A practical silicon-free strategy for differentiation of hydroxy groups in arabinofuranose derivatives

Article abstract of DOI:10.1055/s-0031-1290752

Effective differentiation of 3,5-diol system and 2-hydroxy group in arabinofuranose derivatives, which is required for the preparation of building blocks useful for the synthesis of nucleoside analogues and oligosaccharide fragments of mycobacterial arabinogalactan and lipoarabinomannan, was achieved by using 3,5-di-O-benzoyl-1,2-O-benzylidene-βD-arabinofuranose or 3-O-(chloroacetyl)-β- d-arabinofuranose 1,2,5-orthobenzoate, both readily accessible from inexpensive methylα-d-arabinofuranoside via the corresponding glycosyl bromides. The use of expensive organosilicon protecting groups is completely avoided in this novel strategy, a feature that makes it amenable to scale-up. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290752

PAPER
▌1219
paper
A Practical Silicon-Free Strategy for Differentiation of Hydroxy Groups in
Arabinofuranose Derivatives
Silicon-Free Differentiation of Hydroxy Groups in Arabinofuranose
Polina I. Abronina,a Nikita M. Podvalnyy,a Sergey L. Sedinkin,a Ksenia G. Fedina,a,b Alexander I. Zinin,a
Alexander O. Chizhov,a Vladimir I. Torgov,a Leonid O. Kononov*a
a
N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Leninsky prosp., 47, Moscow 119991, Russian Federation
b
The Higher Chemical College of the Russian Academy of Sciences, Miusskaya pl. 9, Moscow 125047, Russian Federation
Fax +7(499)1355328; E-Mail: kononov@ioc.ac.ru; E-Mail: leonid.kononov@gmail.com
Received: 30.09.2011; Accepted after revision: 15.02.2012
Dedicated to the memory of the late Professor Leon V. Backinowsky
and subsequent removal of the temporary protecting
Abstract: Effective differentiation of 3,5-diol system and 2-hy-
group from the primary hydroxy group. Alternatively,
droxy group in arabinofuranose derivatives, which is required for
building block C can be prepared in one step by ring-
opening of a 3-O-protected arabinose 1,2,5-orthobenzo-
the preparation of building blocks useful for the synthesis of nucle-
oside analogues and oligosaccharide fragments of mycobacterial
arabinogalactan and lipoarabinomannan, was achieved by using ate.1h,5
3,5-di-O-benzoyl-1,2-O-benzylidene-β-D-arabinofuranose or 3-O-
Arabinose thioglycosides with a nonprotected 2-hydroxy
(chloroacetyl)-β-D-arabinofuranose 1,2,5-orthobenzoate, both read-
ily accessible from inexpensive methyl α-D-arabinofuranoside via
the corresponding glycosyl bromides. The use of expensive organo-
silicon protecting groups is completely avoided in this novel strate-
gy, a feature that makes it amenable to scale-up.
group (building block A) are accessible (Scheme 2) main-
ly through selective protection of the 3,5-diol function in
arabinofuranose-based 2,3,5-triol F with cyclic organosil-
icon protecting groups such as 3,5-O-tetraisopropyldisil-
oxanylidene
(TIPDS)1c,e,i,j
or
di-tert-butylsilyl
Key words: carbohydrates, protecting groups, acetals, oligosac-
(DTBS),1a,b,e,g which are introduced by using expensive
reagents such as 1,3-dichloro-1,1,3,3-tetraisopropyldisil-
oxane (F → A1 or A2). Protection of the 2-OH group in
building blocks A1 or A2 with an orthogonal protecting
group gives rise to building blocks D1 or D2, respectively,
which are useful as glycosyl donors.1a,b,e,i Desilylation of
building blocks D1 or D2 gives 3,5-diol B (F → A → D
→ B).1a,g Although this synthesis of building blocks A and
B is very short and efficient, the preparative utility of this
approach is somewhat restricted by the high cost of the re-
agents.
charides, nucleosides
There has been a recent growth in interest in the synthesis
of D-arabinofuranose (Ara) oligosaccharides related to the
mycobacterial cell-wall components arabinogalactan, lipo-
arabinomannan, and arabinomannan of Mycobacterium
tuberculosis,1 because of the need to develop methods for
the diagnosis, prevention, and treatment of human tuber-
culosis, which is a major health problem worldwide.2 The
nonreducing end of each of these polysaccharides consists
of a common branched hexasaccharide motif (Ara6) that
plays an important role in the pathogenicity of mycobac-
teria (Scheme 1).1
An alternative and more attractive approach (Scheme 2)
for large-scale preparation of building block A, which is
Because the structure of Ara6 contains both α-1–5-linkag-
es (residue I) and β-1–2-linkages (residues III and IV) as
well as a 3,5-branching (residue II), the building blocks
A–C, selectively protected at O-2, O-3, and O-5 are re-
quired for the assembly of the hexasaccharide (Scheme 1).
Various strategies have been developed for the prepara-
tion of selectively protected arabinofuranose monosac-
charide building blocks (Scheme 2), none of which is free
of problems.1
R1O
OH
OH
O
VI
O
XR
R4O
HO
R2O
HO
A
O
O
IV
OR3
HO
O
O
OH
OH
O
II
XR
HO
B
O
OH
III
O
OH
O
I
Building block C with a free 5-OH group can be prepared
in a fairly straightforward manner by selective protection
of the primary hydroxy group in the 2,3,5-triol F (Scheme
2) with one of several suitable protecting groups, such as
benzoate,3 trityl,4 or tert-butyl(diphenyl)silyl,1a followed
by blocking of the remaining secondary hydroxy groups
O
HO
R4O
O
OR
HO
OH
HO
OR3
O
O
V
XR
R2O
OH
Ara6
C
Scheme 1 Structures of the common hexasaccharide moiety of my-
cobacterial arabinogalactan and lipoarabinomannan and of the key
building blocks. R = aglycone; X = O or S; R1, R2, R3 = protecting
groups; R4 = H or capping group.
SYNTHESIS 42170012, 44,81219–1225
Advanced online publication: 22.03.2012
DOI: 10.1055/s-0031-1290752; Art ID: SS-2011-N0937-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1220
P. I. Abronina et al.
PAPER
required for multistep syntheses of oligoarabinofurano- We hypothesized that the reaction of 2-O-benzoylated
sides,6 relies on the introduction of a 1,2-O-isopropyli- glycosyl bromides with sodium borohydride might be ex-
dene group into the 5-O-silylated arabinose G7 to give tended to furanoses and might be used for the synthesis of
building block H followed by straightforward blocking of 1,2-O-benzylidene derivatives of arabinofuranose
the 3-OH group with temporary protection and (Scheme 3). Indeed, the related 3,5-di-O-(4-methylben-
elaboration1k of the 1,2-diol E, obtained by removal of the zoyl)-1,2-O-(4-methylbenzylidene)-β-L-arabinofuranose
1,2-O-isopropylidene group (G → H → E → D → A). Se- has been obtained (as an undesired product during the
lective protection of the 5-OH group of arabinose is vital synthesis of 2-deoxy-L-ribose) by treatment of 2,3,5-tri-
for ensuring efficient formation of the furanose at the O-(4-methylbenzoyl)-α-L-arabinofuranosyl bromide with
acetalization step (Scheme 2).
