TMSOTf-catalyzed silylation: Streamlined regioselective one-pot protection and acetylation of carbohydrates

Article abstract of DOI:10.1002/ejoc.201101267

A highly efficient TMSOTf-catalyzed HMDS silylation of sugars, which can easily be integrated with subsequent reactions in one-pot fashion, has been developed. Its usefulness was demonstrated by applications to streamlined regioselective one-pot protection and nonenzymatic acetylation of unprotected sugars. Monosaccharide and trehalose building blocks with orthogonally well-differentiated hydroxy groups were efficiently prepared starting with free sugars in one-pot fashion without the need for prior per-O-silylation. Regioselectively protected and acetylated building blocks were prepared directly from unprotected sugars in a one-pot manner involving up to five TMSOTf-catalyzed reactions, including a new TMSOTf-catalyzed silylation of carbohydrates. Copyright

Full text of DOI:10.1002/ejoc.201101267

FULL PAPER
DOI: 10.1002/ejoc.201101267
TMSOTf-Catalyzed Silylation: Streamlined Regioselective One-Pot Protection
and Acetylation of Carbohydrates
A. Abragam Joseph,[a,b] Ved Prakash Verma,[a] Xin-Yi Liu,[a] Chia-Hui Wu,[a]
Vijay M. Dhurandhare,[c] and Cheng-Chung Wang*[a,c]
Keywords: Carbohydrates / Glycosides / Protecting groups / Synthetic methods
A highly efficient TMSOTf-catalyzed HMDS silylation of
sugars, which can easily be integrated with subsequent reac-
tions in one-pot fashion, has been developed. Its usefulness
was demonstrated by applications to streamlined regioselec-
tive one-pot protection and nonenzymatic acetylation of un-
protected sugars. Monosaccharide and trehalose building
blocks with orthogonally well-differentiated hydroxy groups
were efficiently prepared starting with free sugars in one-pot
fashion without the need for prior per-O-silylation.
the key O4,O6-arylidenation[7] and O3-regioselective re-
ductive arylmethylation[8] reactions. Moreover, the impor-
tance of TMS in carbohydrate synthesis has been signifi-
cantly increasing in recent years. Hindsgaul et al., starting
from per-O-trimethylsilylated sugars, reported glycosylation
reactions mediated by per-O-TMS glycosyl iodide.[9] A one-
pot stereoselective glycosylation protocol by way of per-O-
trimethylsilylated glycosyl iodides[10] generated in situ and
more recently the regioselective nonenzymatic acetylation
of monosaccharides[11] with involvement of per-O-TMS
monosaccharides have been established by Gervay-Hague
et al. Furthermore, selective removal of the primary 6,6Ј-
TMS ethers of per-O-TMS trehalose has been applied in
various syntheses of 6,6Ј-symmetrically[12] and dissymmetri-
cally[13] substituted trehalose-based glycolipids. However,
these methodologies cannot proceed with unprotected
sugars, which because of their multiple hydroxy groups are
insoluble in most organic solvents. TMS protection im-
Introduction
Glycans are essential in a wide range of biological pro-
cesses, such as viral and bacterial infections, cell prolifera-
tion and growth, immunoresponses, and cell–cell communi-
cations.[1] Chemical syntheses of complicated oligosaccha-
rides and glycoconjugates provide indispensable materials
for study of their biological roles.[2] Such efforts rely heavily
upon building blocks that each contain one specific hydroxy
group that is regioselectively well differentiated from the
rest and a suitable orthogonal protecting group[3] pattern
that can be manipulated chemoselectively.[4] Endeavors to
prepare these building blocks are generally tedious and in-
volve lengthy routes that lead to low overall yields and poor
efficiency.
In an effort to overcome this, Hung et al. have recently
developed a regioselective one-pot protection platform as
an alternative.[5] Per-O-trimethylsilylated glycosides were
used as the starting materials and sequential reactions
catalyzed by trimethylsilyl trifluoromethanesulfonate
(TMSOTf) could be performed in a single vessel. A series
of d-glucoside[5a,5b] and d-glucosamine[5a,5c] building blocks
have been prepared and successfully applied in the assembly
of heparin and heparan sulfate,[5f] respectively. Although
different catalysts, such as Cu(OTf)2 and FeCl3·6H2O,[6]
can also be used, trimethylsilyl groups (TMS) are indispens-
able in this approach and play a pivotal role that mediates
[a] Institute of Chemistry, Academia Sinica, Nankang,
Taipei 115, Taiwan
Fax: +886-2-2783-1237
E-mail: wangcc@chem.sinica.edu.tw
[b] Department of Chemistry, National Tsing Hua University,
Hsinchu 300, Taiwan
[c] Chemical Biology and Molecular Biophysics Program, Taiwan
International Graduate Program (TIGP), Academia Sinica,
Nankang, Taipei 115, Taiwan
Scheme 1. Streamlined one-pot regioselective protection and
acetylation of unprotected carbohydrates.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101267.
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One-Pot Protection and Acetylation of Carbohydrates
proves sugar solubility and hence leads to homogeneous Table 1. Silylation of sugars with HMDS in the presence of
TMSOTf (0.1 equiv.) at room temp. in CH2Cl2.[a]
conditions, which are crucial for regioselective reactions.
Here we report streamlined one-pot reactions that utilize
unprotected sugars as the starting materials for concise and
efficient production of regioselectively protected[5] and acet-
ylated[11] building blocks for carbohydrate syntheses
through a new TMSOTf-catalyzed silylation procedure
(Scheme 1).
Results and Discussion
Traditional silylation methods usually require harsh con-
ditions, long reaction times, and large excesses of bases[3]
and hence – especially in per-O-silylation of sugars – inevi-
tably produce multiple-equivalent quantities of salts as by-
products. The workup and purification of the silylated
products are difficult, and subsequent reactions are nearly
impossible until the silylated products are isolated and puri-
fied. Therefore, prior to these platforms, an extra synthetic
step to prepare and to isolate these labile silylated starting
materials is always deemed necessary. We therefore con-
ceived that a silylation methodology that reduces the use of
bases and the formation of byproducts to the minimum
should allow subsequent one-pot reactions immediately af-
ter the silylation reaction.
Here, we used as the silylation reagent the inexpensive
1,1,1,3,3,3-hexamethyldisilazane (HMDS), which can be ac-
tivated by various heterogeneous protic[14] and Lewis ac-
ids,[15] as well as by neat nitromethane as solvent.[16] Al-
though TMSOTf has itself been identified as a strong Lewis
acid and a powerful silylating reagent,[17] activation of
HMDS by use of homogeneous TMSOTf and its applica-
tion to per-O-silylate sugars have yet to be reported in the
literature. We thus examined the scope of these conditions,
and the results are shown in Table 1.
In Entries 1 and 2, with treatment with HMDS
(2.2 equiv.) in the presence of TMSOTf (0.1 equiv.), the
conversion of methyl α-d-glucopyranoside (1a) and p-tolyl
1-thio-β-d-glucopyranoside (1b) into the products 2a[5b]
[a] TMS = trimethylsilyl; Tol = tolyl; TCA = trichloroacetyl.
[b] Isolated yield. [c] HMDS (2.2 equiv.). [d] HMDS (1.6 equiv.).
and 2b[5b] proceeded smoothly in quantitative yields in
[e] HMDS (4.4 equiv.). [f] HMDS (2.8 equiv.). [g] Determined by
1H NMR analysis of the crude reaction mixture. [h] HMDS
(9.9 equiv.). [i] HMDS (12.0 equiv.).
