Exploring the native chemical ligation concept for highly stereospecific glycosylation reactions

Article abstract of DOI:10.1021/jo400020q

Various O-alkyl glycosides were obtained in a highly stereospecific manner with retention of configuration at the anomeric center. Our method has customized native chemical ligation concept for glycoconjugates synthesis, utilizing a meticulously controlle

Full text of DOI:10.1021/jo400020q

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Article
Exploring Native Chemical Ligation Concept for
Highly Stereospecific Glycosylation Reactions
Kim Le Mai Hoang, Yaguang Bai, Xin Ge, and Xue-Wei Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400020q • Publication Date (Web): 02 May 2013
Downloaded from http://pubs.acs.org on May 5, 2013
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Exploring Native Chemical Ligation Concept for Highly
Stereospecific Glycosylation Reactions
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Kim Le Mai Hoang, Yaguang Bai, Xin Ge and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 21 Nanyang Link, Singapore 637371
xuewei@ntu.edu.sg
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Table of Contents (TOC) graphic
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ABSTRACT: Various O-alkyl glycosides were obtained in a highly stereospecific manner with
retention of configuration at the anomeric center. Our method has customized native chemical ligation
concept for glycoconjugates synthesis, utilizing a meticulously controlled activating system. To
explain the origin of stereoselective preference, an SNi mechanism was proposed and corroborated by
computational calculation.
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KEYWORDS: native chemical ligation • stereospecific • glycosylation • SNi mechanism
INTRODUCTION
Ubiquitously decked on the surfaces of all cell types in nature, complex glycoconjugates play central
roles in the development, cooperation and vitality of an organism1-5. Recent technical advances have
allowed scientists to obtain the precise structure of these macromolecules, henceforth ushering in the
need to synthesize such important glycans. Multitudinous approaches to make glycosidic bonds in a
highly stereoselective manner, have steadily emerged for the last two decades6-8, including those of
intramolecular aglycon delivery concept9. Nonetheless, an efficient and universal method to confidently
prepare various glycoconjugates have yet been established, especially one that is applicable for large
scale and combinatorial chemistry.
There are many reasons for the current state of carbohydrate researches, including the formation of
new stereogenic center following every glycosylation step, the arduous characterization and purification
thereafter, as well as the common expression of carbohydrate chains in a nonlinear, branched fashion.
Efforts are ongoing in our research group to overcome these challenges.
Native chemical ligation (NCL) is by far the most used form of chemical ligation, a technique for
building a polypeptide from two unprotected peptides10, 11. A classical NCL involved a reaction between
a C-terminal thioester peptide with another peptide bearing an N-terminal cysteine residue.
Transthioesterification occurred reversibly to yield a thioester-bridged intermediate; this intermediate
rearranged irreversibly to form the desired peptide bond, replacing the temporal thio-linkage. This
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method lies at the heart of modern chemical protein synthesis12, 13, and has been our routine method to
prepare various proteins and enzymes14-16. In addition, there were previous reports by Ley and
coworkers demonstrating the use of 2-benzenesulfonyl derivatives as viable leaving groups for various
C-nucleophiles17-18 and O-nuceophiles19 substitution using organozinc reagents. A successful adaptation
of NCL philosophy would be of great value to our glycosylation studies.
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RESULTS AND DISCUSSION
Motivated by this notion, we studied glycosylation reaction bearing an analogous pattern to
NCL. 2,3,4,6-tetra-O-acetyl glucose was firstly attached to a sulfide tether to give 1a. Initial
experiments scrutinizing over various thiophilic activators were conducted in the search for a
suitable candidate to break the thio-linkage and stereoselectively form the O-glycoside product. This
prompted us to DMTSF (dimethyl(methylthio)sulfonium tetrafluoroborate) as the best reagent.
Reaction under dry condition in dichloromethane at room temperature proceeded smoothly to
give very good yield and stereoselec i i i
h i i - - i i
(Table 1, entry 3). Assessments on solvents indicated DCM to be the most suitable medium, amidst
Et2O, MeCN, THF (Table 1, entries 4-6). We found that 3 equivalents of DMTSF in DCM at room
temperature was sufficient for the reaction. On the complete stereoretention of product, it was
ambiguous whether contiguous acetyl protecting groups were responsible f ki g α-face of
intermediate 4a through the formation of a transient bridging cation20-22 or this was an intrinsic
character of the sulfide tether.
Table 1. Optimization studies with DMTSF[a].
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Entry
1
5
R
Temp.
Solvent
Yields[b]
α:β[c]
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2
3
4
5
6
7
8
9
r.t.[d]
-
-
r.t.[d]
r.t.[d]
r.t.[d]
r.t.[d]
r.t.[d]
r.t.[d]
1
2
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1n
1n
1n
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5n
5n
5n
Ac
Ac
Ac
Ac
Ac
Ac
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
90
51
β
β
3
trace
72
β
4
β
10
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5
MeCN
THF
49
β
6
66
β
7
CH2Cl2
MeCN
Et2O
70
1:1.4
1:3.6
1:2.9
1:2.5
1:2.1
1:5
1:7
β
8
53
9
62
10
11
12
13
14
15
16
17
r.t.[d]
r.t.[d]
Dioxane
THF
17
31
-
-
-
r.t.[d]
r.t.[d]
-
MeCN
EtCN
33
29
60[e]
EtCN
CH2Cl2
Et2O
68
2.2:1
2.5:1
α
66
62[e]
Et2O
[a] Unless otherwise specified, all of the reactions were carried out with 1 equivalent of 1a or 1b, 3 equivalents of DMTSF,
i i Ǻ 5 L f i hours. [b] isolated yield. [c] determined by 1H-NMR integration. [d]
room temperature. [e] reaction time was 48 hours.
To answer this question, we conducted the reaction with 2,3,4,6-tetra-O-benzyl-β-thioglucoside 1b,
which was protected by non-participating groups. Under identical condition, we obtained an anomeric
ix f i 7 % i i h α:β i : 7 Mix f
suggested existence of glucosyl oxocarbenium ion during reaction course23, of which the hydroxyl
acceptor on sulfide tether can approach from either faces of the carbocation, resulting in both
diastereoisomers. Such implication suggested that variance in solvents and temperatures can greatly
influence the outcome of reaction24-25 A g “ f h ”26, nitrile solvents27 favored more
β-anomer whereas ethereal solvents28 f α- I i i α-anomer was often found in
larger percentage due to its stronger anomeric effect29. Surprisingly, the results contradicted our initial
speculation that the reaction was a competition between SN1 and SN2 pathway: even though reaction in
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i i i h high i f β-isomer (Table 1, entry 8), ethereal solvents similarly
xhi i i i i i f β-stereoconfiguration in the product (Table 1, entries 9-11).
hi i h f f h x g x i i f β-face insinuated the
mechanism being internal nucleophilic substitution (SNi) rather than a pure SN1/SN2 contention30. With
this empirical guide, we geared i i i g i g x i h i
i - igh i -7 i i i i i ff
β-anomer as the only stereoisomer in 60% yield after 48 hours (Table 1, entry 14). Interestingly, a
f i i h h α-anomer of 1b, compound 1n, was subjected to
g i i i : x f α-isomer 5n was observed (Table 1, entries 15-17). Longer
reaction time was necessary in order to achieve a reasonable conversion rate. It was noteworthy that
meticulous maneuvers were crucial in obtaining the stereochemically pure isomer. Based on these
optimization results, we established that three equivalents of DMTSF in propionitrile or diethyl ether
-7 i h i i i β-retention α-retention products, respectively. With the protocol
delineated, evaluation on the versatility of this reaction was carried out by studying a diversified
substrate scope.
