
2c
2d
2e
2f
8a
8b
8c
9
Me
Ac
Me
Ac
10b
10c
10d
10e
10f
80
N/A
86
>30:1
N/A
c
Ac
20
3
Bn
Bn
Ac
3
3
3
2
3
>20:1
>30:1
>30:1
>30:1
>30:1
only α
8:1
4
allyl
TBS
Bn
allyl
TBS
Bn
allyl
TBS
Bn
80
5
79
d
6
11a
11b
11c
12a
12b
40
7
O[Si(i-Pr)2]2
O[Si(i-Pr)2]2
O[Si(i-Pr)2]2
Bn
81
82
74
c
8
OTIPS
−
−
6
9
3
c
10
9
O[Si(i-Pr)2]2
6
87
d
10:1
a
b
c
Isolated yield. Determined by 1H NMR. Reaction performed at 45 °C, 1.5 equiv of donor, and 0.2 equiv of thiourea. Mixture of Ferrier product
and disaccharide were produced. N/A: No reaction.
Scheme 2. One-Pot Trisaccharide Synthesis
EXPERIMENTAL SECTION
■
General. Dry DCM was obtained by distillation using standard
procedures or by passage through a column of anhydrous alumina.
Reactions requiring anhydrous conditions were performed under
nitrogen. Glassware and needles were either flame-dried immediately
prior to use or placed in an oven (150 °C) for at least 2 h and allowed
to cool either in a desiccators or under reduced pressure. Liquid
reagents, solutions, or solvents were added via syringe through rubber
septa. Solid reagents were added via Schlenk-type adapters. Reactions
were monitored by TLC on Kieselgel 60 F254 (Merck). Detection was
by examination under UV light (254 nm) and by charring with 10%
sulfuric acid in ethanol. Flash column chromatography was performed
using silica gel [Merck, 230−400 mesh (40−63 μm)]. Extracts were
Scheme 3. Proposed Mechanism
concentrated in vacuo using both a Buchi rotary evaporator (bath
̈
temperatures up to 40 °C) at a pressure of either 15 mmHg
(diaphragm pump) or 0.1 mmHg (oil pump), as appropriate, and a
high-vacuum line at room temperature. 1H NMR and 13C NMR
spectra were measured in the solvent stated at 400 or 500 MHz.
Chemical shifts are quoted in parts per million from residual solvent
peak (CDCl3: 1H, 7.26 ppm and 13C, 77.16 ppm) and coupling
constants (J) given in Hertz. Multiplicities are abbreviated as bs
(broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
or combinations thereof. Positive ion matrix-assisted laser desorption
ionization time-of-flight (MALDI-TOF) mass spectra were recorded
using an HP-MALDI instrument using gentisic acid matrix. Electro-
spray ionization (ESI) mass spectra were recorded on a Micromass
LCT mass spectrometer or a VG Quattro mass spectrometer.
General Glycosylation Procedure. Monosaccharide donor (1
equiv) and acceptor (0.83 equiv (∼0.1 mmol)) were weighed into a
microwave vial and placed under vacuum for 1 h, after which time the
microwave vial was filled with N2. A mixture of chiral acid (0.1 equiv)
and thiourea (0.1 equiv for primary acceptors and 0.2 equiv for
secondary acceptors) in anhydrous DCM (1 mL) was stirred for 30
min and then added to the microwave vial containing the donor and
acceptor. The reaction mixture was stirred at RT (primary acceptors)
the cooperative catalysis between organocatalysts and chiral
acids for the stereoselective synthesis of other important
glycosides and chiral acetals.
D
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or heated at reflux (secondary acceptors) until the reaction was
determined to be complete by either TLC or NMR analysis of the
crude material. The reaction mixture was purified by silica gel flash
column chromatography.
column chromatography (Hexane:EtOAc, 7:1 to 4:1): 7d as a white
solid (82 mg 82%). Spectroscopic data in agreement with literature.7
Phenyl 2-Deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-hexapyranosyl (7e).
