Facile synthesis of sugar lactols via bromine-mediated oxidation of thioglycosides

Article abstract of DOI:10.1080/07328303.2019.1581889

Synthesis of a variety of sugar lactols (hemiacetals) has been accomplished in moderate to excellent yields by using bromine-mediated oxidation of thioglycosides. It was found that acetonitrile is the optimal solvent for this oxidation reaction. This approach involving bromine as oxidant is superior to that using N-bromosuccinimide (NBS) which produces byproduct succinimide often difficult to separate from the lactol products.

Full text of DOI:10.1080/07328303.2019.1581889

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: https://www.tandfonline.com/loi/lcar20
Facile synthesis of sugar lactols via bromine-
mediated oxidation of thioglycosides
Shuai Meng, Bishwa Raj Bhetuwal, Padam P. Acharya & Jianglong Zhu
To cite this article: Shuai Meng, Bishwa Raj Bhetuwal, Padam P. Acharya & Jianglong Zhu
(2019): Facile synthesis of sugar lactols via bromine-mediated oxidation of thioglycosides, Journal
of Carbohydrate Chemistry, DOI: 10.1080/07328303.2019.1581889
To link to this article: https://doi.org/10.1080/07328303.2019.1581889
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JOURNAL OF CARBOHYDRATE CHEMISTRY
https://doi.org/10.1080/07328303.2019.1581889
Facile synthesis of sugar lactols via bromine-mediated
oxidation of thioglycosides
Shuai Meng, Bishwa Raj Bhetuwal, Padam P. Acharya, and Jianglong Zhu
Department of Chemistry and Biochemistry and School of Green Chemistry and Engineering, The
University of Toledo, Toledo, USA
ABSTRACT
ARTICLE HISTORY
Received 18 December 2018
Accepted 9 February 2019
Synthesis of a variety of sugar lactols (hemiacetals) has been
accomplished in moderate to excellent yields by using brom-
ine-mediated oxidation of thioglycosides. It was found that
acetonitrile is the optimal solvent for this oxidation reaction.
This approach involving bromine as oxidant is superior to that
using N-bromosuccinimide (NBS) which produces byproduct
succinimide often difficult to separate from the lactol prod-
ucts.
KEYWORDS
Bromine; hemiacetals;
oxidation; sugar lactols;
thioglycosides
GRAPHICAL ABSTRACT
Introduction
Glycosyl hydroxides, i.e. sugar lactols or hemiacetals, serve as important
glycosyl donors (1-hydroxy glycosyl donors) and synthetic intermediates
for chemical synthesis of complex biologically significant carbohydrate mol-
ecules.[1–5] Back in 1890s, sugars lactols were first used as glycosyl donors
in the well-known Fischer glycosylation.[6–7] Recently, Gin[8–14] and
Bennett[15–16] reported dehydrative glycosylations using 1-hydroxy glycosyl
donors. In addition, in 1970s Schmidt pioneered the studies of stereoselect-
ive synthesis of oligosaccharides and glycoconjugates via anomeric O-alkyl-
ation of sugar lactols.[17–22] Based on Schmidt’s work, recently our
group[23–27] and others[28–33] resurrected the use of anomeric O-alkylation
for stereoselective construction of challenging glycosidic linkages.
Specifically, our group disclosed stereoselective synthesis of several classes
of challenging glycosides via anomeric O-alkylation of the corresponding
CONTACT Jianglong Zhu
Jianglong.Zhu@Utoledo.edu
Department of Chemistry and Biochemistry and
School of Green Chemistry and Engineering, The University of Toledo, 2801 W. Bancroft Street, Toledo, Ohio
43606, USA
ß 2019 Taylor & Francis Group, LLC

2
S. MENG ET AL.
Scheme 1. Representative strategies for preparation of sugar lactols.
sugar hemiacetals, e.g. 2-deoxy-b-glycosides,[23–24] 2-deoxy-a-glycosides,[25]
as well as b-mannosides.[26–27] Furthermore, sugar hemiacetals are used as
precursors for the preparation of commonly used glycosyl donors, e.g. tri-
chloroacetimidates,[34] N-(phenyl)trifluoroacetimidates,[35] phosphites and
phosphates,[36–37] or ortho-alkynylbenzoates,[38] carbonates,[39–42] sulfo-
nates,[43–44] and glycosyl esters.[45–46]
Typically, lactols (2) are obtained by methanolysis of glycosyl esters (1,
X ¼ OCOR),[47–48] hydrolysis of glycosyl halides (1, X ¼ halides)[49–50] or
methyl glycosides (1, X ¼ OMe),[51] or oxidation of thioglycosides (3)[52–53]
(a and b, Sch. 1). Among those methods, oxidation of readily available and
stable thioglycosides (3) to lactols is one of the most popular strategies for
preparation of sugar hemiacetals and N-bromosuccinimide (NBS) is usually
employed as the oxidant (b, Sch. 1). Despite its mild nature, the reaction
employing NBS generates the byproduct succinimide which oftentimes is
difficult to separate from the desired lactol products, especially when the
lactols become quite polar. Therefore, our group has been searching for
alternative oxidant to facilitate the purification process.
Bromine is often used to oxidize thioglycosides to the corresponding
glycosyl bromide donors for the synthesis of various oligosaccharides and
glycoconjugates.[54–57] In addition, there was limited report that sugar hem-
iacetals can be prepared by bromine-mediated oxidation of thioglycosides
via a two-step sequence: 1) bromine-mediated oxidation of thioglycosides
in dry dichloromethane to the corresponding glycosyl bromide; 2) hydroly-
sis of isolated glycosyl bromide.[58] Use of bromine as oxidant is