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Table 2. Exploration of substrate scope[a]
Entry
1
Sugar
Product
Yield[b] (%)
α:β[c]
90[d]
β
2
60
β
3
4
55
49
1:1.1
β
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7
51
49
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β
β
β
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8
81[d]
β
9
91[d]
β
β
10
89[d]
11
12
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14
59
β
α
93[d]
63
α
α
62[f]
[a] Unless otherwise specified, all of the reactions were carried out with 3 equivalents of DMTSF, activated molecular sieves
Ǻ i N -7 i h i i i 1H-NMR integration. [d] CH2Cl2, room temperature.
ix f α: β f 2O -7
A f i f i β-glycosyl sulfides having different protecting groups,
including acetate 1a, benzyl ether 1b, methyl ether 1e proceeded smoothly to afford the ligated
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O-glycosides in good to excellent yields (51-9 % i h β-exclusivity. However, TBS-protected ether 1c,
gave α: β ix S h i could be attributed to the suppression of SNi pathway: the steric
bulk of silyl ethers could destabilize the transient species. In this cases, reaction was likely to follow
SN1/SN2 mechanism, resulting in mixed anomers. Nevertheless, extension of reaction to
2,3,4,6-tetra-O-methyl-1-β-D-thioglucoside 1d-1g bearing aliphatic tethers of different lengths proved
to be successful. It was noteworthy that under this reaction condition even the longest carbon chain
between hydroxyl acceptor and the sulfide tether can afford the lipid-like O-glycoside 5g
stereospecifically. Interestingly, aromatic tethers showed mixed results: O-benzyl glucoside 5h starting
from benzyl alcohol 1h was obtained as expected, whereas phenol 1i, prepared from the reaction
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between
2,3,4,6-tetra-O-acetyl-β-D-thioglucoside
and
2-bromomethyl
phenol,
afforded
methyldisulfanyl-1-β-D-glucoside 5i in 91% yield. Upon closer examination, we reasoned that the
thiobenzyl S-CH2Ph bond was weaker than thioglycoside S-Csugar bond, hence it was preferable for
sulfonium intermediate 4i to dispatch the aromatic moiety rather than the glycosyl donor. There were no
significant differences in reaction yields and stereochemical outcomes when reactions were conducted
with other epimeric sugars (galactosyl 1j-1k and mannosyl 1l-1m). In addition, we were able to obtain
optically pure O-α-glucoside 5n f h i g α-thioglucoside 1n. The glycosylated products
β-5b i f β-1b α-5n f α-1n validated the capability of our method in making
glycosides with preservation of stereochemical information.
Cross-over experiments were further conducted to study the extent of intramolecular against
intermolecular impacts. 1.3 equivalents of n-butanol, which acted as a competitive nucleophile, were
transferred to the reaction mixture before DMTSF was added. As seen from Table 3, the intramolecular
products were obtained as the major product in all cases. Although the armed thioglucoside 1b showed
less preference for 5b at room temperature compared to the disarmed 1a under same condition (Table 3,
entries 1-2), reaction of 1b under optimized condition yielded the desired 5b seven times more than
butyl glucoside 6b (Table 3, entry 3), with complete stereocontrol.
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Table 3. Cross-over experiments[a].
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[b]
[b]
Entry
1
R
Temp.
Solvent
Yi f 5 % α:β
Yi f % α:β
1
2
3
1a
1b
1b
Ac
Bn
Bn
r.t.[c]
r.t.[c]
CH2Cl2
CH2Cl2
EtCN
5a (76% β
6a (15% β
5a (58%, 1:1.6)
6a (22%, 1:1)
[d]
[d]
-78 C
5 55% β
6b (8% β
[a] Unless otherwise specified, all of the reactions were carried out with 1 equivalent of 1a or 1b, 3 equivalents of DMTSF,
1.3 equivalents of n-BuOH, i i Ǻ 5 L f i h i i α:β i
determined by 1H-NMR integration. [c] room temperature. [d] reaction time was 48 hours.
Next, theoretical calculations on conformations of 1e along the reaction pathway to understand the
retentive anomeric outcome was carried out31. A plausible mechanism was depicted in Scheme 1. The
compound could go through either an internal nucleophilic substitution pathway (route A) or a typical
SN1/SN2 competition by intermolecular route B.
Scheme 1. Proposed mechanism for the retention of stereoconfiguration.
In route A, with the possbile presence of an internal H-bonding between hydroxyl acceptor and the
ring oxygen, conformation Ia is more energetically favored than the unrestrictive conformation Ib, by a
difference of 4.24 kJ/mol (Scheme 1, DFT, B3LYP/6-31+G(d) level). This conformational preference
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for Ia facilitates anchoring of h x g h β-face of the molecule during transitional state IIa.
Being brought closer to reaction center, the glycosyl acceptor can readily target the anomeric position to
give the retention product, especially at very low temperature, where thermal energy causing the
sulfonium tether to freely dissociate from the carbohydrate species, was minimal. Counter-wise, if the
two intermediates were to be separated in route B, reattachment of them would result in a mixture of
f hi h h α:β io was dependent on solvent choice as well as temperature. As the
β- f β-thioglucoside 1e i O β-
-7 h i i i h i α-coordination of this nitrile
i h β-face of intermediate IIb was accessible to the
glycosyl acceptor. Calculation for compound 1b showed a similar profile, whereas in the case of
α-substituted 1n, it was energetically favorable for hydr x g i h α-face throughout
h i i i g x i α-isomer.
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Based on cross-over experiments as well as calculation results, we inferred that intramolecular
pathway to be the prevalent factor in determining stereocontrol, while other factors including
temperature, solvents and competing nucleophiles showing complement effects.
CONCLUSION
In conclusion, we have developed a simple yet effective method for highly stereospecific
O-glycosylation based on the philosophy of native chemical ligation concept. The many subtle variables
affecting stereochemical outcome were duly controlled to give good to excellent yields and
stereoselectivity. Future work on mechanistic study as well as refining of this reaction for the synthesis
of various glycoconjugates, especially glycolipids are in progress.
EXPERIMENTAL SECTION
All reactions were conducted under an atmosphere of nitrogen, unless otherwise indicated. Anhydrous
solvents were transferred via oven-dried syringe. Flasks were flame-dried and cooled under a stream of
nitrogen. All reagents and solvents were obtained from commercial suppliers and used without further
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purification unless otherwise stated. Chromatograms were visualized by fluorescence quenching with
UV light at 254 i i g i g i i f i g i f
g i i hi i i h h
Product purification by flash column chromatography was accomplished using silica gel 60
(0.010-0.063 mm). Technical grade solvents were used for chromatography and distilled prior to use.
Optical rotations were measured in CHCl3 with a 1 cm cell (c given in g/100 mL). Melting points were
obtained in open capillary tubes in melting point apparatus. IR spectra were recorded using FTIR and
reported in cm-1. High resolution mass spectra (HRMS) were recorded on Q-TOF mass spectrometer.
Accurate masses are reported for the molecular ion [M+H]+ or a suitable fragment ion. NMR spectra
were recorded at room temperature on a 400 MHz and 500 MHz NMR spectrometer. The residual
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1
solvent signals were taken as the reference (7.26 ppm for H-NMR spectroscopy and 77.23 ppm for
13C-NM h i hif i δ i arts per million (ppm)
fi f i h i MS h i hif δ i f i f i g
constants (J) are given in Hz. Following abbreviations classify the multiplicity: s = singlet, d = doublet,
dd = doublet of doublet, t = triplet, q =quartet, m = multiplet, br = broad or unresolved. Assignments
were based on analysis of coupling constants and COSY, HMQC spectra. Compound numbers used in
the experimental section correspond to those employed in the main paper.
Synthesis of compound 1a
To a magnetically stirred solution of 2,3,4,6-tetra-O-acetyl-β-D-thioglucoside31 (2.7g, 7.5 mmol) in
DCM (5 mL) and triethylamine (Et3N, 2 mL, 0.015 mol) was added dropwise 3-bromopropanol-1 (0.9
mL 9 75 i h i f
starting materials was observed after 3 hours. Reaction mixture was dissolved in DCM (30 mL), washed
with water (50 mL), brine (50 mL). Organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure, after which flash chromatography on silica gel (hexane/EtOAc = 1:2) afforded
compound 1a (2.85g, 90% yield) as a white solid.
-20.5 (c 2.79, CHCl3); m.p. 86-88 °C; IR
1
(KBr): 3429, 2943, 1747, 1371, 1230, 1037 cm-1; H NMR (400 MHz, CDCl3): δ 5.22 (t, 1H, J = 9.6
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Hz, H-3), 5.07 (t, 1H, J = 9.8 Hz, H-4), 5.05 (t, 1H, J = 9.6 Hz, H-2), 4.48 (d, 1H, J = 10.1 Hz, H-1),
4.23 (dd, 1H, J = 13.2 Hz, J = 3.3 Hz, H- ’ H J = 13.1 Hz, J = 2.3 Hz, H-6), 3.73-3.69 (m,
3H, H-5, CH2OH), 2.88-2.72 (m, 2H, SCH2), 2.08, 2.06, 2.02, 2.00 (s, 12H, 4xCOCH3), 1.87-1.64 (m,
1
2
3
4
5
6
7
8
13
2H, -CH2-) ppm; C NMR (100 MHz, CDCl3): δ 170.9, 170.4, 169.8, 169.6 (COCH3 x4), 83.7 (C-1),
9
76.2 (C-5), 73.9 (C-2), 69.9 (C-3), 68.4 (C-4), 62.2 (C-6), 60.7 (-CH2OH), 32.2 (-CH2-), 26.3 (SCH2),
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20.9, 20.8, 20.7 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C17H26O10S [M+Na]+, 445.1144, found:
445.1136.