Following the general glycosylation procedure, donor 2a (50 mg, 0.12
mmol) and acceptor 6e (9 mg, 0.10 mmol) afforded the following
purification by column chromatography (Hexane:EtOAc 20:1 to
12:1): 7e as a colorless oil (43 mg 84%): 1H NMR (400 MHz;
CDCl3) δ 7.42−6.98 (20H, m, Ph), 5.59 (1H,d, J = 3.4 Hz, H-1), 4.85
(1H, d, J = 11.5 Hz, OCHHPh), 4.72 (2H, bs, OCH2Ph), 4.67 (1H, d,
J = 11.5 Hz, OCHHPh), 4.28 (1H, d, J = 11.6 Hz, OCHHPh), 4.24
(1H, d, J = 11.6 Hz, OCHHPh), 4.02 (1H,ddd, H-3), 3.93 (1H, t, J =
7.3 Hz, H-5), 3.80 (1H, bs, H-4), 3.53 (1H, dd, J = 9.3, 7.3 Hz, H-6a),
3.40 (1H, dd, J = 9.3, 5.7 Hz, H-6b), 2.28 (1H, td, J = 12.4, 3.6 Hz, H-
2a), 2.08 (1H, dd, J = 12.4, 4.4 Hz, H-2b); 13C NMR (101 MHz;
CDCl3) δ 156.8 (4 °C), 138.8 (4 °C), 138.4 (4 °C), 138.0 (4 °C),
128.4 (CH), 128.3 (CH), 128.2 (CH), 128.2 (CH), 128.1 (CH),
128.2 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 127.3 (CH),
121.9 (CH), 116.6 (CH), 96.5 (C-1), 74.5 (CH2Ph), 74.4 (C-3), 73.3
(CH2Ph), 72.8 (C-4), 70.6 (CH2Ph), 70.5 (C-5), 69.1 (C-6), 31.2 (C-
Methyl 2,3,4-Tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-α-D-
lyxo-hexapyranosyl)-α-D-glucopyranoside (5). Following the general
glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 3
(46 mg, 0.10 mmol) afforded the following purification by column
chromatography (Hexane:EtOAc, 6:1 to 3:1): 5 as a yellow oil (68 mg,
89%). 1H NMR (400 MHz; CDCl3) δ 7.39−7.19 (30H, m, Ph), 5.02
(1H, app d, J = 2.4 Hz, H-1′), 4.98 (1H, d, J = 10.8 Hz, OCH HPh),
4.91 (1H, d, J = 11.6 Hz, OCH HPh), 4.84 (1H, d, J = 10.9 Hz, OCH
HPh), 4.80 (1H, d, J = 10.8 Hz, OCHH Ph), 4.79 (1H, d, J = 12.2 Hz,
OCH HPh), 4.68 (1H, d, J = 12.2 Hz, OCHH Ph), 4.60 (1H, d, J =
3.6 Hz, H-1), 4.60 (1H, d, J = 11.6 Hz, OCHH Ph), 4.57 (2H, s,
OCH2 Ph), 4.52 (1H, d, J = 10.9 Hz, OCHH Ph), 4.41 (1H, d, J =
12.0 Hz, OCH HPh), 4.34 (1H, d, J = 12.0 Hz, OCHH Ph), 3.98 (1H,
t, J = 9.2 Hz, H-3), 3.90−3.84 (3H, m, H-3′, H-4′, H-5′), 3.81 (1H, dd,
J = 11.2, 4.6 Hz, H-6a), 3.72 (1H, ddd, J = 10.0, 4.5, 1.6 Hz, H-5), 3.61
(1H, dd, J = 11.4, 1.7 Hz, H-6b), 3.54 (1H, dd, J = 9.5, 7.3 Hz, H-6a′),
3.51 (1H, dd, J = 9.5, 3.5 Hz, H-2), 3.50 (1H, dd, J = 9.5, 5.9 Hz, H-
6b′), 3.46 (1H, dd, J = 9.9, 9.0 Hz, H-4), 3.31(3H, s, OCH3), 2.20
(1H, td, J = 12.4, 3.7 Hz, H-2a′), 2.01 (1H, app dd, J = 12.7, 4.5 Hz,
H-2b′); 13C NMR (126 MHz; CDCl3) δ 139.0 (4 °C), 138.9 (4 °C),
138.5 (4 °C), 138.4 (4 °C), 138.30 (4 °C), 138.27 (4 °C), 128.6
(CH), 128.54 (CH), 128.45 (CH), 128.33 (CH), 128.32 (CH),
128.18 (CH), 128.16 (CH), 128.0 (CH), 127.82 (CH), 127.81
(CH),127.78 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 98.4 (C-
1′), 98.0 (C-1), 82.3 (C-3), 80.1 (C-2), 78.1 (C-4), 76.0 (C H2 Ph),
75.1 (C H2 Ph), 74.41, 74.35 (C-3′, C H2 Ph), 73.5 (C H2 Ph), 73.4
(C H2 Ph), 73.1 (C-4′), 70.4, 70.2 (C-5′, CH2Ph), 70.0 (C-5), 69.5
(C-6′), 66.2 (C-6), 55.2 (OCH3), 31.2 (C-2′). Spectroscopic data in
agreement with literature.7
+
2). ESI-HRMS for C33H34NaO5 (MNa+) calcd: 533.2304; found:
533.2296. [α]D = +36 (c = 1, CHCl3).