JOURNAL OF CARBOHYDRATE CHEMISTRY
3
advantageous as it can avoid the production of difficultly separable byprod-
ucts. However, this two-step procedure may not be suitable for carbohy-
drate substrates containing acid-sensitive protecting groups or free
hydroxyl groups. We wondered if it is possible to develop a one-pot oxida-
tion/hydrolysis under suitable conditions for the preparation of sugar hemi-
acetals from thioglycosides using bromine as the oxidant. In this
Communication, we wish to report the facile synthesis of sugar lactols via
bromine-mediated oxidation of thioglycosides in a mixture of acetonitrile
and water (c, Sch. 1).
Results and Discussion
Phenyl 3,4,6-tri-O-benzyl-1-thio-a-D-mannopyranoside (4, Table 1) was
chosen as the substrate for preparing 3,4,6-tri-O-benzyl-D-mannose 5
under bromine-mediated oxidation. It is worth noting that a stock solution
of bromine in dichloromethane (5.0 M) was prepared for use instead of
pure bromine due to easy handling and safety concerns.[59] Initially, we
used a mixture of acetone and water (10/1, v/v), the solvent system for
NBS-mediated oxidation of thioglycosides, for bromine-mediated oxidation.
This reaction was sluggish at 0 ꢀC and took 24 hours to complete and 3,4,6-
tri-O-benzyl-D-mannose 5 was isolated in 83% yield (a/b ¼ 3/1, entry 1,
Table 1). The slow reaction rate may be due to that Br2 is also able to
a–brominate acetone, which competes with the oxidation of thioglycosides.
Addition of bromine solution at lower temperature followed by warming
up to 0 ꢀC did not help (entry 2). Switching to dichloromethane, the
Table 1. Synthesis of 3,4,6-tri-O-benzyl-D-mannose by bromine-mediated oxidation of corre-
sponding thioglycoside.a
Entry
Solvent/Temp/Timeb
Yield,c a/b ratiod
83%, 3/1
79%, 4/1
trace
1
2
3
4
5
6
7
8
acetone/H2O (10/1, v/v), 0 oC, 24 h
acetone/H2O (10/1, v/v), ꢁ30 to 0 oC, 26 h
CH2Cl2/H2O (10/1, v/v), ꢁ30 to 0 oC, 3.5 h
CH2Cl2/H2O (10/1, v/v), 0 oC, 3 h
trace
THF/H2O (10/1, v/v), 0 oC, 12 h
81%, 4/1
CH3CN/H2O (10/1, v/v), 0 oC, 2 h
97% (98%,e 91%f), 4/1
Br2, CH2Cl2,
0
oC, 0.5 h; then acetone/H2O (4/1, v/v), RT, 2 hg
34%
82%
NBS (3.0 eq.), acetone/H2O (10/1, v/v), 0 oC, 2 h
aAll reactions were performed using 0.1 mmol of phenyl 3,4,6-tri-O-benzyl-1-thio-D-mannopyranoside 4 (1.0 eq.)
and 60 mL of 5.0 M Br2 in CH2Cl2 (3.0 eq.) in 0.5 mL organic solvent and 50 mL H2O unless otherwise noted;
bWhen TLC showed the substrate was completely consumed; cIsolated yield; dDetermined by 1H NMR;
f
eIsolated yield obtained on 0.2 mmol scale. Isolated yield on a 1 gram scale. gsee reference 58.

