Synthesis of glycosylthiols and reactivity studies

Article abstract of DOI:10.1021/jo200624e

The acid-catalyzed reaction of 1,2-anhydro-3,4,6-tri-O-benzyl-α-d- glucopyranose (7) as glycosyl donor with bis-trimethylsilyl sulfide as acceptor affords the α-thiol. Hence, this sterically hindered S-nucleophile as acceptor should provide with O-glycosyl trichloroacetimidates as glycosyl donors that have nonparticipating groups at C-2, glycosylthiols with the thiol group in axial position. This was confirmed for various donors (4, 16-19) with the exception of the corresponding mannosyl donor (20). However, powerful participating groups at C-2 of the donor (23-28) governed the anomeric selectivity.

Full text of DOI:10.1021/jo200624e

NOTE
pubs.acs.org/joc
Synthesis of Glycosylthiols and Reactivity Studies
Ravindra T. Dere,† Amit Kumar,† Vipin Kumar,† Xiangming Zhu,*,‡ and Richard R. Schmidt*,†
†Fachbereich Chemie, Universit€at Konstanz, Fach 725, D-78457 Konstanz, Germany
‡College of Chemistry & Life Sciences, Zhejiang Normal University, Jinhua 321004, Zhejiang, China
S Supporting Information
b
ABSTRACT: The acid-catalyzed reaction of 1,2-anhydro-3,4,6-tri-O-
benzyl-R-D-glucopyranose (7) as glycosyl donor with bis-trimethyl-
silyl sulfide as acceptor affords the R-thiol. Hence, this sterically
hindered S-nucleophile as acceptor should provide with O-glycosyl
trichloroacetimidates as glycosyl donors that have nonparticipating
groups at C-2, glycosylthiols with the thiol group in axial position.
This was confirmed for various donors (4, 16À19) with the exception
of the corresponding mannosyl donor (20). However, powerful participating groups at C-2 of the donor (23À28) governed the
anomeric selectivity.
lycoconjugates, particularly those containing lipid and/or
protein moieties, play essential roles in many biological
thioacetate as S-nucleophiles leading in the presence of base
(Scheme 1, d) in an SN2 reaction to glycosylthiols with the thiol
group in equatorial position.3,13,16 Glycosyl donor activation by
acid catalysts/promoters in the presence of H2S or equivalents
(Scheme 1, e) often leads to anomeric glycosylthiol mixtures.3,17
This is also found for the direct formation of glycosylthiols from
1-O-unprotected sugars and Lawesson’s reagent.6
Hence, as glycosylthiols with the thiol group in axial position
are not as readily available as their equatorial counterparts,3,18 the
recently reported stereospecific formation of R-glycosylthiols by
opening of 1,6-anhydro sugars with bis(trimethylsilyl) sulfide
(BTMSS) in the presence of trimethylsilyl trifluoromethanesul-
fonate (TMSOTf) as catalyst (Scheme 2) is a major advance.11c,d
Thus, from levoglucosan 1 the corresponding R-thiol 2r was
obtained, as presumed in an SN2-type fashion.11c,d The presence
of two unprotected functional groups, the availability of other
types of anhydro sugars and the required further investigation of
the reaction mechanism were reason to continue our studies with
BTMSS as S-nucleophile.
G
processes.1 Hence, the development of readily available glyco-
conjugate mimetics as tools for model studies or even therapeutic
intervention has gained great interest.2 In this context glyco-
sylthiols have been shown to be useful intermediates as they have
been successfully employed, for instance, for high-yielding
syntheses of sulfur-containing glycolipids, glycopeptides, and
glycoprotein analogues.3À12 The generally observed configura-
tional stability of glycosylthiols and the high nucleophilicity of the
derived glycosylthiolates (the intermediates in “base-promoted
anomeric thiol group S-alkylations”, Scheme 1, c) provide advan-
tages in the synthesis of glycoconjugate mimetics.3,13 Also worth
mentioning is the radical-induced glycosylthiolÀene coupl-
ing that can be employed as a click process.14 Furthermore,
thioglycosidic linkages generally exhibit higher chemo- and
enzymatic stability than their oxygen counterparts, and corre-
sponding glycoconjugate mimetics are tolerated by most biolo-
gical systems.3,15
The reactivity studies with 2r exhibited that alkylation under
mild basic conditions leads to S-alkylation. For instance, benzyla-
tion of 2r with benzyl bromide in a biphasic system in the
presence of NaHCO3 furnished the known benzyl 1-thio-gluco-
pyransoside 3 (Scheme 2).19 Surprisingly, acid-catalyzed glyco-
sylation of 2r with R-D-glucopyranosyl trichloroacetimidate 420
as glycosyl donor led, presumably as a result of steric reasons, to
β-selective 6-O-attack, thus providing gentiobiosylthiol 5 in good
yield. The structural assignment was confirmed by 1-S-acetyla-
tion with acetic anhydride in pyridine furnishing disaccharide 6
(1H NMR: 1a-H, δ 6.17, J = 5.3 Hz; 1b-H, δ 4.29, J = 7.8 Hz).
Thus, it was proven that the thiol group was not oxidized to the
For the construction of thioglycosides the acid-promoted
S-glycosylation (Scheme 1, a) has similar drawbacks as O-glycosy-
lation, as it is often not stereoselective.3,13 Because of the high
nucleophilicity of thiol groups under basic conditions, base-
promoted S-glycosylation (Scheme 1, b) is often employed.3,13
This way, the readily available glycosyl halides with the halide in
axial position lead via an SN2-substitution reaction stereoselec-
tively to the corresponding inverted thioglycosides. However,
glycosyl halides with the halide in the equatorial position are
not readily available. As alternative the base-promoted anomeric
thiol group S-alkylation (Scheme 1, c) is of interest.3 However,
the formation of the glycosylthiols that are required as R- and
β-anomers, respectively, has the same limitations as discussed
for thioglycoside generation. The most frequently employed
method for glycosylthiol formation starts from glycosyl
halides, with the halide in axial orientation, and thiourea or
Received: April 20, 2011
Published: July 28, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Synthesis of Glycosylthiols and Thioglycosidesa
a B = base, X = leaving group. (a) Acid-promoted S-glycosylation. (b) Base-promoted S-glycosylation. (c) Anomeric thiol group S-alkylation.
