Matched/Mismatched interactions in chiral br?nsted acid-catalyzed glycosylation reactions with 2-deoxy-sugar trichloroacetimidate donors

Article abstract of DOI:10.1080/07328303.2014.927882

The stereochemical outcome of glycosylation reactions of 2-deoxy-sugar trichloroacetimidates promoted by chiral Br?nsted acids is shown to be dependent on both the chirality of the catalyst and the configuration of the leaving group. High levels of select

Full text of DOI:10.1080/07328303.2014.927882

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Matched/Mismatched Interactions
in Chiral Brønsted Acid-Catalyzed
Glycosylation Reactions with 2-Deoxy-
Sugar Trichloroacetimidate Donors
Deshan Liua, Soshian Sarrafpoura, Wen Guoa, Brian Goularta & Clay S.
Bennetta
a Department of Chemistry, Tufts University, Medford, MA 02155,
USA
Published online: 23 Jun 2014.
To cite this article: Deshan Liu, Soshian Sarrafpour, Wen Guo, Brian Goulart & Clay S. Bennett (2014)
Matched/Mismatched Interactions in Chiral Brønsted Acid-Catalyzed Glycosylation Reactions with 2-
Deoxy-Sugar Trichloroacetimidate Donors, Journal of Carbohydrate Chemistry, 33:7-8, 423-434, DOI:
10.1080/07328303.2014.927882
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Journal of Carbohydrate Chemistry, 33:423–434, 2014
ꢀ
C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2014.927882
Matched/Mismatched
Interactions in Chiral Brønsted
Acid-Catalyzed Glycosylation
Reactions with 2-Deoxy-Sugar
Trichloroacetimidate Donors
Deshan Liu, Soshian Sarrafpour, Wen Guo, Brian Goulart,
and Clay S. Bennett
Department of Chemistry, Tufts University, Medford, MA 02155, USA
The stereochemical outcome of glycosylation reactions of 2-deoxy-sugar trichloroacetim-
idates promoted by chiral Brønsted acids is shown to be dependent on both the chirality
of the catalyst and the configuration of the leaving group. High levels of selectivity (1:16
α:β) can be obtained with (S)-catalysts and an α-trichloroacetimidate donor. Conversely,
(R)-catalysts require longer reaction times and provide the product in much lower se-
lectivity (6.6:1 α:β). These observations demonstrate that stereochemical “match” and
“mismatch” between donor and acceptor are important factors in chiral Brønsted acid-
promoted glycosylations.
Keywords Glycosylation; Diastereoselectivity; Brønsted acid; Deoxy-sugars
The routine construction of stereodefined glycosidic linkages remains a
major challenge in organic chemistry. While a number of elegant approaches
have been developed to control the stereochemical outcome of glycosylation re-
actions,[1] a general promoter system that provides high levels of selectivity
with a broad range of substrates remains to be developed. This is especially
true of glycosylation reactions utilizing 2-deoxy-sugar donors, which, owing
to the lack of stabilizing and/or directing groups at C-2, frequently provide
products as mixtures of anomers.[2–4] Particularly challenging is the case of β-
linked 2-deoxy-sugars, for which only a handful of methods for direct synthesis
Received April 9, 2014; accepted May 21, 2014.
Address correspondence to Clay S. Bennett, Department of Chemistry, Tufts University,
Medford, MA 02155, USA. E-mail: clay.bennett@tufts.edu
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/lcar.
423