4
S. MENG ET AL.
solvent used for preparation of glycosyl bromide by bromine oxidation of
thioglycosides, did not work well and complex mixtures were obtained
(entries 3 and 4). Use of THF as solvent gave similar results as acetone,
albeit the reaction was found to be a little faster (entry 5). Finally, we
found acetonitrile was the optimal solvent for this reaction which was com-
plete in two hours and gave almost quantitative yield of the corresponding
lactol 5 (entry 6). The method was also applied to 0.2 mmol and 1 gram
scale of thioglycoside 4 which furnished the desired lactol 5 in 98% and
91% yield, respectively (entry 6). Application of previously reported two-
step procedure for this oxidation–hydrolysis only gave 34% yield of the lac-
tol 5 (entry 7). In comparison, use of NBS as the oxidant instead of brom-
ine afforded lactol 5 in 82% yield (entry 8).
With the optimal condition established, the bromine-mediated oxidation
of thioglycosides was applied to the synthesis of a variety of sugar hemiace-
tals (Table 2). In general, sugar hemiacetals were obtained in good to excel-
lent yields. It was also found that both aryl (e.g. phenyl) and alkyl (e.g.
ethyl) thioglycosides can be oxidized smoothly to afford the corresponding
lactols in good yields (entry 1). Various functional groups, such as carba-
mate, amide, imide, azide, and carboxylic ester, are tolerated. For thioglyco-
sides containing acid-sensitive protecting groups, such as silyl ethers (entry
2), benzylidene acetals (entries 10-12), and 1,2-diketals (entry 13), solid
sodium bicarbonate needs to be added to buffer the acidity of the reaction
in order to achieve good yields. Interestingly, methoxyethoxymethyl
(MEM) ether was found to be stable in this type of reaction and no sodium
bicarbonate was added necessarily (entry 9). Obviously, deoxy sugars, such
as 6-deoxy and 2,6-dideoxy sugars, are very reactive substrates towards
bromine oxidation (entries 2-4). Sugar substrates with acyl protecting
groups, i.e. “disarmed donors”, including thioglycoside of peracetylated
N-acetyl neuraminic acid (18), D-mannose-derived thioglycoside (30) and
phenyl 2,3,4,6-tetra-O-acetyl-1-thio-b-glucopyranoside (32), were found to
be relatively unreactive and produced corresponding hemiacetals in moder-
ate yields, probably due to the inductive effect. Allowing the reaction to
proceed for an additional period of time or adding more Br2 did not help,
probably due to the decomposition of the starting materials or lactols over
time (entries 7, 13 and 14).
In conclusion, an approach for the synthesis of sugar hemiacetals has
been developed via bromine-mediated oxidation of thioglycosides in a mix-
ture of acetonitrile/water. Various functional groups and protecting groups
are tolerated and a wide range of sugar lactols were obtained in moderate
to excellent yields. This method is advantageous as it avoids the production
of byproducts difficult to separate.

JOURNAL OF CARBOHYDRATE CHEMISTRY
5
Table 2. Synthesis of various sugar lactols by bromine-mediated oxidation of thioglycosides.a
Yield,b α/β ratio,c
Entry
1
Thioglycosides
Lactols
Reaction Condition,
Time
84%, 2/1 from 6a, A, 2 h;
86%, 2/1 from 6b, A, 2 h
2
3
95%, 1.4/1, B, 1 h
90%, 1/1, A, 2 h
4
93%, 2/1, A, 2 h
94%, α only, A, 2 h
5
6
84%, 2.5/1, A, 2 h
66%,d 1/10, A, 12 h;
63%, e 1/10, A, 12 h
7
8
75%, 10/1, A, 4 h
(continued)

6
S. MENG ET AL.
9
81%, 2.5/1, A, 3 h
15%, 2/1, A, 2 h;
72%, 2/1, B, 3 h
10
11
12
64%, β only, B, 5 h
61%, 1.4/1, B, 5 h
60%,f >20/1, B, 18 h;
, g, >20/1, B, 36 h;
59%h
13
20%,i 4/1, 2 h;
38%,j 4/1, 12 h
14
15
86%, 2/1, 3 h
aAll reactions were performed using 0.2 mmol of thioglycosides (1.0 eq.) and 120 mL of 5.0 M Br2 in CH2Cl2 (3.0
eq.) in 1 mL acetonitrile and 0.1 mL H2O at 0 ꢀC; bIsolated yield; cDetermined by 1H NMR; d29% of starting
f
material was recovered; e4.5 eq. of bromine was used. Trace amount of starting material was recovered; 31%
of starting material was recovered; gThe reaction was stirred for 36 hours and 24% of starting material was
recovered; hNBS (3.0 eq.) was used and the reaction was stirred for 18 hours and 29% of starting material was
i
j
recovered; 64% of starting material was recovered; 24% of starting material was recovered.
Experimental
Materials and Methods
Proton and carbon nuclear magnetic resonance spectra (1H NMR and 13C
NMR) were recorded on either Bruker 600 (1H NMR-600 MHz; 13C NMR
150) or INOVA 600 (1H NMR-600 MHz; 13C NMR-150 MHz) at ambient
temperature with CDCl3 as the solvent unless otherwise stated. Chemical
shifts are reported in parts per million relative to residual protic solvent