Synthesis of compound 1b
To
a
magnetically stirred solution of 2,3,4,6-tetra-O-benzyl-β-D-(4-monomethoxytrityl)
thioglucoside32 (1.85g, 2.31 mmol) in DCM (10 mL) was added trifluoroacetic acid (TFA, 5
mL-per-mmol substrate). Complete consumption of starting materials was observed after 1 hour.
Reaction mixture was dissolved in DCM (30 mL) and washed with ice-water (30 mL), aq. NaHCO3 (30
mL), brine (30 mL). Organic layers were dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was dissolved in a solution of DCM (5 mL) and triethylamine (Et3N, 0.65
mL, 4.63 mmol), followed by dropwise addition of 3-bromopropanol-1 (0.27 mL
Reaction was allowed to reach room temperature and complete consumption of starting materials was
observed after 3 hours. Reaction mixture was dissolved in DCM (30 mL), washed with water (50 mL),
brine (50 mL). Organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure,
after which flash chromatography on silica gel (hexane/EtOAc = 2:1) afforded compound 1b (1.27g,
89% yield) as a white solid.
+17.4 (c 1.36, CHCl3); m.p. 65-68 °C; IR (KBr): 3414, 2866, 1653,
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1454, 1066 cm-1; H NMR (400 MHz, CDCl3): δ 7.38-7.12 (m, 20H, aromatic), 4.93-4.49 (m, 8H,
4xOCH2Ph), 4.44 (d, 1H, J = 9.8 Hz, H-1), 3.84-3.69 (m, 2H, CH2OH), 3.69-3.56 (m, 2H, H-6), 3.64 (t,
1H, J = 8.7 Hz, H-3), 3.52 (t, 1H, J = 8.7 Hz, H-4), 3.65-3.54 (m, 1H, H-5), 3.43 (t, 1H, J = 9.7 Hz,
H-2), 2.96-2.75 (m, 2H, SCH2), 2.3 (t, 1H, J = 5.5 Hz, OH), 1.91-1.79 (m, 2H, -CH2-) ppm; 13C NMR
(100 MHz, CDCl3): δ 138.1, 128.6, 128.5, 128.2, 128.1, 127.9 (m, aromatic), 86.7 (C-1), 85.9 (C-3),
81.7 (C-2), 78.9 (C-4), 78.1 (C-5), 75.9, 75.7, 75.3, 73.6 (-OCH2Ph x4), 69.2 (C-6), 60.2 (CH2OH), 32.8
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(-CH2-), 27.6 (SCH2-) ppm; HRMS (ESI): m/z calcd for C37H42O6S [M+Na]+, 637.2601, found:
637.2587.
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Synthesis of compound 1c
To a magnetically stirred solution of 1-thio-β-D-Glucose34 (0.27g, 1.42 mmol) in anhydrous DMF (10
mL) and Et3N (0.4 mL, 2.84 mmol) was added dropwise a solution of 3-bromopropyl acetate (0.33g,
1.85 mmol) in 10 mL of anhydrous DMF. Complete consumption of starting materials was observed
after 3 hours, after which 2,6-lutidine (0.37 mL, 3.26 mmol) was added, followed by dropwise addition
of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 0.47 mL i
was allowed to reach room temperature, after which complete consumption of starting materials was
observed after 4 hours. Reaction mixture was quenched by addition of ice-water (30 mL), followed by
dissolution in ethyl ether (Et2O, 30 mL) and washed with aq. NaHCO3 (2x30 mL), brine (2x30 mL).
The crude product was dissolved in MeOH (10 mL), followed by addition of catalytic amount of K2CO3
(2.85mg, 0.02 mmol). Complete consumption of starting materials was observed after 3 hours. Reaction
mixture was dissolved in DCM (30 mL), washed with water (50 mL), brine (50 mL). Organic layers
were dried over Na2SO4, filtered and concentrated under reduced pressure, after which flash
chromatography on silica gel (hexane/EtOAc = 2:1) afforded compound 1c (0.21g, 72% yield over 2
i i g ix f α:β = : IR (KBr): 3413, 1616, 1249, 1091, 781
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cm-1; H NMR (400 MHz, CDCl3): δ 5.23 (d, 1H, J = 4 Hz, H- α 7 H J = 7.7 Hz, H- β
3.9-3.89 (m, 1H), 3.81-3.71 (m, 6H), 3.65-3.63 (m, 1H), 2.87-2.68 (m, 2H, SCH2), 1.96 (t, 1H, J = 5.84
Hz, OH), 1.89-1.80 (m, 2H, -CH2-), 0.89-0.88 (m, 36H, 4xSiC(CH3)3), 0.13-0.05 (m, 24H, 4xSi(CH3)2)
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ppm; C NMR (100 MHz, CDCl3): δ 84.5 (C-1), 83.6 (C-5), 78.1 (C-3), 76.7 (C-2), 70.4 (C-4), 64.6
(C-6), 60.9 (CH2OH), 32.5 (-CH2-), 27.6, 26.2, 26.1, 26.0 (C(CH3)3 x4), 18.6, 18.3, 18.1, 18.0 (C(CH3)3
x4), -3.8, -3.9, -4.0, -4.1 (Si(CH3)2 x4) ppm; HRMS (ESI): m/z calcd for C33H75O6SSi4 [M+H]+,
711.4362, found: 711.4362.
Synthesis of compound 1d
To a magnetically stirred solution of 2,3,4,6-tetra-O-methyl-β-D-thioglucose31 in DCM (5 mL) and
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triethylamine (Et3N, 0.13 mL, 0.9 mmol), followed by dropwise addition of 2-bromoethanol (0.04 mL
5 i h i f
starting materials was observed after 3 hours. Reaction mixture was dissolved in DCM (30 mL), washed
with water (50 mL), brine (50 mL). Organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure, after which flash chromatography on silica gel (hexane/EtOAc = 2:1) afforded
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compound 1d (0.25g, 89% yield) as a white solid.
+24.1 (c 0.46, CHCl3); m.p. 41-42 °C; IR
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(KBr): 3419, 1635, 1458, 1093, 665 cm-1; H NMR (400 MHz, CDCl3): δ 4.28 (d, 1H, J = 9.92 Hz,
H-1), 3.81-3.75 (m, 2H, OCH2), 3.63-3.37 (m, 11H, 3xOCH3, H-6), 3.37 (s, 3H, OCH3), 3.34-3.33 (m,
1H, H-5), 3.18 (t, 1H, J = 8.8 Hz, H-4), 3.09 (t, 1H, J = 9.5 Hz, H-3), 2.96 (t, 1H, J = 9.9 Hz, H-2),
2.95-2.75 (m, 2H, SCH2) ppm; 13C NMR (100 MHz, CDCl3): δ 88.6 (C-1), 86.4 (C-3), 83.3 (C-2), 79.6
(C-4), 78.6 (C-5), 71.6 (C-6), 63.3 (CH2OH), 61.2, 61.1, 60.0, 59.4 (OCH3 x4), 36.7 (SCH2-) ppm;
HRMS (ESI): m/z calcd for C12H24O6S [M+Na]+, 319.1191, found: 319.1190.
Synthesis of compound 1e
Folowing the synthesis of compound 1d using 3-bromopropanol-1 afforded 1e (0.23g, 80% yield) as
a white solid.