Scheme 2. O- versus S-Glycosylation of Acceptor 2r
However, glycosylation of 8r with 4 as glycosyl donor in the
presence of TMSOTf as catalyst did not lead to 2-O-glycosyla-
tion; instead R-selective 1-S-glycosylation was observed furnish-
ing thiotrehalose derivative 11, which was transformed into the
2-O-acetyl derivative 12 in order to further confirm the structural
assignment (1H NMR: 1a-H: δ 5.75, J1,2 = 5.7 Hz; 1b-H: δ 5.57,
J = 4.9 Hz). 8r was also reacted with dichloromethane in the
presence of DBU as base, thus leading via 1-S-chloromethyl
glucosyl-thiol 13 (which can be isolated) to oxothiolane deriva-
tive 14. This compound seems to be an interesting glycosyl
donor as the oxothiolane moiety, although opened upon activa-
tion with a thiophilic reagent, could serve as an anchimerically
assisting group favoring β-product formation.22 (Product 14A
formed with isopropanol; see Supporting Information)
The ring opening of 1,2-anhydro-glucose 7 with BTMSS
indicates that glycosylthiols with axial thiol groups should be
accessible directly from standard glycosyl donors with BTMSS as
acceptor. Due presumably to its steric demand, the reaction leads
first to a glycosyl cation, and then stereoelectronically favored
axial attack takes place. Hence, glucosyl donor 4 was treated with
BTMSS in the presence of TMSOTf as catalyst affording, as
expected, only known R-glucosyl thiol 15r11a in very good yield
(Scheme 4, Table 1). The application of this procedure to other
glycosyl donors is shown in Table 1. Thus, similar results were
obtained for galactosyl, fucosyl, and 2-azido-2-deoxy-galactosyl
and -lactosyl donors (entries 2À5, transformation of 16,23 17,24
18, 1925 into 29r, 30r,6 31r, 32r). Unexpectedly, mannopyr-
anosyl donor 2026 and O-acetyl protected glucopyranosyl and
galactopyranosyl donors 2120 and 2227 afforded R/
β-mixtures of the glycosylthiols 33r,β,6 34r,β,28 35r,β,28
respectively (entries 6À8). Obviously, as supported by previous
work, attack at the naked glycosyl cation intermediate is decisive
for the anomeric stereocontrol.29 For instance, the generated
mannopyranosyl cation can adopt a twist-boat conformation
that favors β-product formation. Hence, from 2-O-benzoyl or 2-
N-dimethylmaleoyl (DMM) protected glycosyl donors (entries
9À14, transformation of donors 23,30 24, 25,31 26,32 27,33 2834
disulfide stage in the transformations from starting material 1 to
disaccharide 5.
The convenient transformation of 1,6-anhydro sugars upon
acid-catalyzed treatment with BTMSS into R-glycosylthiols11c,d
led us to related studies with 1,2-anhydro sugars. Hence, readily
available 1,2-anhydro-glucose derivative 721 was treated with
BTMSS in the presence of TMSOTf as catalyst (Scheme 3).
Surprisingly, the major product was R-glycosyl thiol 8r and not
the expected β-glucosylthiol 8β (R/β = 2:1), thus indicating that
the reaction course is essentially or exclusively SN1 type leading
mainly to the stereoelectronically favored R-product. For the
structural assignment, 8r was fully acetylated, thus providing
1-S,2-O-diacetyl derivative 9 that showed the required 1H
NMR data (1-H: δ 6.23, J1,2 = 5.3 Hz; 2-H: δ 5.24, J2,3 = 9.9
Hz). 8r underwent selective 1-S-benzylation under the biphasic
conditions as described above providing benzylated product 10.
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The Journal of Organic Chemistry
NOTE
Scheme 3. Ring Opening of 1,2-Anhydro-glucose 7 and O- versus S-Alkylation and -Glycosylation of 8ra
a eq = equivalents.
Scheme 4. Synthesis of Glycosylthiol 15r
of (NH4)6Mo7O24 4H2O (20 g) and Ce(SO4)2 (0.4 g) in sulfuric acid
3
(10%, 400 mL) and then by heating to 120 °C. Flash chromatography
was performed on silica gel (230À400 mesh) at a pressure of 0.2 bar.
Optical rotations were measured at 22 °C using the sodium D line.
Commercial grade BTMSS and ethyl propiolate were used.
Benzyl 2,3,4-Tri-O-benzyl-1-thio-R-D-glucopyranoside (3).
A pH 8.5 solution of NaHCO3 (3 mL) followed by TBAHS (274 mg,
0.80 mmol) was added to a solution of 2 (110 mg, 0.23 mmol) and
benzyl bromide (45 mg, 0.25 mmol) in EtOAc (3 mL). The reaction
mixture was vigorously stirred at room temperature for 24 h and then
diluted with EtOAc and washed successively with saturated aqueous
NaHCO3 and brine. The organic layer was dried over MgSO4 and
concentrated in vacuo to give a crude product that was purified by flash
column chromatography with petroleum ether/EtOAc (8:1) to afford 3
(94 mg, 72%) as a colorless oil. The physical properties found for 3 are in
accordance with those reported previously.19
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1À6)-2,3,4-
tri-O-benzyl-1-thio-R-D-glucopyranose (5). To a solution of
2r (200 mg, 0.42 mmol) and 4 (288 mg, 0.42 mmol) in dry CH2Cl2
(10 mL) was added TMSOTf (0.016 mL, 0.08 mmol) at À78 °C. The
reaction mixture was then stirred at À78 °C until TLC indicated
complete consumption of the starting material and then quenched by
adding triethyl amine. The reaction mixture was diluted with CH2Cl2
(10 mL) washed with water. The organic layer was dried over MgSO4
and concentrated in vacuo to give a residue that was purified by flash
column chromatography with petroleum ether/EtOAc (8:1) to afford
5 (322 mg, 76%) as a white solid. [R]D = +34.0 (c 0.35, CHCl3).
HRMS (C61H64O10S): [M + Na]+ m/z 1011.4118, found 1011.4110.
Acetylation of 5 under standard conditions afforded 2,3,4,6-tetra-O-
benzyl-β-D-glucopyranosyl-(1À6)-1-S-acetyl-2,3,4-tri-O-benzyl-1-
thio-R-D-glucopyranose (6) as a white solid (87%). [R]D = +21.0
(c 0.31, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.24À7.21 (m, 16 H),
7.20À7.16 (m, 13 H), 7.12À7.07 (m, 6 H), 6.17 (d, J = 5.3 Hz, 1 H),
4.88À4.80 (m, 3 H), 4.73À4.68 (m, 2 H), 4.67À4.63 (m, 2 H), 4.60 (d,
J = 6.8 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 4.50À4.48 (m, 2 H), 4.46 (s,
1 H), 4.44 (dd, J = 5.6, 3.5 Hz, 2 H), 4.29 (d, J = 7.8 Hz, 1 H), 4.09 (dd,
J = 11.1, 1.6 Hz, 1 H), 3.80 (dd, J = 9.2, 5.3 Hz, 1 H), 3.75 (dd, J = 9.3, 3.0
Hz, 1 H), 3.64À3.59 (m, 3 H), 3.57À3.55 (m, 1 H), 3.51 (d, J = 4.2 Hz, 1
H), 3.48 (d, J = 3.8 Hz, 1 H), 3.46À3.44 (m, 1 H), 3.39 (d, J = 8.1 Hz, 1
H), 3.35À3.32 (m, 1 H), 2.21 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
192.8, 138.64, 138.61, 138.5, 138.3, 138.2, 138.1, 137.4, 128.5, 128.41,
into thiols 36βÀ39β, 40r, 41β) having more efficient anchi-
meric assistance only the 1,2-trans glycosylthiols were obtained.