Methyl 2,3-Di-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-
hexapyranosyl)-α-D-glucopyranoside (7f). The general glycosylation
procedure was followed using donor 2a (50 mg, 0.12 mmol) and
acceptor 6f (53 mg, 0.10 mmol). The crude material was then
dissolved in a 1 M THF solution of TBAF (0.5 mL, 0.5 mmol) and
stirred for 2 h. The solution was then concentrated in vacuo and
purified by column chromatography (Hexane:EtOAc, 6:1 to 4:1),
affording 7f as a colorless oil (58 mg, 74%). Spectroscopic data in
agreement with literature.7
3-O-(2-Deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-hexapyranoside)-
1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside (7g). Following the
general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and
acceptor 6g (26 mg, 0.10 mmol) afforded the following purification by
column chromatography (Hexane:EtOAc, 6:1 to 3:1): 7g as a white
solid (53 mg 78%). Spectroscopic data in agreement with literature.19
O-(2-Deoxy-3,4,6-tri-O-benzyl-D-lyxo-hexapyranosyl)-N-(tert-bu-
toxycarbonyl)-L-serine Methyl Ester (7h). Following the general
glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor
6h (22 mg, 0.10 mmol) afforded the following purification by column
chromatography (Hexane:EtOAc, 10:1 to 4:1): 7h as a pale yellow oil
(53 mg 83%). Spectroscopic data in agreement with literature.20
O-(2-Deoxy-3,4,6-tri-O-benzyl-D-lyxo-hexapyranosyl)-N-(tert-bu-
toxycarbonyl)-L-threonine Methyl Ester (7i). Following the general
glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor
6i (23 mg, 0.10 mmol) afforded the following purification by column
chromatography (Hexane:EtOAc, 10:1 to 4:1): 7i as a pale yellow oil
Benzyl 2-Deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-hexapyranoside (7a).
Following the general glycosylation procedure, donor 2a (50 mg, 0.12
mmol) and acceptor 6a (11 mg, 0.10 mmol) afforded the following
purification by column chromatography (Hexane:EtOAc, 10:1 to 8:1):
7a as a colorless oil (42 mg, 80%).1H NMR (500 MHz, CDCl3) δ
7.37−7.22 (20H, m, Ph), 5.08 (1H, d, J = 3.5 Hz, H-1), 4.93 (1H, d, J
= 11.6 Hz, OCHHPh), 4.67 (1H, d, J = 11.9 Hz, OCHHPh), 4.62
(1H, d, J = 11.7 Hz, OCHHPh), 4.59 (1H, m, OCH2Ph), 4.50 (1H, d,
J = 11.8 Hz, OCHHPh), 4.47 (2H, d, J = 11.9 Hz, OCHHPh), 4.43
(1H, d, J = 11.8 Hz, OCHHPh), 3.99 (1H, ddd, J = 12.0, 4.6, 2.5 Hz,
H-3), 3.96 (1H, t, J = 6.7 Hz, H-5), 3.94 (1H, bs, H-4), 3.61 (1H, dd, J
= 9.4, 6.8 Hz, H-6a), 3.56 (1H, dd, J = 9.4, 6.0 Hz, H-6b), 2.25 (1H,
td, J = 12.4, 3.8 Hz, H-2a), 2.07−2.01 (1H, m, H-2b); 13C NMR (126
MHz, CDCl3) δ 139.1 (4 °C), 138.7 (4 °C), 138.3 (4 °C), 138.0 (4
°C), 128.54 (CH), 128.52 (CH), 128.51 (CH), 128.37 (CH), 128.35
(CH), 128.1 (CH), 127.9 (CH), 127.81 (CH), 127.77 (CH), 127.7
(CH), 127.6 (CH), 127.5 (CH), 97.3 (H-1), 75.0 (C-3), 74.4
(OCH2Ph), 73.6 (OCH2Ph), 73.2 (C-4), 70.7 (OCH2Ph), 70.3 (C-5),
1
(56 mg 85%). H NMR (500 MHz; CDCl3) δ 7.37−7.23 (15H, m,
Ph), 5.14 (1H, J = 9.8 Hz, NH), 4.94−4.89 (2H, m, H-1, OCHHPh),
4.62−4.53 (3H, m, OCH2Ph, H-6a), 4.51 (1H, d, J = 11.8 Hz,
OCHHPh), 4.43 (1H, d, J = 11.8 Hz, OCHHPh), 4.30−4.25 (2H, m,
OCHHPh, OCH(CH3)CH(NH)), 3.94−3.89 (2H, m, H-6b, OCH-
(CH3)CH(NH)), 3.84 (1H, m, H-3), 3.72 (3H, s, OCH3), 3.60−3.51
(2H, m, 2H-4, H-5), 2.15 (1H, td, J = 12.3, 3.8 Hz, H-2a), 1.86 (1H,
dd, J = 12.4, 4.4 Hz, H-2b), 1.48 (9H, s, 3 × CH3), 1.25 (3H, d, J = 6.5
Hz, OCH(CH3)CH(NH)); 13C NMR (126 MHz; CDCl3) δ 171.6
(CO), 156.0 (CO), 138.7 (4 °C), 138.3 (4 °C), 138.0 (4 °C), 128.4
(CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 127.6
(CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 99.3 (C-1), 80.0 (4 °C),
75.3 (CH2Ph), 74.2 (CH2Ph), 74.2 (C-3), 73.5 (CH2Ph), 72.9 (C-4),
70.3 [OCH(CH3)CH(NH)], 70.3 (C-6), 58.2 [OCH(CH3)CH-
(NH)], 52.2 (OCH3), 31.2 (C-2), 28.3 (3 x OCH3), 18.3
[OCH(CH3)CH(NH)]. ESI-HRMS for C37H47NO9Na+ (MNa+)
calcd: 672.3149; found: 672.3144. [α]D = +20 (c = 1, CHCl3).