10 min without production of large amounts of salts. Other
triflate catalysts such as Cu(OTf)2 and AgOTf were tested,
but the reactions were much slower and did not go to com-
pletion even after 24 h. For activation of HMDS with protic
acids the reaction in the presence of TfOH (0.1 equiv.) af- silylated product 8 without its trichloroacetamido function-
forded 2a and 2b quantitatively but took 1–2 h to go to ality being affected (Entry 6). The full silylation of α,αЈ-
completion; however, the reaction catalyzed by camphor- trehalose (9) to afford the corresponding product 10[13] was
sulfonic acid (CSA, 0.1 equiv.) did not go to completion also excellent (Entry 7). It was noticed that longer reaction
even after stirring for 2 d. We therefore chose TMSOTf as times were needed for d-glucose (11), d-galactose (13), and
the catalyst for further studies. In cases involving reagents d-mannose (15), probably due to the weaker nucleophilici-
other than d-glucosides, the silylation of d-galacto- and d- ties of their anomeric oxygen atoms and their lower solubili-
mannopyranosides 3, 5a, and 5b also gave the correspond- ties in CH2Cl2 (Entries 8 to 10). These unprotected sugars
ing silylated products 4, 6a, and 6b in excellent yields de- were converted into their per-O-silylated derivatives 12,[11]
spite the slightly longer reaction times expected due to the 14,[11] and 16[11] in 96%, 97%, and 95% yields, respectively.
steric hindrance of the axial hydroxy groups (Entries 3 to Notably, in the silylation of α- (17) and β-cyclodextrin (19),
5). More importantly, silylation of the d-glucosamine deriv- although the amounts of HMDS we used (9.9 equiv. and
ative 7 could be achieved in excellent yield to afford the 12.0 equiv., respectively) were sufficient to persilylate 17 and
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19, regioselective per-2,6-di-O-trimethylsilylations were ob- cellent yields. Instead of subzero (–78 to –86 °C) tempera-
served and afforded the corresponding products 18[18] and tures,[5a,5b] we found that the O4,O6-benzylidenation and
20[18] smoothly, notwithstanding their polyhydroxy systems the O3-benzylation steps could be carried out at the more
(Entries 11 and 12). The regioselectivity was confirmed by conveniently accessible 0 °C, with yields nearly identical to
careful comparison of the obtained 1H and 13C spectra with those obtained at –78 °C (yields are listed in parentheses in
literature data[18] and the cross-signals between the free hy- Scheme 3). The fully orthogonally protected building blocks
droxy groups and H3 observed in the 1H–1H COSY spectra 22a and 22b were furnished in good yields after the
of 18 and 20 (see the Supporting Information).
TMSOTf-catalytic cycles were extended to acylation
A postulated mechanism is illustrated in Scheme 2. [step (e)].[19] Further regioselective reductive O4- or O6-
TMSOTf and HMDS could initially form complex A, with benzylidene ring-opening of the fully protected intermedi-
its Si–N bond polarized and activated, and this could then ates 22a and 22b in the same pot by use of trifluoroacetic
react with one equivalent of alcohol to give the correspond- acid/Et3SiH[20] or TMSOTf/BH3·THF[21] [steps (f) or (g)]
ing TMS ether and complex B, which could react with an- gave the corresponding 4-alcohols 23a and 23b or 6-
other equivalent of alcohol to produce another equivalent alcohols 24a and 24b in good yields even after five consecu-
of TMS ether. Finally, complex C would be formed and the tive reactions in one-pot fashion. After O4,O6-benzyliden-
catalytic cycle could circulate again with the evolution of ation and TBAF treatment to form the 2,3-diol intermedi-
gaseous ammonia and the regeneration of TMSOTf.
ates in situ, the 3-alcohols 25a and 25b were obtained from
1a and 1b, respectively, through regioselective O2-benzo-
ylation[22] in good yields.
Scheme 2. Postulated catalytic cycle for TMSOTf-catalyzed HMDS
silylation of alcohols.
Scheme 3. Streamlined regioselective one-pot protection of d-
glucopyranosides 1a and 1b. Reagents and conditions: a) HMDS,
cat. TMSOTf, CH2Cl2, room temp., 1 h; b) PhCHO, cat. TMSOTf,
0 °C or –78 °C; c) PhCHO, Et3SiH, cat. TMSOTf, 0 °C or –78 °C;
d) TBAF, room temp.; e) Ac2O, cat. TMSOTf, 0 °C; f) Et3SiH,
CF3COOH, –78 °C; g) BH3·THF, TMSOTf, 0 °C; h) Bz2O, Et3N,
room temp. [a] The yields in parentheses were obtained when
steps (b) and (c) were performed at –78 °C.
Consistently with the experimental results, one equiva-
lent of HMDS is capable of silylating two equivalents of
hydroxy groups and is therefore more economical than
traditional methods involving trimethylsilyl chloride
(TMSCl). Thanks to its high reactivity, the reaction times
were shortened from hours to minutes and large excesses of
The fully protected glucosamine derivative 27 and the in-
TMSCl and bases were no longer necessary. Most import- dividual alcohols 26, 28, and 29, useful for the syntheses of
antly, the pH of this silylation reaction changed from glucosamine-containing oligosaccharides and glycoconju-
strongly basic to neutral when the reaction had gone to gates, were prepared directly from the triol 7 in a one-pot
completion because the basic HMDS transformed into manner (Scheme 4). Similarly, 7 was treated with HMDS
NH3 and was then lost. Successive one-pot Lewis acid-cata- and a catalytic amount of TMSOTf [step (a)] to form the
lyzed or basic reactions immediately in the same vessel are per-O-silylated intermediate 8 in situ, and this was then fur-
therefore feasible, and this allowed us to carry out subse- ther protected with a benzylidene group at O4 and O6
quent reactions starting from unprotected glycosides and to [step (b)]. Removal of O3-TMS with TBAF [step (c)] gave 3-
treat the per-O-trimethylsilylated sugars as intermediates.
alcohol 26, or successive reductive O3-benzylation [step (d)]
As shown in Scheme 3, after the TMSOTf-catalyzed efficiently formed the fully protected glucosamine derivative
HMDS silylation of the d-glucosides 1a and 1b to form the 27. Opening of the benzylidene ring of 27 at O4
per-O-silylated intermediates 2a and 2b in situ, consecutive [step (e)][20] or O6 [step (f)][21] furnished the 4-alcohol 28
TMSOTf-catalyzed O4,O6-benzylidenation and regioselec- and the 6-alcohol 29, respectively, in excellent yields.
tive reductive O3-benzylation [steps (b) and (c)] could be
Transformations of α,αЈ-d-trehalose (9), which is a basic
performed directly.[5a,5b] Removal of the O2-TMS group core in various glycoconjugates, were also conducted
with tetra-n-butylammonium fluoride [TBAF, step (d)] in (Scheme 5). Without prior preparation and isolation of the
the same vessel furnished the 2-alcohols 21a and 21b in ex- per-O-trimethylsilylated material, silylation of 9 to form the
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One-Pot Protection and Acetylation of Carbohydrates
Table 2. Streamlined one-pot nonenzymatic regioselective acetyl-
ation of d-glucose (11), d-galactose (13), and d-mannose (15).
Scheme 4. Streamlined regioselective one-pot protection of glucos-
amine derivative 7. Reagents and conditions: a) HMDS, cat.
TMSOTf, CH2Cl2, room temp., 1 h; b) PhCHO, cat. TMSOTf,
0 °C; c) TBAF, room temp.; d) PhCHO, Et3SiH, 0 °C; e) Et3SiH,
CF3COOH, –78 °C; f) BH3·THF, TMSOTf, 0 °C.
silylated intermediate 10 in situ followed by symmetrical
4,6,4Ј,6Ј-di-O-benzylidenation and 3,3Ј-di-O-benzylation in
one-pot fashion at 0 °C furnished the diol 30[6b] in an excel-
lent 91% yield. Extension of the tandem sequence to acet-
ylation by introduction of acetic anhydride (4.0 equiv.) af-
forded the 2,2Ј-di-O-acetylated product 31[6b] in a good
yield (88%).
1
[a] Determined by H NMR analysis of the isolated products.
Scheme 5. Streamlined regioselective one-pot protection of α,αЈ-d-
trehalose (9). Reagents and conditions: a) HMDS, cat. TMSOTf,
CH2Cl2, room temp., 1 h; b) PhCHO, cat. TMSOTf, 0 °C;
c) PhCHO, Et3SiH, 0 °C; d) TBAF, room temp.; e) Ac2O, cat.
TMSOTf, 0 °C.
After TMSOTf-catalyzed silylation of d-glucose (11), d-
galactose (13), and d-mannose (15) and formation of their
per-O-trimethylsilylated intermediates 12, 14, and 16 in situ
as described in Table 1, Gervay–Hague’s regioselective non-
enzymatic acetylation[11] was tested. Through the introduc-
tion of pyridine, acetic anhydride, and acetic acid directly
into the same vessel after the silylation was complete, 6-O-
acetylglucose 32 (78%) 6-O-acetylgalactose 34 (81%), and
6-O-acetylmannose 36 (64%), as well as their correspond-
ing 1,6-di-O-acetates 33 (17%), 35 (15%), and 37 (18%),
which can easily be deprotected to provide useful synthetic
intermediates, were successfully furnished in one-pot fash-
ion (Table 2).[23]
Scheme 6. Streamlined regioselective one-pot protection and non-
enzymatic regioselective acetylation of β-p-tolyl-maltose 38. Rea-
gents and conditions: a) HMDS (4.1 equiv.), cat. TMSOTf, CH2Cl2,
room temp., 1 h; b) PhCHO, cat. TMSOTf, 0 °C; c) PhCHO,
Et3SiH, 0 °C; d) Ac2O, cat. TMSOTf, 0 °C; e) AcOH, Ac2O, pyr.,
room temp., 48 h.[a] Compound 39 can be isolated in a quantitative
yield.