Thus, the simplicity and efficiency of this procedure to accessing
various glycosyl thiols in either R- and/or β-configuration has
been demonstrated.
As glycosyl thioacrylates are interesting intermediates,
Michael-type addition of glucosylthiol 15r to ethyl propiolate
was studied (Scheme 5, Table 2).35 Variation of solvent, base,
and temperature exhibited that DABCO as base in acetonitrile or
THF as solvent (entries 8 and 9) gave excellent product yields;
mainly the (E)-isomer (E)-42 was obtained. This way the avail-
ability of a nonoxidized thiol group is also confirmed. Accord-
ingly, reaction of 30r with ethyl propiolate furnished adduct 43
(E/Z = 94:6)
In conclusion, the acid-catalyzed ring opening of O-benzyl
protected 1,6-anhydro- and 1,2-anhydro-glucopyranose, respec-
tively, with BTMSS leads to exclusive or preferential formation of
R-glucopyranosylthiols. Hence, for O-glycosyl trichloroacetimi-
date donors having no anchimeric assistance the sterically
hindered BTMSS acceptor permits the generation of glycopyr-
anosylthiols with the thiol group in the axial position (generally
1,2-cis orientation). The availability of the thiol groups in these
products was proven by Michael-type additions leading to
glycopyranosyl thioacrylates.
’ EXPERIMENTAL SECTION
General Methods. Solvents were purified by standard proce-
dures. NMR spectra were recorded at 22 °C; tetramethylsilane
(TMS) or the resonance of the undeuterated solvent was used as
internal standards. Mass spectra were recorded with a ESI MS mass
spectrometer. Thin-layer chromatography was performed on silica gel
plastic plates; compounds were visualized by treatment with a solution
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NOTE
Table 1. Synthesis of Glycothiols 15 and 29À41a
Scheme 5. Synthesis of β-(Glycosylthio)acrylate 42 and 43
Table 2. Reaction Conditions for the Synthesis of 42
entry
basea
solvent temp (°C)
time
yield (%)
E/Z
1
2
NMM
NMM
NMM
Et3N
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
Et2O
rt
12 h
90
90
87
88
81
86
85
92
89
81
68/32
75/25
73/27
78/22
78/22
76/24
66/44
93/07
94/06
72/28
À78
0
12 h
12h
3
4
0
12 h
5
Et3N
0
12 h
6
Et3N
0
12 h
7
DBU
0
12 h
8
DABCO CH3CN
DABCO THF
Cs2CO3 Et2O
0
30 min
30 min
12 h
9
0
10
0
a Abbreviations: NMM = N-methyl morpholine, DABCO = 1,4-
diazabicyclo[2.2.2]octane.
77.2, 75.69, 75.65, 75.1, 74.9, 74.79, 74.71, 73.5, 72.7, 69.0, 68.1, 31.4.
HRMS (C63H66O11S): [M + Na]+ m/z 1053.4224, found 1053.4233.
3,4,6-Tri-O-benzyl-1-thio-R,β-D-glucopyranose (8r,β). To
a solution of7(200 mg, 0.46 mmol) and bis(trimethylsilyl) sulfide (146 μL,
0.69 mmol) in CH2Cl2 (10 mL) was added TMSOTf (0.042 mL,
0.23 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C until
TLC indicated complete consumption of the starting material (3 h),
then poured into aqueous NaHCO3, and extracted with EtOAc. The
organic layer was washed successively with water and brine, dried over
MgSO4, and concentrated in vacuo to give a residue that was purified by
flash column chromatography with petroleum ether/EtOAc (4:1) to
afford 8 (120 mg, 56%) (R/β = 64:36) as a colorless oil. 8r,β [R]D
=
+29.0 (c 0.21, CHCl3). HRMS (C27H30O5S): [M + Na]+ m/z 489.1712,
found 489.1722.
Acetylation under standard conditions afforded 1,2-di-S,O-acetyl-
3,4,6-tri-O-benzyl-1-thio-R-D-glucopyranose (9r,β) as a colorless oil
(96%). [R]D = +14.2 (c 0.23, CHCl3). 1H NMR (400 MHz, CDCl3) δ
7.47À7.05 (m, 24H), 6.25 (d, J = 5.4 Hz, 1H), 5.27À5.23 (dd, J = 10.0,
5.2 Hz, 1H), 5.17 (t, J = 8.4 Hz, 1H), 5.13 (dd, J = 10.0, 2.0 Hz, 1H),
4.86À4.80 (m, 4H), 4.76 (d, J = 12.8 Hz, 1H),4.70 (d, J = 12.0 Hz, 2H),
4.60 (dd, J = 12.2, 4.4 Hz, 2H), 4.53 (dd, J = 12.0, 3.9 Hz, 2H),
3.82À3.78 (m, 4H), 3.70 (t, J = 8.6 Hz, 2H), 3.65 (tt, J = 2.4 Hz, 1H)
2.44 (s, 3H), 2.41 (s, 1H), 2.01 (s, 3H), 1.97 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 192.2, 192.1, 169.6, 138.2, 137.94, 137.91, 128.45,
128.40, 128.0, 127.8, 127.75, 127.71, 127.6, 127.5, 84.4, 81.6, 81.0, 80.9,
79.7, 77.2, 75.4, 75.3, 75.2, 75. 0, 73.58, 73.51, 71.7, 71.1, 68.3, 68.2, 31.4,
a All reactions were carried out under the conditions shown in Scheme 4.
b Isolated yields following chromatography. Abbreviations: DMM =
dimethylmaleoyl; TBDPS = tert-butyldiphenylsilyl; TIPS = tri-isopro-
pylsilyl; PA = phenoxyacetyl.
128.40, 128.37, 128.34, 128.1, 128.0, 127.96, 127.90, 127.77, 127.75,
127.6, 127.59, 127.56, 127.50, 103.6, 84.8, 83.5, 81.9, 81.8, 78.5, 77.9,
7542
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NOTE
30.9, 20.87, 20.80. HRMS (C31H34O7S): [M + Na]+ m/z 573.1923,
found 573.1916.
NMR (100 MHz, CDCl3) δ 138.1, 137.8, 128.5, 128.4, 128.3, 128.2,
128.0, 127.9, 127.89, 127.87, 127.6, 85.8, 82.5, 76.8, 75.7, 73.3, 73.0, 72.4,
71.3, 70.6, 69.3. HRMS (C28H30O5S): [M + Na]+ m/z 501.1712, found
501.1719. Addition of only 1 equiv of DBU permitted the isolation of
chloromethyl 3,4,6-tri-O-benzyl-1-thio-R-D-glucopyranoside (13) inter-
mediate. [R]D = +5.1 (c 0.46, CHCl3). HRMS (C28H31ClO5S): [M +
Na]+ m/z 537.1478, found 537.1489.