Cholesteryl (2-Deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-hexapyranosyl)
(7j). Following the general glycosylation procedure, donor 2a (50
mg, 0.12 mmol) and acceptor 6j (39 mg, 0.10 mmol) afforded the
following purification by column chromatography (Hexane:EtOAc,
10:1 to 6:1): 7j as a colorless oil (57 mg 74%). Spectroscopic data in
agreement with literature.21
+
69.7 (C-6), 69.1 (OCH2Ph), 31.3 (C-2). ESI-HRMS for C34H36NaO5
(MNa+) calcd: 547.2460; found: 547.2459. [α]D = +24 (c = 1,
CHCl3).
Methyl 2,3,4-Tri-O-benzoyl-6-O-(3,4,6-tri-O-benzyl-2-deoxy-α-D-
lyxo-hexapyranosyl)-α-D-glucopyranoside (7b). Following the gen-
eral glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and
acceptor 6b (50 mg, 0.10 mmol) afforded the following purification by
column chromatography (Hexane:EtOAc, 6:1 to 4:1): 7b as a white
solid (79 mg, 86%). Spectroscopic data in agreement with literature.7
6-O-(3,4,6-Tri-O-benzyl-2-deoxy-α-D-lyxo-hexapyranosyl)-1,2,3,4-
di-O-isopropylidene-α-D-galactopyranoside (7c). Following the
general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and
acceptor 6x (26 mg, 0.10 mmol) afforded the following purification by
column chromatography (Hexane:EtOAc, 6:1 to 3:1) 7c as a colorless
oil (56 mg, 83%). Spectroscopic data in agreement with literature.7
Phenyl 2,3,4-Tri-O-benzoyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-α-D-
lyxo-hexapyranosyl)-α-D-thioglucopyranoside (7d). Following the
general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and
acceptor 6d (58 mg, 0.10 mmol) afforded the following purification by
E
DOI: 10.1021/acs.joc.6b02498
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-methoxy-α-D-
lyxo-hexapyranosyl)-α-D-glucopyranoside (10b). Following the
general glycosylation procedure, donor 2b (23 mg, 0.12 mmol) and
acceptor 3 (47 mg, 0.10 mmol) afforded the following purification by
column chromatography (Hexane:EtOAc, 4:1 to 2:1): 5b as a colorless
oil (52 mg, 80%): 1H NMR (400 MHz; CDCl3) δ 7.41−7.22 (15H, m,
Ph), 5.02−4.96 (2H, m, H-1′, OCHHPh), 4.92 (1H,d, J = 10.9 Hz,
OCHHPh), 4.83−4.77 (2H, m, 2 OCHHPh), 4.68 (1H, d, J = 12.2
Hz, OCHHPh), 4.62 (1H, d, J = 4.6 Hz, OCHHPh), 4.60 (1H, d, J =
2.9 Hz, H-1), 4.01 (1H, t, J = 9.2 Hz, H-3), 3.88−3.79 (2H, m, H-4,
6a′), 3.74 (1H, ddd, J = 9.9, 4.4, 1.8 Hz, H-5), 3.63 (1H, dd, J = 11.4,
2.0 Hz, H-6b′), 3.61−3.56 (2H, m, 3′,5′), 3.56−3.51 (5H, m, H-4′,
OCH3, H-2), 3.51−3.40 (2H, m, H-6a, H-6b), 3.39, 3.37 (6H, 2s, 2 ×
OCH3), 3.30 (3H, s, OCH3), 2.04−1.90 (2H, m, H-2a′,H-2b′). 13C
NMR (101 MHz, CDCl3) δ 138.6 (4 °C), 138.2 (4 °C), 138.1 (4 °C),
128.5 (CH), 128.4 (CH), 128.4 (CH), 128.1 (CH), 128.1 (CH),
127.9 (CH), 127.7 (CH), 98.2 (C-1′), 97.9 (C-1), 82.1 (C-3), 80.0
(C-2), 77.8 (C-1), 75.9, 75.8, 74.9 (C-3′, C-4′, C-5′), 74.4 (CH2Ph),
73.3 (CH2Ph), 71.5 (CH2Ph), 69.7 (C-6), 69.7 (C-5), 66.1 (C-4), 60.9
(OCH3), 59.1 (OCH3), 56.1 (OCH3), 55.1 (OCH3), 30.7 (C-2′) .
(CH), 116.9 (CHCH2), 116.8 (CHCH2), 116.6 (CHCH2),
98.2 (C-1′), 97.9 (C-1), 82.1 (C-3), 80.0 (C-5′), 77.9 (C-2), 75.8
(CH2Ph), 74.9 (CH2Ph), 73.9 (C-4′), 73.5 (OCH2CH), 73.3
(CH2Ph), 72.4 (H-5), 72.2 (OCH2CH), 69.8 (2C, C-4, C-3′), 69.2
(OCH2CH), 69.1 (C-6), 66.0 (C-6′), 55.0 (OCH3), 31.1 (C-2′). ESI-
+
HRMS for C43H54NaO10 (MNa+) calcd: 753.3615; found: 753.3610.