sodium cyanoborohydride.9
OR3
HO
Ph
Ph
H
Ph
O
O
+
XR
R1O
R1O
R1O
O
O
O
O
O
[H–]
Br–
HO
O
O
O
B
Br
R2O
R2O
R2O
R1O
R1O
R1O
OR3
Scheme 3 Formation of 1,2-O-benzylidene acetal by reductive de-
bromination of a 2-O-benzoylglycosyl bromide
OH
OH
O
O
O
XR
XR
R2O
A, A1, A2
for
A1, A2
R2O
R2O
OH
for
A1, A2
The fully O-benzoylated arabinofuranosyl bromide 210a
(Scheme 4), which is required for this transformation, can
be prepared by treatment of readily available methyl tri-
O-benzoyl-α-D-arabinofuranoside (1)10 with hydrogen
bromide in either acetic acid or dichloromethane.5 Treat-
ment of glycosyl bromide 2 with sodium borohydride in
acetonitrile gave the desired 1,2-O-benzylidene acetal 3,
isolated as a single isomer in 90% yield. Acid hydrolysis
removed the benzylidene function to give the 1,2-diol 4
(building block E) as a 1:1 anomeric mixture. The diol 4
was converted into the corresponding 1,2-di-O-acetate 5
or the 1,2-bis-O-chloroacetate 6 in high yields. Treatment
of O-acetate 5 with benzenethiol and boron trifluoride
etherate in dichloromethane gave thioglycoside 7 (build-
ing block D) with an orthogonal 2-O-acetyl protecting
group as a single α-isomer in 85% yield. Similar treatment
of 1,2-bis-O-chloroacetate 6 gave thioglycoside 9 with 2-
O-chloroacetyl protecting groups as a single α-isomer in
83% yield.
D, D1, D2
E
D-Ara
R1O
R1O
O
O
HO
OH
OH
O
O
O
XR
OH
HO
HO
HO
F
G
H
Scheme 2 Known approaches to the synthesis of building blocks A
and B. R = aglycone; X = O or S; R1,R2,R3 = protecting groups: for
A1 or D1, R1R2 = Si(i-Pr)2OSi(i-Pr)2 (TIPDS); for A2 or D2, R1R2 =
Si(t-Bu)2 (DTBS); for G and H, R1 = Si(t-Bu)Ph2, Bz, Tr.
Here we describe an approach for the selective function-
alization of arabinofuranose that extends the existing
methodologies and which does not rely on the use of any
organosilicon protecting groups.
We reasoned that the known problem of controlling the
size of the sugar ring during formation of the 1,2-O-iso-
propylidene moiety in arabinose (the synthesis of building
block H in Scheme 2) might be solved by the introduction
of a cyclic 1,2-O-acetal moiety into a derivative with an
existing furanose ring, rather than into an acyclic arabi-
nose.
The 2-O-acetyl protected derivative 7 was subjected to
acid-catalyzed methanolysis under mild conditions;11 this
selectively cleaved the acetate esters, but did not affect the
O-benzoyl groups, giving the 2-hydroxy derivative 8
(building block A) in 89% yield. The structure of the
product 8 was supported by the upfield shift of the signal
for H-2 in its 1H NMR spectrum compared with that in the
spectrum of the starting compound 7. Chloroacetylation
of the alcohol 8 by treatment with chloroacetic anhydride
and 2,4,6-trimethylpyridine in dichloromethane gave
thioglycoside 9, identical to that described above, in 91%
yield (Scheme 4).
Such a cyclization is known in the pyranose series and is
based on reductive debromination by sodium borohydride
of glycopyranosyl bromides with a 2-O-benzoyl protect-
ing group.8 The reaction proceeds through neighboring-
group participation of the acyl protecting group at the C-2
atom of the glycosyl bromide and it involves the genera-
tion of an acyloxonium ion. The ease of formation of this
benzylic cation, which is stabilized by delocalization of
the positive charge, is apparently the driving force for this
reaction. Subsequent attack on the acyloxonium ion by a
hydride anion leads to the 1,2-O-benzylidene derivative,
which is the isolable product of the reaction.
As a result of the high efficiency of each step in the syn-
thesis of phenyl thioglycoside 9 (building block D) in our
approach, we developed a procedure for the preparation of
9 on a ~14-gram scale that involves only one chromato-
graphic separation, that of purification of the final product
9, which was obtained in 71% overall yield from the start-
ing methyl glycoside 1 (Scheme 4, step h). Our procedure
Synthesis 2012, 44, 1219–1225
© Georg Thieme Verlag Stuttgart · New York

PAPER
Silicon-Free Differentiation of Hydroxy Groups in Arabinofuranose
1221
for the preparation of building blocks A and D, with a free from 11 by treatment with aqueous pyridine cleanly gave
or orthogonally protected hydroxy group at C-2, compares diol 13 (building block B) in 86% yield (Scheme 5),
well with the protocols based on the use of organosilicon which corresponds to 53% yield of 13 from methyl glyco-
protecting groups (Scheme 2) in terms of both the overall side 1 or 24% overall yield from D-arabinose. Compare
efficiency and the cost of the reagents. The yield of thio- the latter yield to the 49% overall yield of building block
glycoside 9 from commercially available D-arabinose is B (RX = TolS; R3 = Bn) that is obtained by using the much
32%, because methyl glycoside 1 can be easily prepared10 more expensive TIPDS1c protecting group.
in 45% yield and in multigram quantities from D-arabi-
The diol 13 can be converted into compound 18 (building
nose. The similar thioglycosides D1 and D2 (RX = TolS;
block D, similar to 9) by the selective protection and de-
R3 = Bn), with much more expensive TIPDS and DTBS
protection operations outlined in Scheme 5. Although
protecting groups (Scheme 2), were obtained from D-
most steps proceed efficiently, the yield of thioglycoside
18 with the selectively removable 2-O-chloroacetyl group
arabinose in 49%1c and 52%1e overall yields, respectively.
was only 34% from diol 13. This value corresponds to
Ph
H
18% yield from methyl glycoside 1 or 8% overall yield
from D-arabinose. The large number of steps and the over-
all inefficiency make this route less favorable for the prep-
aration of building block D (compounds 9 and 18) than the
route via the 1,2-O-benzylidene derivative (Scheme 4).
O
BzO
BzO
BzO
OBz
OBz
Br
BzO
c
O
a
b
O
O
O
OMe
OBz
OBz
OBz
1
2
3
h
Ph
OR
O
O
BzO
e
OR
O
O
O
HO
RO
OBz
OBz
O
O
OR
g
a or b
c
O
SPh
OBz
ref. 5
OBz
SEt
SEt
OCA
RO
OCA
7 R = Ac
8 R = H
4 R = H
5 R = Ac
6 R = CA
f
g
d
10
11
12 R = CA
13 R = H
9 R = CA
g
e
TrO
RO
OR
OCA
SEt
e
O
O
8
9
9
5
7
9
h
e
SEt
1
6
OTr
OR
14 R = Bz
15 R = H
16 R = CA
17 R = H
d
f
Scheme 4 Reagents and conditions: (a) 32% HBr/AcOH, CH2Cl2,
~20 °C; (b) NaBH4, MeCN, ~20 °C (90%, two steps); (c) CH2Cl2–
TFA–H2O (100:10:1), ~20 °C (90%); (d) Ac2O, py (93%); (e) PhSH,
BF3·Et2O, CH2Cl2, 0 °C → 20 °C (85% of 7, 83% of 9); (f) 4%
HCl/MeOH, CH2Cl2, ~20 °C (89%); (g) (ClCH2CO)2O, 2,4,6-tri-
methylpyridine, CH2Cl2, 0 °C (76% of 6 from 3, two steps; 91% of 9);
(h) 1. HBr, CH2Cl2, 0 °C; 2. NaBH4, MeCN; 3. CH2Cl2–TFA–H2O
(100:10:1); 4. (ClCH2O)2O, 2,4,6-trimethylpyridine, CH2Cl2, 0 °C. 5.