Benzyl 3,4,6-Tri-O-benzyl-1-thio-R-D-glucopyranoside
(10). As described for 3, 10 (40 mg, 67%) was obtained from 8 (50 mg,
0.10 mmol) as a colorless oil. [R]D = +37.0 (c 0.45, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 7.39À7.28 (m, 18 H), 7.26À7.18 (m, 2 H), 5.35
(d, J = 5.4 Hz, 1 H), 4.85 (dd, J = 24.6, 11.2 Hz, 3 H), 4.67 (d, J = 12.1 Hz,
1 H), 4.56 (dd, J = 10.8, 7.9 Hz, 2 H), 4.19À4.17 (br. m, 1 H), 3.94 (dd, J
= 8.9, 5.6 Hz, 1 H), 3.84 (d, J = 13.3 Hz, 1 H), 3.78À3.75 (m, 2 H), 3.68
(dd, J = 6.0, 3.5 Hz, 2 H), 3.56 (dd, J = 10.7, 1.9 Hz, 1 H), 2.14 (d, J = 5.8
Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 138.4, 138.0, 137.9, 137.8,
129.0, 128.56, 128.51, 128.42, 128.41, 127.9, 127.87, 127.85, 127.77,
127.74, 127.1, 85.0, 83.5, 75.3, 74.8, 73.5, 72.1, 71.5, 68.4, 34.5. HRMS
(C34H36O5S): [M + Na]+ m/z 579.2181, found 579.2175.
O-(2-Azido-3,4-di-O-benzyl-6-O-tert-butyldiphenylsilyl-2-
deoxy-R-D-galactopyranosyl) Trichloroacetimidate (18). Gen-
eral procedure for the synthesis of 18 and 24. To a solution of the 1-O-
unprotected sugar (1 mmol) in CH2Cl2 (5 mL) were added successively
Cl3C-CN (1 mL, 10 mmol) and DBU (35 μL, 0.25 mmol) at 0 °C. After
stirring for 15 min, the mixture was directly chromatographed on SiO2
(toluene/EtOAc) to give 18 and 24, respectively, in practically quantita-
1
S-(2,3,4,6-Tetra-O-benzyl-R-D-glucopyranosyl)-3,4,6-tri-
O-benzyl-1-thio-R-D-glucopyranoside (11). To a solution of 8
(35 mg, 0.07 mmol) and 4 (50 mg, 0.07 mmol) in dry CH2Cl2 (5 mL)
was added TMSOTf (0.007 mL, 0.03 mmol) at 0 °C. The reaction
mixture was then stirred at 0 °C until TLC indicated complete
consumption of the starting material. The reaction was quenched by
adding triethyl amine. The reaction mixture was diluted with CH2Cl2
(10 mL) washed with water. The organic layer was dried over MgSO4
and concentrated in vacuo. The residue was purified by flash column
chromatography with petroleum ether/EtOAc (10:3) to afford 11 (45 mg,
tive yield. 18: [R]D = +4.62 (c 1.50, CHCl3). H NMR (400 MHz,
CDCl3) δ 8.59 (s, 1H), 7.73À7.69 (m, 3H), 7.39À7.30 (m, 17H), 6.64
(d, J = 3.4 Hz, 1H), 4.98 (t, J = 10.0 Hz, 2H), 4.86 (dd, J = 12.2,11.0 Hz,
2H), 4.72 (dd, J = 13.7, 11.7 Hz, 2H), 4.19À4.09 (m, 1H), 3.99À3.85 (m,
3H), 3.80 (dd, J = 9.5, 3.5 Hz, 1H), 1.00 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 161.3,138.5, 138.1, 135.8, 135.6, 133.5, 133.1, 129.66,
129.62,128.46, 128.42, 128.32, 128.2, 128.0, 127.8, 127.68, 127.63,
127.5, 94.3, 91.4, 81.5, 79.9, 75.8, 75.4, 74.3, 72.9, 62.4, 26.8, 19.3. HRMS
(C38H41Cl3N4O5Si): [M + Na]+ m/z 789.1809, found 789.1826.
O-(2,6-Di-O-benzoyl-3,4-O-isopropylidene-R-D-galacto-
pyranosyl) Trichloroacetimidate (24). From 2,6-di-O-benzoyl-
3,4-O-isopropylidene-D-galactose,36 24 was obtained as described in
1
61%) as a white solid. [R]D = +25.0 (c 0.38, CHCl3). H NMR (400
MHz, CDCl3) δ 7.38À7.29 (m, 31 H), 7.23À7.17 (m, 4 H), 5.68 (d, J =
4.4 Hz, 1 H), 5.57 (d, J = 5.4 Hz, 1 H), 4.98 (d, J = 10.8 Hz, 1 H), 4.88 (d,
J = 10.8 Hz, 4 H), 4.81 (d, J = 10.8 Hz, 1 H), 4.74 (d, J = 11.8 Hz, 1 H),
4.64À4.61(m, 3 H), 4.58À4.54 (m, 3 H), 4.51À4.48 (m, 2 H), 4.30 (d,
J = 6.2 Hz, 2 H), 3.99 (dd, J = 5.4, 9.4 Hz, 1 H), 3.89À3.87 (m, 2 H),
3.78À3.73 (m, 2 H), 3.70 (s, 2 H), 3.68 (s, 2 H), 3.66 (s, 1 H); 13C NMR
(100 MHz, CDCl3) δ 138.6, 138.4, 138.2, 137.9, 137.8, 137.6, 128.5,
128.42, 128.41, 128.38, 128.35, 128.0, 127.99, 127.91, 127.89, 127.85,
127.7, 127.6, 83.7, 83.3, 82.6, 81.4, 78.9, 77.5, 75.7, 75.4, 75.0,74.8, 74.7,
73.5, 73.4, 72.4, 72.1, 71.9, 71.2, 68.6, 29.7. HRMS (C61H64O10S): [M +
Na]+ m/z 1011.4118, found 1011.4128.
1
the procedure for 18. 24: [R]D = +55.6 (c 1.00, CHCl3). H NMR
(400 MHz, CDCl3) δ 8.59 (s, 1 H), 8.06À8.04 (m, 4 H), 7.60À7.56
(m, 2 H), 7.46 (td, J = 7.8, 2.6 Hz, 4 H), 6.61 (d, J = 3.7 Hz, 1 H), 5.55
(dd, J = 7.1, 3.8 Hz, 1 H), 4.74À4.68 (m, 3 H), 4.62À4.59 (m, 1 H),
4.53À4.51 (m, 1 H), 1.62 (s, 3 H), 1.41 (s, 3 H). 13C NMR (100 MHz,
CDCl3) δ 166.3, 165.5, 160.4, 133.4, 133.1, 129.89, 129.84, 129.7,
129.2, 128.43, 128.40, 110.7, 93.4, 90.8, 73.1, 72.9, 69.7, 68.8, 63.6,
27.6, 26.1. HRMS (C25H24Cl3NO8): [M + Na]+ m/z 594.0465,
found 594.0442.