Conclusions
In summary, we have developed a highly efficient
Finally, as well as to the nonreducing trehalose, we also TMSOTf-catalyzed per-O-silylation procedure for sugars
applied this new reagent system to β-p-tolyl-maltose 38 with use of HMDS as the silylating reagent. The per-O-
(Scheme 6). After TMSOTf-catalyzed HMDS silylation, silylation is more efficient and economical than traditional
per-O-silylated disaccharide 39 can either be isolated quan- methods and is free of large quantities of bases despite the
titatively or can be treated as an intermediate in situ for intrinsic polyhydroxy systems on sugar molecules. Most im-
subsequent benzylidenation, benzylation, and acetylation to portantly, subsequent reactions can be carried out directly
produce the fully protected maltose 40 (50%) or for further in the same vessel immediately after the silylated products
regioselective acetylation to afford the 6,6Ј-di-O-acetylated are formed with no need to isolate or to purify the silylated
product 41 (69%).
intermediates. The usefulness of the procedure is verified by
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C.-C. Wang et al.
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and the residue was dissolved in hexane (200 mL) and washed with
water (3ϫ50 mL). The aqueous layer was extracted with hexane
(3ϫ50 mL) and the organic layers were combined, washed with
brine, dried with MgSO4, filtered, and concentrated in vacuo to
furnish the per-O-trimethylsilylated 2a (24.9 g, quant.). Analytical
and spectroscopic data were found to be in agreement with re-
ported literature.[5b]
its application to one-pot protections of a series of useful
d-glucoside, d-glucosamine, α,αЈ-d-trehalose, and maltose
building blocks with their hydroxy groups well differen-
tiated by integration of up to five TMSOTf catalytic cycles
in one-pot processes starting directly from unprotected
sugars. The applicability of this TMSOTf-catalyzed sil-
ylation procedure has also been demonstrated in regioselec-
tive nonenzymatic acetylations on d-glucose, d-galactose,
and d-mannose, and the efficiency of these two platforms
involving TMS protection has been further expedited. More
research into incorporation of these methodologies with
Wong’s one-pot programmable glycosylation[24] and Seeber-
Methyl 2,3,4,6-Tetra-O-trimethylsilyl-α-D-galactopyranoside (4):
Colorless syrup (236 mg, 0.489 mmol, 95%). [α]2D3 = +81.5 (c = 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.60 (s, 1 H), 3.91–3.87
(m, 2 H), 3.38–3.77 (m, 1 H), 3.69 (t, J = 6.5 Hz, 1 H), 3.63–3.54
(m, 2 H), 3.34 (s, 3 H), 0.12 (s, 9 H), 0.11 (s, 9 H), 0.11 (s, 9 H),
0.09 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 100.2, 72.2,
ger’s solid-phase automated synthesis of carbohydrates[25] 70.9, 69.7, 61.3, 55.2, 0.6 (ϫ 2), 0.5, 0.3 ppm. IR (thin film): ν =
˜
2957, 1251, 1105, 841 cm–1. HRMS (ESI): calcd. for C19H47O6Si4
to synthesize biologically potent oligosaccharides and gly-
coconjugates is currently in progress in our group.
[M + H]+ 483.2450; found 483.2446.
Methyl 2,3,4,6-Tetra-O-trimethylsilyl-α-D-mannopyranoside (6a):
Colorless syrup (234 mg, 0.485 mmol, 94%). [α]2D3 = +9.8 (c = 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.44 (s, 1 H), 3.78–3.65
(m, 5 H), 3.42–3.38 (m, 1 H), 3.29 (s, 3 H), 0.13 (s, 9 H), 0.11 (s, 9
H), 0.10 (s, 9 H), 0.09 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 100.5, 74.5, 73.3, 72.6, 68.3, 62.5, 54.2, 0.6, 0.4, 0.3, –0.2 ppm.
Experimental Section
General: Dichloromethane was purified and dried through acti-
vated aluminum oxide under argon. All other solvents and chemi-
cals were purchased from commercial sources such as Aldrich,
Acros, Alfa Aesar, and Merck and were used without further purifi-
cation unless otherwise mentioned. All moisture-sensitive reactions
were conducted in flame-dried glassware under dry nitrogen. Flash
column chromatography was carried out as recommended with sil-
ica gel (60, 230–400 mesh, E. Merck). TLC was performed on pre-
coated glass plates of silica gel (60 F254, 0.25 mm, E. Merck); de-
tection was carried out under UV (254 nm) or by spraying with
solutions of Ce(NH4)2(NO3)6 or (NH4)6Mo7O24, as well as H2SO4,
IR (thin film): ν = 2956, 1250, 839 cm–1. HRMS (ESI): calcd. for
˜
C19H46O6Si4Na [M + Na]+ 505.2269; found 505.2262.
p-Tolyl
2,3,4,6-Tetra-O-trimethylsilyl-thio-α-D-mannopyranoside
(6b): Colorless syrup (189 mg, 0.328 mmol, 94%). [α]2D3 = +116.6 (c
= 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J =
7.6 Hz, 2 H), 7.07, (d, J = 7.6 Hz, 2 H), 5.17 (s, 1 H), 4.00–3.98
(m, 2 H), 3.87–3.69 (m, 3 H), 3.52–3.22 (m, 1 H), 2.30 (s, 3 H),
0.17 (s, 9 H), 0.13 (s, 9 H), 0.09, (s, 18 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.2, 132.1, 131.3, 129.6, 89.9, 75.5, 74.8,
73.3, 68.5, 62.3, 21.0, 0.6, 0.5, 0.3, –0.2 ppm. HRMS (ESI): m/z:
calcd. for C25H50O5Si4SNa [M + Na]+ 597.2354; found 597.2360.
in water and subsequent heating on a hot plate. H and 13C NMR
1
spectra were recorded with Bruker AV 400, AMX 400, DRX 500,
or AV 600 MHz instruments. Chemical shifts are in ppm from
Me4Si, generated from the CDCl3 lock signal at δ = 7.24 ppm. Mul-
tiplicities are reported with use of the following abbreviations: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad; J = coupling constant values in Hertz. Mass spectra were
obtained with a JEOL JMS-700 mass spectrometer in FAB mode
or a Waters Premier XE mass spectrometer in ESI mode. IR spectra
were taken with a Perkin–Elmer Paragon 1000 FT-IR spectrometer.
Ethyl 2-Deoxy-2-N-trichloroacetamido-1-thio-β-D-glucopyranoside
(7): Sodium methoxide (21 mg, 0.40 mmol, 0.2 equiv.) was added
at room temp. to a solution of ethyl 3,4,6-tri-O-acetyl-2-deoxy-2-N-
trichloroacetamido-thio-β-d-glucopyranoside[26] (1.0 g, 2.02 mmol)
in MeOH (5 mL). The solution was stirred for 4 h and was neutral-
ized with acidic Amberlite resin IR-120. The resin was filtered off
and washed with MeOH (10 mL). The filtrate was concentrated in
vacuo to afford the desired triol product 7 as a white solid (677 mg,
1.84 mmol, 91%); m.p. 75–76 °C. [α]2D3 = –28.2 (c = 0.5, MeOH).
1H NMR (400 MHz, CD3OD): δ = 8.67 (d, J = 8.8 Hz, 1 H), 4.60
(d, J = 10.4 Hz, 1 H), 3.81 (dd, J = 1.6, 12.0 Hz, 1 H), 3.72–3.52
(m, 3 H), 3.30–3.22 (m, 2 H), 2.74–2.64 (m, 2 H), 1.18 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 164.2, 94.2,
84.9, 82.3, 76.6, 72.5, 72.3, 63.0, 58.2, 25.0, 15.3 ppm. IR (thin
General Procedure for TMSOTf-Catalyzed HMDS Silylation of
Sugars: TMSOTf (0.1 equiv.) was added at room temp. under N2
to a suspension of the free sugar (100 mg) and HMDS (equiv. as
indicated in Table 1) in CH2Cl2 (10 mLg–1). The suspension disap-
1
peared in minutes, and the reaction was monitored by TLC or H
NMR spectroscopy. Upon completion, the mixture was diluted
with hexane and washed with water. The aqueous layer was ex-
tracted with EtOAc and the organic layers were combined, washed
with brine, dried with MgSO4, filtered, and concentrated in vacuo
to furnish the desired product with the yields as shown in Table 1.