PhSH, BF3·Et2O, CH2Cl2, 0 °C → 20 °C; 6. chromatography (silica
gel) (71% of 9 with respect to 1 over five steps; ~14 g scale). CA =
chloroacetyl.
18 R = Bz
a
Scheme 5 Reagents and conditions: (a) (ClCH2CO)2O, 2,4,6-tri-
methylpyridine, CH2Cl2 (88% 12, 99% of 16); (b) py–H2O (2:1),
60 °C (86% of 13); (c) TrClO4, Et3N, CH2Cl2 (90% of 14 from 13);
(d) NaOMe, MeOH, CH2Cl2 (84%); (e) AcOH, H2O, 80 °C (54% of
17 from 16); (f) BzCl, py (97%). CA = chloroacetyl.
Compounds 9, 11, and 12 have recently been used in the
synthesis of spacer-containing glycosides of the hexaara-
binofuranoside fragment of M. tuberculosis LAM, which
after conjugation with recombinant mycobacterial pro-
teins MPB-64 and Rv0934 produced artificial tuberculo-
sis antigens.12
The similar building block D with an ethanesulfenyl agly-
con (compound 18 in Scheme 5) and building block B
with two hydroxy groups at C-3 and C-5 (compound 13 in
Scheme 5) can be prepared by another route that relies on
the ready availability1h of 3-O-protected arabinose 1,2,5-
orthobenzoates. We have recently studied the ring-open-
ing reactions of 3-O-acyl-β-D-arabinofuranose 1,2,5-or-
thobenzoates with thiols and have demonstrated their
synthetic utility.5 In the context of this communication, it
is important to note that a novel β-D-arabinofuranose
1,2,5-orthobenzoate with a 3-O-chloroacetyl group 105
can be transformed into the corresponding ethyl thiogly-
coside 11 with a 5-hydroxy group in 94% yield.5 Chloro-
acetylation of the single hydroxy group of 11 gave
thioglycoside 12 (yield 88%) with selectively removable
O-chloroacetyl groups at O-3 and O-5; this product is use-
ful as glycosyl donor D, corresponding to the 3,5-diol
building block B. Removal of the chloroacetyl groups
In conclusion, we achieved effective differentiation of
3,5-diol system and 2-hydroxy group in arabinofuranose
derivatives by using 3,5-di-O-benzoyl-1,2-O-benzyli-
dene-β-D-arabinofuranose or 3-O-chloroacetyl-β-D-arabi-
nofuranose 1,2,5-orthobenzoate, both of which are readily
accessible from cheap methyl α-D-arabinofuranoside via
the corresponding glycosyl bromide. An appealing feature
of this practical strategy is the complete avoidance of the
use of expensive organosilicon protecting groups, which
may prove to be essential for large-scale syntheses. The
importance of our finding is not limited to oligosaccharide
synthesis, because the known syntheses of various nucle-
oside analogues,13 some of which are potential antivi-
rals,14 often rely on effective differentiation of the 3,5-diol
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1219–1225

1222
P. I. Abronina et al.
PAPER
system15 and the 2-hydroxy group in arabinofuranose de-
rivatives.
mL). The organic phase was filtered through a layer of a ~1:1 mix-
ture of (v/v) Celite and powdered Na2SO4 then concentrated and
dried in vacuo to give a white solid; yield: 0.74 g (90%; 1:1 mixture
α- and β-anomers); Rf = 0.20 (toluene–EtOAc, 4:1).
The reactions were performed by using commercial reagents (Al-
drich, Fluka, Acros Organics). Solvents were distilled, purified, and
dried (where appropriate) by standard procedures. Column chroma-
tography was performed on silica gel 60 (40–63 µm; Merck). TLC
was carried out on plates of silica gel 60 on glass or aluminum foil
(Merck). Spots were visualized under UV radiation or by heating
the plates after immersion in a 1:10 (v/v) mixture of 85% aq H3PO4
and 95% aq EtOH. The 1H and 13C NMR spectra were recorded for
solutions in CDCl3 on a Bruker AC-200 instrument (200.13, and
50.32 MHz, respectively) or a Bruker AM-300 instrument (300.13,
and 75.48 MHz, respectively). The 1H NMR chemical shifts are re-
ferred to the residual signal of CHCl3 (δH = 7.27 ppm), whereas the
13C NMR shifts are referred to the CDCl3 signal (δC = 77.0 ppm).
Signals in the NMR spectra were assigned by means of 2D-spec-
troscopy (COSY, HSQC, NOESY, and HMBC) and by APT
(DEPT-135 or JMODXH) experiments. High-resolution mass spec-
tra (ESI) were recorded on a Bruker micrOTOF II mass spectrome-
ter by using 2 × 10–5 M solns in MeCN or MeOH. Optical rotations
were measured using a PU-07 automatic polarimeter (Russia). IR
spectra were recorded on a Bruker ALPHA-T FTIR spectrometer
over the 500–4000 cm–1 range by using KBr pellets.
IR (KBr): 3065, 2929, 1721, 1602, 1452, 1276 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 4.25–4.37 (m, 1.5 H, H-2β, H-
4β, H-4α), 4.40–4.71 (m, 2.5 H, H-5aα, H-5bα, H-5aβ, H-5bβ, H-
2α), 5.04 (dd, J = 5.1, 2.4 Hz, 0.5 H, H-3α), 5.03 (dd, J = 5.2, 2.3
Hz, 0.5 H, H-3β), 5.28 (m, 1 H, H-1α, H-1β), 7.22–7.56 (m, 4 H),
7.85–8.02 (m, 6 H).
13C NMR (75.48 MHz, CDCl3): δ = 64.2 (C-5β), 65.5 (C-5α), 76.2
(C-2β), 78.9 (C-4β), 79.7 (C-2α), 80.4 (C-3β), 81.4 (C-4α), 81.7 (C-
3α), 96.8 (C-1β), 102.8 (C-1α), 128.3, 128.4, 128.5, 129.7, 129.8,
133.2, 133.7 (Ph), 165.5, 165.8, 166.0, 166.1 (CO).
HRMS–ESI: m/z [M + Na]+ calcd for C19H18O7Na: 381.0950;
found: 381.0966.
1,2-Di-O-acetyl-3,5-di-O-benzoyl-D-arabinofuranose (5)
Ac2O (0.5 mL, 1.27 mmol) was added to a soln of diol 4 (90.7 mg,
0.25 mmol) in pyridine (1 mL). After 30 min, the mixture was dilut-
ed with CH2Cl2 (50 mL) and washed successively with H2O (50
mL), 1 M aq KHSO4 (50 mL), H2O (50 mL), and sat. aq NaHCO3
(50 mL). The organic phase was concentrated and dried in vacuo to
give a colorless syrup; yield: 104 mg, (93%; 1:1 mixture α- and β-
anomers), Rf = 0.47 (toluene–EtOAc, 5:1).