General Procedure A for the Synthesis of Glycosylthiols
15 and 29À41. Synthesis of 2,3,4,6-tetra-O-benzyl-1-thio-R-D-gluco-
pyranose (15r). To a solution of 420 (100 mg, 0.14 mmol) and
bis(trimethylsilyl) sulfide (0.031 mL, 0.14 mmol) in CH2Cl2 (5 mL)
was added TMSOTf (0.005 mL, 0.02 mmol) at 0 °C. The mixture was
stirred at 0 °C until TLC indicated complete consumption of the starting
material, then poured into aqueous NaHCO3, and extracted with
EtOAc. The organic layer was washed successively with water and
brine, dried over MgSO4, and concentrated in vacuo. The crude product
was purified by flash column chromatography with petroleum ether/
EtOAc (10:2) to afford 15r (70 mg, 86%) as a colorless oil. The physical
properties found for 15r are in accordance with those reported
previously.11a
6-O-Acetyl-2,3,4-tri-O-benzyl-1-thio-R-D-galactopyra-
nose (29r). By means of general procedure A 29r was obtained from
1623 and BTMSS; see Table 1. [R]D = +32.0 (c 0.46, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 7.20À7.10 (m, 15 H), 5.63 (t, J = 4.3 Hz, 1 H),
4.77 (d, J = 11.4 Hz, 1 H), 4.68 (d, J = 11.7 Hz, 1 H), 4.57 (d, J = 4.9 Hz, 1
H), 4.54 (d, J = 4.6 Hz, 1 H), 4.50 (d, J = 11.5 Hz, 1 H), 4.44 (d, J = 11.4
Hz, 1 H), 4.14À4.10 (m, 1 H), 4.05 (dd, J = 9.4, 5.1 Hz, 1 H), 3.98 (dd,
J = 11.4, 6.9 Hz, 1 H), 3.91 (dd, J = 11.4, 5.4 Hz, 1 H), 3.70À3.69 (m,
1 H), 3.63 (dd, J = 9.5, 2.6 Hz, 1 H), 1.81 (s, 3 H), 1.67 (d, J = 4.1 Hz, 1
H). 13C NMR (100 MHz, CDCl3) δ 170.6, 138.4, 138.0, 137.8, 128.47,
128.43, 128.42, 127.96, 127.91, 127.8, 127.7, 127.5, 79.1, 78.4, 75.9, 74.5,
74.3, 73.6, 72.7, 69.8, 63.0, 20.8. HRMS (C29H32O6S): [M + Na]+ m/z
531.1817, found 531.1833.
Acetylation of 11 under standard conditions afforded S-(2,3,4,6-tetra-
O-benzyl-R-D-glucopyranosyl) 2-O-acetyl-3,4,6-tri-O-benzyl-1-thio-R-
D-glucopyranoside (12) as a colorless oil (69%). [R]D = +31.0 (c 0.32,
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.24À7.19 (m, 31 H), 7.11
(dd, J = 7.8, 2.4 Hz, 2 H), 7.04 (dd, J = 7.5, 3.3 Hz, 2 H), 5.73 (d, J = 5.7
Hz, 1 H), 5.57 (d, J = 4.9 Hz, 1 H), 4.96 (dd, J = 10.0, 5.7 Hz, 1 H), 4.87
(d, J = 10.8 Hz, 1 H), 4.76À4.64 (m, 5 H), 4.60À4.55 (m, 2 H), 4.48 (s, 1
H), 4.45À4.43 (m, 2 H), 4.40À4.34 (m, 3 H), 4.25À4.20 (m, 1 H), 3.94
(d, J = 9.9 Hz, 1 H), 3.85 (t, J = 9.5 Hz, 1 H), 3.75À3.69 (m, 3 H),
3.64À3.58 (m, 3 H), 3.55À3.51 (m, 2 H), 1.89 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 169.9, 138.7, 138.3, 138.1, 137.96, 137.93, 137.6, 128.4,
128.39, 128.38, 128.02, 128.00, 127.96, 127.93, 127.8, 127.74, 127.70,
82.7, 81.1, 80.6, 79.1, 78.7, 77.7, 77.1, 75.7, 75.5, 75.2, 74.9, 73.6, 73.5,
73.0, 72.1, 71.8, 71.4, 68.1, 29.7, 20.9. HRMS (C63H66O11S): [M + Na]+
m/z 1053.4224, found 1053.4232.
3,4,6-Tri-O-benzyl-1-S,2-O-methylidene-1-thio-R-D-glu-
copyranose (14). To a solution of 8 (50 mg, 0.10 mmol) in dry
CH2Cl2 (5 mL) was added DBU (0.032 mL, 0.21 mmol) at room
temperature. The reaction mixture was then stirred at room temperature
until TLC indicated complete consumption of the starting material and
then concentrated in vacuo. The residue was purified by flash column
chromatography with petroleum ether/EtOAc (10:1) to afford 14 (21 mg,
1
40%) as a white solid. [R]D = +41.0 (c 0.22, CHCl3). H NMR (400
MHz, CDCl3) δ 7.28À7.19 (m, 13 H), 7.12À7.10 (m, 2 H), 6.01 (d, J =
4.8 Hz, 1 H), 5.11 (d, J = 5.7 Hz, 1 H), 4.67 (d, J = 5.7 Hz, 1 H), 4.61 (d,
J = 11.9 Hz, 1 H), 4.56À4.50 (m, 2 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.41
(d, J = 12.1 Hz, 1 H), 4.31 (d, J = 11.4 Hz, 1 H), 4.00À3.95 (m, 2 H),
3.91 (t, J = 4.2 Hz, 1 H), 3.68À3.65 (m, 1 H), 3.52À3.51 (m, 2H); 13C
2-Azido-3,4-di-O-benzyl-6-O-tert-butyldiphenylsilyl-2-
deoxy-1-thio-R-D-galactopyranose (31r). By means of gen-
eral procedure A 31r was obtained from 18 and BTMSS; see
7543
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The Journal of Organic Chemistry
NOTE
Table 1. [R]D = +37.5 (c 0.59, CHCl3). 1H NMR (400 MHz, CDCl3)
δ 7.55À7.51(m, 3H), 7.20À7.10 (m, 17 H), 5.65 (t, J = 4.9 Hz, 1 H),
4.78 (t, J = 10.0 Hz, 2H), 4,65 (dd, J = 13.8, 10.7 Hz, 2H),4,52 (dd, J =
10.7, 6.4 Hz, 2H), 3.99 (dd, J = 9.8, 1.7 Hz, 1H), 3.85 (dd, J = 11.5, 3.5
Hz, 1H), 3.79À3.61 (m, 2H), 1.71 (d, J = 4.5 Hz, 1H), 0.91 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 138.56, 138.30, 137.7, 135.85,
135.66, 134.81, 129.6, 129.60, 128.51, 128.45, 128.42, 128.0, 127.9,
127.8, 127.7, 127.5, 81.9, 79.7, 78.8, 75.9, 75.1, 72.5, 72.3,62.7, 26.8,
19.3.HRMS (C36H41N3O4SSi): [M + Na]+ m/z 662.2485, found
662.2465.