The obtained analytical data for compounds 2a,[5b] 2b,[5b] 10,[6b]
12,[10a] 14,[10a] 16,[10a] 18,[18] 20[18] are in agreement with reported
literature.
film): ν = 3335 (br), 2925, 1704, 1261, 1026 cm–1. HRMS (ESI):
˜
m/z: calcd. for C10H15NO5Cl3 [M – H]– 365.9737; found 365.9735.
Ethyl
2-Deoxy-2-N-trichloroacetamido-3,4,6-tri-O-trimethylsilyl-
thio-β-
D
-glucopyranoside (8): White solid (154 mg, 0.263 mmol,
1
97%); m.p. 142–143 °C. [α]2D5 = –18.2 (c = 0.5, CHCl3). H NMR
(400 MHz, CDCl3): δ = 7.08 (d, J = 10.2 Hz, 1 H), 4.68 (d, J =
10.9 Hz, 1 H), 3.93–3.70 (m, 6 H), 3.43 (dd, J = 6.2, 12.4 Hz, 1 H),
2.71–2.62 (m, 2 H), 1.24 (t, J = 5.6 Hz, 3 H), 0.16 (s, 9 H), 0.14 (s,
9 H), 0.10 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.6,
92.8, 82.4, 81.4, 75.0, 70.9, 62.5, 57.1, 25.0, 15.2, 0.8, 0.6, –0.1 ppm.
Large-Scale Preparation of Methyl 2,3,4,6-Tetra-O-trimethylsilyl-α-
D-glucopyranoside (2a): TMSOTf (0.933 mL, 5.15 mmol, 0.1 equiv.)
was added at room temp. under N2 to a suspension of methyl α-
d-glucopyranoside (1a, 10.0 g, 51.5 mmol) and HMDS (24.1 mL,
113.3 mmol, 2.2 equiv.) in CH2Cl2 (100 mL). Caution! Large quan-
tities of ammonia are produced! The suspension disappeared in min-
IR (thin film): ν = 3312, 2958, 1694, 1250 cm–1. HRMS (ESI):
calcd. for C19H40NO5Si3Cl3Na [M
606.0901.
˜
+
Na]+ 606.0898; found
1
utes, and the reaction was monitored by TLC or H NMR spec-
Methyl 3-O-Benzyl-4,6-O-benzylidene-α-
D-glucopyranoside (21a)
troscopy. Upon completion, the reaction mixture was concentrated
and p-Tolyl 3-O-Benzyl-4,6-O-benzylidene-thio-β-D-glucopyranoside
748
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Eur. J. Org. Chem. 2012, 744–753

One-Pot Protection and Acetylation of Carbohydrates
(21b): TMSOTf (9 μL, 0.05 mmol, 0.1 equiv.) was added at room
temp. under a nitrogen flow to a suspension of methyl α-d-glucopy-
ranoside (1a, 100 mg, 0.515 mmol) or p-tolyl thio-β-d-glucopyr-
anoside (1b, 147 mg, 0.515 mmol) and HMDS (236 μL, 1.13 mmol,
2.2 equiv.) in CH2Cl2 (1.0 mL). After the system had been stirred
for 1 h, CH2Cl2 (1.5 mL), molecular sieves (4 Å, 150 mg), and benz-
aldehyde (111 μL, 1.10 mmol, 2.15 equiv.) were added, and the mix-
ture was allowed to stir at room temp. for 1 h. The mixture was
then cooled to 0 or –78 °C, and TMSOTf (18 μL, 0.10 mmol,
0.2 equiv.) was added. After the system had been stirred for 1 h,
triethylsilane (90 μL, 0.56 mmol, 1.1 equiv.) and TMSOTf (9 μL,
was then cooled to 0 or –78 °C, and TMSOTf (18 μL, 0.10 mmol,
0.2 equiv.) was added. After the system had been stirred for 1 h,
triethylsilane (90 μL, 0.56 mmol, 1.1 equiv.) and TMSOTf (9 μL,
0.05 mmol, 0.1 equiv.) were added. After the system had been
stirred for another 3 h, acetic anhydride (96 μL, 1.02 mmol,
2.0 equiv.) and TMSOTf (36 μL, 0.20 mmol, 0.4 equiv.) were suc-
cessively added at 0 °C. The mixture was stirred at same tempera-
ture for 1 h and was then cooled to –78 °C. Triethylsilane (407 μL,
2.55 mmol, 5.0 equiv.) and trifluoroacetic acid (156 μL, 2.04 mmol,
4.0 equiv.) were added, and the mixture was allowed to stir at the
same temperature overnight. The mixture was allowed to warm to
0.05 mmol, 0.1 equiv.) were added. After the system had been room temp. and filtered through a pad of Celite. The filtrate was
stirred for another 3 h, TBAF (1.02 mL, 1.02 mmol, 2.0 equiv.) was
added, and the mixture was allowed to warm gradually to room
temp. and kept stirring overnight. The mixture was filtered through
a pad of Celite, and the filtrate was diluted with EtOAc (10 mL)
and washed with saturated NaHCO3 (aq., 10 mL). The aqueous
layer was extracted with EtOAc (3ϫ10 mL), and the combined or-
ganic layers were washed with brine, dried with anhydrous MgSO4,
filtered, and concentrated in vacuo. The mixture was purified by
flash column chromatography on silica gel to furnish the desired
product 21a [0 °C: (172 mg, 0.461 mmol, 90%); –78 °C: (180 mg,
0.483 mmol, 94%)] or 21b [0 °C: (215 mg, 0.461 mmol, 90%)]. The
obtained analytical data are in agreement with reported litera-
ture.[5a,5b]
carefully quenched with saturated NaHCO3 (aq., 20 mL). The
aqueous layer was extracted with EtOAc (3ϫ10 mL), and the com-
bined organic layers were washed with brine, dried with anhydrous
MgSO4, filtered, and concentrated in vacuo. The mixture was puri-
fied by flash column chromatography on silica gel to furnish the
desired 4-alcohol 23a [0 °C: (124 mg, 0.299 mmol, 58%); –78 °C:
(118 mg, 0.283 mmol, 55%)] or 23b [0 °C: (136 mg, 0.268 mmol,
52%)]. The obtained analytical data are in accordance with re-
ported literature values.[5a,5b]
Methyl 2-O-Acetyl-3,4-di-O-benzyl-α-
D-glucopyranoside (24a) and
p-Tolyl 2-O-Acetyl-3,4-di-O-benzyl-thio-β-D-glucopyranoside (24b):
TMSOTf (9 μL, 0.05 mmol, 0.1 equiv.) was added at room temp.