+1.5 (c 0.65, CHCl3); m.p. 48-49 °C; IR (KBr): 3419, 2933, 1627, 1448, 1095 cm-1;
1H NMR (400 MHz, CDCl3): δ 4.27 (d, 1H, J = 9.8 Hz, H-1), 3.85-3.69 (m, 2H, OCH2), 3.64-3.50 (m,
11H, 3xOCH3, H-6), 3.38 (s, 3H, OCH3), 3.33-3.28 (m, 1H, H-5), 3.18 (t, 1H, J = 8.8 Hz, H-4), 3.05 (t,
1H, J = 9.5 Hz, H-3), 2.96 (t, 1H, J = 9.8 Hz, H-2), 2.95-2.74 (m, 2H, SCH2), 2.57 (t, 1H, J = 5.8 Hz,
OH), 1.86-1.66 (m, 2H, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 88.6 (C-1), 85.8 (C-3), 83.5 (C-2),
79.9 (C-4), 78.6 (C-5), 71.9 (C-6), 63.2 (CH2OH), 61.1, 60.7, 59.9, 59.3 (OCH3 x4), 32.7 (-CH2-), 27.7
(SCH2-) ppm; HRMS (ESI): m/z calcd for C13H26O6S [M+Na]+, 333.1348, found: 333.1351.
Synthesis of compound 1f
Folowing the synthesis of compound 1d using 4-bromobutanol-1 afforded 1f (0.18g, 83% yield) as a
white solid.
+29.1 (c 0.32, CHCl3); m.p. 54-55 °C; IR (KBr): 3419, 2933, 1627, 1458, 1095 cm-1;
1H NMR (400 MHz, CDCl3): δ 4.24 (d, 1H, J = 9.8 Hz, H-1), 3.63-3.48 (m, 13H, 3xOCH3, OCH2,
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H-6), 3.35 (s, 3H, OCH3), 3.27-3.23 (m, 1H, H-5), 3.15 (t, 1H, J = 8.7 Hz, H-4), 3.06 (t, 1H, J = 9.4 Hz,
H-3), 2.93 (t, 1H, J = 9.8 Hz, H-2), 2.74-2.65 (m, 2H, SCH2), 1.74-1.22 (m, 4H, -CH2CH2-), 2.00 (s, 1H,
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OH) ppm; C NMR (100 MHz, CDCl3): δ 88.6 (C-1), 85.3 (C-3), 83.5 (C-2), 79.7 (C-4), 78.8 (C-5),
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71.8 (C-6), 62.2 (OCH2OH), 61.1, 60.9, 60.6, 59.4 (OCH3 x4), 31.7 (SCH2CH2CH2), 31.0 (SCH2-), 26.2
(SCH2CH2-) ppm; HRMS (ESI): m/z calcd for C14H28O6S [M+Na]+, 347.1504, found: 347.1508.
Synthesis of compound 1g
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Folowing the synthesis of compound 1d using 5-bromopentanol-1 afforded 1g (0.22g, 86% yield) as a
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white solid.
+0.5 (c 0.31, CHCl3); m.p. 63-65 °C; IR (KBr): 3419, 2933, 1627, 1095 cm-1; H
NMR (400 MHz, CDCl3): δ 4.25 (d, 1H, J = 9.8 Hz, H-1), 3.66-3.51 (m, 13H, 3xOCH3, OCH2, H-6),
3.38 (s, 3H, OCH3), 3.26-3.24 (m, 1H, H-5), 3.18 (t, 1H, J = 8.8 Hz, H-4), 3.10 (t, 1H, J = 9.4 Hz, H-3),
2.96 (t, 1H, J = 9.8 Hz, H-2), 2.93-2.67 (m, 2H, SCH2), 2.04-1.43 (m, 7H, -CH2CH2CH2-, OH) ppm;
13C NMR (100 MHz, CDCl3): δ 88.7 (C-1), 85.4 (C-3), 83.6 (C-2), 79.7 (C-4), 71.8 (C-5), 62.8 (C-6),
61.1 (CH2OH), 61.0, 60.7, 59.5 (OCH3 x4), 32.3 (CH2CH2OH), 31.1 (SCH2CH2), 29.8 (SCH2), 25.1
(SCH2CH2CH2) ppm; HRMS (ESI): m/z calcd for C15H30O6S [M+Na]+, 361.1661, found: 361.1664.
Synthesis of compound 1h
To a magnetically stirred solution of 2,3,4,6-tetra-O-acetyl-α-D-glucosyl bromide33 (0.41g, 1 mmol)
in anhydrous acetonitrile (10 mL) was added Et3N (0.28 mL, 2 mmol), followed by potionwise addition
of 2-mercaptobenzyl alcohol (0.18g, 1.3 mmol). Complete consumption of starting materials was
observed after 4 hours. Reaction mixture was dissolved in DCM (30 mL), washed with water (2x50 mL),
brine (30 mL). Organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure,
after which flash chromatography on silica gel (hexane/EtOAc = 1:1) afforded compound 1h (0.36g,
77% yield) as a white solid.
+28.8 (c 0.35, CHCl3); m.p. 80-83 °C; IR (KBr): 3439, 1635, 1369,
1228, 1037 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.59-7.28 (m, 4H, aromatic), 5.21 (t, 1H, J = 9.4 Hz,
H-3), 5.03 (t, 2H, J = 9.8 Hz, H-2, H-4), 4.88 (dd, 1H, J = 12.7 Hz, J = 5.7 Hz, OCH2Ph), 4.67 (dd, 1H,
J = 12.6 Hz, J = 7.8 Hz, OCH2Ph), 4.64 (d, 1H, J = 10.1 Hz, H-1), 4.19-4.09 (m, 2H, H-6), 3.66-3.62
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(m, 1H, H-5), 2.76-2.73 (m, 1H, OH), 2.14, 2.04, 2.01, 2.00 (s, 12H, 4xCOCH3) ppm; C NMR (100
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MHz, CDCl3): δ 170.8, 170.4, 169.6, 169.5 (COCH3 x4), 145.5, 136.4, 130.2, 129.7, 128.9 (m,
aromatic), 87.1 (C-1), 76.1 (C-5), 74.0 (C-3), 70.4 (C-2), 68.1 (C-4), 63.8 (CH2O), 61.9 (C-6), 21.0,
20.8, 20.7 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C21H26O10S [M+Na]+, 493.1144, found:
493.1140.
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Synthesis of compound 1i
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To a magnetically stirred solution of 2,3,4,6-tetra-O-acetyl-β-D-thioglucoside31 (0.36g, 1 mmol) in
anhydrous DCM (10 mL) and Et3N (0.28 mL, 2 mmol) was added dropwise a solution of
2-bromomethyl phenol (0.24g, 1.3 mmol) in 10 mL of anhydrous DCM. Complete consumption of
starting materials was observed after 3 hours. Reaction mixture was dissolved in DCM (30 mL), washed
with water (30 mL), brine (30 mL). Organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure, after which flash chromatography on silica gel (hexane/EtOAc = 1:1) afforded
compound 1i (0.38g, 81% yield) as a white solid.
+131.6 (c 0.06, CHCl3); m.p. 54-55 °C; IR
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(KBr): 3415, 1629, 1230, 1037 cm-1; H NMR (400 MHz, CDCl3): δ 7.26-7.11 (m, 2H, aromatic),
6.88-6.83 (m, 1H, aromatic), 6.13 (br, 1H, OH), 5.19 (t, 1H, J = 9.2 Hz, H-3), 5.13-5.06 (m, 2H, H-2,
H-4), 4.43 (d, 1H, J = 9.9 Hz, H-1) 4.24 (dd, 1H, J = 12.4 Hz, J = 4.8 Hz, H- ’ H J = 12.4
Hz, J = 2.5 Hz, H-6), 4.00 (d, 1H, J = 13.1 Hz, SCH2Ph), 3.85 (d, 1H, J = 13.1 Hz, SCH2Ph), 3.70-3.66
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(m, 1H, H-5), 2.11, 2.05, 2.02, 2.01 (s, 12H, 4xCOCH3) ppm; C NMR (100 MHz, CDCl3): δ 171.0,
170.3, 170.0, 169.6 (COCH3 x4), 154.9, 130.8, 129.7, 122.3, 120.8, 117.1 (m, aromatic), 82.3 (C-1),
76.1 (C-5), 73.7 (C-2), 69.8 (C-3), 68.5 (C-4), 62.3 (C-6), 29.1 (SCH2), 21.0, 20.9, 20.8, 20.7 (COCH3
x4) ppm; HRMS (ESI): m/z calcd for C21H26O10S [M+Na]+, 493.1144, found: 493.1143.
Synthesis of compound 1j
Folowing the synthesis of compound 1a starting from D-galactose afforded 1j (0.12g, 65% yield) as a
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colorless oil.