D. Liu et al.
424
have been reported.[5–9] Consequently, many routes to 2-deoxy sugars rely on
the use of temporary directing groups or de novo synthesis,[2,4] which neces-
sarily requires the addition of several transformations to the synthetic route.
Our group has an interest in addressing this issue through the development
of promoters designed to place the stereoselectivity of glycosylation reactions
with 2-deoxy-sugar donors entirely under the control of the glycosylation pro-
moter.[10–13] In our continued effort in this area, we chose to examine chiral
promoters that could be used in a catalytic fashion to control the selectivity of
glycosylations.
The use of chiral catalysts to control the selectivity of additions to oxo-
nium cations has gained significant interest in recent years.[14] Reports de-
scribing the application of this technology to glycosylation reactions are much
less common. In 2010, Fairbanks and coworkers demonstrated that chiral
BINOL-derived phosphoric acids could promote stereoselective glycosylation
reactions between galactose-derived trichloroacetimidates and various accep-
tors.[15] While selectivity in the reaction was sensitive to the nature of the
protecting groups on the donor, the reaction provided an elegant example of
how diastereoselectivity in glycosylation reactions can be placed entirely un-
der the control of the promoter. More recently, both the Toshima and Nagorny
groups reported the use of similar catalysts for resolution of racemic accep-
tors during glycosylation and regioselective protection of carbohydrate diols,
respectively.[16,17] In their study, the Toshima group noted that activation of α-
trichloroacetimido-2,3,4,6-tetra-O-benzyl-D-glucopyranoside with (S)-BINOL
provided useful levels of selectivity in glycosylations when simple acceptors
were employed in the reaction. Intrigued by these results, we chose to examine
whether a similar relationship between catalyst chirality and leaving group
configuration existed with 2-deoxy-sugar donors. Here we report the results of
model studies to determine these relationships.
For this study, we chose to examine the reaction between deoxy-sugar 1
and 1-octanol (2) as an achiral acceptor in order to eliminate any matching
or mismatching between chiral reactants.[18] The diastereomerically enriched
known imidates[19] 1α and 1β were prepared by treating the corresponding
hemiacetal with trichloroacetonitrile in the presence of either NaH or K2CO3,
according to the method of Schmidt.[20,21] It should be noted that these com-
pounds were extremely reactive and had to be purified using aminopropyl sil-
ica gel and used immediately after purification. Owing to the instability of
these molecules, we opted to conduct the study at low temperature (–40◦C) to
minimize substrate decomposition in the presence of the acid catalyst. We first
examined the reaction between 1 and 2 promoted by achiral phosphoric acid 3
in order to determine the intrinsic diastereofacial preference of each substrate
(Sch. 1). Under these conditions, the α-linked imidate 1α reacted in a modestly
selective fashion, providing the product 4 as a 1:5 mixture of α:β isomers (Sch.

Chiral Brønsted Acid-Catalyzed Glycosylation Reactions
425
1a). In contrast, the reaction using donor 1β proceeded in lower yield and was
much less selective (1.5:1 α:β, Sch. 1b).
Scheme 1: Relationship between imidate configuration and product stereochemistry.
Since 1α afforded higher levels of selectivity with achiral catalysts, we
chose to use this substrate for catalyst optimization. To this end, we synthe-
sized and screened a small library of catalysts in the reaction. We initially
chose to examine (S)-catalysts, as both the Fairbanks and Toshima groups re-
ported that they provide higher levels of induction than the corresponding (R)-
catalysts in glycosylations.[15,16] Similar to control reactions, we used 1-octanol
as a model acceptor and conducted the glycosylation at –40◦C. The crude prod-
1
ucts from the reactions were analyzed using H NMR to determine the di-
astereoselectivity of the reaction (Table 1). Through these studies we identified
two catalysts, (S)-5 and (S)-11, both of which increased the β-selectivity of the
reaction from 5:1 to 16:1.
Having established which catalysts to use for optimal selectivity, we exam-
ined the effect of catalyst chirality on the course of the reaction. Upon scale-up,
both (S)-5 and (S)-11 provided the desired glycosylation product in good yield

D. Liu et al.
426
Table 1: Chiral Brønsted acid screen
entry
catalyst
catalyst backbone
R
α:β
1
2
3
4
5
6
7
8
9
5
6
I
I
2,4,6-i-Pr3Ph
4-adamantyl-2,6-i-Pr2Ph
3,5-t-Bu2Ph
1:16
1:10
NR
7
I
8
9
10
11
12
13
I
CHPh2
1:8
II
II
II
II
II
Adamantyl
1:6
CH2Ph
1:12
1:16
1:10
1:10
4-adamantyl-2,6-i-Pr2Ph
CH(4-t-BuPh)2
CH(3,5-t-Bu2Ph)2
(80% and 75%, respectively) without a loss in selectivity (Table 2, entries 1 and
2). In an attempt to reverse the selectivity of the reaction, we examined the
ability of catalysts (R)-5 and (R)-11 to promote the reaction. The use of these
catalysts resulted in a decrease in the selectivity of the reaction compared
to both (S)-catalysts and achiral 4 (Table 2, entries 3 and 4). These results
indicate that the chirality of the catalyst is mismatched to the α-imidate
donor. The lower selectivity observed with the larger (R)-11 is presum-
ably due to the bulky adamantyl group further reinforcing substrate/catalyst
mismatch.
We reasoned that these results were due to the (S)-catalysts being
“matched” with the α-imidate, while the (R)-catalysts were “mismatched” with
this donor.[22] To establish that this was due to the configuration of the leav-
ing group, we next examined the use of donor 1β in the reaction (Table 3).
We reasoned that since the (S)-catalysts gave high levels of selectivity with
α-imidates, the corresponding (R)-catalysts would be able to reverse the selec-
tivity of the reaction when the β-imidate was used as a donor. Once again we
examined both enantiomers of 5 and 11 in the reaction. These studies showed