under a nitrogen flow to a suspension of methyl α-d-glucopyrano-
Methyl
anoside (22a) and p-Tolyl 2-O-Acetyl 3-O-Benzyl-4,6-O-benzylidene-
thio-β- -glucopyranoside (22b): TMSOTf (9 μL, 0.05 mmol,
0.1 equiv.) was added at room temp. under a nitrogen flow to a
suspension of methyl α-d-glucopyranoside (1a, 100 mg,
0.515 mmol) or p-tolyl thio-β-d-glucopyranoside (1b, 147 mg,
0.515 mmol) and HMDS (236 μL, 1.13 mmol, 2.2 equiv.) in
CH2Cl2 (1.0 mL). After the system had been stirred for 1 h, CH2Cl2
(1.5 mL), molecular sieves (4 Å, 150 mg), and benzaldehyde
2-O-Acetyl-3-O-benzyl-4,6-O-benzylidene-α-D-glucopyr- side (1a, 100 mg, 0.515 mmol) or p-tolyl thio-β-d-glucopyranoside
(1b, 147 mg, 0.515 mmol) and HMDS (236 μL, 1.13 mmol,
2.2 equiv.) in CH2Cl2 (1.0 mL). After the system had been stirred
for 1 h, CH2Cl2 (1.5 mL), molecular sieves (4 Å, 150 mg), and benz-
aldehyde (111 μL, 1.097 mmol, 2.15 equiv.) were added, and the
mixture was allowed to stir at room temp. for 1 h. The mixture
was then cooled to 0 or –78 °C, and TMSOTf (18 μL, 0.10 mmol,
0.2 equiv.) was added. After the system had been stirred for 1 h,
triethylsilane (90 μL, 0.56 mmol, 1.1 equiv.) and TMSOTf (9 μL,
D
(111 μL, 1.097 mmol, 2.15 equiv.) were added, and the mixture was 0.05 mmol, 0.1 equiv.) were added. After the system had been
allowed to stir at room temp. for 1 h. The mixture was then cooled
to 0 or –78 °C, and TMSOTf (18 μL, 0.10 mmol, 0.2 equiv.) was
added. After the system had been stirred for 1 h, triethylsilane
stirred for another 3 h, acetic anhydride (96 μL, 1.02 mmol,
2.0 equiv.) and TMSOTf (36 μL, 0.20 mmol, 0.4 equiv.) were suc-
cessively added at 0 °C. The mixture was stirred at same tempera-
(90 μL, 0.56 mmol, 1.1 equiv.) and TMSOTf (9 μL, 0.05 mmol, ture for 1 h, BH3·THF (1.0 m in THF) (2.55 mL, 2.55 mmol,
0.1 equiv.) were added. After the system had been stirred for an-
other 3 h, acetic anhydride (96 μL, 1.02 mmol, 2.0 equiv.) and
TMSOTf (36 μL, 0.20 mmol, 0.4 equiv.) were successively added at
0 °C. The mixture was stirred at same temperature for 1 h, and was
then allowed to warm to room temp. and filtered through a pad of
Celite. The filtrate was washed with saturated NaHCO3 (aq.,
20 mL). The aqueous layer was extracted with EtOAc (3ϫ10 mL),
and the combined organic layers were washed with brine, dried
with anhydrous MgSO4, filtered, and concentrated in vacuo. The
mixture was purified by flash column chromatography on silica gel
to furnish the desired product 22a [0 °C: (173 mg, 0.417 mmol,
81%); –78 °C: (175 mg, 0.419 mmol, 82%)] or 22b [0 °C: (222 mg,
0.438 mmol, 85%)]. The obtained analytical data are in agreement
with reported literature.[5a,5b]
5.0 equiv.) and TMSOTf (45 μL, 0.23 mmol, 0.5 equiv.) were then
added, and the mixture was stirred for another 6 h at 0 °C. The
reaction was quenched slowly with MeOH (10 mL) at 0 °C, and
the mixture was filtered through a pad of Celite. The filtrate was
coevaporated with MeOH (3ϫ10 mL) in vacuo. The mixture was
diluted with EtOAc (20 mL) and washed with water (20 mL), and
the aqueous layer was extracted with EtOAc (3ϫ10 mL). The com-
bined organic layers were washed with brine, dried with anhydrous
MgSO4, filtered, concentrated in vacuo, and purified by flash col-
umn chromatography (Hex/EtOAc 3:1) on silica gel to give the de-
sired 6-alcohol 24a [0 °C: (133 mg, 0.319 mmol, 62%); –78 °C:
(120 mg, 0.288 mmol, 56%)] or 24b [0 °C: (134 mg, 0.263 mmol,
51%)]. The obtained analytical data are in accordance with re-
ported literature values.[5a,5b]
Methyl 2-O-Acetyl-3,6-di-O-benzyl-α-
D-glucopyranoside (23a) and
Methyl 2-O-Benzoyl-4,6-O-benzylidene-α-
D-glucopyranoside (25a)
p-Tolyl 2-O-Acetyl-3,6-di-O-benzyl-thio-β-D-glucopyranoside (23b):
and p-Tolyl 2-O-Benzoyl-4,6-O-benzylidene-thio-β-D-glucopyranos-
TMSOTf (9 μL, 0.05 mmol, 0.1 equiv.) was added at room temp.
under a nitrogen flow to a suspension of methyl α-d-glucopyrano-
side (1a, 100 mg, 0.515 mmol) or p-tolyl thio-β-d-glucopyranoside
(1b, 147 mg, 0.515 mmol) and HMDS (236 μL, 1.13 mmol,
2.2 equiv.) in CH2Cl2 (1.0 mL). After the system had been stirred
for 1 h, CH2Cl2 (1.5 mL), molecular sieves (4 Å, 150 mg), and benz-
aldehyde (111 μL, 1.097 mmol, 2.15 equiv.) were added, and the
mixture was allowed to stir at room temp. for 1 h. The mixture
ide (25b): TMSOTf (9 μL, 0.05 mmol, 0.1 equiv.) was added at
room temp. under a nitrogen flow to a suspension of methyl α-
d-glucopyranoside (1a, 100 mg, 0.515 mmol) or p-tolyl thio-β-d-
glucopyranoside (1b, 147 mg, 0.515 mmol) and HMDS (224 μL,
1.07 mmol, 2.1 equiv.) in CH2Cl2 (1.0 mL). After the system had
been stirred for 1 h, CH2Cl2 (1.5 mL), molecular sieves (4 Å,
150 mg), and benzaldehyde (62 μL, 0.61 mmol, 1.2 equiv.) were
added, and the mixture was allowed to stir at room temp. for 1 h.
Eur. J. Org. Chem. 2012, 744–753
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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749

C.-C. Wang et al.
FULL PAPER
The mixture was then cooled to 0 °C and TMSOTf (18 μL,
0.10 mmol, 0.2 equiv.) was added. After the system had been stirred
for another 1 h, TBAF (2.04 mL, 2.04 mmol, 4.0 equiv.) was added,
and the mixture was allowed to warm gradually to room temp. and
kept stirring overnight. Et3N (638 μL, 4.59 mmol, 9.0 equiv.) and
Bz2O (237 mg, 1.94 mmol, 3.8 equiv.) were added and the system
was stirred at room temp. for 48 h. MeOH (103 μL, 2.55 mmol,
5.0 equiv.) was added and the mixture was stirred for another 1 h
to quench the reaction. The mixture was filtered through a pad of
Celite, and the filtrate was diluted with EtOAc (10 mL) and washed
with water (10 mL). The aqueous layer was extracted with EtOAc
(3ϫ10 mL), and the combined organic layers were washed with
brine, dried with anhydrous MgSO4, filtered, and concentrated in
vacuo. The mixture was purified by flash column chromatography
on silica gel to furnish the desired product 25a (115 mg,
0.299 mmol, 58%) or 25b (138 mg, 0.288 mmol, 56%). The analyti-
cal data are in accordance with reported literature values.[5a,5b]
through a pad of Celite. The filtrate was carefully neutralized with
saturated NaHCO3 (aq., 20 mL). The aqueous layer was extracted
with EtOAc (3ϫ10 mL), and the combined organic layers were
washed with brine, dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The mixture was purified by flash column
chromatography (Hex/EtOAc 10:1 to 5:1) on silica gel to furnish
the desired product 27 as a white solid (134 mg, 0.244 mmol, 90%);
m.p. 203–204 °C. [α]2D3 = –10.7 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.39–7.33 (m, 3 H),
7.28–7.25 (m, 5 H), 6.82 (d, J = 8 Hz, 1 H), 5.0 (d, J = 10.4 Hz, 1
H), 4.88 (d, J = 11.2 Hz, 1 H), 4.36 (dd, J = 5.1, 13.0 Hz, 1 H),
4.14 (t, J = 9.2 Hz, 1 H), 3.81–3.52 (m, 4 H), 2.77–2.64 (m, 2 H),
1.25 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
161.9, 137.9, 137.4, 129.3, 128.7, 128.5, 128.2, 126.2, 101.5, 92.6,
83.6, 82.8, 75.0, 70.7, 68.8, 57.7, 24.9, 15.3 ppm. IR (thin film): ν
˜
= 3300, 2924, 1690, 1538, 1072, 833 cm–1. HRMS (ESI): calcd. for
C24H26NO5SCl3Na [M + Na]+ 568.0495; found 568.0485.