+1.9 (c 1.06, CHCl3); IR (KBr): 3421, 1747, 1635, 1369, 1228, 1047 cm-1; H
NMR (400 MHz, CDCl3): δ 5.41 (dd, 1H, J = 3.4 Hz, J = 0.7 Hz, H-4), 5.23 (t, 1H, J = 9.9 Hz, H-2),
5.02 (dd, 1H, J = 10.0 Hz, J = 3.3 Hz, H-3), 4.46 (d, 1H, J = 9.9 Hz, H-1), 4.16-4.05 (m, 2H, H-6), 3.92
(m, 1H, H-5), 3.71 (m, 2H, CH2OH), 2.89-2.73 (m, 2H, SCH2), 2.13, 2.05, 2.03, 1.96 (s, 12H,
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4xCOCH3), 1.91-1.87 (m, 2H, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 170.6, 170.4, 170.2, 169.9
(COCH3 x4), 84.2 (C-1), 74.7 (C-5), 71.9 (C-2), 67.5 (C-3), 67.2 (C-4), 61.7 (C-6), 60.8 (CH2OH), 32.2
(SCH2CH2), 26.5 (SCH2), 21.2, 20.9, 20.7 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C17H26O10S
[M+Na]+, 445.1144, found: 445.1151.
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Synthesis of compound 1k
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Folowing the synthesis of compound 1b starting from D-galactose afforded 1k (0.13g, 80% yield) as
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a colorless oil.
+118.7 (c 0.1, CHCl3); IR (KBr): 3419, 1647, 1095, 790 cm-1; H NMR (500
MHz, CDCl3): δ 7.45-7.32 (m, 20H, aromatic), 5.01-4.46 (m, 8H, 4xOCH2Ph), 4.45 (d, 1H, J = 11.8 Hz,
H-1), 3.96 (d, 1H, J = 2.45 Hz, H-4), 3.90 (t, 1H, J = 11.8 Hz, H-2), 3.79-3.73 (m, 2H, OCH2),
3.72-3.60 (m, 3H, H-3, H-5, H-6), 3.55-3.31 (m, 1H, H-6), 2.97-2.77 (m, 2H, SCH2), 2.41 (br, 1H, OH),
1.91-1.84 (m, 2H, -CH2-) ppm; 13C NMR (125 MHz, CDCl3): δ 138.8, 138.6, 138.4, 138.3, 137.9,
137.8, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6 (m, aromatic), 85.9 (C-1),
84.1 (C-3), 75.8 (C-2), 74.5 (C-4), 73.6 (C-5), 72.9, 69.1 (OCH2Ph x4), 60.5 (C-6), 32.6 (SCH2CH2),
27.3 (SCH2) ppm; HRMS (ESI): m/z calcd for C37H42O6S [M+Na]+, 637.2601, found: 637.2596.
Synthesis of compound 1l
Folowing the synthesis of compound 1a starting from D-mannose afforded 1l (0.14g, 72% yield) as a
white solid.
+67.2 (c 2.32, CHCl3); m.p. 76-77 °C; IR (KBr): 3485, 2939, 1747, 1371, 1228,
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1051 cm-1; H NMR (400 MHz, CDCl3): δ 5.34-5.24 (m, 4H, H-1, H-2, H-3, H-4), 4.39-4.36 (m, 1H,
H-5), 4.30 (dd, 1H, J = 9.7 Hz, J = 4.3 Hz, H- ’ H J = 9.7 Hz, J = 1.6 Hz, H-6), 3.75-3.74
(m, 2H, CH2OH), 2.82-2.70 (m, 2H, SCH2), 2.16, 2.09, 2.05, 2.99 (s, 12H, 4xCOCH3), 1.91-1.86 (m,
2H, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 170.9, 170.2, 170.0, 169.9 (COCH3 x4) , 83.0 (C-1),
71.4 (C-5), 69.6 (C-3), 69.3 (C-2), 66.6 (C-4), 62.7 (OCH2), 61.1 (C-6), 32.2 (SCH2CH2), 28.2 (SCH2),
21.1, 20.9, 20.9, 20.8 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C17H26O10S [M+Na]+, 445.1144,
found: 445.1138.
Synthesis of compound 1m
Folowing the synthesis of compound 1b starting from D-galactose afforded 1m (0.11g, 82% yield) as
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1
a colorless oil.
+78.7 (c 0.53, CHCl3); IR (KBr): 3439, 1635, 1093, 1026, 786 cm-1; H NMR
(400 MHz, CDCl3): δ 7.42-7.19 (m, 20H, aromatic), 5.43 (d, 1H, J = 0.6 Hz, H-1), 4.96-4.55 (m, 8H,
4xOCH2Ph), 4.23-4.20 (m, 1H, H-5), 3.97 (t, 1H, J = 7.32 Hz, H-4), 3.91-3.84 (m, 2H, H-2, H-3),
3.83-3.78 (m, 2H, H-6), 3.77-3.69 (m, 2H, OCH2), 2.81-2.67 (m, 2H, SCH2), 2.07 (br, 1H, OH),
1.92-1.74 (m, 2H, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 138.5, 138.3, 138.2, 128.5, 128.1,
127.8, 127.7 (m, aromatic), 82.9 (C-1), 80.4 (C-3), 76.5 (C-2), 75.3 (C-4), 73.5, 72.3, 72.2 (OCH2Ph x4),
69.4 (C-5), 60.8 (C-6), 32.3 (SCH2CH2), 28.3 (SCH2) ppm; HRMS (ESI): m/z calcd for C37H42O6S
[M+Na]+, 637.2601, found: 637.2599.
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Synthesis of compound 1n
To a magnetically stirred solution of 2,3,4,6-tetra-O-benzyl-α-D-thioglucose35 was dissolved in DCM
(10 mL), to which was added Et3N (0.24 mL, 1.7 mmol), followed by dropwise addition of
3-bromopropanol-1 (0.1 mL i h
complete consumption of starting materials was observed after 3 hours. Reaction mixture was dissolved
in DCM (30 mL), washed with water (30 mL), brine (30 mL). Organic layers were dried over Na2SO4,
filtered and concentrated under reduced pressure, after which flash chromatography on silica gel
(hexane/EtOAc = 1:1) afforded compound 1n (0.34g, 66% yield over 2 steps) as a white solid.
+47.4 (c 1.35, CHCl3); m.p. 65-67 °C; IR (KBr): 3414, 2866, 1653, 1454, 1066 cm-1; H NMR (400
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MHz, CDCl3): δ 7.34-7.21 (m, 18H, aromatic), 7.09-7.07 (m, 2H, aromatic), 5.32 (d, 1H, J = 4.7 Hz,
H-1), 4.91-4.39 (m, 8H, 4xOCH2Ph), 4.16-4.13 (m, 1H, H-5), 3.81-3.78 (m, 2H, H-2, H-3), 3.69-3.58
(m, 4H, H-6, CH2OH), 3.52 (t, 1H, J = 9.7 Hz, H-4), 2.66-2.58 (m, 2H, SCH2), 1.83-1.80 (m, 2H,
-CH2-), 1.67 (t, 1H, J = 5.5 Hz, OH) ppm; 13C NMR (100 MHz, CDCl3): δ 138.8, 138.3, 137.9, 128.6,
128.5, 128.3, 128.2, 128.1, 127.9, 127.8, 83.8 (C-1), 82.7 (C-3), 79.7 (C-2), 77.7 (C-4), 75.3, 73.6, 72.7,
70.8 (OCH2Ph x4), 68.9 (C-5), 61.5 (C-6), 32.2 (SCH2CH2), 26.5 (SCH2) ppm; HRMS (ESI): m/z calcd
for C37H43O6S [M+H]+, 615.2780, found: 615.2780.
Synthesis of compound 5a
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To a magnetically stirred solution of compound 1a (0.1g, 0.24 mmol) in anhydrous DCM (5 mL) was
charged with pre- i i Ǻ g-per- mmol substrate), after which DMTSF
(0.14g, 72 mmol) was added in one portion. After complete consumption of starting materials was
observed, reaction mixture was quenched with aq. NaHCO3 (5 mL), followed by dissolution in DCM
(10 mL), washed with water (30 mL), brine (30 mL). Organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure, after which flash chromatography on silica gel
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(hexane/EtOAc = 1.3:1) afforded compound 5a (0.1g, 90% yield) as a colorless oil.