JOURNAL OF CARBOHYDRATE CHEMISTRY
7
1
internal standard CDCl3: H NMR at d 7.26, 13C NMR at d 77.16. Data for
1H NMR are reported as follows: chemical shift, integration, multiplicity
(app ¼ apparent, par obsc ¼ partially obscure, ovrlp ¼ overlapping,
s ¼ singlet, d ¼ doublet, dd ¼ doublet of doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet) and coupling constants in Hertz. All 13C NMR spectra were
recorded with complete proton decoupling. High resolution mass spectra
(HRMS) were acquired on a Waters Acuity Premiere XE TOF LC-MS by
electrospray ionization. Optical rotations were measured with Autopol-IV
digital polarimeter; concentrations are expressed as g/100 mL.
All reagents and chemicals were purchased from Acros Organics, Sigma
Aldrich, Fisher Scientific, Alfa Aesar, and Strem Chemicals and used with-
out further purification. THF, methylene chloride, toluene, and diethyl
ether were purified by passing through two packed columns of neutral alu-
mina (Innovative Technology). Anhydrous DMF and benzene were pur-
chased from Acros Organics and Sigma-Aldrich and used without further
drying. All reactions were carried out in oven-dried glassware under an
argon atmosphere unless otherwise noted. Analytical thin layer chromatog-
raphy was performed using 0.25 mm silica gel 60-F plates. Flash column
chromatography was performed using 200-400 mesh silica gel (Scientific
Absorbents, Inc.). Yields refer to chromatographically and spectroscopically
pure materials, unless otherwise stated.
General procedure for synthesis of sugar lactols by bromine-mediated
oxidation of thioglycosides
General procedure A
Thioglycosides (0.2 mmol) were dissolved by 1.0 mL acetonitrile in a 10 mL
flask, followed by the addition of 0.1 mL water. The mixture was stirred at
0 ꢀC for 30 min. 120 mL of Br2 (3.0 eq.) solution in CH2Cl2 (5.0 M) was
added dropwise and then the yellow mixture was stirred at this temperature
until the TLC showed that the substrate was completely consumed. Then
the mixture was diluted by 5 mL saturated NaHCO3 aqueous solution and
evaporated under reduced pressure to remove acetonitrile. The residue was
extracted by CH2Cl2 (10 mL ꢂ 3, for lactol 11 10% n-butanol was used
together). The organic layers were combined and dried over anhydrous
Na2SO4. The filtrate was concentrated and purified by flash column chro-
matography to give the desired lactols.
General procedure B
Thioglycosides (0.2 mmol) were dissolved by 1.0 mL acetonitrile in a 10 mL
flask, followed by the addition of 0.1 mL water and 168 mg of NaHCO3
(10.0 eq.). The mixture was stirred at 0 ꢀC for 30 min. 120 mL of Br2

8
S. MENG ET AL.
(3.0 eq.) solution in CH2Cl2 (5.0 M) was added dropwise and then the yel-
low mixture was stirred at this temperature until the TLC showed that the
substrate was completely consumed. Then the mixture was diluted by 5 mL
saturated NaHCO3 aqueous solution and evaporated under reduced pres-
sure to remove acetonitrile. The residue was extracted by CH2Cl2 (10 mL ꢂ
3). The organic layers were combined and dried over anhydrous Na2SO4.
The filtrate was concentrated and purified by flash column chromatography
to give the desired lactol.
3,4,6-Tri-O-benzyl-a/b-D-mannopyranose (5). Lactol 5 was prepared from thi-
oglycoside 4[60] (109 mg, 0.201 mmol) following the general procedure A.
The crude reaction mixture was purified by flash column chromatography
(Hexanes/EtOAc ¼ 2/1 to CH2Cl2/MeOH ¼ 15/1) to give 88.8 mg
1
(0.197 mmol, 98%) of lactol 5 (a/b ¼ 4/1) as colorless syrup. H and 13C
NMR data of 5 were in agreement with reported ones.[61]
2,3,4,6-Tetra-O-benzyl-a/b-D-glucopyranose (7). Lactol 7 was prepared from
thioglycoside 6[62] (127 mg, 0.201 mmol) following the general procedure A.
The crude reaction mixture was purified by flash column chromatography
(Hexanes/EtOAc ¼ 5/1 to CH2Cl2/MeOH ¼ 20/1) to give 90.8 mg
1
(0.168 mmol, 84%) of lactol 7 (a/b ¼ 2/1) as white solids. H and 13C
NMR data of 7 were in agreement with reported ones.[63]
3,4-Di-O-tert-butyldimethylsilyl-2,6-dideoxy-a/b-D-glucopyranose (9). Lactol 9
was prepared from thioglycoside 8[64] (93.7 mg, 0.2 mmol) following the
general procedure B. The crude reaction mixture was purified by flash col-
umn chromatography (Hexanes/EtOAc ¼ 35/1) to give 71.5 mg (0.19 mmol,
23
95%) of lactol 9 (a/b ¼ 1.4/1) as colorless syrup. ½aꢃD ¼ þ61.5 (c 0.1,
1
CHCl3). H NMR (600 MHz, CDCl3) d 5.28 (d, J ¼ 2.9 Hz, 1H), 4.85 (ddd,
J ¼ 8.8, 6.1, 2.2 Hz, 0.6H), 4.01 (ddd, J ¼ 10.5, 7.6, 4.4 Hz, 1H), 3.89 (dq,
J ¼ 8.5, 6.5 Hz, 1H), 3.69 (dddd, J ¼ 10.8, 7.8, 4.6, 1.0 Hz, 0.6H), 3.41 (d,
J ¼ 6.7 Hz, 0.6H), 3.37 – 3.28 (m, 0.6H), 3.26 – 3.11 (m, 1.6H), 2.81 – 2.60
(m, 1H), 2.24 (ddd, J ¼ 12.8, 4.7, 2.2 Hz, 0.6H), 2.16 – 2.01 (m, 1H), 1.68
(ddd, J ¼ 13.6, 10.2, 3.6 Hz, 1H), 1.62 – 1.52 (m, 0.6H), 1.31 (d, J ¼ 6.4 Hz,
1.8H), 1.26 (d, J ¼ 6.5 Hz, 3H), 0.97 – 0.86 (m, 29H), 0.17 – 0.02 (m, 19H).
13C NMR (150 MHz, CDCl3) d 93.66, 91.60, 77.90, 77.44, 73.06, 72.86,
70.44, 69.90, 41.82, 39.27, 26.40, 26.37, 26.22, 19.10, 18.78, 18.44, 18.42,
18.22, 18.19, -2.69, -2.79, -2.97, -3.15, -3.81, -3.93, -4.12, -4.26. ESIHRMS
calculated for C18H40O4Si2Na [M þ Na]þ 399.2363, found 399.2363.
2-O-Methyl-4-O-benzyl-6-deoxy-a/b-D-allopyranose (11). Lactol 11 was pre-
pared from thioglycoside 10[64] (69.7 mg, 0.194 mmol) following the general