Ethyl 4,6-O-Benzylidene-2-deoxy-2-N-trichloroacetamido-thio-β-
D-
Ethyl
3,6-Di-O-benzyl-2-deoxy-2-N-trichloroacetamido-thio-β-D-
glucopyranoside (26): TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) was
glucopyranoside (28): TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) was
added at room temp. under a nitrogen flow to a suspension of ethyl
added at room temp. under a nitrogen flow to a suspension of ethyl
2-deoxy-2-N-trichloroacetamido-thio-β-d-glucopyranoside
(7,
2-deoxy-2-N-trichloroacetamido-thio-β-d-glucopyranoside
(7,
100 mg, 0.271 mmol) and HMDS (90 μL, 0.434 mmol, 1.6 equiv.)
in CH2Cl2 (1.0 mL). After the system had been stirred for 1 h,
CH2Cl2 (1.5 mL), molecular sieves (4 Å, 150 mg), and benzalde-
hyde (30 μL, 0.29 mmol, 1.1 equiv.) were added, and the mixture
was allowed to stir at room temp. for 1 h. The mixture was then
cooled to 0 °C, and TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) was
added. The mixture was kept stirring at the same temperature for
2 h. TBAF (1.02 mL, 1.02 mmol, 3.8 equiv.) was added, and the
mixture was allowed to warm to room temp. and kept stirring over-
night. The mixture was filtered through a pad of Celite, and the
filtrate was diluted with EtOAc (10 mL) and washed with saturated
NaHCO3 (aq., 10 mL). The aqueous layer was extracted with
EtOAc (3ϫ10 mL), and the combined organic layers were washed
with brine, dried with anhydrous MgSO4, filtered, and concentrated
in vacuo. The mixture was purified by flash column chromatog-
raphy (Hex/EtOAc 1:1) on silica gel to furnish the desired product
26; yield: 116 mg (94%); m.p. 204–205 °C. [α]2D3 = –39.7 (c = 0.5,
100 mg, 0.271 mmol) and HMDS (90 μL, 0.434 mmol, 1.6 equiv.)
in CH2Cl2 (1.0 mL). After the system had been stirred for 1 h,
CH2Cl2 (1.5 mL), molecular sieves (4 Å, 150 mg), and benzalde-
hyde (58 μL, 0.56 mmol, 2.1 equiv.) were added, and the mixture
was allowed to stir at room temp. for 1 h. The mixture was then
cooled to 0 °C, and TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) was
added. The mixture was kept stirring at the same temperature for
2 h. Triethylsilane (46 μL, 0.28 mmol, 1.05 equiv.) and TMSOTf
(5 μL, 0.03 mmol, 0.1 equiv.) were sequentially added, and the mix-
ture was stirred for another 5 h. The mixture was then cooled to
–78 °C, triethylsilane (407 μL, 2.55 mmol, 9.4 equiv.), trifluoro-
acetic acid (156 μL, 2.04 mmol, 7.5 equiv.), and trifluoroacetic an-
hydride (4 μL, 0.03 mmol, 0.1 equiv.) were added, and the mixture
was allowed to stir at the same temperature overnight. The mixture
was allowed to warm gradually to room temp. and filtered through
a pad of Celite. The filtrate was carefully neutralized with saturated
NaHCO3 (aq., 20 mL). The aqueous layer was extracted with
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.47–7.44 (m, 2 H), EtOAc (3ϫ10 mL), and the combined organic layers were washed
7.37–7.35 (m, 3 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.53 (s, 1 H), 4.93 with brine, dried with anhydrous MgSO4, filtered, and concentrated
(d, J = 10.3 Hz, 1 H), 4.34 (dd, J = 4.4, 10.8 Hz, 1 H), 4.21 (t, J =
in vacuo. The mixture was purified by flash column chromatog-
7.6 Hz, 1 H), 3.78–3.65 (m, 2 H), 3.58–3.53 (m, 2 H), 2.90 (s, 1 raphy (Hex/EtOAc 10:1 to 5:1) on silica gel to furnish the desired
H), 2.77–2.67 (m, 2 H), 1.26 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR product 28 as a white solid (129 mg, 0.236 mmol, 87%); m.p. 84–
(100 MHz, CDCl3):
δ
=
162.1, 136.8, 129.4, 128.4, 126.3,
85 °C. [α]2D3 = –16.7 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
101.8, 92.3, 83.4, 81.3, 71.4, 70.4, 68.4, 57.7, 24.5, 15.0 ppm. IR δ = 7.35–7.26 (m, 10 H), 6.83 (d, J = 8.4 Hz, 1 H), 4.87 (d, J =
(thin film): ν = 3556, 3325, 2926, 1691, 1530, 1081, 822 cm–1. 10.4 Hz, 1 H), 4.76 (d, J = 11.1 Hz, 2 H), 4.56 (ABq, J = 12.0 Hz,
˜
HRMS (ESI): calcd. for C17H19NO5SCl3 [M – H]– 454.0050; found 2 H), 3.86 (dd, J = 8.8, 10.0 Hz, 1 H), 3.78–3.60 (m, 4 H), 3.53 (dt,
454.0052.
J = 4.4, 5.2 Hz, 1 H), 2.86 (s, 1 H), 2.75–2.61 (m, 2 H), 1.24 (t, J
= 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.8,
138.2, 137.8, 128.8, 128.7, 128.3, 128.2, 128.1, 128.0, 92.7, 83.0,
81.6, 78.1, 75.0, 74.0, 73.7, 70.9, 57.2, 24.7, 15.3 ppm. IR (thin
Ethyl
amido-thio-β-
3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-N-trichloroacet-
-glucopyranoside (27): TMSOTf (5 μL, 0.03 mmol,
D
0.1 equiv.) was added at room temp. under a nitrogen flow to a
suspension of ethyl 2-deoxy-2-N-trichloroacetamido-thio-β-d-gluc-
opyranoside (7, 100 mg, 0.271 mmol) and HMDS (90 μL,
0.434 mmol, 1.6 equiv.) in CH2Cl2 (1.0 mL). After the system had
been stirred for 1 h, CH2Cl2 (1.5 mL), molecular sieves (4 Å,
150 mg), and benzaldehyde (58 μL, 0.56 mmol, 2.1 equiv.) were
added, and the mixture was allowed to stir at room temp. for 1 h.
The mixture was then cooled to 0 °C, and TMSOTf (5 μL,
film): ν = 3478 (br), 3320, 2870, 1690, 1529, 1061, 821 cm–1. HRMS
˜
(ESI): calcd. for C24H28NO5SCl3Na [M + Na]+ 570.0651; found
570.0653.
Ethyl
3,4-Di-O-benzyl-2-deoxy-2-N-trichloroacetamido-thio-β-D-
glucopyranoside (29): TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) was
added at room temp. under a nitrogen flow to a suspension of ethyl
2-deoxy-2-N-trichloroacetamido-thio-β-d-glucopyranoside
(7,
0.03 mmol, 0.1 equiv.) was added. The mixture was kept stirring 100 mg, 0.271 mmol) and HMDS (90 μL, 0.434 mmol, 1.6 equiv.)
at the same temperature for 2 h. Triethylsilane (46 μL, 0.28 mmol,
1.05 equiv.) and TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) were se-
quentially added, and the mixture was stirred for another 5 h. The
mixture was allowed to warm gradually to room temp. and filtered
in CH2Cl2 (1.0 mL). After the system had been stirred for 1 h,
CH2Cl2 (1.5 mL), molecular sieves (4 Å, 150 mg), and benzalde-
hyde (58 μL, 0.56 mmol, 2.1 equiv.) were added, and the mixture
was allowed to stir at room temp. for 1 h. The mixture was then
750
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 744–753

One-Pot Protection and Acetylation of Carbohydrates
cooled to 0 °C, and TMSOTf (5 μL, 0.03 mmol, 0.1 equiv.) was
added. The mixture was kept stirring at the same temperature for
2 h. Triethylsilane (46 μL, 0.28 mmol, 1.05 equiv.) and TMSOTf
(5 μL, 0.03 mmol, 0.1 equiv.) were sequentially added, and the mix-
ture was stirred for another 5 h. BH3·THF (1.0 m in THF, 1350 μL,
1.35 mmol, 5.0 equiv.) and TMSOTf (25 μL, 1.5 mmol, 0.5 equiv.)
were added, and the mixture was allowed to stir at 0 °C for 7 h.