+31.7 (c 0.13,
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CHCl3); IR (KBr): 3018, 1755, 1215, 1039, 754 cm-1; H NMR (400 MHz, CDCl3): δ 5.2 (t, 1H, J =
7.6 Hz), 5.08 (t, 1H, J = 7.8 Hz), 4.98 (t, 1H, J = 8.4 Hz), 4.51 (d, 1H, J = 6.4 Hz, H-1), 4.26 (dd, 1H, J
= 9.8 Hz, J = 3.8 Hz, H- ’ H J = 9.6 Hz, J = 1.9 Hz, H-6), 3.97-3.95 (m, 1H, OCH2),
3.71-3.68 (m, 1H, H-5), 3.65-3.63 (m, 1H, OCH2), 2.76-2.72 (m, 2H, SCH2), 2.39 (s, 3H, SSCH3),
2.09-1.95 (m, 14H, 4xCOCH3, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 170.9, 170.5, 169.6, 169.5
(COCH3), 101.1 (C-1), 73.0 (C-5), 72.0 (C-3), 71.5 (C-2), 68.6 (C-4), 68.1 (OCH2), 62.1 (C-6), 34.1
(SCH2), 28.8 (SCH2CH2), 23.3 (SSCH3), 21.0, 20.9, 20.8 (COCH3 x4) ppm; HRMS (ESI): m/z calcd
for C18H28O10S2 [M+Na]+, 491.1022, found: 491.1022.
Synthesis of compound 5b
To a magnetically stirred solution of compound 1b (0.1g, 0.16 mmol) in anhydrous propionitrile (5
mL h g i h - i i Ǻ g- - i
-7 f 5 i f hi h DM SF 95g 9 i i
Reaction was maintained at this temperature till complete consumption of starting materials was
observed, after which reaction mixture was directly quenched with aq. NaHCO3 (5 mL -7 h
suspension was allowed to reach room temperature, followed by dissolution in DCM (20 mL), washed
with water (30 mL), brine (30 mL). Organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure, after which flash chromatography on silica gel (hexane/EtOAc = 6:1) afforded
compound 5b (63mg, 60% yield) as a colorless oil.
+25.1 (c 0.37, CHCl3); IR (KBr): 2916, 1496,
1454, 1070, 754 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.52-7.27 (m, 18H, aromatic), 7.16-7.14 (m, 2H,
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aromatic), 4.93-4.51 (m, 8H, 4xOCH2Ph), 4.39 (d, 1H, J = 7.7Hz, H-1), 4.06-4.01 (m, 1H), 3.75-3.56
(m, 5H), 3.46-3.42 (m, 2H), 2.81 (t, 2H, J = 7.7 Hz, SCH2), 2.37 (s, 3H, SSCH3), 2.09-2.04 (m, 2H,
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-CH2-) ppm; C NMR (100 MHz, CDCl3): δ 138.6, 138.3, 130.9, 128.6, 128.3, 128.2, 128.1, 128.0,
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127.9, 127.8 (m, aromatic), 103.8 (C-1), 84.9 (C-3), 82.5 (C-2), 75.2 (C-4), 75.1 (m, OCH2Ph), 73.7
(C-5), 68.3 (C-6), 29.9 (d, SCH2CH2, SCH2), 29.5 (SSCH3) ppm; HRMS (ESI): m/z calcd for
C38H44O6S2 [M+Na]+, 683.2477, found: 683.2476.
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Synthesis of compound 5c
Folowing the synthesis of compound 5b starting from compound 1c α:β = : afforded 5c (58mg,
55% i i i g ix f α:β = : IR (KBr): 3419, 1635, 1095,
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1056 cm-1; H NMR (400 MHz, CDCl3): δ 5.25 (2, 1H, H- α 7 H J = 6.8 Hz, H- β
3.96-3.38 (m, 16H, H- α β H- α β H- α β H-5α β H- α β O H2α β -2.73 (m, 4H, SCH2α
SCH2β H SS H3α SS H3β 7-1.99 (m, 2H, -CH2β-), 1.94-1.87 (m, 2H, -CH2α-),
0.92-0.87 (m, 72H, 4xSiC(CH3)3α xSi H3)3β -0.01 (m, 48H, 4xSi(CH3)2α xSi H3)2β ;
HRMS (ESI): m/z calcd for C34H76O6S2Si4 [M+H]+, 779.4058, found: 779.4055.
Synthesis of compound 5d
Folowing the synthesis of compound 5b starting from compound 1d afforded 5d (56mg, 49% yield)
as a colorless oil.
+19.8 (c 0.68, CHCl3); IR (KBr): 3419, 2918, 1635, 1095 cm-1; 1H NMR (400
MHz, CDCl3): δ 4.26 (d, 1H, J = 7.6 Hz, H-1), 4.14-4.1 (m, 1H, OCH2); 3.81-3.78 (m, 1H, OCH2),
3.63-3.52 (m, 11H, 3xOCH3, H-5, H-6), 3.40 (s, 3H, OCH3), 3.28-3.25 (m, 1H, H-4), 3.25-3.13 (m, 2H,
H-3, H-6), 3.01-2.98 (m, 1H, H-2), 2.94 (t, 2H, J = 6.7 Hz, SCH2), 2.40 (s, 3H, SSCH3) ppm; 13C NMR
(100 MHz, CDCl3): δ 103.7 (C-1), 86.6 (C-3), 83.8 (C-2), 79.5 (C-4), 74.8 (C-5), 71.5 (C-6), 68.3
(OCH2), 61.1, 60.8, 60.6, 59.6 (OCH3 x4), 37.8 (SCH2), 23.6 (SSCH3) ppm; HRMS (ESI): m/z calcd
for C13H26O6S2 [M+Na]+, 365.1069, found: 365.1066.
Synthesis of compound 5e
Folowing the synthesis of compound 5b starting from compound 1e afforded 5e (58g, 51% yield) as a
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colorless oil.
+22.1 (c 0.37, CHCl3); IR (KBr): 3419, 2918, 1627, 1095 cm-1; H NMR (400
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MHz, CDCl3): δ 4.22 (d, 1H, J = 7.7 Hz, H-1), 4.01-3.96 (m, 1H, OCH2); 3.64-3.53 (m, 12H, 3xOCH3,
OCH2, H-5, H-6), 3.40 (s, 3H, OCH3), 3.28-3.24 (m, 1H, H-4), 3.17-3.11 (m, 2H, H-3, H-6), 3.00-2.96
(m, 1H, H-2), 2.80 (t, 2H, J = 7.4 Hz, SCH2), 2.40 (s, 3H, SSCH3); 2.05-1.98 (m, 2H, -CH2-) ppm; 13C
NMR (100 MHz, CDCl3): δ 103.6 (C-1), 86.6 (C-3), 83.9 (C-2), 79.5 (C-4), 74.8 (C-5), 71.5 (C-6),
68.1 (OCH2), 61.0, 60.7, 60.6, 59.6 (OCH3 x4), 34.7 (SCH2), 29.5 (SCH2CH2), 23.4 (SSCH3) ppm;
HRMS (ESI): m/z calcd for C14H28O6S2 [M+Na]+, 379.1225, found: 379.1225.
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Synthesis of compound 5f
Folowing the synthesis of compound 5b starting from compound 1f afforded 5f (55mg, 49% yield) as
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+1.24 (c 1.7, CHCl3); IR (KBr): 3419, 2918, 1635, 1446, 1095 cm-1; H NMR
(400 MHz, CDCl3): δ 4.21 (d, 1H, J = 7.8 Hz, H-1), 3.95-3.91 (m, 1H, OCH2); 3.63-3.51 (m, 12H,
3xOCH3, OCH2, H-5, H-6), 3.40 (s, 3H, OCH3), 3.27-3.24 (m, 1H, H-4), 3.15-3.10 (m, 2H, H-3, H-6),
2.98-2.75 (m, 1H, H-2), 2.73-2.46 (m, 2H, SCH2), 2.40 (s, 3H, SSCH3); 1.83-1.71 (m, 4H, -CH2CH2-)
ppm; 13C NMR (100 MHz, CDCl3): δ 103.5 (C-1), 86.6 (C-3), 83.9 (C-2), 79.6 (C-4), 74.7 (C-5), 71.6
(C-6), 69.4 (OCH2), 62.6, 61.0, 60.7, 59.6 (OCH3 x4), 38.1 (SCH2), 31.6 (OCH2CH2), 28.6 (SCH2CH2),
23.5 (SSCH3) ppm; HRMS (ESI): m/z calcd for C15H30O6S2 [M+Na]+, 393.1382, found: 393.1396.