Chiral Brønsted Acid-Catalyzed Glycosylation Reactions
427
Table 2: Selectivities of catalyst with α-imidates
entry
catalyst
t(h)
yield(%)
α:β
1
2
3
4
(S)-5
(S)-11
(R)-5
60
44
168
168
80
75
73
33
1:16
1:16
1:4
(R)-11
1:2.5
that changing the chirality of the catalyst affected the selectivity of the re-
action; however, only catalyst (R)-11 provided a significant enrichment of one
anomer of the product over the other, albeit in low yield and with long reaction
times (entry 4).
The fact that we were unable to obtain the high levels of β-selectivity us-
ing the β-imidate and the (S)-catalysts further underlines the importance of
the leaving group configuration. We believe that different reaction manifolds
are at play here, with both the configuration of the imidate and the catalyst dic-
tating what pathway the reaction will take. In the case of the highly β-selective
reaction between the α-imidate and the (S)-catalyst, the reaction most likely
proceeds through hydrogen bond activation, leading to an SN2-like manifold,
similar to what has been proposed by the Toshima group.[16] The much lower
selectivity observed with this catalyst and the β-imidate is more consistent
with substrate ionization and subsequent SN1 reaction with the resulting oxo-
carbenium cation. In addition, the longer reaction times point to stereochemi-
cal mismatch between the D-pyranose backbone and the (R)-catalyst.
Having established the optimal combination of donor reactivity and cata-
lyst chirality, we turned our attention to the ability of the catalyst to promote
the formation of disaccharides. To this end, we examined the ability of the (S)-
11 to promote the reaction between 1α and 14 (Sch. 2). While the reaction again

D. Liu et al.
428
Table 3: Selectivities of catalyst with β-imidate
entry
catalyst
t(h)
yield(%)
α:β
1
2
3
4
(S)-5
(S)-11
(R)-5
42
77
83
78
79
39
1:2
1:1.6
1.4:1
6.6:1
77
(R)-11
168
appeared to be selective for one anomer, the product 15[13] was obtained in very
low yield (>15%) and was accompanied by significant amounts of glucal forma-
tion. The results indicate that these catalysts are not effective promoters for
the reaction between 2-deoxy-sugar imidates and complex alcohol acceptors.
Scheme 2: Attempts to extend methodology to more hindered acceptors.
From these observations, we conclude that the ability of the chiral phos-
phoric acids to control diastereoselective glycosylations is highly sensitive to
the configuration of the leaving group. Accordingly, we feel it unlikely that a
single enantiomeric pair of catalysts will be able to serve as universally se-
lective glycosylation promoters. Rather, for this approach to be successful, it
will be necessary to construct a toolbox of chiral promoters, based on different
scaffolds, for different classes of monosaccharides.
In conclusion, we have demonstrated that for chiral Brønsted acids to be
effective promoters for glycosylations with trichloroacetimidate donors, they
must be carefully matched to the configuration of the leaving group. These re-
sults indicate that this particular class of catalysts may at best have utility as
promoters for a small subset of diastereoselective glycosylation reactions. More
importantly, they illustrate that great care must be taken when attempting to
use chiral Brønsted acid catalysts to control diastereoselectivity in glycosyla-
tion reactions, even in cases such as 2-deoxy-sugars where chirality is distal
from the reaction center.