3,5-Di-O-benzoyl-1,2-O-benzylidene-β-D-arabinofuranose (3)
Methyl 2,3,5-tri-O-benzoyl-α-D-arabinofuranoside (1)10 (10.0 g,
21.0 mmol) was dissolved in anhyd CH2Cl2 (21 mL) and the soln
was cooled to 0 °C. A 32% soln of HBr in AcOH was prepared by
dropwise addition a soln of H2O (5 mL) in AcOH (18.3 mL) to a
soln of AcBr (27.4 mL) in AcOH (15 mL) at 0 °C. The two solns
were mixed and stirred at 0 °C for 30 min, then diluted with CH2Cl2
(500 mL), washed sequentially with ice-cold H2O (2 × 500 mL) and
ice-cold sat. aq NaHCO3 (500 mL), filtered through a cotton-wool
plug, concentrated under reduced pressure, and dried in vacuo to
give 2,3,5-tri-O-benzoyl-α-D-arabinofuranosyl bromide (2).
1H NMR (300.13 MHz, CDCl3): δ = 2.06 (s, 1.5 H, CH3), 2.07 (s,
1.5 H, CH3), 2.14 (s, 1.5 H, CH3), 2.21 (s, 1.5 H, CH3), 4.44–4.81
(m, 3 H, H-5aα, H-5bα, H-5aβ, H-5bβ, H-4α, H-4β), 5.41 (s, 0.5 H,
H-2α), 5.46 (d, 0.5 H, J = 3.2 Hz, H-3α), 5.60 (dd, 0.5 H, J = 7.0,
4.7 Hz, H-2β), 5.83 (d, 0.5 H, J = 7.0 Hz, H-3β), 6.32 (s, 0.5 H, H-
1α), 6.49 (d, 0.5 H, J = 4.7 Hz, H-1β), 7.34–7.50 (m, 4 H, Ph), 7.51–
7.65 (m, 2 H, Ph), 7.99–8.11 (m, 4 H, Ph).
13C NMR (75.5 MHz, CDCl3): δ = 20.3, 20.5, 20.8, 20.9 (CH3CO),
63.4 (C-5β), 64.5 (C-5α), 75.1 (C-2β), 75.3 (C-3β), 77.4 (C-2α),
79.8 (C-4α), 80.4 (C-3α), 83.1 (C-4β), 93.5 (C-1β), 99.3 (C-1α),
128.2 (Ph), 129.7 (Ph), 133.1, 133.6 (Ph), 165.4, 165.7, 169.1, 169.6
(CO).
The crude glycosyl bromide 2 was dissolved in anhyd MeCN (42
mL), and NaBH4 (1.6 g, 42.0 mmol) was added. The mixture was
stirred for 12 h at 20 °C then diluted with CH2Cl2 (500 mL), washed
with H2O (2 × 500 mL), filtered through Celite, and concentrated.
The residue was dried in vacuo and crystallized from PE–EtOAc to
give benzylidene derivative 3 as white crystals. Concentration of
mother liquors and purification of the residue by column chroma-
tography [silica gel, toluene–EtOAc (2:1)] gave an additional por-
tion of 3 as a white solid; combined yield of 3: 8.34 g (90%); mp
159–162 °C (PE–EtOAc); [α]D22–2.2 (c 1.0, CHCl3); Rf = 0.63
(toluene–EtOAc, 2:1).
HRMS–ESI: m/z [M + Na]+ calcd for C23H22NaO9: 465.1162;
found: 465.1156.
3,5-Di-O-benzoyl-1,2-bis-O-(chloroacetyl)-D-arabinofuranose
(6)
2,4,6-Trimethylpyridine (0.36 mL, 2.7 mmol) was added to a stirred
soln of diol 4 (120 mg, 0.33 mmol) in anhyd CH2Cl2 (1.2 mL). The
mixture was cooled to 0 °C, and a soln of (ClCH2CO)2O (230 mg,
1.34 mmol) in CH2Cl2 (1.3 mL) was added dropwise. The mixture
was stirred at 0 °C for 30 min, then diluted with CH2Cl2 (50 mL) and
washed successively with H2O (50 mL), 1 M aq KHSO4 (50 mL),
H2O (50 mL), and sat. aq NaHCO3 (50 mL). The organic phase was
filtered through a layer of a ~1:1 (v/v) mixture of silica gel and
powdered Na2SO4, concentrated, and dried in vacuo to give a white
solid; yield: 130 mg (76% from 3 over two steps; 1:1.5 mixture α-
and β-anomers); Rf = 0.59 (toluene–EtOAc, 5:1).
IR (KBr): 1723, 1601, 1452, 1280, 1268 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 4.51–4.60 (m, 2 H, H-5a, H-
5b), 4.63–4.75 (m, 1 H, H-4), 4.92 (d, J = 4.0 Hz, 1 H, H-2), 5.59 (s,
1 H, H-3), 6.05 (s, 1 H, PhCH), 6.25 (d, J = 4.0 Hz, 1 H, H-1), 7.35–
7.65 (m, 11 H, Ph), 8.02–8.13 (m, 4 H, Ph).
13C NMR (75.48 MHz, CDCl3): δ = 64.3 (C-5), 77.6 (C-3), 84.1 (C-
2), 85.5 (C-4), 105.7 (PhCH), 106.2 (C-1), 126.5, 127.9, 128.2,
128.3, 128.4, 128.5, 129.1, 129.2, 129.4, 129.6, 129.7, 129.8, 132.8,
133.0, 133.6, 135.5 (Ph), 165.3, 166.0 (CO).
IR (KBr): 2958, 1769, 1719, 1275 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.84 (s, 1.6 H, CH2Cl), 3.91 (s,
1.6 H, CH2Cl), 4.01 (s, 2.4 H, CH2Cl), 4.04 (s, 2.4 H, CH2Cl), 4.42–
4.71 (m, 3 H, H-5αa, H-5bα, H-5aβ, H-5bβ, H-4α, H-4β), 5.41 (s,
0.8 H, H-2α, H-3α), 5.60 (dd, J = 4.6, 2.2 Hz, 0.6 H, H-2β), 5.71–
5.87 (m, 0.6 H, H-3β), 6.31 (s, 0.4 H, H-1α), 6.47 (d, J = 4.6 Hz, 0.6
H, H-1β), 7.27–7.56 (m, 12 H, Ph), 7.87–8.02 (m, 8 H, Ph).
HRMS–ESI: m/z [M + Na]+ calcd for C26H22NaO7: 469.1258;
found: 469.1263.
Anal. Calcd for C26H22O7: C, 69.95; H, 4.97. Found: C, 69.55; H,
5.10.
13C NMR (75.5 MHz, CDCl3): δ = 40.38, 40.42, 40.72, 40.80 (4 ×
CH2Cl), 63.28 (C-5α), 64.4 (C-5β), 75.2 (C-3β), 76.9 (C-3α), 77.1
(C-2β), 80.8 (C-4β), 81.9 (C-2α), 83.9 (C-4α), 95.2 (C-1β), 100.4
(C-1α), 128.6, 128.7, 128.9, 123.0, 130.1, 133.56, 134.2 (Ph),
165.1, 165.4, 165.5, 165.7, 165.8, 165.9, 166.2 (CO).
3,5-Di-O-benzoyl-D-arabinofuranose (4)
A 9:1 mixture of TFA and H2O (1.5 mL) was added to a soln of
acetal 3 (1.03 g, 2.3 mmol) in CH2Cl2 (15 mL). The mixture was
stirred for 4 h at 20 °C then diluted with CH2Cl2 (200 mL) and
washed successively with H2O (200 mL) and sat. aq NaHCO3 (200
Synthesis 2012, 44, 1219–1225
© Georg Thieme Verlag Stuttgart · New York

PAPER
Silicon-Free Differentiation of Hydroxy Groups in Arabinofuranose
1223
HRMS–ESI: m/z [M + Na]+ calcd for C23H20Cl2NaO9: 533.0377;
found: 533.0375.