The reaction was quenched slowly with MeOH (10 mL) at 0 °C,
and the mixture was filtered through a pad of Celite. The filtrate
was coevaporated with MeOH (3ϫ10 mL) in vacuo. The mixture
was diluted with EtOAc (20 mL) and washed with water (20 mL),
and the aqueous layer was extracted with EtOAc (3ϫ10 mL). The
combined organic layers were washed with brine, dried with anhy-
drous MgSO4, filtered, and concentrated in vacuo. The mixture was
purified by flash column chromatography (Hex/EtOAc 10:1 to 5:1)
on silica gel to furnish the desired product 29 as a white solid
(131 mg, 0.238 mmol, 88%); m.p. 146–147 °C. [α]2D3 = –4.1 (c = 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 10 H),
6.81 (d, J = 10.2 Hz, 1 H), 4.92 (d, J = 10.2 Hz, 1 H), 4.82 (d, J =
11.3 Hz, 1 H), 4.82 (d, J = 10.2 Hz, 1 H), 4.71 (d, J = 10.9 Hz, 2
H), 4.66 (d, J = 11.0 Hz, 2 H), 4.04 (t, J = 8.9 Hz, 1 H), 3.89–3.87
(m, 1 H), 3.73–3.61 (m, 3 H), 3.50–3.45 (m, 1 H), 2.73–2.68 (m, 2
H), 1.87 (m, 1 H), 1.24 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.6, 137.7, 137.6, 128.5, 128.0, 127.9,
92.4, 82.8, 81.6, 79.7, 78.2, 75.3, 74.9, 61.9, 57.5, 24.7, 15.1 ppm.
HRMS (ESI): calcd. for C24H28NO5SCl3Na [M + Na]+ 570.0651;
found 570.0656.
(110 μL, 1.17 mmol, 4.0 equiv.) and TMSOTf (32 μL, 0.175 mmol,
0.6 equiv.) were added and the mixture was stirred at the same tem-
perature for another 1 h. The whole mixture was filtered through
a pad of Celite, and the filtrate was washed with saturated
NaHCO3 (aq., 10 mL). The aqueous layer was extracted with
EtOAc (3ϫ15 mL), and the combined organic layers were washed
with brine, dried with anhydrous MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy on silica gel to provide the desired product 31 (201 mg,
0.257 mmol, 88%). The obtained analytical data are in agreement
with reported literature.[6b]
Procedure for One-Pot Nonenzymatic Regioselective Acetylation of
D-Glucose (11), D-Galactose (13), and D-Mannose (15): TMSOTf
(10 μL, 0.06 mmol, 0.1 equiv.) was added at room temp. under N2
to a suspension of d-glucose (11), d-galactose (13), or d-mannose
(15) (100 mg, 0.56 mmol) and HMDS (327 μL, 1.56 mmol,
2.8 equiv.) in CH2Cl2 (1.0 mL). After the system had been stirred
for 40 min, pyridine (1.1 mL), acetic anhydride (0.83 mL), and
acetic acid (126 μL, 2.24 mmol, 4.0 equiv.) were added with stir-
ring. The mixture was allowed to stir at room temp. for 48 h. The
mixture was concentrated and purified by column chromatography
(Hex/EtOAc 20:1) to yield the 6-O-monoacetate glucose product
32 (223 mg, 78%), the galactose product 34 (231 mg, 81%), or the
mannose product 36 (183 mg, 64%), together with the 1,6-O-di-
acetate glucose product 33 (44 mg, 17%), galactose product 35
(39 mg, 15%), or mannose product 37 (47 mg, 18%). The obtained
analytical data are in agreement with reported literature.[11]
3,3Ј-Di-O-benzyl-4,6,4Ј,6Ј-di-O-benzylidene-α,αЈ-D-trehalose (30):
p-Tolyl 4-O-(α-D-Glucopyranosyl)-thio-β-D-glucopyranoside (38):
HMDS (256 μL, 1.23 mmol, 4.2 equiv.) and TMSOTf (5 μL,
29.2 μmol, 0.1 equiv.) were added at room temp. under a nitrogen
flow to a suspension of α,αЈ-d-trehalose (9, 100 mg, 0.292 mmol)
in CH2Cl2 (1.5 mL), and the mixture was stirred at room temp. for
3 h. CH2Cl2 (2 mL), benzaldehyde (125 μL, 1.226 mmol,
4.2 equiv.), and molecular sieves (4 Å, 150 mg) were added and the
mixture was stirred for another 1 h. The mixture was cooled to
0 °C, and TMSOTf (11 μL, 58.4 μmol, 0.2 equiv.) was added. After
the system had been stirred at the same temperature for 1 h, trieth-
ylsilane (150 μL, 0.701 mmol, 2.4 equiv.) and TMSOTf (9 μL,
43.8 μmol, 0.15 equiv.) were sequentially added. After the system
had been stirred for another 2 h, TBAF (1.2 mL, 1.20 mmol,
4.1 equiv.) was added, the ice bath was removed, and the mixture
was kept stirring overnight. The whole mixture was filtered through
a pad of Celite, and the filtrate was washed with saturated
NaHCO3 (aq., 20 mL). The aqueous layer was extracted with
EtOAc (3ϫ15 mL), and the combined organic layers were washed
with brine, dried with anhydrous MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy on silica gel to provide the desired product 30 (171 mg,
0.266 mmol, 91%). The obtained analytical data are in agreement
with reported literature.[6b]
Sodium methoxide (122 mg, 2.3 mmol, 0.2 equiv.) was added at
room temp. to a solution of p-tolyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-
tetra-O-acetyl-α-d-glucopyranosyl)-thio-β-d-glucopyranoside[27]
(8.4 g, 11.3 mmol) in MeOH (80 mL). The solution was stirred for
16 h and was neutralized with acidic Amberlite resin IR-120. The
resin was filtered off and washed with MeOH (20 mL). The fíltrate
was concentrated in vacuo to afford the desired product 38 as a
white foam (4.5 g, 10.1 mmol, 89%). [α]2D3 = +78.1 (c = 0.1,
1
MeOH). H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.0 Hz, 2
H), 7.14 (d, J = 7.9 Hz, 2 H), 5.17 (d, J = 3.7 Hz, 1 H), 4.54 (d, J
= 9.6 Hz, 1 H), 3.91–3.78 (m, 3 H), 43.71–3.59 (m, 4 H), 3.53 (t, J
= 9.4 Hz, 1 H), 3.46–3.22 (m, 5 H), 3.32 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.9, 133.7, 131.1, 130.6, 102.9, 89.7, 80.9,
80.7, 79.54, 75.2, 74.8, 74.3, 73.4, 71.6, 62.8, 62.4, 21.2 ppm. IR
(thin film): ν = 3327 (br), 2922, 1492, 1275, 1145, 1016, 806 cm–1.
˜
HRMS (ESI): calcd. for C19H28O10SNa [M + Na]+ 471.1301; found
471.1302.
p-Tolyl
silyl-α-
2,3,6-Tri-O-trimethylsilyl-4-O-(2,3,4,6-tetra-O-trimethyl-
-glucopyranosyl)-thio-β- -glucopyranoside (39): TMSOTf
D
D
(4 μL, 22.3 μmol, 0.1 equiv.) was added at room temp. under N2
to a suspension of 38 (100 mg, 0.223 mmol) and HMDS (191 μL,
0.914 mmol, 4.1 equiv.) in CH2Cl2 (10 mLg–1). The suspension dis-
2,2Ј-Di-O-acetyl-3,3Ј-di-O-benzyl-4,6,4Ј,6Ј-di-O-benzylidene-α,αЈ-D-
trehalose (31): HMDS (256 μL, 1.23 mmol, 4.2 equiv.) and appeared in minutes. After the system had been stirred for 40 min,
TMSOTf (5 μL, 29.2 μmol, 0.1 equiv.) were added at room temp.
under a nitrogen flow to a suspension of α,αЈ-d-trehalose (9,
the mixture was diluted with hexane and washed with water. The
aqueous layer was extracted with EtOAc, and the organic layers
100 mg, 0.292 mmol) in CH2Cl2 (1.5 mL), and the mixture was were combined, washed with brine, dried with MgSO4, filtered, and
stirred at room temp. for 3 h. CH2Cl2 (2 mL), benzaldehyde
(125 μL, 1.23 mmol, 4.2 equiv.), and molecular sieves (4 Å, 150 mg)
were added and the mixture was stirred for another 1 h. The mix-
ture was cooled to 0 °C, and TMSOTf (11 μL, 58.4 μmol,
0.2 equiv.) was added. After the system had been stirred for at same
temperature for 1 h, triethylsilane (150 μL, 0.701 mmol, 2.4 equiv.)
and TMSOTf (9 μL, 43.8 μmol, 0.15 equiv.) were sequentially
added. After the system had been stirred for another 2 h, Ac2O
concentrated in vacuo to furnish the desired product 39 as a color-
less syrup (212 mg, 0.222 mmol, quant.). [α]2D3 = +56.5 (c = 0.1,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 8.0 Hz, 2
H), 7.09 (d, J = 8.0 Hz, 2 H), 5.06 (d, J = 3.4 Hz, 1 H), 4.82 (d, J
= 8.5 Hz, 1 H), 3.95 (t, J = 4.9 Hz, 1 H), 3.86 (t, J = 5.1 Hz, 1 H),
3.80 (d, J = 4.2 Hz, 2 H), 3.76–3.66 (m, 4 H) 3.62 (d, J = 11.4 Hz,
1 H), 3.52 (d, J = 6.2 Hz, 2 H), 3.41 (dd, J = 8.9, 3.4 Hz, 1 H),
2.33 (s, 3 H), 0.20 (s, 9 H), 0.18 (s, 9 H), 0.167 (s, 9 H), 0.16 (s, 9
Eur. J. Org. Chem. 2012, 744–753
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751

C.-C. Wang et al.
