Practical synthesis of neoponkoranol and its related sulfonium salt, an optimised protocol using isopropylidene as an effective protecting group

Article abstract of DOI:10.3184/174751913X13823645011477

A practical synthesis of neoponkoranol and its related sulfonium salt as potent α-glucosidase inhibitors has been developed in which the key step of coupling reaction was optimised by using isopropylidene as an effective protecting group. The characteristic intramolecular cyclisation of the coupling precursor previously encountered as a side reaction has not been detected and coupling yields were dramatically improved in the present study.

Full text of DOI:10.3184/174751913X13823645011477

JOURNAL OF CHEMICAL RESEARCH 2013
DECEMBER, 715–719
RESEARCH PAPER 715
Practical synthesis of neoponkoranol and its related sulfonium salt, an
optimised protocol using isopropylidene as an effective protecting group
Dan Liua, Weijia Xiea,b*, Long Liua, Jinyi Xua,b, Hequan Yaoa,b, Genzoh Tanabec, Osamu Muraokac
and Xiaoming Wua,b
aDepartment of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P.R. China
bState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China
cSchool of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
A practical synthesis of neoponkoranol and its related sulfonium salt as potent α‑glucosidase inhibitors has been developed in
which the key step of coupling reaction was optimised by using isopropylidene as an effective protecting group. The characteristic
intramolecular cyclisation of the coupling precursor previously encountered as a side reaction has not been detected and
coupling yields were dramatically improved in the present study.
Keywords: neoponkoranol, natural product, synthetic study, Salacia, α‑glucosidase inhibitor
The inhibition of glucosidases is considered to be one of the most
effective therapeutic approach to treat diseases such as diabetes,1
cancers,2 viral infections3 and Gaucher’s disease.4 In the late
1990s, salacinol (1) was isolated by Yoshikawa and co‑workers
as a potent α‑glucosidases inhibitor from an Indian Ayurvedic
medicinal plant Salacia reticulate.5,6 Shortly thereafter, its
related side chain analogues salaprinol7 (2), ponkoranol7 (3) and
kotalanol8 (4) as well as the de‑O‑sulfonated sulfonium salts
neosalacianol9 (5), neosalaprinol10 (6), neoponkoranol10 (7) and
neokotalanol11 (8) were subsequently isolated from the same
species of plants. Other than (2) and (6), the α‑glucosidase
inhibitory activities of six sulfonium salts were revealed to be as
potent as those of acarbose and voglibose which are widely used
clinically as antidiabetics. Their intriguing bioactivities as well
as unique chemical structures, bearing a 1,4‑anhydro‑1,4‑thio‑
D‑arabinitol core and a polyhydroxylated side chain, (Fig. 1)
made them potential lead compounds which could be further
developed as a new class of hypoglycaemic drug candidates.
Based on structure–activity relationship (SAR) studies12–17 on
this group of natural products, it was recently revealed that the
de‑O‑sulfonated versions such as 5, 6, 7 and 8 usually present
higher inhibitory potency in contrast with their 3ʹ‑sulfonates
1, 2, 3 and 4 (Fig. 1), making de‑O‑sulfonated salts more
attractive as candidates for further structure modification.10,12–15
The reported synthetic protocol to prepare this type of de‑O‑
sulfonated sulfonium salts relies on coupling reaction between
protected thiosugar and a corresponding epoxide15,19–21 or
tosylate.22 The former procedure usually provides a pair of
diastereomers at the stereogenic sulfur centre as the coupled
product, which is difficult for further purification. On the other
hand, it is usually time consuming when tosylate is used as the
coupling partner, and the desired product is obtained in poor
yield.
Recently, the chemical synthesis of neoponkoranol (7)
and its side chain epimers as potent α‑glucosidase inhibitors
has been reported.10 The key synthetic procedure addressed
was the coupling reaction between a protected thiosugar
(9) and a triflate, during which process, the desired coupled
products were obtained in relatively low yield. (Fig. 2, part
I) After carefully analysing the structures of side products
14 and 15 isolated from the coupling reaction, the formation
of the two compounds could be explained by a characteristic
intramolecular cyclisation of triflate (11), which was triggered
by nucleophilic attack from the sulfur atom of thiosugar
(9) to the methylene carbon at the C3‑benzyloxy moiety of
11 (conformation B) as shown in Fig. 2 part II. On the other