13C NMR (75.5 MHz, CDCl3): δ = 40.7 (CH2Cl), 63.5 (C-5), 77.0
(C-3), 80.9 (C-2), 83.2 (C-4), 91.0 (C-1), 128.0, 128.3, 128.5, 128.7,
129.1, 129.7, 129.9 132.5, 132.6, 133.0, 133.2, 133.7 (Ph), 165.5,
166.1, 169.5 (CO).
HRMS–ESI: m/z [M + Na]+ calcd for C27H23ClNaO7S: 549.0751;
found: 549.0655.
Phenyl 2-O-Acetyl-3,5-di-O-benzoyl-1-thio-α-D-arabinofurano-
side (7)
BF3·Et2O (30 μL, 0.24 mmol) was added to a stirred soln of acetate
5 (57 mg, 0.12 mmol) in CH2Cl2 (1 mL) at 0 °C. The mixture was
stirred for 10 min then PhSH (25 μL, 0.25 mmol) was added. After
1 h, the reaction was quenched by addition of Et3N (50 μL). The
mixture was diluted with CH2Cl2 (50 mL), washed with H2O (50
mL), concentrated, and dried in vacuo. The residue was purified by
column chromatography [silica gel, PE–EtOAc (9:1 to 5:1)] to give
a colorless syrup; yield: 54 mg (85%); [α]D22 +104.3 (c 1.0, CHCl3);
Rf = 0.60 (toluene–EtOAc, 10:1).
Method B
2,4,6-Trimethylpyridine (0.43 mL, 3.21 mmol) was added to a
stirred soln of alcohol 8 (362 mg, 0.8 mmol) in anhyd CH2Cl2 (4
mL). The mixture was cooled to 0 °C and a soln of (ClCH2CO)2O
(275 mg, 1.61 mmol) in CH2Cl2 (2 mL) was added dropwise. The
mixture was stirred for 30 min at 0 °C then diluted with CH2Cl2 (75
mL) and washed successively with H2O (75 mL), 1 M aq KHSO4
(50 mL), H2O (75 mL), and sat. aq NaHCO3 (75 mL). The organic
phase was filtered through a layer of a ~1:1 (v/v) mixture of Celite
and powdered Na2SO4, concentrated, and dried in vacuo to give a
colorless syrup; yield: 0.40 g (91%).
IR (KBr): 3062, 2960, 1749, 1723, 1602, 1452, 1273 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.06 (s, 3 H, CH3), 4.71–4.91
(m, 2 H, H-5a, H-5b), 4.77–4.85 (m, 1 H, H-4), 5.50 (s, 2 H, H-2,
H-3), 5.68 (s, 1 H, H-1), 7.22–7.69 (m, 11 H, Ph), 8.07–8.13 (m, 4
H, Ph).
Method C
13C NMR (75.5 MHz, CDCl3): δ = 20.6 (CH3), 63.3 (C-5), 77.0 (C-
3), 81.2 (C-2), 81.7 (C-4), 91.3 (C-1), 127.1, 127.8, 128.3, 128.5,
129.9, 130.6, 132.2, 133.1, 133.4, 133.7, 136.9 (Ph), 165.5, 166.0,
169.5 (CO).
HRMS–ESI: m/z [M + Na]+ calcd for C27H24NaO7S: 515.1140;
found: 515.1135.
The arabinofuranosyl bromide 2 was prepared from arabinofurano-
side 1 (20.0 g, 42.0 mmol) by treatment with HBr in CH2Cl2 accord-
ing to the published procedure.5 To a soln of the crude bromide 2 in
anhyd MeCN (85 mL), NaBH4 (3.2 g, 84.6 mmol) was added. The
mixture was stirred for 48 h at 20 °C then concentrated in vacuo.
The residue was dissolved in CH2Cl2 (350 mL) and washed twice
with H2O (700 mL + 500 mL). The organic phase was filtered
through a layer of anhyd Na2SO4, concentrated, and dried in vacuo
to give benzylidene derivative 3 as a white solid; yield: 18.9 g
(quant from 1).
Phenyl 3,5-Di-O-benzoyl-1-thio-α-D-arabinofuranoside (8)
A soln of HCl in MeOH [prepared by addition of AcCl (0.8 mL) to
anhyd MeOH (20 mL) at 0 °C] was added to a soln of acetate 7 (0.42
g, 0.85 mmol) in CH2Cl2 (4 mL). After 12 h at 20 °C, the mixture
was diluted with CH2Cl2 (100 mL) and washed successively with
sat. aq NaHCO3 (150 mL) and H2O (100 mL). The organic phase
was filtered through a layer of powdered Na2SO4, concentrated, and
dried in vacuo to give a residue that was purified by column chro-
matography [silica gel, PE–EtOAc (6:1)] to give a colorless syrup;
yield: 0.34 g (89%); [α]D22 +187.2 (c 1.0, CHCl3); Rf = 0.70 (tolu-
ene–EtOAc, 4:1).
F3CCO2H (25 mL) and H2O (2.5 mL) were added to a vigorously
stirred soln of 3 (18.9 g) in CH2Cl2 (250 mL) at 0 °C and the mixture
was allowed to warm to 20 °C and stirred for 4 h at 20 °C. The mix-
ture was then diluted with CH2Cl2 (200 mL) and washed successive-
ly with H2O (400 mL) and sat. aq NaHCO3 (400 mL). The organic
phase was filtered through a cotton-wool plug and concentrated.
The syrupy residue was extracted with light petroleum (4 × 60 mL)
to remove PhCHO and the insoluble product was dried in vacuo to
give diol 4 as a white solid; yield: 11.2 g (74% from 1).
IR (KBr): 3062, 2954, 1722, 1602, 1452, 1272 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.59 (d, J = 3.9 Hz, 1 H, OH),
4.50 (br s, 1 H, H-2), 4.63–4.79 (m, 2 H, H-5a, H-5b), 4.80–4.87 (m,
1 H, H-4), 5.20 (dd, J = 6.2, 3.3 Hz, 1 H, H-3), 5.66 (d, J = 3.1 Hz,
1 H, H-1), 7.21–7.65 (m, 11 H, Ph), 8.10–8.20 (m, 4 H, Ph).
13C NMR (75.5 MHz, CDCl3): δ = 63.7 (C-5), 79.1 (C-4), 81.7 (C-
2), 81.9 (C-3), 92.5 (C-1), 128.4, 129.0, 129.6, 130.0, 131.8, 133.2,
133.82 (Ph), 166.2, 167.8 (CO).
2,4,6-Trimethylpyridine (26 mL, 194 mmol) was added to a stirred
soln of diol 4 (10.6 g, 29.6 mmol) in anhyd CH2Cl2 (85 mL). The
mixture was cooled to 0 °C and a soln of (ClCH2CO)2O (15.22 g, 89
mmol) in CH2Cl2 (25 mL) was added. The mixture was stirred for
25 min at 0 °C then diluted with CH2Cl2 (350 mL) and washed suc-
cessively with H2O (300 mL), 1 M aq KHSO4 (200 mL), H2O (200
mL), and sat. aq NaHCO3 (200 mL). The organic phase was filtered
through a layer of a ~1:1 (v/v) mixture of silica gel and powdered
Na2SO4, concentrated, and dried in vacuo to give the bischloroace-
tate 6 as a white solid; yield: 14.73 g (97%).