JOURNAL OF CARBOHYDRATE CHEMISTRY
9
procedure A. The crude reaction mixture was purified by flash column
chromatography (CH2Cl2/MeOH ¼ 10/1) to give 46.9 mg (0.175 mmol,
23
90%) of lactol 11 (a/b ¼ 1/1) as colorless syrup. ½aꢃD ¼ þ128.5 (c 0.1,
1
CHCl3). H NMR (600 MHz, CDCl3) d 7.38 – 7.27 (m, 10H), 5.18 (s, 2H),
4.96 (dd, J ¼ 7.9, 3.6 Hz, 1H), 4.68 – 4.64 (m, 2H), 4.55 – 4.51 (m, 2H),
4.45 (m, 1H), 4.39 (t, J ¼ 2.9 Hz, 1H), 4.19 (s, 1H), 4.08 (m, 1H), 3.89 (m,
1H), 3.51 (s, 3H), 3.47 (s, 3H), 3.27 (s, 1H), 3.18 (m, 1H), 3.10 – 3.06 (m,
2H), 2.95 (dd, J ¼ 7.8, 2.9 Hz, 1H), 2.58 (s, 1H), 1.28 (d, J ¼ 6.2 Hz, 3H),
1.26 (d, J ¼ 6.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 137.48, 137.23,
128.70, 128.60, 128.33, 128.14, 128.08, 128.02, 93.68, 91.61, 81.15, 79.87,
79.43, 76.27, 71.52, 71.46, 68.27, 67.53, 65.44, 61.28, 58.16, 56.72, 17.91,
17.76. ESIHRMS calculated for C14H20O5Na [M þ Na]þ 291.1208,
found 291.1213.
2,3,4-Tri-O-benzyl-6-deoxy-a/b-L-galactopyranose (13). Lactol 13 was prepared
from thioglycoside 12[65] (108.9 mg, 0.201 mmol) following the general pro-
cedure A. The crude reaction mixture was purified by flash column chro-
matography (Hexanes/EtOAc ¼ 2/1) to give 78.7 mg (0.181 mmol, 90%) of
1
lactol 13 (a/b ¼ 2/1) as colorless syrup. H and 13C NMR data of 13 were
in agreement with reported ones.[66]
2-N-(Benzyloxy)carbonyl-3,4,6-tri-O-benzyl-2-deoxy-2-amino-a-D-mannopyra-
nose (15). Lactol 15 was prepared from thioglycoside 14 (134.4 mg,
0.199 mmol) following the general procedure A. The crude reaction mixture
was purified by flash column chromatography (Hexanes/EtOAc ¼ 3/1 to 1/
1) to give 109.4 mg (0.187 mmol, 94%) of lactol 15 (a only) as white solids.
23
1
½aꢃD ¼ þ89.0 (c 0.1, CHCl3). H NMR (600 MHz, CDCl3) d 7.40 – 7.28
(m, 18H), 7.16 (dd, J ¼ 7.0, 2.3 Hz, 2H), 5.34 – 5.28 (m, 1H), 5.26 (d,
J ¼ 8.8 Hz, 1H), 5.15 (s, 2H), 4.87 (d, J ¼ 10.8 Hz, 1H), 4.79 (d, J ¼ 11.0 Hz,
1H), 4.59 (d, J ¼ 12.2 Hz, 1H), 4.52 (d, J ¼ 11.1 Hz, 1H), 4.47 (d,
J ¼ 12.2 Hz, 1H), 4.45 – 4.38 (m, 2H), 4.18 (d, J ¼ 3.9 Hz, 1H), 4.14 (dd,
J ¼ 9.4, 4.5 Hz, 1H), 4.06 (ddd, J ¼ 9.9, 4.8, 2.1 Hz, 1H), 3.66 (dd, J ¼ 10.5,
4.8 Hz, 1H), 3.62 (dd, J ¼ 10.4, 2.3 Hz, 1H), 3.56 (t, J ¼ 9.6 Hz, 1H). 13C
NMR (150 MHz, CDCl3) d 156.55, 138.24, 138.04, 137.63, 136.29, 128.63,
128.50, 128.44, 128.40, 128.29, 128.26, 128.24, 128.19, 128.02, 127.90,
127.76, 93.83, 77.47, 75.15, 74.29, 73.44, 71.20, 70.31, 68.85, 67.12, 51.54.
ESIHRMS
found 606.2469.
calculated
for
C35H37NO7Na
[M þ Na]þ
606.2468,
2-N-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-amino-a/b-D-mannopyranose
(17).
Lactol 17 was prepared from thioglycoside 16[67] (116.6 mg, 0.2 mmol) fol-
lowing the general procedure A. The crude reaction mixture was purified