Chiral Brønsted Acid-Catalyzed Glycosylation Reactions
429
EXPERIMENTAL
General Experimental
All reactions were carried out in oven- or flame-dried glassware under
an argon atmosphere unless otherwise noted. Reactions were monitored by
analytical thin layer chromatography (TLC) using Merck precoated silica gel
plates or Wako precoated NH2 silica gel (both 0.25 mm) with F254 indicator.
Visualization was accomplished by UV light (254 nm) and phosphomolybdic
acid stain. Yields refer to chromatographically and spectrographically pure
compounds, unless otherwise noted. Reagents and solvents were purchased at
the highest commercial quality and used as received unless otherwise noted.
Toluene, dichloromethane, and THF were dried using a PURE SOLV solvent
purification system from Innovative Technology. 1-Octanol (99+%) purchased
from Aldrich was dried over sodium, distilled under reduced pressure, and
◦
˚
stored over 4A molecular sieves. Potassium carbonate was heated to 100 C
under high vacuum overnight prior to use. H and 13C NMR spectra were
1
recorded on a Bruker Avance 500-HMZ spectrometer. Mass spectra were ob-
tained with a Thermo-Finnigan LTQ ESI mass spectrometer. Optical rotations
were measured using an AUTOPOL IV digital polarimeter (Rudolph Research
Analytical, NJ).
Synthesis of Glycosyl Donors
The compounds 3,4,6-tri-O-benzyl-2-deoxy-α/β-D-glucopyranosyl trichlo
roacetimidate[19] were prepared according to the procedures introduced by
Schmidt et al.[20,21]
3,4,6-Tri-O-benzyl-2-deoxy-α-D-glucopyranosyl trichloroacetimidate (1α).
NaH (neat 27 mg, pretreated with anhydrous pentane) was added to a so-
lution of 3,4,6-Tri-O-benzyl-2-deoxyglucopyranose[23] (270 mg, 0.62 mmol, 1.0
eq) and trichloroacetonitrile (0.30 mL, 5.0 eq) in dichloromethane (3 mL) at
rt. After stirring for 1 h, hexanes (6 mL) were added and the reaction mix-
ture was filtered through a plug of aminopropyl silica gel, washed with hex-
anes/dichloromethane (2:1), and concentrated in vacuo to afford 1α (348 mg,
97% yield, α:β = 25:1) possessing spectroscopic data identical with literature
values.
3,4,6-Tri-O-benzyl-2-deoxy-β-D-glucopyranosyl trichloroacetimidate (1β).
Freshly dried potassium carbonate (260 mg) was added to a solution
of 3,4,6-tri-O-benzyl-2-deoxyglucopyranose (226 mg, 0.52 mmol, 1.0 eq) in
dichloromethane (2.6 mL) under ice cooling (3◦C). Then trichloroacetonitrile
(0.13 mL, 2.5 eq) was added to the mixture. After 4 h of stirring at this tem-
perature, hexane (5.2 mL) was added and the mixture was filtered through
a short pad of aminopropyl silica gel, washed with n-hexane/dichloromethane