Synthesis of compound 5g
Folowing the synthesis of compound 5b starting from compound 1g afforded 5g (57mg, 50% yield)
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as a colorless oil.
+6.8 (c 0.93, CHCl3); IR (KBr): 3421, 1627, 1074, 794 cm-1; H NMR (400
MHz, CDCl3): δ 4.21 (d, 1H, J = 7.8 Hz, H-1), 3.94-3.88 (m, 1H, OCH2); 3.63-3.45 (m, 12H, 3xOCH3,
OCH2, H-5, H-6), 3.40 (s, 3H, OCH3), 3.26-3.24 (m, 1H, H-4), 3.17-3.09 (m, 2H, H-3, H-6), 2.99-2.96
(m, 1H, H-2), 2.70 (t, 2H, J = 7.4 Hz, SCH2), 2.40 (s, 3H, SSCH3); 1.76-1.25 (m, 6H, -CH2CH2CH2-)
ppm; 13C NMR (100 MHz, CDCl3): δ 103.6 (C-1), 86.6 (C-3), 83.9 (C-2), 79.6 (C-4), 74.7 (C-5), 71.6
(C-6), 69.8 (OCH2), 62.9, 61.0, 60.6 (OCH3 x4), 29.5 (SCH2), 29.1 (OCH2CH2), 25.2 (SCH2CH2), 24.8
(SCH2CH2CH2), 23.5 (SSCH3) ppm; HRMS (ESI): m/z calcd for C16H32O6S2 [M+Na]+, 407.1538,
found: 407.1535.
Synthesis of compound 5h
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Folowing the synthesis of compound 5a starting from compound 1h afforded 5h (0.088g, 81% yield)
-1.19 (c 0.57, CHCl3); IR (KBr): 3421, 1749, 1629, 1226, 1039 cm-1; 1H NMR
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(400 MHz, CDCl3): δ 7.78-7.76 (m, 1H, aromatic), 7.37-7.28 (m, 3H, aromatic), 5.18 (t, 1H, J = 9.4 Hz,
H-3), 5.13-5.04 (m, 2H, H-4, H-2), 4.98 (d, 1H, J = 12.5 Hz, OCH2Ph), 4.81 (d, 1H, J = 12.5 Hz,
OCH2Ph), 4.55 (d, 1H, J = 7.8 Hz, H-1), 4.29 (dd, 1H, J = 12.3 Hz, J = 4.8 Hz, H- ’ H J =
12.2 Hz, J = 2.4 Hz, H-6), 3.72-3.68 (m, 1H, H-5), 2.42 (s, 3H, SSCH3), 2.11, 2.02, 2.02, 1.99 (s, 12H,
4xCOCH3) ppm; 13C NMR (100 MHz, CDCl3): δ 170.9, 170.5, 169.6 (COCH3 x4), 136.1, 129.4, 129.3,
129.0, 127.6 (m, aromatic), 99.5 (C-1), 73.0 (C-5), 72.1 (C-3), 71.4 (C-2), 68.7 (C-4), 68.6 (OCH2), 62.1
(C-6), 22.9 (SSCH3), 21.0, 20.8 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C22H28O10S2 [M+Na]+,
539.1022, found: 539.1021.
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Synthesis of compound 5i
Folowing the synthesis of compound 5a starting from compound 1i afforded 5i (0.1g, 91% yield) as a
colorless oil.
-51.0 (c 1.1, CHCl3); IR (KBr): 3419, 1747, 1635, 1224, 1041 cm-1; 1H NMR (400
MHz, CDCl3): δ 5.48-5.23 (m, 2H, H-3, H-4), 5.11 (t, 1H, J = 9.4 Hz, H-2), 4.57 (d, 1H, J = 9.4 Hz,
H-1), 4.21-4.14 (m, 2H, H-6), 3.76-3.72 (m, 1H, H-5), 2.47 (s, 3H, SSCH3), 2.07, 2.06, 2.03, 2.01 (s,
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12H, 4xCOCH3) ppm; C NMR (100 MHz, CDCl3): δ 170.7, 170.4, 169.6, 169.4 (COCH3 x4), 88.1
(C-1), 76.2 (C-5), 74.0 (C-3), 69.2 (C-2), 68.2 (C-4), 62.2 (d, OCH2, C-6), 24.8 (SSCH3), 20.9, 20.8,
20.7 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C15H22O9S2 [M+Na]+, 433.0603, found: 433.0606.
Synthesis of compound 5j
Folowing the synthesis of compound 5a starting from compound 1j afforded 5j (0.99g, 89% yield) as
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+26.9 (c 0.33, CHCl3); IR (KBr): 3018, 1755, 1218, 1037, 754 cm-1; H NMR
(400 MHz, CDCl3): δ 5.38 (dd, 1H, J = 3.4 Hz, J = 0.9 Hz), 5.19 (dd, 1H, J = 10.5 Hz, J = 7.9 Hz), 5.01
(dd, 1H, J = 10.5 Hz, J = 3.4 Hz), 4.46 (d, 1H, J = 7.9 Hz, H-1), 4.17-4.09 (m, 2H), 3.98-3.96 (m, 1H),
3.92-3.90 (m, 1H), 3.65-3.63 (m, 1H), 2.77-2.71 (m, 2H, SCH2), 2.39 (s, 3H, SSCH3), 2.14-1.95 (m,
14H, 4xCOCH3, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 170.6, 170.5, 170.4, 169.6 (COCH3 x4),
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101.6 (C-1), 71.1 (C-5), 70.8 (C-3), 69.0 (C-2), 68.1 (C-4), 67.2 (OCH2), 61.5 (C-6), 34.1 (SCH2), 28.8
(SCH2CH2), 23.2 (SSCH3), 21.0, 20.9, 20.8 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for C18H28O10S2
[M+Na]+, 491.1022, found: 491.1023.
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Synthesis of compound 5k
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Folowing the synthesis of compound 5b starting from compound 1k afforded 5k (62mg, 59% yield)
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as a colorless oil.
+112.7 (c 0.1, CHCl3); IR (KBr): 2916, 1497, 1455, 1070, 754 cm-1; 1H NMR
(400 MHz, CDCl3): δ 7.36-7.27 (m, 20H, aromatic), 4.95-4.39 (m, 8H, 4xOCH2Ph), 4.35 (d, 1H, J =
7.7Hz, H-1), 4.01-3.98 (m, 2H, OCH2), 3.89 (t, 1H, J = 2.6 Hz, H-4), 3.80 (dd, J = 9.7 Hz, J = 7.7 Hz,
H-6), 3.64-3.50 (m, 5H, OCH2, H-2, H-3, H-5, H-6), 2.79 (t, 2H, J = 7.32 Hz, SCH2), 2.36 (s, 3H,
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SSCH3), 2.05-2.01 (m, 2H, -CH2-) ppm; C NMR (100 MHz, CDCl3): δ 128.6, 128.5, 128.3, 128.1,
128.0, 127.8, 127.7, 104.1 (C-1), 82.5 (C-3), 79.7 (C-2), 77.5 (C-4), 75.5, 74.7, 73.6 (OCH2Ph x4), 73.0
(C-5), 69.0 (C-6), 68.2 (OCH2), 34.9 (SCH2), 29.6 (SCH2CH2), 23.5 (SSCH3) ppm; HRMS (ESI): m/z
calcd for C38H44O6S2 [M+Na]+, 683.2477, found: 683.2467.
Synthesis of compound 5l
Folowing the synthesis of compound 5a starting from compound 1l afforded 5l (0.104g, 93% yield)
as a colorless oil.