[α]D = +20 (c = 1, CHCl3).
Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-tert-butyldi-
methylsilyl-α-D-lyxo-hexapyranosyl)-α-D-glucopyranoside (10f).
Following the general glycosylation procedure, donor 2f (50 mg,
0.10 mmol) and acceptor 3 (39 mg, 0.09 mmol) afforded the following
purification by column chromatography (Hexane:EtOAc, 5:1 to 4:1):
1
10f as a colorless oil (64 mg, 79%): H NMR (400 MHz, CDCl3) δ:
7.38−7.24 (15H, m, Ph), 4.99−4.95 (2H, m, H-1′, OCHHPh), 4.87
(1H, d, J = 10.8 Hz, OCHHPh), 4.83 (1H, d, J = 10.7 Hz, OCHHPh),
4.80 (1H, d, J = 12.2 Hz, OCHHPh), 4.67 (1H, d, J = 12.2 Hz,
OCHHPh), 4.61 (1H, d, J = 10.8 Hz, OCHHPh), 4.57 (1H, d, J = 3.6
Hz, H-1), 4.05 (1H, m, H-3′), 3.99 (1H, t, J = 9.2 Hz, H-2), 3.80 (1H,
bs, H-4′), 3.77−3.73 (2H, m, H-3, H-6′a), 3.70−3.62 (4H, m, H-5′, H-
6a, H-6b, H-6′b), 3.49 (1H, dd, J = 9.6, 3.6 Hz, H-4), 3.42 (1H, t, J =
9.6 H-5), 3.36 (3H, s, OCH3), 2.08 (1H, td, J = 12.1, 3.5, H-2a′), 1.65
(1H, dd, J = 12.7, 4.5 H-2b′), 0.94−0.86 (27H, m, 3 × SiC(CH3)3),
0.12−0.00 (18H, m, 6 x SiCH3); 13C NMR (126 MHz; CDCl3) 138.7
(4 °C), 138.2 (4 °C), 138.1 (4 °C), 128.4−127.7 (Ph), 97.9 (C-1′),
97.6 (C-1), 82.1 (C-2), 79.9 (C-4), 78.5 (C-5), 75.8 (OCH2Ph), 75.1
(OCH2Ph), 73.3 (OCH2Ph), 72.7 (C-5′), 70.3 (C-4′), 68.3 (C-3′),
65.2 (C-6′), 62.6 (C-6), 54.7 (OCH3), 33.5 (C-2′), 26.2 (SiC(CH3)3),
26.1 (SiC(CH3)3), 25.8 (SiC(CH3)3), 18.6 (SiC(CH3)3), 18.5
(SiC(CH3)3), 18.1 (SiC(CH3)3), −3.9 (SiCH3), −4.4 (SiCH3), −4.8
+
ESI-HRMS for C37H48NaO10 (MNa+) calcd: 675.3145; found:
675.3144. [α]D = +51 (c = 1, CHCl3).
Methyl 2,3,4-Tri-O-benzyl-4-O-6-O-(6-O-acetyl-2-deoxy-3,4-di-O-
benzyl-α-D-lyxo-hexapyranosyl)-α-D-glucopyranoside (10d). Follow-
ing the general glycosylation procedure, donor 2d (50 mg, 0.12 mmol)
and acceptor 3 (47 mg, 0.10 mmol) afforded the following purification
by column chromatography (Hexane:EtOAc 6:1 to 3:1): 10d as a
colorless oil (73 mg, 86%): 1H NMR (400 MHz; CDCl3) δ 7.41−7.19
(25H, m, Ph), 5.03 (1H, d, J = 3.3 Hz, H-1′), 4.99 (1H, d, J = 10.7 Hz,
OCHHPh), 4.94 (1H, d, J = 11.7 Hz, OCHHPh), 4.87 (1H, d, J = 11.0
Hz, OCHHPh), 4.83−4.77 (2H, m, OCHHPh), 4.72−4.63 (2H, m,
OCHHPh), 4.63−4.55 (3H, m, H-1, OCHHPh), 4.48 (1H, d, J = 11.1
Hz, OCHHPh), 4.11−3.95 (3H, m, H-3, H-6a′,H-6b′), 3.84 (1H, ddd,
J = 11.9, 4.5, 2.3 Hz, H-3′), 3.74 (4H, m, H-4′, H-6a, H-2, H-5), 3.60
(1H, d, J = 10.5 Hz, H-6b), 3.51 (1H, dd, J = 9.6, 3.6 Hz, H-2), 3.43
(1H, t, J = 9.3 Hz, H-4), 3.31 (3H, s, OCH3), 2.20 (1H, td, J = 12.3,
3.6 Hz, H-2a′), 2.03 (1H, dd, J = 12.5, 4.4 Hz, H-2b′), 1.85 (3H, s,
CH3CO). 13C NMR (101 MHz,CDCl3) δ 170.5 (CH3CO) 138.6 (4
°C), 138.4 (4 °C), 138.2 (4 °C), 128.5 (CH), 128.4 (CH), 128.4
(CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.9 (CH), 127.7
(CH), 127.7 (CH), 127.5 (CH), 127.4 (CH), 98.0 (C-1′), 97.8 (C-1),
82.1 (C-3), 79.9 (C-2), 77.9 (C-4), 75.8 (CH2Ph), 74.9 (CH2Ph), 74.2
(C-3′), 74.0 (CH2Ph), 73.2 (CH2Ph), 72.5 (C-5′), 70.3 (CH2Ph), 69.7
(H-4′), 69.1(H-5), 65.9 (C-6), 64.0 (C-6′), 55.0 (OCH3), 30.7 (C-2′),
(SiCH3), −5.0 (SiCH3), −5.3 (SiCH3), −5.4 (SiCH3). ESI-HRMS for
+
C52H84NaSi3O10 (MNa+) calcd: 975.5270; found: 975.5277. [α]D
=
+16 (c = 1, CHCl3).