10
S. MENG ET AL.
by flash column chromatography (CH2Cl2/MeOH ¼ 100/1) to give 84.4 mg
1
(0.167 mmol, 84%) of lactol 17 (a/b ¼ 2.5/1) as white solid. H and 13C
NMR data of 17 were in agreement with reported ones.[68]
Methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-acetamido-a/b-D-glycero-D-galacto-
2-nonulopyranosonate (19). Lactol 19 was prepared from thioglycoside 18[69]
(118.0 mg, 0.202 mmol) following the general procedure A. The crude reac-
tion mixture was purified by flash column chromatography (Hexanes/
Acetone ¼ 3/2) to give 65.0 mg (0.132 mmol, 65%) of lactol 19 (a/b ¼ 1/
1
10) as white solids with 34.2 mg (29%) of thioglycoside 18 recovered. H
and 13C NMR data of 19 were in agreement with reported ones.[70]
Benzyl (3,4-di-O-benzyl-a/b-D-mannopyranose) uronate (21). Lactol 21 was
prepared from thioglycoside 20 (106.3 mg, 0.191 mmol) following the gen-
eral procedure A. The crude reaction mixture was purified by flash column
chromatography (Hexanes/EtOAc ¼ 2/1 to CH2Cl2/MeOH ¼ 15/1) to give
66.5 mg (0.143 mmol, 75%) of lactol 21 (a/b ¼ 10/1) as white solids.
23
1
½aꢃD ¼ þ35.3 (c 0.1, CHCl3). H NMR (600 MHz, CDCl3) d 7.34 – 7.25
(m, 15H), 7.23 – 7.20 (m, 2H), 5.38 (t, J ¼ 4.1 Hz, 1H), 5.17 (d, J ¼ 12.1 Hz,
0.1H), 5.12 (d, J ¼ 12.1 Hz, 1H), 5.04 (d, J ¼ 12.2 Hz, 1H), 4.83 (d,
J ¼ 9.8 Hz, 0.1H), 4.71 (d, J ¼ 11.0 Hz, 0.1H), 4.68 (d, J ¼ 11.2 Hz, 1H), 4.66
– 4.61 (m, 0.2H), 4.58 – 4.55 (m, 3H), 4.52 (d, J ¼ 6.8 Hz, 1H), 4.44 (t,
J ¼ 10.5 Hz, 0.1H), 4.15 (t, J ¼ 7.0 Hz, 1H), 4.10 (t, J ¼ 8.1 Hz, 0.1H), 4.05
(d, J ¼ 8.0 Hz, 0.1H), 4.00 (s, 0.1H), 3.95 (t, J ¼ 3.7 Hz, 1H), 3.92 (dd,
J ¼ 7.1, 3.2 Hz, 1H), 3.65 (d, J ¼ 4.7 Hz, 1H), 2.63 (d, J ¼ 5.4 Hz, 1H). 13C
NMR (150 MHz, CDCl3) d 169.60, 169.43, 137.82, 137.74, 137.62, 137.39,
135.19, 135.03, 128.74, 128.72, 128.70, 128.67, 128.64, 128.54, 128.49,
128.25, 128.11, 127.99, 127.97, 127.91, 127.89, 94.43, 93.82, 79.86, 78.21,
75.42, 75.30, 74.57, 74.33, 74.03, 72.50, 72.42, 72.11, 68.94, 67.93, 67.64,
67.37. ESIHRMS calculated for C27H28O7Na [M þ Na]þ 487.1733,
found 487.1732.
3,4-Di-O-benzyl-6-O-(methoxyethoxy)methyl-a/b-D-mannopyranose (23). Lactol
23 was prepared from thioglycoside 22 (109.8 mg, 0.203 mmol) following
the general procedure A. The crude reaction mixture was purified by flash
column chromatography (Hexanes/EtOAc ¼ 1/1 to CH2Cl2/MeOH ¼ 15/1)
to give 74.1 mg (0.165 mmol, 81%) of lactol 23 (a/b ¼ 2.5/1) as colorless
23
1
syrup. ½aꢃD ¼ þ91.0 (c 0.1, CHCl3). H NMR (600 MHz, CDCl3) d 7.39 –
7.27 (m, 14H), 5.27 (d, J ¼ 1.7 Hz, 1H), 4.92 (d, J ¼ 10.9 Hz, 0.4H), 4.89 (d,
J ¼ 11.0 Hz, 1H), 4.77 – 4.66 (m, 6.4H), 4.63 (d, J ¼ 10.9 Hz, 0.4H), 4.59 (d,
J ¼ 11.0 Hz, 1H), 4.11 (ddd, J ¼ 9.3, 6.7, 2.1 Hz, 1H), 4.06 (dd, J ¼ 3.3,