D. Liu et al.
430
(2:1), and concentrated in vacuo to afford 1β (239 mg, 82% yield, β:α = 7:1) as
a colorless syrup with spectroscopic data identical to literature values.
Typical Glycosylation Procedure
Glycosyl donors and phosphate catalysts were individually dried by co-
evaporation with toluene in vacuo (3×). A solution of the catalyst (10 mol%) in
toluene (0.3 mL) was added dropwise to a solution of glycosyl donor (100 mg,
0.17 mmol) and n-octanol (54 μL, 0.34 mmol) in toluene (1.4 mL) at −40◦C.
The reaction mixture was stirred for the time indicated in the tables, then
quenched with triethylamine (0.2 mL), warmed to rt, and concentrated. The
residue was purified by flash chromatography on silica gel using hexanes/ethyl
acetate (8:1) as eluent. The spectroscopic data of the above isolated product
nn–octyl 3,4,6-tri-O-benzyl-2-deoxy-α/β-D-arabino-hexopyranoside were iden-
tical with literature values.[24]
n-Octyl 3,4,6-tri-O-benzyl-2-deoxy-β-D-arabino-hexopyranoside[24] (4β). 1H
NMR (500 MHz, d6-DMSO): δ = 7.24−7.36 (m, 13 H), 7.18−7.22 (m, 2 H), 4.79
(d, J = 11 Hz, 1 H), 4.65 (d, J = 12 Hz, 1 H), 4.46−4.57 (m, 5 H), 3.69−3.75
(m, 1 H), 3.59−3.69 (m, 3 H), 3.37−3.44 (m, 2 H), 3.30−3.35 (m, 1 H), 2.32 (m,
1 H), 1.50 (m, 2 H), 1.17−1.37 (m, 11 H), 0.85 (t, J = 6.9 Hz, 3 H).
n-Octyl 3,4,6-tri-O-benzyl-2-deoxy-α-D-arabino-hexopyranoside[24] (4α). 1H
NMR (500 MHz, d6-DMSO): δ = 7.24−7.36 (m, 13H), 7.18−7.22 (m, 2H),
4.88 (d, J = 2.4 Hz, 1H), 4.79 (d, J = 11.1 Hz, 1H), 4.63 (d, J = 11.9 Hz,
1H), 4.44−4.56 (m, 4H), 3.75−3.83 (m, 1H), 3.58−3.69 (m, 3H), 3.49−3.56 (m,
1H), 3.35−3.43 (m, 1H), 3.28−3.35 (m, 1H), 2.23 (dd, J = 12.2, 5.1 Hz, 1H),
1.44−1.55 (m, 3H), 1.16−1.31 (m, 10H), 0.83 (t, J = 6.9 Hz, 3H).
Synthesis of Catalyst (S)- and (R)-11
The synthesis of catalyst 11 was carried out according to the route shown
in Scheme 3.
(S or R)-3,3ꢁ-Bis[4-(1-adamantyl)-2,6-diisopropylphenyl]-5,5ꢁ,6,6ꢁ,7,7ꢁ,8,8ꢁ-
octahydro-2,2ꢁ-dimethoxy-1,1ꢁ-binaphthyl (16). tert-Butyl lithium (1.7
M
in pentane, 0.51 mL, 4.2 eq) was slowly added to a solution of (S)-3,3’-
Dibromo-5,5’,6,6’,7,7’,8,8’-octahydro-2,2’-dimethoxy-1,1’-binaphthyl[25,26]
(0.10 g, 0.21 mmol, 1.0 eq) in tetrahydrofuran (1 mL) at −78◦C. After 1 h
of stirring, a solution of ZnBr2 (0.13 g, 2.8 eq) in tetrahydrofuran (0.5 mL)
was added. The reaction was stirred at –78◦C for 20 min, then warmed to
rt. After stirring for an additional hour, the reaction was treated with 4-(1-
adamantyl)-2,6-diisopropylphenyl iodide[27] (0.20 g, 2.3 eq) and Pd(PtBu3)2
and heated to 70◦C for 40 h. The reaction was then cooled to rt, treated with
3 N HCl (10 mL), and extracted with dichloromethane (2 × 20 mL). The
combined organic layers were dried over sodium sulfate and concentrated in
vacuo. Flash chromatography (silica gel, 100% hexanes → 40:1 hexanes/ethyl
acetate) afforded a pale yellow solid mixture (0.12 g) of the title product and

Chiral Brønsted Acid-Catalyzed Glycosylation Reactions
431
Scheme 3: Synthesis of catalysts 11.
mono-coupling side product, which could be used for the next step without
further purification. Analytically pure (S)-product was isolated by flash
chromatography on silica gel using hexanes/dichloromethane (8:1), while the
(R)-enantiomer was not further purified and characterized. mp >297◦C (dec.);
27.5◦C
1
α
= +28 (S, c 1.25, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.16 (d, J
[ ]D
= 1.8 Hz, 2H), 7.15 (d, J = 1.8 Hz, 2H), 6.79 (s, 2H), 3.08 (s, 6H), 2.72−2.87
(m, 8H), 2.38−2.47 (m, 2H), 2.18−2.27 (m, 2H), 2.1 (m, 6H), 1.97 (m, 12H),
1.68−1.85 (m, 20H), 1.19 (d, J = 6.8 Hz, 6H), 1.14 (d, J = 6.6 Hz, 6H), 1.13
(d, J = 6.7 Hz, 6H), 1.12 (d, J = 6.7 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ
= 152.9, 150.0, 146.4, 146.2, 135.4, 133.7, 131.4, 131.3, 130.7, 129.8, 118.9,
118.8, 59.1, 43.3, 37.0, 36.4, 30.8, 30.6, 29.4, 29.2, 27.3, 25.6, 25.4, 23.6,
23.4, 23.3, 23.2. MS (ESI) m/z: calcd for C66H86O2Na [M+Na]+ 933.6, found:
933.4. HRMS (ESI) m/z: calcd for C66H86O2Na [M+Na]+ 933.6520, found
933.6513.
(S or R)-3,3ꢁ-Bis[4-(1-adamantyl)-2,6-diisopropylphenyl]-5,5ꢁ,6,6ꢁ,7,7ꢁ,8,8ꢁ-
octahydro-2,2ꢁ-dihydroxy-1,1ꢁ-binaphthyl (17). The above pale yellow crude
solid (0.11 g) was dissolved in dichloromethane (3 mL), cooled at 0◦C, and
treated with boron tribromide (1 M in dichloromethane, 0.85 mL). After 30 min
the reaction mixture was warmed up to rt and stirred for 21 h. The reac-
tion was then cooled to 0◦C, quenched with water (10 mL), and warmed to