Methyl 2,3,4-Tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-α/β-D-
erythrohexapyranosyl)-α-D-glucopyranoside (11a). Following the
general glycosylation procedure, donor 8a (50 mg, 0.10 mmol) and
acceptor 3 (50 mg, 0.08 mmol) afforded the following purification by
column chromatography (Hexane:EtOAc 5:1 to 4:1): 11a as colorless
oil (28 mg, 40%). Spectroscopic data in agreement with literature.6b
Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4-O-(1,1,3,3-tetraiso-
propyldisiloxane-1,3-diyl)-6-O-triisopropylsilyl-α-D-erythro-hexapyr-
anosyl)-α-D-glucopyranoside (11b). Following the general glycosyla-
tion procedure, donor 8b (50 mg, 0.10 mmol) and acceptor 3 (40 mg,
0.08 mmol) afforded the following purification by column
chromatography (Hexane:EtOAc 5:1 to 4:1): 11b as colorless oil
(66 mg, 81%). Spectroscopic data in agreement with literature.6b
Methyl 3-O-Benzyl-4,6-O-benzylidene-2-O-(2-deoxy-3,4-O-
(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-6-O-triisopropylsilyl-α-D-
erythro-hexapyranosyl)-α-D-glucopyranoside (11c). Following the
general procedure, donor 8c (50 mg, 0.10 mmol) and acceptor 6k (30
mg, 0.08 mmol) afforded the following purification by column
chromatography (Hexane:EtOAc 5:1 to 4:1): 11c as colorless oil (60
+
20.8 (COCH3). ESI-HRMS for C50H56NaO11 (MNa+) calcd:
855.3720; found: 855.3711. [α]D = +8 (c = 1, CHCl3).
Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-allyl-α-D-lyxo-
hexapyranosyl)-α-D-glucopyranoside (10e). Following the general
glycosylation procedure, donor 2e (32 mg, 0.12 mmol) and acceptor 3
(46 mg, 0.10 mmol) afforded the following purification by column
chromatography (Hexane:EtOAc, 5:1 to 4:1): 10e as a pale yellow oil
1
1
mg, 82%): H NMR (400 MHz, CDCl3) δ: 7.50−7.44 (2H, m, Ph),
(58 mg, 80%): H NMR (500 MHz; CDCl3) δ 7.41−7.22 (15H, m,
7.41−7.31 (5H, m, Ph), 7.25−7.20 (3H, m, Ph), 5.53 (1H, s,
PhCHO2), 5.09 (1H, d, J = 3.3 Hz, H-1′), 4.99 (1H, d, J = 3.3 Hz, H-
1), 4.88 (1H, d, J = 11.7 Hz, OCHHPh), 4.78 (1H, d, J = 11.7 Hz,
OCHHPh), 4.29 (1H, dd, J = 9.9, 4.5 Hz, CHH), 4.13 (1H, ddd, J =
11.3, 8.3, 5.3 Hz, H-3′), 4.07−4.01 (1H, m, CHH), 3.94 (1H, dd, J =
9.4, 3.4 Hz, H-2), 3.92 (1H, dd, J = 9.4, 8.9 Hz, H-3), 3.87−3.75 (3H,
m, H-5, H-5′, CHH), 3.71 (1H, t, J = 10.1 Hz, CHH), 3.61 (1H, t, J =
9.1 Hz, H-4), 3.51 (1H, dd, J = 9.2, 8.4 Hz, H-4′), 3.43 (3H, s, OCH3),
2.25 (1H, app dd, J = 13.2, 5.1 Hz, H-2a′), 1.73 (1H, ddd, J = 13.5,
11.4, 3.7 Hz, H-2b′), 1.17−0.86 (49H, m, 7 x SiCH(CH3)2); 13C
NMR (101 MHz, CDCl3) δ: 139.0 (4 °C), 137.6 (4 °C), 129.0 (CH),
128.28 (CH), 128.25 (CH), 127.7 (CH), 127.4 (CH), 126.2 (CH),
101.5 (PhCHO2), 97.4 (C-1), 92.9 (C-1′), 81.5 (H-4), 77.3 (C-3),
75.2 (PhCH2O), 74.7 (C-4′), 73.7 (CH), 73.5 (C-2), 71.9 (C-3′),