165.4, 165.3, 133.4, 133.3 (2 C), 129.9À129.8 (3 C), 129.1, 128.9, 128.4
(2 C), 78.8, 73.2, 71.8, 69.2, 65.4. HRMS (C26H22O7S): [M + Na]+ m/z
501.0984, found 501.0965.
3,4-Di-O-benzyl-2-O-benzoyl-6-O-tri-isopropylsilyl-1-thio-
R-D-mannopyranose (40r). By means of general procedure A 40r
was obtained from 2733 and BTMSS; see Table 1. [R]D = +2.2 (c 0.08,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.04À8.01 (m, 2H), 7.53À7.48
(m, 1H), 7.38À7.34 (m, 2H), 7.27À7.17 (m, 10H), 5.60À5.57 (m, 2H),
4.81 (d, J = 10.6 Hz, 1H), 4.70 (d, J = 11.4 Hz, 1H), 4.65 (d, J = 10.6 Hz,
1H), 4.53 (d, J = 11.4 Hz, 1H), 4.12 (t, J = 9.5 Hz, 1H), 4.08 (dd, J = 11.2,
3.2 Hz, 1H), 4.02 (dd, J = 9.4, 3.0 Hz, 1H), 3.94 (m, 1H), 3.88 (dd, J =
11.2, 1.5 Hz, 1H), 2.08 (d, J = 7.2 Hz, 1H), 1.05 À1.00 (m, 21H). 13C
NMR (100 MHz, CDCl3) δ 165.7, 138.5, 137.7, 133.2, 133.0, 129.8,
128.39, 128.34, 128.1, 128.0, 127.7, 127.6, 77.6, 77.2, 75.4, 74.0, 73.9,
72.1, 71.8, 62.3, 18.07, 18.03, 12.0. HRMS (C36H48O6SSi): [M + Na]+
m/z 659.2839, found 659.2820.
3,4,6-Tri-O-acetyl-2-deoxy-2-(2,3-dimethylmaleinimido)-
2-deoxy-1-thio-β-D-glucopyranose (41β). By means of general
procedure A 41β was obtained from 2834 and BTMSS; see Table 1. [R]D =
+6.2 (c 0.10, CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.57 (t, J = 10.0
Hz, 1H), 5.26 (t, J = 10.2 Hz, 1H), 5.08 (t, J = 10.0 Hz, 1H), 4.24 (dd, J =
12.4, 4.7 Hz, 1H), 4.08À4.05 (m. 1H), 3.97 (t, J = 10.3 Hz, 1H),
3.78À3.74 (m, 1H), 2.12 (d, J = 10.2 Hz, 1H), 2.04 (s, 3H), 1.95 s, 3H),
1.90 (s, 6), 1.85 (s, 3H).13C NMR (100 MHz, CDCl3) δ 170.74, 170.0,
169.79, 169.4, 132.6, 106.1 77.2, 76.49, 76.32, 71.3, 68.5, 62.0, 57.6, 20.8,
20.62, 20.53, 8.9. HRMS(C18H23NO9S): [M + Na]+ m/z 452.0991,
found 452.0981.
Ethyl (E/Z)-3-(2,3,4,6-Tetra-O-benzyl-R-D-glucopyransoylthio)-
acrylate [(E/Z)-42]. To a solution of 15r (260 mg, 0.46 mmol) and ethyl
propiolate (46 mg, 0.46 mmol) in dry THF (5 mL) was added DABCO (52
mg, 0.46 mmol) or NMM (47 mg, 0.46 mmol) at room temperature. The
mixture was stirred at room temperature until TLC indicated complete
consumption of the starting material. The organic layer was washed successively
with water and brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography with petroleum ether/
EtOAc (10:1) to afford 42 (272 mg, 89%) as a colorless oil (E/Z mixture, see
Table 2). Eisomer: 1H NMR (400 MHz, CDCl3) δ7.74 (d, J= 15.4 Hz, 1 H),
7.38À7.30 (m, 18 H), 7.19À7.17 (m, 2 H), 6.13 (d, J= 15.4 Hz, 1 H), 5.75 (d,
J = 5.3 Hz, 1 H), 4.98 (d, J = 10.8 Hz, 1 H), 4.87À4.81 (m, 2 H), 4.75 (d, J =
11.6 Hz, 1 H), 4.70À4.64 (m, 2 H), 4.55 (d, J= 10.8 Hz, 1 H), 4.51 (d, J= 12.0
Hz, 1 H), 4.27À4.19 (m, 2 H), 4.02 (d, J = 9.8 Hz, 1 H), 3.97 (dd, J = 9.3, 5.3
Hz, 1 H), 3.88 (d, J = 8.9 Hz, 1 H), 3.83À3.80 (m, 1 H), 3.77 (d, J = 9.3 Hz,
1 H), 3.67 (dd, J= 10.9, 1.8 Hz, 1 H), 1.33 (t, J= 7.1 Hz, 3 H); 13CNMR(100
MHz, CDCl3) δ 165.2, 143.2, 138.4, 138.0 137.7, 137.2, 128.5, 128.42, 128.40,
128.13, 128.10, 127.97, 127.95, 127.8, 127.77, 127.72, 117.4, 84.1, 82.4, 78.8,
76.8, 75.8, 75.1, 73.5, 72.8, 71.8, 68.0, 60.3, 14.3. Zisomer: 1H NMR (400 MHz,
CDCl3) δ6.00 (d, J= 10.3 Hz, 1H), 5.66 (t, J= 5.8 Hz, 2H), 5.51 (d, J= 5.2 Hz,
1H), 5.42 (d, J = 3.8 Hz, 1H), 1.36 (d, J = 7.1 Hz, 3H). HRMS (C39H42O7S):
[M + Na]+ m/z 677.2549, found 677.2527.
Ethyl (E/Z)-3-(2,3,4-Tri-O-benzyl-R-L-fucopyranosylthio)-
acrylate [(E/Z)-43]. By means of the procedure for 42 (E/Z)-43 was
obtained from 30r and ethyl propiolate; see Table 2. 1H NMR (400
MHz, CDCl3) δ 7.68 (d, J = 15.5 Hz, 1 H), 7.35À7.24 (m, 15 H), 6.01
(d, J = 15.5 Hz, 1 H), 5.72 (d, J = 5.4 Hz, 1 H), 4.95 (d, J = 11.5 Hz, 1
H), 4.81 (d, J = 11.9 Hz, 1 H), 4.71À4.62 (m, 4 H), 4.43À4.29 (m, 2
H), 4.39À4.13 (m, 3 H), 3.98 (qt, J = 6.7 Hz, 1 H), 3.72 (dd, J = 9.9, 2.8
Hz, 1 H), 3.63 (d, J = 1.9 Hz, 1 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.11 (d, J =
6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 165.9, 143.9, 138.5,
138.3, 137.7, 128.4À127.5 (9 C), 116.9, 84.7, 79.7, 75.6, 75.0, 73.4,
72.8, 68.3, 60.2, 16.5, 14.3. Z isomer: 1H NMR (400 MHz, CDCl3) δ
7.57 (d, J = 12.2 Hz, 1 H), 6.78 (d, J = 16.0 Hz, 1 H), 6.46 (d, J = 16.0
Hz, 1 H), 5.65 (d, J = 12.2 Hz, 1 H). HRMS (C32H37O6S): [M + H]+
m/z 549.2311, found 549.2325.