D. Liu et al.
432
rt. The mixture was extracted with dichloromethane (2 × 20 mL), and the
combined organic layers were dried over sodium sulfate, filtered, and con-
centrated in vacuo. Flash chromatography (silica gel, 40:1 hexanes/ethyl ac-
etate → 20:1 hexanes/ethyl acetate) afforded the title product (76 mg, 45%
26.5◦C
yield over two steps). mp >292◦C (dec.); α
α
[ ]D
= +35 (S, c 0.75, CHCl3);
[ ]D
27.7◦C
1
= −33 (R, c 1.3, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.22 (d, J
= 1.8 Hz, 2H), 7.19 (d, J = 1.8 Hz, 2H), 6.83 (s, 2H), 4.40 (s, 2H), 2.72−2.85
(m, 6H), 2.66 (septet, J = 6.8 Hz, 2H), 2.30−2.47 (m, 4H), 2.11 (m, 6H), 1.97
(mc, 12H), 1.70−1.85 (m, 20H), 1.15 (d, J = 6.9 Hz, 6H), 1.11 (d, J = 6.9 Hz,
6H), 1.06 (d, J = 6.9 Hz, 6H), 1.00 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz,
CDCl3): δ = 150.8, 148.5, 147.3, 147.1, 135.8, 131.1, 130.9, 129.0, 124.1,
120.5, 119.3, 119.2, 43.2, 36.9, 36.4, 30.8, 30.7, 29.2, 29.1, 27.0, 24.3, 24.1,
23.9, 23.2, 23.1. MS (ESI) m/z: calcd for C64H82O2Na [M+Na]+ 905.6, found:
905.5. HRMS (ESI) m/z: calcd for C64H82O2Na [M+Na]+ 905.6207, found
905.6228
(S or R)-3,3ꢁ-Bis[4-(1-adamantyl)-2,6-diisopropylphenyl]-5,5ꢁ,6,6ꢁ,7,7ꢁ,8,8ꢁ-
octahydro-1,1ꢁ-binaphthyl phosphate (11). Phosphorous oxychloride (0.14 mL,
4.2 eq) was slowly added to a solution of (S)-3,3ꢁ-bis[4-(1-adamantyl)-2,6-
diisopropylphenylꢁ-5,5ꢁ,6,6ꢁ,7,7ꢁ,8,8ꢁ-octahydro-2,2ꢁ-dihydroxy-1,1ꢁ-binaphthyl
(0.32 g, 0.37 mmol, 1.0 eq) in pyridine (3.6 mL) at rt. The reaction mixture
was then heated to 90◦C for 17 h, then cooled to rt. The reaction was then
treated with water (3.6 mL) and heated to 90◦C for 6 h. After cooling to rt,
the solvent was removed in vacuo, and the residue was partitioned between
dichloromethane (30 mL) and 6 N HCl (10 mL). The aqueous layer was ex-
tracted with dichloromethane (30 mL), and the combined organic layers were
dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (silica gel, 100% dichloromethane → 50:1
dichloromethane/methanol → 20:1 dichloromethane/methanol). The product
was partitioned between dichloromethane (50 mL) and 4 N HCl (10 mL), and
the organic layer was dried over sodium sulfate, filtered, and concentrated
to provide 10 (289 mg, 83% yield) as a pale yellow solid. Analytically pure
compound could be obtained by further flash chromatography on silica gel
using hexanes/ethyl acetate (1:1) and acidifying with 4 N HCl. mp >270◦C
27.2◦C
1
(dec.); α
= +89 (S, c 0.49, CHCl3); −85 (R, c 0.40, CHCl3). H NMR
[ ]D
(500 MHz, CDCl3): δ = 7.04 (d, J = 1.6 Hz, 2H), 7.02 (d, J = 1.6 Hz, 2H),
6.94 (s, 2H), 2.74−2.89 (m, 6H), 2.59 (septet, J = 6.8 Hz, 2H), 2.45−2.57
(m, 2H), 2.27−2.38 (m, 2H), 2.06 (m, 6H), 1.68−1.95 (m, 32H), 1.07 (d, J =
6.7 Hz, 6H), 0.98 (m, 6H), 0.89 (d, J = 6.8 Hz, 6H), 0.79 (m, 6H). 13C NMR
(125 MHz, CDCl3): δ = 150.0, 147.2, 146.6, 144.2 (J = 9.0 Hz), 136.5, 133.8,
132.6, 131.5, 129.6, 126.9, 119.2, 118.3, 43.2, 37.0, 36.3, 30.8, 30.7, 29.3, 29.1,
27.9, 26.7, 25.1, 23.5, 23.0, 22.9. MS (ESI) m/z: calcd for C64H80O4P [M-H]−