HRMS–ESI: m/z [M + Na]+ calcd for C25H22NaO6S: 473.1035;
found: 473.1029.
Bischloroacetate 6 (14.50 g, 28.36 mmol) was co-concentrated with
toluene (50 mL), dried in vacuo, and dissolved in anhyd CH2Cl2
(285 mL). The soln was cooled to 0 °C and PhSH (3.21 mL, 31.2
mmol) and BF3·Et2O (3.5 mL, 28.4 mmol) were successively added.
The mixture was stirred at 0 °C for 30 min then allowed to warm to
20 °C and stirred for an additional 3 h at 20 °C. It was then diluted
with CH2Cl2 (200 mL), washed successively with H2O (200 mL)
and sat. aq NaHCO3 (200 mL), and concentrated. The residue was
dried in vacuo and purified by column chromatography [silica gel,
PE–EtOAc (9:1 to 6:1)] to give thioglycoside 9 as a colorless syrup;
yield: 14.61 g (71% with respect to 1 over 5 steps).
Phenyl 3,5-Di-O-benzoyl-2-O-(chloroacetyl)-1-thio-α-D-arabi-
nofuranoside (9)
Method A
BF3·Et2O (30 μL, 0.2 mmol) was added to a stirred soln of bischlo-
roacetate 6 (72.8 mg, 0.13 mmol) in CH2Cl2 (1 mL) at 0 °C. After
10 min, PhSH (25 μL, 0.6 mmol) was added and the mixture was
stirred at 20 °C for 3 h. The reaction was then quenched by addition
of sat. aq NaHCO3 (1 mL) and the mixture was diluted with CH2Cl2
(50 mL), washed with sat. aq NaHCO3 (50 mL), and concentrated.
The residue was dried in vacuo then purified by column chromatog-
raphy [silica gel, toluene–EtOAc (20:1)] to give a light yellow syr-
22
up; yield: 62.2 mg (83%); [α]D +70.4 (c 1.0, CHCl3); Rf = 0.68
Ethyl 2-O-Benzoyl-3,5-bis-O-(chloroacetyl)-1-thio-α-D-arabi-
nofuranoside (12)
(toluene–EtOAc, 10:1).
IR (KBr): 3062, 2956, 1771, 1723, 1602, 1584, 1452, 1271 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 4.00 (s, 2 H, CH2Cl), 4.63–4.85
(m, 3 H, H-4, H-5a, H-5b), 5.51 (d, J = 4.5 Hz, 1 H, H-3), 5.58 (s, 1
H, H-2), 5.70 (s, 1 H, H-1), 7.28–7.66 (m, 11 H, Ph), 8.10 (s, 4 H,
Ph).
2,4,6-Trimethylpyridine (4.0 mL, 30.2 mmol) was added to a stirred
soln of 115 (3.9 g, 10.3 mmol) in anhyd CH2Cl2 (12 mL). The mix-
ture was cooled to 0 °C and a soln of (ClCH2CO)2O (2.3 g, 13.7
mmol) in CH2Cl2 (7.5 mL) was added dropwise. The mixture was
stirred for 30 min at 0 °C then diluted with CH2Cl2 (200 mL) and
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1219–1225

1224
P. I. Abronina et al.
PAPER
washed successively with H2O (150 mL), 1 M aq KHSO4 (80 mL),
H2O (150 mL), and sat. aq NaHCO3 (100 mL). The organic phase
was filtered through a layer of ~1:1 (v/v) mixture of silica gel and
powdered Na2SO4, concentrated, and dried in vacuo. The residue
was purified by column chromatography [PE–EtOAc (9:1)] to give
a colorless syrup; yield: 4.1 g (88%); [α]D +85.4 (c 1.0, CHCl3);
Rf = 0.38 (PE–EtOAc, 5:1).
12 H, Ph), 7.34–7.45 (m, 12 H, Ph), 7.50 (t, J = 7.38, 1 H, Ph), 7.65
(d, J = 7.52, 2 H, Ph).
13C NMR (75.48 MHz, CDCl3): δ = 15.1 (CH3CH2S), 25.5
(CH3CH2S), 63.7 (C-5), 78.7 (C-3), 83.5 (C-2), 83.6 (C-4), 88.7 (C-
1), 126.9, 127.3, 127.7, 128.0, 128.2, 128.9, 128.9, 132.9, 143.8,
143.9 (Ph).
22
HRMS–ESI: m/z [M + Na]+ calcd for C52H46NaO5S: 805.2958;
found: 805.2959.
IR (KBr): 1766, 1727, 1270 cm–1.
1H NMR (200.13 MHz, CDCl3): δ = 1.33 (t, J = 7.4 Hz, 3 H,
CH3CH2S), 2.57–2.84 (m, 2 H, CH3CH2S), 4.07 (s, 2 H, ClCH2CO),
4.18 (s, 2 H, ClCH2CO), 4.41–4.69 (m, 3 H, H-4, H-5a,b), 5.24–
5.30 (m, 1 H, H-3), 5.38 (dd, J = 1.7, 1.5 Hz, 1 H, H-2), 5.54 (s, 1
H, H-1), 7.42–7.53 (m, 2 H, Ph), 7.56–7.67 (m, 1 H, Ph), 8.00–8.10
(m, 2 H, Ph).
13C NMR (50.32 MHz, CDCl3): δ = 14.7 (SCH2CH3), 25.3
(SCH2CH3), 40.5, 40.6 (ClCH2CO), 64.1 (C-5), 79.0, 79.4 (C-2, C-
4), 82.2 (C-3), 87.8 (C-1), 128.6, 128.7, 129.8, 133.8 (Ph), 165.3,
166.7, 166.9 (CO).
Anal. Calcd for C52H46O5S: C, 79.77; H, 5.92. Found: C, 80.05; H,
6.02.
Ethyl 1-Thio-3,5-di-O-trityl-α-D-arabinofuranoside (15)
MeOH (12 mL) and a 1 M soln of MeONa in MeOH (0.2 mL) were
added successively to a stirred soln of benzoate 14 (0.70 g, 1.81
mmol) in anhyd CH2Cl2 (6 mL) and the mixture was stirred at 40 °C
for 12 h. The reaction was quenched by addition of solid CO2 and
the mixture was diluted with CH2Cl2 (200 mL) and washed with
H2O (2 × 200 mL). The organic phase was filtered through a layer
of powdered Na2SO4, concentrated, and dried in vacuo. The residue
was purified by column chromatography [silica gel, PE + 1% Et3N
to PE–EtOAc (20:1) + 1% Et3N) to give a white foam; yield: 1.04 g
HRMS–ESI: m/z [M + Na]+ calcd for C18H20Cl2NaO7S: 473.0199;
found: 473.0190.
22
(84%); [α]D +117.2 (c 1.6, CHCl3); Rf = 0.70 (toluene–EtOAc,
Ethyl 2-O-Benzoyl-1-thio-α-D-arabinofuranoside (13)
10:1).