69.2, 63.5 (C-6, C-6′), 62.6 (CH), 55.3 (OCH3), 38.0 (C-2′), 18.24
(Si(CH(CH3)2)), 18.20 (Si(CH(CH3)2)), 18.15 (Si(CH(CH3)2)),
17.7 (Si(CH(CH3)2)), 17.6 (Si(CH(CH3)2))0, 17.59 (Si(CH-
(CH3)2)), 17.53 (Si(CH(CH3)2)), 17.48 (Si(CH(CH3)2)), 17.45
Ph), 6.00−5.79 (3H, m, CHCH2), 5.30 (1H, dt, J = 3.4, 1.6 Hz,
CHCH2), 5.26 (1H, q, J = 1.8 Hz, CHCH2), 5.23 (1H, tt, J = 2.3,
1.1 Hz, CHCH2), 5.17 (1H, dt, J = 3.4, 1.6 Hz, CHCH2), 5.15−
5.12 (2H, m, CHCH2), 5.01 (1H, d, J = 2.6 Hz, H-1′), 4.99 (1H, d,
J = 10.8 Hz, OCHHPh), 4.91 (1H, d, J = 10.8 Hz, OCHHPh), 4.82
(1H, d, J = 5.3 Hz, OCHHPh), 4.80 (1H, d, J = 6.6 Hz, OCHHPh),
4.69 (1H, d, J = 12.2 Hz, OCHHPh), 4.62 (1H, d, J = 2.5 Hz, H-1),
4.61 (1H, d, J = 4.8 Hz, OCHHPh), 4.35 (1H, ddt, J = 12.7, 5.6, 1.4
Hz, OCHHCHCH2), 4.13−4.06 (1H, m, OCHHCHCH2),
4.05−4.02 (2H, m, OCHHCHCH2, H-3), 4.01−3.97 (1H, m,
OCHHCHCH2), 3.94−3.91 (2H, OCHHCHCH2), 3.88−3.81
(2H, m, H-4, H-6a′), 3.78−3.73 (3H, m, H-4′, H-3′, H-5), 3.64 (1H,
dd, J = 11.4, 2.0 Hz, H-6b′), 3.58 (1H, dd, J = 9.3, 7.3 Hz, H-5′),
3.56−3.52 (1H, m, H-2), 3.51−3.46 (2H, m, H-6a, H-6b), 3.37 (3H, s,
OCH3), 2.14−2.07 (1H, m, H-2a′), 1.95−1.90 (1H, m, H-2b′).13C
NMR (126 MHz, CDCl3) δ 138.7 (4 °C), 138.2 (4 °C), 138.1 (4 °C),
135.6 (CHCH2), 134.8 (CHCH2), 134.6 (CHCH2), 128.5
(CH), 128.4 (CH), 128.04 (CH), 127.9 (CH), 127.7 (CH), 127.7
F
DOI: 10.1021/acs.joc.6b02498
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(Si(CH(CH3)2)), 17.4 (Si(CH(CH3)2)), 13.1 (Si(CH(CH3)2)), 12.5
(Si(CH(CH3)2)), 12.4 (Si(CH(CH3)2)), 12.2 (Si(CH(CH3)2)), 12.2
6b), 3.58−3.54 (2H, m, H-6a, H-2), 3.54−3.51 (1H, m, H-6b), 3.48
(1H, dd, J = 10.1, 8.9 Hz, H-4), 3.33 (3H, s, OCH3), 2.03−1.99 (1H,
m, H-2′). 13C NMR (126 MHz, CDCl3) δ 138.9 (4 °C), 138.7 (4 °C),
138.4 (4 °C), 138.3 (4 °C), 138.16 (4 °C), 138.1 (4 °C), 128.41
(CH), 128.2 (CH), 127.7 (CH), 98.3 (C-1′), 97.9 (C-1), 82.1 (C-3),
80.0 (C-2), 77.9 (C-4), 75.8 (CH2Ph), 74.9 (CH2Ph), 74.3 (CH2Ph),
74.16 (C-3′), 73.3 (CH2Ph), 73.3 (CH2Ph), 72.9 (C-4′), 70.2
(CH2Ph), 70.1 (CH2Ph), (C-5′), 69.8 (C-5), 69.4 (C-6′), 66.0 (C-
+
(Si(CH(CH3)2)). MALDI-HRMS for C48H80NaO11Si3 (MNa+)
calcd: 939.4869; found: 939.4896. [α]2D2 = +51 (c = 0.0030, CHCl3).
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,6-deoxy-3,4-O-(1,1,3,3-tetraiso-
propyldisiloxane-1,3-diyl)-α/β-L-erythro-hexapyranosyl)-α-D-gluco-
pyranoside (12a). Following the general glycosylation procedure,
donor 9 (50 mg, 0.13 mmol) and acceptor 3 (52 mg, 0.11 mmol)
afforded the following purification by column chromatography
(Hexane:EtOAc, 8:1 to 4:1) 12 as a colorless oil (78 mg, 74%, α:β
= 9:1). Spectroscopic data in agreement with literature.7
+
6), 55.0 (OCH3), 29.7 (C-2′). ESI-HRMS for C55H59DNaO10
(MNa+) calcd: 904.4147; found: 904.4142. [α]D = +25 (c = 1,
CHCl3).