Chiral Brønsted Acid-Catalyzed Glycosylation Reactions
433
943.6, found: 943.7. HRMS (ESI) m/z: calcd for C64H80O4P [M-H]− 943.5800,
found 943.5778.
FUNDING
We thank Tufts University and the National Science Foundation (NSF
1300334) for generous financial support.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1. Zhu, X.; Schmidt, R.R. New principles for glycoside-bond formation. Angew. Chem.
Int. Ed. 2009, 48, 1900.
2. Hou, D.; Lowary, T.L. Recent advances in the synthesis of 2-deoxy-glycosides. Car-
bohydr. Res. 2009, 344, 1911.
3. Crich, D. Methodology development and physical organic chemistry: a powerful
combination for the advancement of glycochemistry. J. Org. Chem. 2011, 76, 9193.
4. Borovika, A.; Nagorny, P. Recent advances in the synthesis of natural 2-deoxy-β-
glycosides. J. Carbohydr. Chem. 2013, 31, 255–283.
5. Hashimoto, S.-i.; Sano, A.; Sakamoto, H.; Nakajima, M.; Yanagiya, Y.; Ikegami,
S. An attempt at the direct construction of 2-deoxy-β-glycosidic linkages capitalizing
on 2-deoxyglycopyranosyl diethyl phosphites as glycosyl donors. Synlett 1995, 1271–
1273.
6. Lam, S.N.; Gervay-Hague, J. Efficient route to 2-deoxy β-O-aryl-D-glycosides via
direct displacement of glycosyl iodides. Org. Lett. 2003, 5, 4219–4222.
7. Tanaka, H.; Yoshizawa, A.; Takahashi, T. Direct and stereoselective synthe-
sis of β-linked 2,6-deoxyoligosaccharides. Angew. Chem. Int. Ed. 2007, 46, 2505–
2507.
8. Baryal, K.N.; Adhikari, S.; Zhu, J. Catalytic stereoselective synthesis of β-
digitoxosides: direct synthesis of digitoxin and C1’-epi-digitoxin. J. Org. Chem. 2013,
78, 12469–12476.
9. Zhu, D.; Baryal, K.N.; Adhikari, S.; Zhu, J. Direct synthesis of 2-deoxy-β-glycosides
via anomeric O-alkylation with secondary electrophiles. J. Am. Chem. Soc. 2014, 136,
3172–3175.
10. Nogueira, J.M.; Nguyen, S.N.; Bennett, C.S. Cyclopropenium cation promoted de-
hydrative glycosylations using 2-deoxy- and 2,6-dideoxy-sugars. Org. Lett. 2011, 13,
2814.
11. Nogueira, J.M.; Issa, J.P.; Chu, A.-H.; Sisel, J.A.; Schum, R.S.; Bennett, C.S. Halide
effects on cyclopropenium cation promoted glycosylation with deoxy sugars: highly α-
selective glycosylations using a 3,3-dibromo-1,2-diphenylcyclpropene promoter. Eur. J.
Org. Chem. 2012, 4927–4930.