JOURNAL OF CARBOHYDRATE CHEMISTRY
11
1.8 Hz, 2H), 4.01 (dd, J ¼ 3.3, 1.2 Hz, 0.4H), 3.97 (dd, J ¼ 9.1, 3.2 Hz, 1H),
3.87 – 3.59 (m, 8H), 3.56 – 3.49 (m, 3H), 3.43 (ddd, J ¼ 9.8, 4.7, 2.3 Hz,
0.4H), 3.35 (d, J ¼ 5.7 Hz, 4.2H). 13C NMR (150 MHz, CDCl3) d 138.34,
138.24, 137.94, 137.72, 128.66, 128.63, 128.53, 128.49, 128.12, 128.03,
127.98, 127.96, 127.92, 127.91, 127.82, 96.32, 96.17, 94.21, 93.88, 81.73,
79.84, 75.19, 75.13, 74.92, 74.46, 73.99, 72.04, 71.93, 71.80, 70.59, 68.97,
68.64, 68.33, 67.16, 67.10, 67.08, 59.07, 59.04. ESIHRMS calculated for
C27H32O8Na [M þ Na]þ 471.1995, found 471.1978.
3-O-Benzyl-4,6-O-[(R)-phenylmethylene]-a/b-D-mannopyranose (25). Lactol 25
was prepared from thioglycoside 24[71] (91.4 mg, 0.203 mmol) following the
general procedure B. The crude reaction mixture was purified by flash col-
umn chromatography (Hexanes/Acetone ¼ 2/1 to CH2Cl2/MeOH ¼ 20/1)
to give 52.3 mg (0.146 mmol, 72%) of lactol 25 (a/b ¼ 2/1) as colorless
syrup. 1H and 13C NMR data of 25 were in agreement with
reported ones.[26]
3-O-Benzyl-4,6-O-[(R)-phenylmethylene]-2-deoxy-2-phthalimido-b-D-glucopyra-
nose (27). Lactol 27 was prepared from thioglycoside 26[72] (113.6 mg,
0.196 mmol) following the general procedure B. The crude reaction mixture
was purified by flash column chromatography (Hexanes/Acetone ¼ 4/1 to
1/1) to give 61.2 mg (0.126 mmol, 64%) of lactol 27 (b only) as white solids.
1H and 13C NMR data of 27 were in agreement with reported ones.[73]
3-O-Benzyl-4,6-O-[(R)-phenylmethylene]-2-deoxy-2-azido-a/b-D-mannopyranose
(29). Lactol 29 was prepared from thioglycoside 28[74] (95 mg, 0.2 mmol)
following the general procedure B. The crude reaction mixture was purified
by flash column chromatography (Hexanes/EtOAc ¼ 7/1) to give 47 mg
23
(0.122 mmol, 61%) of lactol 29 (a/b ¼ 1.4/1) as colorless syrup. ½aꢃD
¼
1
þ34.0 (c 0.1, CHCl3). H NMR (600 MHz, CDCl3) d 7.49 (ddd, J ¼ 7.3,
3.8, 1.8 Hz, 3H), 7.43 – 7.27 (m, 14H), 5.63 (s, 1H), 5.61 (s, 0.7H), 5.17
(dd, J ¼ 3.4, 1.5 Hz, 1H), 4.95 – 4.90 (m, 1.7H), 4.80 – 4.71 (m, 2.4H), 4.32
(dd, J ¼ 10.5, 4.9 Hz, 0.7H), 4.23 (dd, J ¼ 10.3, 4.9 Hz, 1H), 4.19 (dd, J ¼ 9.7,
3.7 Hz, 1H), 4.13 (t, J ¼ 9.5 Hz, 1H), 4.08 – 4.00 (m, 3.5H), 3.87 (dd,
J ¼ 9.6, 3.7 Hz, 0.7H), 3.82 (td, J ¼ 10.3, 2.2 Hz, 1.7H), 3.60 (d, J ¼ 11.7 Hz,
0.7H), 3.36 (td, J ¼ 9.7, 4.9 Hz, 0.7H), 2.78 (d, J ¼ 3.5 Hz, 1H). 13C NMR
(150 MHz, CDCl3) d 138.11, 137.76, 137.47, 137.29, 129.19, 129.11, 128.67,
128.56, 128.41, 128.37, 128.13, 127.90, 127.78, 127.66, 126.17, 126.12,
101.75, 101.67, 94.15, 93.28, 79.28, 78.61, 77.57, 75.29, 73.50, 73.45, 68.83,
68.50, 67.13, 65.09, 64.07, 62.99. ESIHRMS calculated for C20H21N3O5Na
[M þ Na]þ 406.1379, found 406.1379.