2,3,4À6-Tetra-O-acetyl-β-D-glucopyranosyl-(1À4)-3,6-di-
O-acetyl-2-azido-2-deoxy-1-thio-R-D-glucopyranose (32r).
By means of general procedure A 32r was obtained from 1925 and
1
BTMSS; see Table 1. [R]D = +22.1 (c 0.21, CHCl3). H NMR (400
MHz, CDCl3) δ 5.43 (t, J = 4.4 Hz, 1 H), 5.13 (d, J = 2.6 Hz, 1 H), 5.08
(t, J = 9.6 Hz, 1 H), 4.89 (dd, J = 10.3, 7.8 Hz, 1 H), 4.74 (dd, J = 10.4, 3.4
Hz, 1 H), 4.26À4.21 (m, 2 H), 4.09À4.05 (m, 1 H), 3.98À3.94 (m, 2
H), 3.92À3.87 (m, 1 H), 3.86À3.82 (m, 1 H), 3.67À3.63 (m, 2 H), 3.49
(t, J = 9.6 Hz, 1 H), 1.93 (s, 3 H), 1.89 (s, 6 H), 1.84 (s, 3 H), 1.82À1.81
(d, J = 4.3 Hz, 4 H), 1.74 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ
170.2, 170.3, 170.17. 170.12, 170.3, 169.3, 168.9, 100.9, 78.0, 76.0, 71.0,
70.79, 70.7, 69.7, 69.0, 66.6, 62.0, 61.6, 60.8, 20.8, 20.6, 20.5. HRMS
(C24H33N3O15S): [M + Na]+ m/z 658.1530, found 658.1504.
2,3-Di-O-benzoyl-4,6-O-benzylidene-1-thio-β-D-glucopyr-
anose (36β). By means of general procedure A 36β was obtained from
2330 and BTMSS; see Table 1. [R]D = +31.1 (c 0.12, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 8.03À8.00 (m, 4 H), 7.57À7.52 (m, 4 H),
7.45À7.38 (m, 7 H), 5.86 (t, J = 9.8 Hz, 1 H), 5.60 (s, 1 H), 5.42 (dd, J =
10.0, 3.6 Hz, 1 H), 4.85 (t, J = 9.9 Hz, 1 H), 4.69 (d, J = 2.8 Hz, 1 H), 4.49
(dd, J = 12.5, 1.5 Hz, 1 H), 4.16 (dd, J = 12.5, 1.7 Hz, 1 H), 3.78 (d, J = 1.0
Hz, 1 H), 2.56 (d, J = 10.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
166.1, 165.5, 133.4, 133.3, 129.9, 129.8, 129.0, 128.46, 128.42, 128.1,
126.2, 100.8, 79.2, 73.8, 73.5, 71.6, 70.6, 69.1. HRMS (C27H24O7S):
[M + Na]+ m/z 515.1140, found 515.1129.
2,6-Di-O-benzoyl-3,4-O-isopropylidene-1-thio-β-D-galac-
topyranose (37β). By means of general procedure A 37β was
obtained from 24 and BTMSS; see Table 1. [R]D = +90.1 (c 1.21,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.02À7.97 (m, 4 H), 7.51 (t,
J = 7.4 Hz, 2 H), 7.40À7.36 (m, 4 H), 5.26À5.22 (m, 1 H), 4.61 (dd, J =
11.8, 4.6 Hz, 1 H), 4.55À4.49 (m, 2 H), 4.32À4.30 (m, 2 H), 4.18À4.15
(m, 1 H), 2.39 (d, J = 9.9 Hz, 1 H), 1.56 (s, 3 H), 1.30 (s, 3 H). 13C NMR
(100 MHz, CDCl3) δ 166.4, 165.7, 133.4, 133.2, 129.9, 129.7, 129.5,
128.4, 111.0, 78.0, 77.3, 75.2, 74.7, 73.6, 63.9, 27.6, 26.2. HRMS
(C23H24O7S): [M + Na]+ m/z 467.1140, found 467.1124.
2-O-Benzoyl-4,6-O-benzylidene-3-O-phenyloxyacetyl-1-
thio-β-D-galactopyranose (38β). By means of general procedure A
38β was obtained from 2531 and BTMSS; see Table 1. [R]D = +10.1
(c 0.11, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.14À7.93 (d, J = 7.1
Hz, 2 H), 7.68À7.40 (m, 8 H), 7.04 (dd, J = 8.6, 7.5 Hz, 2 H), 6.87 (t, J =
7.5 Hz, 1 H), 6.72 (d, J = 8.6 Hz, 2 H), 5.64 (t, J = 9.8 Hz, 1 H), 5.54 (s, 1
H), 5.29 (dd, J = 10.0, 3.6 Hz, 2 H), 4.70 (t, J = 10.2 Hz, 1 H), 4.62 (d, J =
16.5 Hz, 1 H), 4.56À4.47 (m, 2 H), 4.38 (dd, J = 12.6, 1.4 Hz, 1 H), 4.07
(dd, J = 12.6, 1.7 Hz, 1 H), 3.66 (d, J = 1.0 Hz, 1 H), 2.50 (d, J = 10.4 Hz,
1 H). 13C NMR (100 MHz, CDCl3) δ 168.7, 165.4, 157.4, 137.2, 133.6,
129.9, 129.3, 129.2, 129.1, 128.6, 128.3, 126.3, 121.7, 114.3, 101.0, 79.1,
73.5, 73.4, 71.3, 70.3, 69.0, 64.7. HRMS (C28H26O8S): [M + Na]+ m/z
545.1246, found 545.1226.
2,3,4-Tri-O-benzyl-1-thio-β-D-xylopyranose (39β). By means
of general procedure A 39β was obtained from 2632 and BTMSS; see
Table 1. [R]D = +7.1 (c 0.11, CHCl3). 1H NMR (400 MHz, CDCl3) δ
8.04À7.87 (m, 6 H), 7.61À7.45 (m, 3 H), 7.40À7.29(m, 6 H), 5.78(t, J =
8.0 Hz, 1 H), 5.40 (t, J = 7.8 Hz, 1 H), 5.38À5.34 (m, 1 H), 5.00 (dd, J =
9.4, 7.7Hz, 1 H), 4.54(dd, J = 11.9, 4.8Hz, 1 H), 3.69 (dd, J = 11.9, 8.4 Hz,
1 H), 2.44 (d, J = 9.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 165.5,
7544
dx.doi.org/10.1021/jo200624e |J. Org. Chem. 2011, 76, 7539–7545

The Journal of Organic Chemistry
NOTE
’ ASSOCIATED CONTENT
(20) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980,
19, 731–732.