Methyl 3-O-Benzyl-4,6-O-benzylidene-2-O-(2,6-deoxy-3,4-O-
(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-α/β-L-erythro-hexapyra-
nosyl)-α-D-glucopyranoside (12b). Following the general procedure,
donor 9 (50 mg, 1.3 mmol) and acceptor 6k (42 mg, 1.1 mmol)
afforded the following purification by column chromatography
(Hexane:EtOAc 20:1 to 10:1): 12b as colorless oil (72 mg, 87%,
α:β = 10:1): 1H NMR (400 MHz, CDCl3) δ: 7.52−7.48 (2H, m, Ph),
7.40−7.25 (8H, m, Ph), 5.58 (1H, s, PhCHO2 α-anomer), 5.56 (1H, s,
PhCHO2 β-anomer), 5.07 (1H, d, J = 3.9 Hz, H-1′), 4.88−4.84 (2H,
m, H-1, OCHHPh), 4.78 (1H, d, J = 11.4 Hz, OCHHPh), 4.30 (1H,
dd, J = 9.9, 4.5 Hz, H-6a), 4.07 (1H, ddd, J = 11.3, 8.3, 5.3 Hz, H-3′),
3.97 (1H, t, J = 9.3, H-5′), 3.89−3.72 (3H, m, H-4, H-5, H-6b), 3.69−
3.60 (2H, m, H-2, H-3), 3.45 (1H, s, OCH3 β-anomer), 3.45 (1H, s,
OCH3 α-anomer), 3.27 (1H, J = 8.7 Hz, H-4′) (2.24 (1H, app dd, J =
13.2, 5.1 Hz, H-2a′), 1.74 (1H, ddd, J = 13.5, 11.4, 3.7 Hz, H-2b′),
1.29 (3H, d, J = 6.3 Hz, CH3) 1.14−1.02 (28H, m, 4 × SiCH(CH3)2);
13C NMR (101 MHz, CDCl3) δ: 138.66 (4 °C), 137.42 (4 °C), 128.89
(CH), 128.28 (CH), 128.19 (CH), 127.7 (CH), 127.57 (CH), 126.0
(CH), 101.25 (PhCHO2), 100.6 (C-1′), 100.25 (C-1), 82.0 (C-2),
80.37 (C-3), 79.99 (C-4′), 77.94 (C-5), 75.25 (PhCH2O), 71.22 (C-
3′), 69.07 (C-6), 68.3(C-5′), 62.23 (C-4), 55.2 (OCH3), 38.67 (C-2′),
29.7 (CH3), 18.14−12.27 (4 × Si(CH(CH3)2)). ESI-HRMS for
C39H60NaO10+ (MNa+) calcd: 767.3623; found: 767.4002. [α]D = +25
(c = 1, CHCl3). [α]2D2 = +32 (c = 1, CHCl3).
One-Pot Trisaccharide Synthesis: 6-O-(2,3,4-Tri-O-benzoyl-6-O-
(2-deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-hexapyranosyl)-α-D-galacto-
pyranosyl)-1,2:3,4-di-O-isopropylidene-α-D-galactopyranoside (13).
Following general procedure, donor 2a (50 mg, 0.12 mmol), acceptor
6d (58 mg, 0.0998 mmol), and a solution mixture, prepared containing
chiral acid (∼0.012 mmol) and thiourea (∼0.012 mmol) in anhydrous
DCM (1 mL), were mixed together. After 2 h, the disaccharide
formation was determined to be complete by TLC. The reaction
mixture was then cooled to 0 °C, and molecular sieves 4 Å were added.
Once cooled, a solution of 1,2:3,4-di-O-isopropylidene-α-D-galactopyr-
anoside 6c (26 mg, 0.0998 mmol) in anhydrous DCM (0.5 mL) was
added followed by addition of NIS (45 mg, 0.2 mmol) and finally the
dropwise addition of a solution of TMSOTf (95 μL, 40 μL in 20 mL
anhydrous DCM, 0.001 mmol). After 1 h, the reaction was determined
to be complete and was quenched with Et3N (0.1 mL), diluted with
DCM (25 mL), washed with Na2S2O3 (sat. aq.) (25 mL), brine (25
mL), dried over MgSO4, and concentrated in vacuo. Purification by
column chromatography (Hexane:EtOAc, 10:1 to 3:1) afforded
product 13 as a white solid (59 mg, 51%). Spectroscopic data in
agreement with literature.7
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02498.
■
S
Detail NMR experiments and full characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: m.c.galan@bristol.ac.uk.
ORCID
■
M. Carmen Galan: 0000-0001-7307-2871
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by EPSRC CAF EP/L001926/1
(MCG), ERC-COG: 648239 (M.C.G., A.S., and R.W.) and RS
Newton International fellowship (C.P.-N.).
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