12
S. MENG ET AL.
2,6-Di-O-benzoyl-3,4-O-[(1S,2S)-1,2-dimethoxy-1,2-dimethyl-1,2-ethanediyl]-
a/b-D-mannopyranose (31). Lactol 31 was prepared from thioglycoside 30
(119.3 mg, 0.201 mmol) following the general procedure B. The crude reac-
tion mixture was purified by flash column chromatography (Hexanes/
EtOAc ¼ 4/1 to 1/1) to give 60.9 mg (0.121 mmol, 60%) of lactol 31 (a/b
> 20/1) as colorless syrup with 37.1 mg (31%) of thioglycoside 30 recov-
23
1
ered. ½aꢃD ¼ þ123.5 (c 0.1, CHCl3). H NMR (600 MHz, CDCl3) d 8.08 –
8.02 (m, 4H), 7.60 – 7.52 (m, 2H), 7.38 (q, J ¼ 7.7 Hz, 4H), 5.39 (dd,
J ¼ 4.0, 1.6 Hz, 1H), 5.34 (dd, J ¼ 3.0, 1.7 Hz, 1H), 4.62 (dd, J ¼ 12.0, 2.2 Hz,
1H), 4.56 (dd, J ¼ 12.0, 3.5 Hz, 1H), 4.48 (t, J ¼ 10.2 Hz, 1H), 4.38 (dd,
J ¼ 10.3, 3.0 Hz, 1H), 4.34 (dt, J ¼ 10.0, 2.8 Hz, 1H), 3.69 (dd, J ¼ 4.0,
1.6 Hz, 1H), 3.29 (s, 3H), 3.19 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H). 13C NMR
(150 MHz, CDCl3) d 166.59, 166.10, 133.23, 133.21, 130.27, 130.06, 129.97,
129.75, 128.51, 128.49, 100.39, 100.10, 92.98, 71.56, 68.99, 65.86, 63.48,
62.67, 48.28, 48.05, 17.86, 17.76. ESIHRMS calculated for C26H20O10Na
[M þ Na]þ 525.1737, found 525.1743.
2,3,4,6-Tetra-O-acetyl-a/b-D-glucopyranose (33). Lactol 33 was prepared from
thioglycoside 32[75] (88.6 mg, 0.201 mmol) following the general procedure
A. The crude reaction mixture was purified by flash column chromatog-
raphy (Hexanes/Acetone ¼ 2/1) to give 26.9 mg (0.077 mmol, 38%) of lactol
33 (a/b ¼ 4/1) as colorless syrup with 21.3 mg (24%) of thioglycoside 32
recovered. 1H and 13C NMR data of 33 were in agreement with
reported ones.[76]
2,3,6-Tri-O-benzyl-4-O-(2,3,4,6-tetra-O-beznyl-b-D-galactopyranosyl)-a/b-D-glu-
copyranose (35). Lactol 35 was prepared from thioglycoside 34[77] (207.0 mg,
0.194 mmol) following the general procedure A. The crude reaction mixture
was purified by flash column chromatography (Hexanes/EtOAc ¼ 3/1) to
give 163.0 mg (0.167 mmol, 86%) of lactol 35 (a/b ¼ 2/1) as white solids.
1H and 13C NMR data of 35 were in agreement with reported ones.[78]
Funding
We are grateful to National Science Foundation [CHE-1464787], National Institutes of
Health Common Fund Glycosciences Program [1U01GM125289]; NIH Office of the
Director; and The University of Toledo for supporting this research.
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