(21) DiBussolo, V.; Kim, Y.-J.; Gin, D. Y. J. Am. Chem. Soc. 1998,
120, 13515–13516.
(22) Dere, R. T.; unpublished results.
(23) Nynke, M.; Spijker, M.; Westerdiun, P.; van Boeckel, C. A. A.
Tetrahedron 1992, 48, 6297–6316.
(24) Wegmann, B.; Schmidt, R. R. Carbohydr. Res. 1988, 184, 254–261.
(25) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826–
1847.
(26) Watanabe, Y.; Yamamoto, T.; Okazaki, T. Tetrahedron 1997,
53, 903–918.
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: xiangming_zhu@hotmail.com; richard.schmidt@
uni-konstanz.de
(27) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249–
1256.
(28) Floyd, N.; Vijayakrishnan, B.; Koeppe, J. R.; Davis, B. G. Angew.
’ ACKNOWLEDGMENT
This work was supported by the University of Konstanz and
the Fonds der Chemischen Industrie. V.K. is particularly grateful
for a fellowship from the Alexander von Humboldt Foundation.
Chem., Int. Ed. 2009, 48, 7798–7802.
(29) (a) Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000,
41, 8753–8758. (b) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed.
2009, 48, 1900–1934.
(30) Lefeber, D. J.; Kamerling, J. P.; Vliegenthart, J. F. G. Chem.—
Eur. J. 2001, 7, 4411–4421.
’ REFERENCES
(31) Geiger, J.; Barroca, N.; Schmidt, R. R. Synlett 2004, 836–840.
(32) Jiang, Z.; Schmidt, R. R. Liebigs Ann. Chem. 1992, 975–982.
(33) H€olemann, A.; Stocker, B. L.; Seeberger, P. H. J. Org. Chem.
2006, 71, 8071–8088.
(34) Aly, M. R. E.; Castro-Palomino, J. C.; Ibrahim, E.-S. I.; El-Ashry,
E.-S. H.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 2305–2316.
(35) Forrelatedstudies, see:Hirsenkorn, J. DiplomaThesis, Universit€at
Konstanz, 1981.
(1) (a) Varki, A. Glycobiology 1993, 3, 97–130. (b) Dwek, R. A.
Chem. Rev. 1996, 96, 683–720. (c) Doores, K. J.; Gamblin, D. P.; Davis,
B. G. Chem.—Eur. J. 2006, 12, 656–665.
(2) (a) Hang, H.; Bertozzi, C. R. Acc. Chem. Res. 2001, 34, 727–736.
(b) Murphy, N.; Zhu, X.; Schmidt, R. R. In Specialist Periodical Reports:
Carbohydrate ChemistryÀChemical and Biological Approaches; Royal
Society of Chemistry: London, 2010; Vol. 36, pp 64À100.
(3) Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106, 160–187.
(4) Watt, G. M.; Lund, J.; Levens, M.; Kolli, V. S. K.; Jefferis, R.;
Boons, G.-J. Chem. Biol. 2003, 10, 807–814.
(36) Nukada, T.; Berces, A.; Whitfield, D. M. J. Org. Chem. 1999,
64, 9030–9045.
(5) (a) Davis, B. G.; Maughan, M. A. T.; Green, M. P.; Ullman, A.;
Jones, J. B. Tetrahedron: Asymmetry 2000, 11, 245–262. (b) Rendle,
P. M.; Seger, A.; Rodrigues, J.; Oldham, N. J.; Bott, R. R.; Jones, J. B.;
Cowan, M. M.; Davis, G. B. J. Am. Chem. Soc. 2004, 126, 4750–4751.
(c) Grayson, E. J.; Ward, S. J.; Hall, A. L.; Rendle, P. M.; Gamblin, D. P.;
Batsanov, A. S.; Davis, B. G. J. Org. Chem. 2005, 70, 9740–9754.
(6) Bernardes, G. J. L; Gamblin, D. P.; Davis, B. G. Angew. Chem., Int.
Ed. 2006, 45, 4007–4011.
(7) Knapp, S.; Myers, D. S. J. Org. Chem. 2002, 67, 2995–2999.
(8) Zhu, Y.; Gieselman, M. D.; Zhou, H.; Averin, O.; van der Donk,
W. A. Org. Biomol. Chem. 2003, 1, 3304–3315.
(9) (a) Eisele, T.; Schmidt, R. R. Liebigs Ann. 1997, 865–872. (b) Zhu,
X.; Pachamuthu, K.; Schmidt, R. R. J. Org. Chem. 2003, 68, 5641–5651.
(c) Pachamuthu, K.; Zhu, X.; Schmidt, R. R. J. Org. Chem. 2005, 70,
3720–3723.
(10) Thayer, D. A.; Henry, N. Y.; Galan, M. C.; Wong, C.-H. Angew.
Chem., Int. Ed. 2007, 44, 4596–4599.
(11) (a) Zhu, X. Tetrahedron Lett. 2006, 47, 7935–7938. (b) Zhu, X.;
Jin, Y.; Wickham, J. J. Org. Chem. 2007, 72, 2670–2673. (c) Dere, R. T.;
Wang, Y.; Zhu, X. Org. Biomol. Chem. 2008, 6, 2061–2063. (d) Dere,
R. T.; Zhu, X. Org. Lett. 2008, 10, 4641–4644.
(12) Driguez, H. Top. Curr. Chem. 1997, 187, 85–116.
(13) Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52, 179–205.
(14) Fiore, M.; Marra, A.; Dondoni, A. J. Org. Chem. 2009, 74,
4422–4425.
(15) (a) Capon, B. Chem. Rev. 1969, 69, 407–498. (b) Stallings-
Mann, M.; Jamieson, L.; Regala, R. P.; Weems, C.; Murray, N. R.; Fields,
A. P. Cancer Res. 2006, 66, 1767–1774.
(16) (a) Lee, Y. C.; Stowell, C. P.; Krantz, M. J. Biochemistry 1976,
15, 3956–3963. (b) Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2000,
65, 4607–4617.
(17) (a) Ibatullin, F. M.; Shabalin, K. A.; J€anis, J. V.; Shavva, A. G.
Tetrahedron Lett. 2003, 44, 7961–7964. (b) Defaye, J.; Gadelle, A.;
Pedersen, C. Carbohydr. Res. 1991, 217, 51–58.
(18) Holick, S. A.; Anderson, L. Carbohydr. Res. 1974, 34, 208–213.
(19) Fei, C.; Chan, T. H. Acta. Chim. Sinica (Engl. Ed.) 1989,
258–264.
7545
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