-72.8 (c 0.15, CHCl3); IR (KBr): 3019, 1756, 1215, 1039, 755 cm-1; 1H NMR
(400 MHz, CDCl3): δ 5.33-5.22 (m, 3H, H-2, H-3, H-4), 4.81 (d, 1H, J = 1.6 Hz, H-1), 4.27 (dd, 1H, J
= 12.2 Hz, J = 5.4 Hz, H- ’ H J = 9.2 Hz, J = 2.4 Hz, H-6), 3.99-3.95 (m, 1H, H-5),
3.85-3.80 (m, 1H, OCH2), 3.57-3.52 (m, 1H, OCH2), 2.78 (t, 2H, J = 7 Hz, SCH2), 2.40 (s, 3H, SSCH3),
2.15-1.98 (m, 14H, 4xCOCH3, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 170.8, 170.3, 170.1, 169.9
(COCH3 x4), 97.8 (C-1), 69.7 (C-5), 69.3 (C-3), 68.8 (C-2), 66.4 (C-4), 66.3 (OCH2), 62.6 (C-6), 34.3
(SCH2), 28.6 (SCH2CH2), 23.2 (SSCH3), 21.0, 20.9 (COCH3 x4) ppm; HRMS (ESI): m/z calcd for
C18H28O10S2 [M+Na]+, 491.1022, found: 491.1025.
Synthesis of compound 5m
Folowing the synthesis of compound 5b starting from compound 1m afforded 5m (66mg, 63% yield)
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as a colorless oil.
+23.6 (c 0.05, CHCl3); IR (KBr): 2926, 1496, 1454, 1070, 744 cm-1; 1H NMR
(400 MHz, CDCl3): δ 7.39-7.24 (m, 18H, aromatic), 7.17-7.1(m, 2H, aromatic), 4.86 (d, 1H, J = 1.7Hz,
H-1), 4.88-4.49 (m, 8H, 4xOCH2Ph), 3.95 (t, 1H, J = 9.2 Hz, H-4), 3.87 (dd, J = 9.6 Hz, J = 2.9 Hz,
H-3), 3.78-3.71 (m, 5H, OCH2, H-2, H-5, H-6), 3.47-3.44 (m, 1H, OCH2), 2.69 (t, 2H, J = 7.0 Hz,
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SCH2), 2.37 (s, 3H, SSCH3), 1.95-1.91 (m, 2H, -CH2-) ppm; C NMR (100 MHz, CDCl3): δ 138.7,
138.6, 128.6, 128.5, 128.3, 128.0, 127.9, 127.8 (m, aromatic), 104.7 (C-1), 98.2 (C-3), 80.3 (C-2), 77.5
(C-4), 75.4, 75.1, 74.9, 73.6 (OCH2Ph x4), 72.2 (C-5), 69.5 (C-6), 65.8 (OCH2), 34.8 (SCH2), 29.1
(SCH2CH2), 23.4 (SSCH3) ppm; HRMS (ESI): m/z calcd for C38H44O6S2 [M+Na]+, 683.2477, found:
683.2476.
Synthesis of compound 5n
To a magnetically stirred solution of compound 1n (0.1g, 0.16 mmol) in anhydrous Et2O (5 mL
h g i h - i i Ǻ g- - i
-7 f 5 i es, after which DMTSF (0.95g, 0.49 mmol) was added in one portion. Reaction was
maintained at this temperature till complete consumption of starting materials was observed, after which
reaction mixture was directly quenched with aq. NaHCO3 (5 mL -7 . The suspension was allowed
to reach room temperature, followed by dissolution in Et2O (20 mL), washed with water (30 mL), brine
(30 mL). Organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure, after
which flash chromatography on silica gel (hexane/EtOAc = 6:1) afforded compound 5n (65mg, 62%
yield) as a colorless oil.
+50.1 (c 0.03, CHCl3); IR (KBr): 2912, 1495, 1453, 1068, 752 cm-1; 1H
NMR (400 MHz, CDCl3): δ 7.52-7.28 (m, 18H, aromatic), 7.14-7.11 (m, 2H, aromatic), 4.99-4.45 (m,
8H, 4xOCH2Ph), 4.48 (d, 1H, J = 2.7 Hz, H-1), 3.96 (t, 1H, J = 9.3 Hz, H-4); 3.78-3.70 (m, 3H, OCH2,
H-6), 3.65-3.61 (m, 2H, H-3, H-5), 3.57-3.48 (m, 2H, OCH2, H-2), 2.82-2.77 (m, 2H, SCH2), 2.38 (s,
3H, SSCH3), 2.07-1.99 (m, 2H, -CH2-) ppm; 13C NMR (100 MHz, CDCl3): δ 128.7, 128.6, 128.2,
128.1, 127.9, 97.4 (C-1), 82.3 (C-3), 80.3 (C-2), 77.5 (C-4), 75.9, 75.3, 73.7 (OCH2Ph x4), 73.5 (C-5),
70.5 (C-6), 66.4 (OCH2), 34.7 (SCH2), 30.1 (SCH2CH2) 23.4 (SSCH3) ppm; HRMS (ESI): m/z calcd
for C38H44O6S2 [M+Na]+, 683.2477, found: 683.2476.
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Compound 6a:
-15.0 (c 1.15, CHCl3); m.p. 47-48 °C; IR (KBr): 3435, 3299, 2959, 2875,
1
2
3
4
5
6
7
8
9
1750, 1372, 1227 cm-1; H NMR (500 MHz, CDCl3): δ 5.18 (t, 1H, J = 9.6 Hz, H-3), 5.06 (t, 1H, J =
9.6 Hz, H-4), 4.96 (t, 1H, J = 9.6 Hz, H-2), 4.50 (d, 1H, J = 8.0 Hz, H-1), 4.27 (dd, 1H, J = 12.3 Hz, J =
4.8 Hz, H-6a), 4.14 (dd, 1H, J = 12.3 Hz, J = 2.4 Hz, H-6b), 3.88 (dt, 1H, J = 9.7 Hz, J = 6.3 Hz, OCH2),
3.70 (ddd, 1H, J = 9.6 Hz, J = 4.8 Hz, J = 2.4 Hz, H-5), 3.49 (dt, 1H, J = 9.7 Hz, J = 6.8 Hz, OCH2),
2.06-1.98 (m, 12H, 4xCOCH3), 1.56 (m, 2H, OCH2CH2), 1.35 (m, 2H, OCH2CH2CH2), 0.91 (t, 3H, J =
7.4 Hz, CH3) ppm; 13C NMR (125 MHz, CDCl3): δ 170.9, 170.5, 169.6, 169.5 (COCH3 x4), 101.0
(C-1), 73.1 (C-3), 71.9 (C-5), 71.5 (C-2), 70.1 (OCH2), 68.7 (C-4), 62.2 (C-6), 31.5 (CH2), 20.9, 20.8,
20.7, 19.1 (CH2), 13.9 (CH3) ppm; HRMS (ESI): m/z calcd for C18H28O10Na [M+Na]+, 427.1580, found:
427.1584.
1
10
11
12
13
14
15
16
17
18
19
20
21
22
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27
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48
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60
Compound 6b:
+16.5 (c 1.3, CHCl3); m.p. 69-71 °C; IR (KBr): 2912, 1495, 1453, 1068, 752
cm-1; H NMR (400 MHz, CDCl3): δ 7.36-7.25 (m, 18H, aromatic), 7.17-7.14 (m, 2H, aromatic),
4.94-4.51 (m, 8H, 4xOCH2Ph), 4.39 (d, 1H, J = 7.8 Hz, H-1), 3.96 (dt, 1H, J = 12.5 Hz, J = 5.9 Hz,
OCH2); 3.73 (dd, 1H, J = 10.5 Hz, J = 1.9 Hz, H-6a), 3.69-3.54 (m, 5H), 3.46-3.44 (m, 2H, OCH2, H-2),
1
13
1.65-1.25 (m, 4H, OCH2CH2), 0.93 (s, 3H, J = 7.26 Hz, CH3) ppm; C NMR (100 MHz, CDCl3): δ
138.8, 138.7, 138.4, 138.3, 128.6-127.7 (aromatic), 103.8 (C-1), 84.9 (C-3), 82.5 (C-4), 78.2 (C-5), 77.5,
75.9, 75.2 75.0 (OCH2Ph x4), 70.0 (C-6), 69.2 (OCH2), 32.1 (OCH2CH2), 19.5 (OCH2CH2CH2), 14.1
(CH3) ppm; HRMS (ESI): m/z calcd for C38H45O6 [M+H]+, 597.3211, found: 597.3213.
ACKNOWLEDGMENT
We gratefully acknowledge Nanyang Technological University (RG50/08) and the Ministry of
Education, Singapore (MOE 2009-T2-1-030) for the financial support of this research.
Supporting Information Available: Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at http://pubs.acs.org.
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