Chloroacetate 115 (6.11 g, 16.3 mmol) was dissolved in a 2:1 (v/v)
mixture of pyridine and H2O (45 mL) and the soln was stirred at
80 °C for 1 h, then concentrated, co-concentrated with toluene (500
mL), diluted with CH2Cl2 (500 mL), and washed successively with
1 M aq KHSO4 (500 mL), H2O (500 mL), and sat. aq NaHCO3 (500
mL). The organic phase was filtered through a layer of powdered
Na2SO4, concentrated, and dried in vacuo. The residue was purified
by column chromatography [silica gel, PE–EtOAc (1:1)] to give a
white foam; yield: 4.19 g (86%); [α]D22 +154.6 (c 1.0, CHCl3); Rf =
0.40 (toluene–EtOAc, 1:1).
IR (KBr): 3058, 2926, 1491, 1448 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.27 (t, J = 7.4 Hz, 3 H,
CH3CH2S), 2.56–2.70 (m, 3 H, CH3CH2S, H-5a), 3.05 (d, J = 10.1
Hz, 1 H, OH), 3.29 (dd, J = 10.4, 1 H, 2.4 Hz, H-5b), 3.52 (d,
J = 10.1 Hz, 1 H, H-2), 3.83 (d, J = 2.4 Hz, 1 H, H-3), 4.02–4.07 (m,
1 H, H-4), 5.16 (s, 1 H, H-1), 7.00–7.32 (m, 30 H, Ph).
13C NMR (75.5 MHz, CDCl3): δ = 15.3 (SCH2CH3), 26.1
(SCH2CH3), 63.4 (C-5), 81.0 (C-3), 81.6 (C-2), 84.5 (C-4), 87.7,
88,3 (Ph3C), 91.8 (C-1), 127.2, 127.2, 127.9, 128.8, 128.9, 143.1,
144.2 (Ph).
IR (KBr): 2931, 1716, 1601, 1451, 1270 cm–1.
1H NMR (200.13 MHz, CDCl3): δ = 1.35 (t, 3 H, J = 7.4 Hz,
CH3CH2S), 1.92 (s, 1 H, OH), 2.54–2.89 (m, 2 H, CH3CH2S), 3.44
(d, J = 3.5 Hz, 1 H, OH), 3.82 (dd, J5a,5b = 12.1 Hz, J5a,4 = 3.3 Hz, 1
H, H-5a), 3.95 (dd, J5a,5b = 12.1 Hz, J5b,4 = 2.5 Hz,, 1 H, H-5b),
4.16–4.37 (m, 2 H, H-3, H-4), 5.05 (dd, J2,3 = 2.6 Hz, J1,2 = 2.5 Hz,
1 H, H-2), 5.56 (d, J2,1 = 2.5 Hz, 1 H, H-1), 7.38–7.49 (m, 2 H, Ph),
7.55–7.66 (m, 1 H, Ph), 7.97–8.04 (m, 2 H, Ph).
13C NMR (50.32 MHz, CDCl3): δ = 14.7 (SCH2CH3), 25.2
(SCH2CH3), 61.5 (C-5), 76.7 (C-3), 82.78 (C-4), 86.2 (C-2), 87.6
(C-1), 128.6, 129.8, 133.72 (Ph), 167.0 (CO).
HRMS–ESI: m/z [M + Na]+ calcd for C45H42NaO4S: 701.2702;
found: 701.2696.
Ethyl 2-O-(Chloroacetyl)-1-thio-α-D-arabinofuranoside (17)
2,4,6-Trimethylpyridine (0.8 mL, 5.8 mmol) was added to a stirred
soln of alcohol 15 (0.99 g, 1.46 mmol) in anhyd CH2Cl2 (7 mL). The
mixture was cooled to 0 °C and a soln of (ClCH2CO)2O (0.5 g, 2.9
mmol) in CH2Cl2 (3 mL) was added dropwise. The mixture was
stirred at 0 °C for 30 min then diluted with CH2Cl2 (50 mL) and
washed successively with H2O (50 mL), 1 M KHSO4 (50 mL), H2O
(50 mL), sat. aq NaHCO3 (50 mL). The organic phase was filtered
through a layer of ~1:1 (v/v) mixture of Celite and powdered
Na2SO4 then concentrated and dried in vacuo to give chloroacetate
16 as a white foam; yield: (1.0 g, 99%).
HRMS–ESI: m/z [M + Na]+ calcd for C14H18NaO5S: 321.0767;
found: 321.0763.
Ethyl 2-O-Benzoyl-1-thio-3,5-di-O-trityl-α-D-arabinofurano-
side (14)
The soln of chloroacetate 16 (0.54 g, 7.1 mmol) in AcOH (6 mL)
and H2O (3 mL) was heated at 80 °C for 2 h. The mixture was then
co-concentrated with H2O (2 × 3 mL) and the residue was purified
by column chromatography [silica gel, benzene–acetone (1:4 to
2:3)] (CAUTION: benzene is a carcinogen) to give diol 17 as a
2,4,6-Trimethylpyridine (1.3 ml, 10 mmol) and TrClO4 (1.3 g, 3.9
mmol) were added to a stirred soln of diol 13 (0.50 g, 1.7 mmol) in
anhyd CH2Cl2 (7 mL) at 0 °C. The mixture was stirred for 15 min at
0 °C before the reaction was quenched by addition of sat. aq
NaHCO3 (1 mL). The mixture was diluted with CH2Cl2 (200 mL)
and washed successively with 1 M aq KHSO4 (200 mL), H2O (200
mL), and sat. aq NaHCO3 (200 mL). The organic phase was filtered
through a layer of powdered Na2SO4, concentrated, and dried in
vacuo. The residue was purified by column chromatography (silica
gel, PE + 1% Et3N to PE–EtOAc (95:5) + 1% Et3N] to give a white
foam; yield: 1.21 g (90%); Rf = 0.33 (toluene).
22
light yellow syrup; yield: 380 mg (54%); [α]D +167.2 (c 2.6,
CHCl3); Rf = 0.46 (toluene–EtOAc, 1:1).
1H NMR (300.13 MHz, CDCl3): δ = 1.31 (t, J = 7.4 Hz, 3 H,
CH3CH2S), 2.30 (br s, 1 H, OH), 2.57–2.80 (m, 2 H, CH3CH2S),
3.42 (br s, 1 H, OH), 3.78 (dd, J = 12.3, 3.4 Hz, 1 H, H-5a), 3.91 (dd,
J = 2.8, Hz, 1 H, H-5b), 4.11–4.24 (m, 2 H, H-3, H-4), 4.14 (s, 2 H,
COCH2Cl), 4.93 (t, J = 2.7, 2.3 Hz, 1 H, H-2), 5.39 (d, J = 2.3 Hz,
1 H, H-2).
IR (KBr): 3032, 2926, 1723, 1599, 1491, 1449, 1277 cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.36 (t, J = 7.4 Hz, 3 H,
CH3CH2S), 2.68–2.82 (m, 2 H, CH3CH2S), 3.21 (dd, J = 10.2, 6.5
Hz, 1 H, H-5a), 3.37 (dd, 1 H, J = 10.2, 3.4 Hz, H-5b), 4.28 (d,
J = 4.3 Hz, 1 H, H-3), 4.38 (s, 1 H, H-2), 4.77 (dt, J = 6.7, 3.4 Hz, 1
H, H-4), 5.26 (s, 1 H, H-1), 7.07–7.15 (m, 8 H, Ph), 7.20–7.33 (m,
13C NMR (75.48 MHz, CDCl3): δ = 14.6 (CH3CH2S), 25.1
(CH3CH2S), 40.6 (COCH2Cl), 61.2 (C-5), 76.2 (C-3), 82.8 (C-4),
85.9 (C-1), 87.9 (C-2), 167.7 (CO).