H), 0.14 (s, 9 H), 0.12 (s, 9 H), 0.10 (s, 9 H) ppm. 13C NMR J = 11.6, 4.2 Hz, 1 H, 6aЈ-H), 4.28 (dd, J = 11.5, 7.2 Hz, 1 H, 6bЈ-
FULL PAPER
(125 MHz, CDCl3): δ = 137.0, 131.7, 129.6, 97.3, 87.7, 79.7, 78.1,
H), 4.23 (dd, J = 11.8, 2.1 Hz, 1 H, 6a-H), 3.98 (dd, J = 11.8,
5.6 Hz, 1 H, 6b-H), 3.94–3.91 (m, 1 H, 5-H), 3.87 (t, J = 4.6 Hz, 1
H, 4-H), 3.83–3.81 (m, 1 H, 5Ј-H), 3.70–3.65 (m, 3 H, 2-H, 3-H,
76.2, 74.7, 74.3, 73.5, 73.2, 71.7, 63.2, 61.7, 21.2, 1.5, 1.4, 1.2, 1.0,
0.9, 0.7, 0.2 ppm. IR (thin film): ν = 2956, 1248, 1149, 833 cm–1.
˜
HRMS (ESI): calcd. for C40H84O10SSi7Na [M + Na]+ 975.4068; 3Ј-H), 3.45 (dd, J = 8.5, 3.3 Hz, 1 H, 2Ј-H), 3.40 (dd, J = 9.4,
found 975.4072.
7.5 Hz, 1 H, 4Ј-H), 2.29 (s, 3 H, CH3), 2.02 (s, 6 H, CH3 ϫ2), 0.17
(s, 9 H, TMS), 0.14 (s, 9 H, TMS), 0.12 (s, 9 H, TMS), 0.11 (s, 9
H, TMS), 0.10 (s, 9 H, TMS) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.9 (C), 170.6 (C), 137.2 (CH), 131.7 (CH), 129.66 (CH),
98.2 (CH), 88.3 (CH), 76.8 (CH), 76.4 (CH), 75.4 (CH), 74.5 (CH),
73.1 (CH), 72.5 (CH), 71.2 (CH), 65.2 (CH2), 63.9 (CH2), 21.2
(CH3), 21.0 (CH3), 20.9 (CH3), 1.27 (CH3), 1.2 (CH3), 0.97 (CH3),
p-Tolyl
2,3-Di-O-acetyl-6-O-benzyl-4-O-(2-O-acetyl-3-O-benzyl-
4,6-O-benzylidene-α-D-glucopyranosyl)-thio-β-D-glucopyranoside
(40): HMDS (198 μL, 0.936 mmol, 4.2 equiv.) and TMSOTf (4 μL,
22.2 μmol, 0.1 equiv.) were added at room temp. under a nitrogen
flow to a suspension of compound 38 (100 mg, 0.222 mmol) in
CH2Cl2 (1.0 mL), and the mixture was stirred at room temp. for
3 h. CH2Cl2 (2 mL), benzaldehyde (75 μL, 0.735 mmol, 3.3 equiv.),
and molecular sieves (4 Å, 150 mg) were added and the mixture
was stirred for another 2 h. The mixture was cooled to 0 °C, and
TMSOTf (8 μL, 44.4 μmol, 0.2 equiv.) was added. After the system
had been stirred at same temperature for 1 h, triethylsilane (86 μL,
0.535 mmol, 2.4 equiv.) and TMSOTf (4 μL, 22.2 μmol, 0.1 equiv.)
were sequentially added. After the system had been stirred for an-
other 2 h, Ac2O (67 μL, 0.713 mmol, 3.2 equiv.) and TMSOTf
(8 μL, 22.2 μmol, 0.2 equiv.) were added and the mixture was
stirred at the same temperature for another 1 h. The whole mixture
was filtered through a pad of Celite, and the filtrate was washed
with saturated NaHCO3 (aq., 10 mL). The aqueous layer was ex-
tracted with EtOAc (3ϫ15 mL), and the combined organic layers
were washed with brine, dried with anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel to provide the desired product 40
(93 mg, 0.111 mmol, 50%). [α]2D3 = +57.1 (c = 0.1, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m, 2 H, Ph), 7.43–7.39
(m, 5 H, Ph), 7.38–7.29 (m, 10 H, Ph), 7.08 (d, J = 8.0 Hz, 2 H,
Ph), 5.57 (s, 1 H, PhCH), 5.36 (d, J = 4.1 Hz, 1 H, 1Ј-H), 5.31 (t,
J = 9.0 Hz, 1 H, 3-H), 4.89 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.84
(dd, J = 9.6, 4.1 Hz, 1 H, 2Ј-H), 4.81 (t, J = 9.4 Hz, 1 H, 2-H),
4.70 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.66 (d, J = 7.6 Hz, 1 H, 1-H),
4.12 (t, J = 9.6 Hz, 1 H, 6axЈ-H), 4.10 (t, J = 6.1 Hz, 1 H, 4-H),
3.93 (t, J = 9.6 Hz, 1 H, 3Ј-H), 3.92 (dd, J = 8.0, 4.3 Hz, 1 H, 6eqЈ-
H), 3.83–3.80 (m, 2 H, 5-H, 5Ј-H), 3.69 (t, J = 9.6 Hz, 1 H, 4Ј-H),
3.66–3.60 (m, 2 H, 6a-H, 6b-H), 2.34 (s, 3 H, CH3), 2.09 (s, 3 H,
CH3), 2.06 (s, 3 H, CH3), 2.0 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.9 (C), 170.6 (C), 169.7 (C), 138.9 (C),
138.6 (C), 138.3 (C), 137.5 (C), 134.5 (CH), 129.8 (CH), 129.1
(CH), 128.5 (CH), 128.51 (CH), 128.4 (CH), 127.78 (CH), 127.73
(CH), 127.2 (C), 126.2 (CH), 101.4 (CH), 96.3 (CH), 85.1 (CH),
81.9 (CH), 78.8 (CH), 76.1 (CH), 75.0 (CH2), 73.9 (CH2), 72.5
(CH), 71.0 (CH), 70.8 (CH), 68.8 (CH2), 63.7 (CH), 21.3 (CH3),
0.91 (CH ), 0.5 (CH ) ppm. IR (thin film): ν = 2956, 1744, 1493,
˜
3
3
1146, 1249, 835 cm–1. HRMS (ESI): calcd. for C38H72O12SSi5Na
[M + Na]+ 915.3489; found 915.3484.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of new compounds and
the 1H, 13C and 2D NMR spectra of compound 18 and 20 are
provided.
Acknowledgments
We thank Prof. Chin-Hsing Chou (NSYSU) and Dr. Der-Lii Tzou
(I.O.C., Academia Sinica) for valuable discussions. This work was
supported by the National Science Council of Taiwan (NSC) (NSC
grant number 99-2113-M-001-010-MY2).
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˜
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3
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6-O-Acetyl-2,3-di-O-trimethylsilyl-4-O-(6-O-acetyl-2,3,4-
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D
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[α]2D3 = +53.7 (c = 0.1 , CHCl3). H NMR (600 MHz, CDCl3): δ =
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www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: August 30, 2011
Published Online: December 5, 2011
Eur. J. Org. Chem. 2012, 744–753
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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