D. Liu et al.
434
12. Issa, J.P.; Lloyd, D.; Steliotes, E.; Bennett, C.S. Reagent controlled β-specific dehy-
drative glycosylation reactions with 2-deoxy-sugars. Org. Lett. 2013, 15, 4170–4173.
13. Issa, J.P.; Bennett, C.S. A reagent-controlled SN2-glycosylation for the direct syn-
thesis of β-linked 2-deoxy-sugars. J. Am. Chem. Soc. 2014, 136, 5740–5744.
14. Brak, K.; Jacobsen, E.N. Asymmetric ion-pairing catalysis Angew. Chem. Int. Ed.
2013, 52, 534–561.
15. Cox, D.J.; Smith, M.D.; Fairbanks, A.J. Glycosylation catalyzed by a chiral
Brønsted acid. Org. Lett. 2010, 12, 1452.
16. Kimura, T.; Sekine, M.; Takahashi, D.; Toshima, K. Chiral Brønsted acid medi-
ated glycosylation with recognition of alcohol chirality. Angew. Chem. Int. Ed. 2013, 52,
12131–12134.
17. Mensah, E.; Camasso, N.; Kaplan, W.; Nagorny, P. Chiral phosphoric acid directed
regioselective acetalization of carbohydrate-derived 1,2-diols. Angew. Chem. Int. Ed.
2013, 52, 12932–12936.
18. Spijker, N.M.; van Boeckel, C.A.A. Double stereodifferentiation in carbohydrate
coupling reactions: the mismatched interaction of donor and acceptor as an unprece-
dented factor governing the α/β ratio of glycoside formation. Angew. Chem. Int. Ed.
Engl. 1991, 30, 180.
19. Schene, H.; Waldman, H. Synthesis of deoxy glycosides under neutral conditions
in LiClO4/solvent mixtures. Synthesis 1999, 1411.
20. Schmidt, R.R.; Michel, J.; Roos, M. Glycosylimidate, 12 direkte synthese von O-α-
und O-β-glycosylimidaten. Liebigs Ann. Chem. 1984, 1343.
21. Schmidt, R.R.; Stumpp, M. Glycosylimidate, 8. Synthese von 1-thioglycosiden.
Liebigs Ann. Chem. 1983, 1249.
22. Masamune, S.; Choy, W.; Peterson, J.S.; Sita, L.R. Double asymmetric synthesis
and a new strategy for stereochemical control in organic synthesis. Angew. Chem. Int.
Ed. 1985, 24, 1.
23. Barnes, N.J.; Probert, M.A.; Wightman, R.H. Synthesis of 2-deoxy-α- and –β-
arabino-hexopyranosyl phosphonic acids and related compounds. J. Chem. Soc., Perkin
Trans. 1 1996, 431.
24. Rauter, A.P.; Almeida, T.; Vicente, A.I.; Ribeiro, V.; Bordado, J.C.; Marques, J.P.;
Ribeiro, F.R.; Ferreira, M.J.; Oliveira, C.; Guisnet, M. Reactions of N-, S-, and O-
nucleophiles with 3,4,6-tri-O-benzyl-D-glucal mediated by triphenylphosphane hydro-
bromide versus those with HY zeolite. Eur. J. Org. Chem. 2006, 2429.
25. McDougal, N.T.; Trevellini, W.L.; Rodgen, S.A.; Kliman, L.T.; Schaus, S.E. The
development of the asymmetric Morita-Baylis-Hillman reaction catalyzed by chiral
Brønsted acids. Adv. Synth. Catal. 2004, 346, 1231.
26. Schrock, R.R.; Jamieson, J.Y.; Dolman, S.J.; Miller, S.A.; Bonitatebus Jr., P.J.; Hov-
eyda, A.H. New chiral molybdenum catalysts for asymmetric olefin metathesis that
contain 3,3’-disubstituted octahydrobinaphtholare or 2,6- dichlorophenylimido ligands.
Organometallics 2002, 21, 409.
27. Jiao, P.; Nakashima, D.; Yamamoto, H. Enantioselective 1,3-dipolar cycloaddition
of nitrones with ethyl vinyl ether: the difference between Brønsted and Lewis acids.
Angew. Chem. Int. Ed. 2008, 47, 2411.