HRMS–ESI: m/z [M + Na]+ calcd for C9H15ClNaO5S: 293.0226;
found: 293.0221.
Synthesis 2012, 44, 1219–1225
© Georg Thieme Verlag Stuttgart · New York

PAPER
Silicon-Free Differentiation of Hydroxy Groups in Arabinofuranose
1225
Ethyl 3,5-Di-O-benzoyl-2-O-(chloroacetyl)-1-thio-α-D-arabino-
furanoside (18)
Lowary, T. L. J. Org. Chem. 2002, 67, 892. (j) Gadikota, R.
R.; Callam, C. S.; Appelmelk, B. J.; Lowary, T. L.
J. Carbohydr. Chem. 2003, 22, 459. (k) Mereyala, H. B.;
Hotha, S.; Gurjar, M. K. Chem. Commun. (Cambridge)
1998, 685. (l) Tam, P.-H.; Lowary, T. L. Carbohydr. Chem.
2010, 36, 38; and references cited therein.
BzCl (0.80 mL, 0.87 mmol) was added to the soln of diol 17 (59 mg,
0.218 mmol) in pyridine (2 mL) at 0 °C and the mixture was stirred
at 0 °C for 0.5 h. The reaction was quenched by addition of sat. aq
NaHCO3 (1 mL) and the mixture was diluted with CH2Cl2 (50 mL)
and washed successively with H2O (50 mL) and sat. aq NaHCO3 (50
mL). The organic phase was filtered through a layer of a ~1:1 (v/v)
mixture of Celite and powdered Na2SO4 then concentrated and
dried in vacuo. The residue was purified by column chromatogra-
phy [silica gel, benzene–EtOAc (1:9)] to give a colorless syrup;
yield: 102 mg (97%).
(2) Health Topics: Tuberculosis; World Health Organization:
Geneva, 2012, http://www.who.int/topics/tuberculosis/en
(accessed March 15, 2012).
(3) Pathak, A. K.; Pathak, V.; Bansal, N.; Maddry, J. A.;
Reynolds, R. C. Tetrahedron Lett. 2001, 42, 979.
(4) Mei, X.; Ning, J. Synlett 2005, 2267.
(5) Podvalnyy, N. M.; Sedinkin, S. L.; Abronina, P. I.; Zinin, A.
I.; Fedina, K. G.; Torgov, V. I.; Kononov, L. O. Carbohydr.
Res. 2011, 346, 7.
(6) Ishiwata, A.; Ito, Y. J. Am. Chem. Soc. 2011, 133, 2275.
(7) Dahlman, O.; Garegg, P. J.; Mayer, H.; Schramek, S. Acta
Chem. Scand., Ser. B 1986, 40, 15.
(8) Kochetkov, N. K.; Byramova, N. É.; Tsvetkov, Y. E.;
Backinowsky, L. V. Tetrahedron 1985, 41, 3363.
(9) Jung, M. E.; Xu, Y. Org. Lett. 1999, 1, 1517.
(10) (a) Ness, R. K.; Fletcher, H. G. J. Am. Chem. Soc. 1958, 80,
2007. (b) Callam, C. S.; Lowary, T. L. J. Chem. Educ. 2001,
78, 73.
1H NMR (200.13 MHz, CDCl3): δ = 1.35 (t, J = 7.4 Hz, 3 H,
CH3CH2S), 2.63–2.87 (m, 2 H, CH3CH2S), 4.01 (s, 2 H, COCH2Cl),
4.61–4.85 (m, 3 H, H-4, H-5a, H-5b), 5.40 (dd, J = 1.4, 1.5 Hz, 1 H,
H-2), 5.44–5.53 (m, 2 H, H-1, H-3), 7.34–7.70 (m, 6 H, Ph), 8.02–
8.13 (m, 4 H, Ph).
13C NMR (50.32 MHz, CDCl3): δ = 14.8 (CH3CH2S), 25.3
(CH3CH2S), 40.3 (CH2Cl), 63.2 (C-5), 77.8 (C-3), 80.5 (C-2), 83.6
(C-4), 87.7 (C-1), 128.3, 128.5, 128.8, 129.7, 130.0, 133.2, 133.7
(Ph), 165.5, 166.2 (CO).
Acknowledgment
(11) Byramova, N. É .; Ovchinnikov, M. V.; Backinowsky, L. V.;
Kochetkov, N. K. Carbohydr. Res. 1983, 124, C8.
(12) Abronina, P. I.; Podvalnyy, N. M.; Melnikova, T. M.; Zinin,
A. I.; Fedina, K. G.; Kachala, V. I.; Torgov, V. I.; Kononov,
L. O.; Panferzev, E. A.; Baranova, E. V.; Mochalov, V. V.;
Dyatlova, V. I.; Biketov, S. F. Russ. Chem. Bull. 2010, 59,
2333.
Authors are grateful to Professor L. V. Backinowsky for bringing to
our attention the possibility of preparing 1,2-O-benzylidene deriva-
tives from the corresponding glycosyl bromides. This work was fi-
nancially supported by the Russian Foundation for Basic Research
(Projects No. 07-03-00830 and No. 10-03-01019).
(13) (a) Pathak, T. Chem. Rev. 2002, 102, 1623. (b) Zatsepin, T.
S.; Romanova, E. A.; Oretskaya, T. S. Russ. Chem. Rev.
2004, 73, 701.
(14) (a) Antiviral Nucleosides: Chiral Synthesis and
Chemotherapy; Chu, C. K., Ed.; Elsevier: Amsterdam, 2003.
(b) De Clercq, E. Antiviral Res. 2005, 67, 56. (c) Mathéa, C.;
Gosselin, G. Antiviral Res. 2006, 71, 276.
(15) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective
Groups in Organic Synthesis, 4th ed.; Wiley-Interscience:
Hoboken, 2007, 239. (b) Wuts, P. G. M.; Greene, T. W.
Greene’s Protective Groups in Organic Synthesis, 4th ed.;
Wiley-Interscience: Hoboken, 2007, 353. (c) Kocieński, P.
J. Protecting Groups, 3rd ed.; Thieme: Stuttgart, 2005, 171.
References
(1) (a) Joe, M.; Bai, Y.; Nacario, R. C.; Lowary, T. L. J. Am.
Chem. Soc. 2007, 129, 9885. (b) Zhu, X.; Kawatkar, S.; Rao,
Y.; Boons, G.-J. J. Am. Chem. Soc. 2006, 128, 11948.
(c) Ishiwata, A.; Akao, H.; Ito, Y. Org. Lett. 2006, 8, 5525.
(d) Lee, Y. J.; Lee, K.; Jung, E. H.; Jeon, H. B.; Kim, K. S.
Org. Lett. 2005, 7, 3263. (e) Crich, D.; Pedersen, C. M.;
Bowers, A. A.; Wink, D. J. J. Org. Chem. 2007, 72, 1553.
(f) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.; López, J. C.
Tetrahedron: Asymmetry 2006, 17, 2449. (g) Liang, X.-Y.;
Deng, L.-M.; Liu, X.; Yang, J.-S. Tetrahedron 2010, 66,
6687. (h) Marotte, K.; Sanchez, S.; Bamhaoud, T.; Prandi, J.
Eur. J. Org. Chem. 2003, 3587. (i) Yin, H.; D’Souza, F. W.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1219–1225