hand, the direct attack from the sulfur atom of thiosugar (9)
to the methylene at C6 bearing leaving group (TfO–) in 11
(conformation A) provided the desired coupled product (13) in
low yield. Due to the unique structure features and excellent
bioactivities, it is necessary to develop an efficient protocol to
construct the de‑O‑sulfonated sulfonium salt moiety which is
the characteristic structure of these series of natural inhibitors.
As a continuous synthetic study on this group of sulfonium
salts, we now present our latest efforts to optimise the coupling
reaction between thiosugar and triflate, which would greatly
facilitate the subsequent structure modification of this group of
natural products.
OH
OH
H
O
S+
S+
R
R
HO
HO
HO
OH
OH
HO
-
-
salacinol (1) : R = OSO3
neosalacinol (5) : R = OH
salaprinol (2) : R = OSO3
neosalaprinol (6) : R = OH
OH
OH
OH
OH
OH
OH
3'
5'
7'
1'
OH
S+
S+
R
OH
R
OH
H
O
HO
Based on our proposed mechanism of the previously
reported coupling reaction (Fig. 2, part II), it was speculated
that protection with appropriate group which could tightly fix
the C3 hydroxy moiety of the monosaccharide structure could
be an effective way to prevent the undesired intramolecular
cyclisation reaction of the corresponding triflate. Thus,
OH
HO
OH
ponkoranol (3) : R = OSO3
neoponkoranol (7): R = OH
H
O
-
-
kotalanol (4) : R = OSO3
neokotalanol (8) : R = OH
Fig. 1 Sulfonium salts isolated from Salacia species as a new class of
α‑glucosidase inhibitor.
benzyl
2,3‑O‑isopropylidene‑6‑O‑tert‑butyldimethylsilyl‑
α‑D‑mannopyranoside (16)23 which was prepared from
* Correspondent. E‑mail: weijiaxie@cpu.edu.cn
D‑mannose through four steps with the overall yield of 65%
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716 JOURNAL OF CHEMICAL RESEARCH 2013
OBn
OBn
OBn
OBn
OH OH
Part I
O
O
3'
5'
1'
OH
OBn
Cl-
4'
TfO-
2'
OBn
S+
S+
OH
OBn
OH
TfO
OBn
10
BnO
HO
12 (64% yield)
OH
HO
BnO
OBn
7
S
BnO
OBn
OBn
OH OH
OBn
OBn
OBn
O
BnO
O
1
3
OH
9
TfO-
Cl-
OBn
6
OBn
S+
OH
OH
S+
OBn
TfO
OBn
11
HO
BnO
13 (37% yield)
OH
5'-epi-7
HO
BnO
OBn
Ph
+
TfO-
O
S+
OBn
O
OBn
BnO
OBn
BnO
OBn
15
14
BnO
OBn
BnO
S
OBn
OBn
Ph
S
OTf
BnO
TfO
OBn
O
OBn
1
TfO
BnO
5
O
9
5
O
1
9
5
1
BnO
BnO
OBn
OBn
OBn
O
3
3
OBn
OBn
3
conformation A
conformation B
11
OBn
Part II
OBn
Ph
OBn
O
O
TfO-
S+
OBn
OBn
O
+
TfO-
BnO
OBn
S+
OBn
OBn
BnO
OBn
BnO
13
14
15
OBn
BnO
Fig. 2 Previously reported synthesis of 7 and its side chain epimer and plausible mechanism of coupling reaction between
triflate (11) and thiosugar (9).
was selected as the starting material to synthesise 5ʹ‑epi‑7.
The secondary alcohol of compound 16 was first benzylated
with benzyl bromide in the presence of sodium hydroxide in
DMF to give benzyl 2,3‑O‑isopropylidene‑4‑benzyl‑6‑O‑tert‑
butyldimethylsilyl‑α‑D‑mannopyranoside (17) in 97% yield.
Selective deprotection of the TBS group in 17 was accomplished
by using TBAF to give benzyl 2,3‑O‑isopropyridene‑4‑benzyl‑
α‑D‑mannopyranoside (18) with the yield of 95% (Scheme 1).
The subsequent sulfonation of 18 with trifluoromethanesulfonic
anhydride in the presence of 2,6‑lutidine in dry dichloromethane
afforded benzyl 2,3‑O‑isopropylidene‑4‑benzyl‑6‑O‑
trifluoromethanesulfonyl‑α‑D‑mannopyranoside (19) in
85% yield, which was directly coupled with 9 in dry THF
for 3 days to give the desired sulfonium salt (S)‑2,3,5‑tri‑O‑
benzyl‑1‑deoxy‑S‑(1,4‑di‑O‑benzyl‑2,3‑O‑isopropylidene‑6‑
deoxy‑α‑D‑mannopyrananos‑6‑yl)‑4‑thio‑D‑arabinofuranose
trifluoromethanesulfonate (20) in 87% yield while no other
side product was isolated. Thus, by applying isopropylidene as
OBn
O
O
OBn
O
O
OBn
O
O
TfO
BnO
4 steps
RO
BnO
TBSO
HO
c
a
D-mannose
65% yield
O
O
O
19
16
:
:
=
=
17
R
R
TBS
H
b
18
OBn
OBn
OH
OH
OH
OH
O
OH
O
O
TfO-
e,f
Cl-
g
d
OH
O
Cl-
OH
S+
S+
OH
OH
S+
HO
BnO
HO
HO
OH
OBn
BnO
21
20
HO
OH
5'-epi-7
Scheme 1 Reagents and conditions: (a) BnBr, NaH, DMF, rt, 1 h (97%); (b) TBAF, THF, rt, 12 h (95%); (c) Tf O, 2,6‑lutidine,
–20–0 °C, 30 min (85%); (d) thiosugar (9), THF, rt, 72 h (87%); (e) H2, 10% Pd–C, 50% aq. TFA, 50 °C, 482h; (f) IRA 400J
(Cl‑ form), CH3OH, rt, 3 h; (g) NaBH4, H2O, 0 °C, 20min (51% from 20).
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JOURNAL OF CHEMICAL RESEARCH 2013 717
O
O
TfO
H
O
H
O
O
O
-
O
Tf
O
O
O
O
3 steps
b
O
a
HO
O
O
O
O
S+
O
O
HO
85% yield
O
O
O
BnO
22
23
24
25
BnO
OBn
HO
O
OH
H
O
H
O
O
OH
OH
H
O
3'
c
e
d f
, ,
+
-
OH
TfO-
Tf
H
O
O
OH
l-
C
S+
OH
S+
S+
OH
OH
BnO
HO
BnO
7
a
26
26b
BnO
OBn
HO
OH
BnO
OBn
Scheme 2 Reagents and conditions: (a) Tf2O, 2,6‑lutidine, –20–0 °C, 30 min (91%); (b) thiosugar, THF, rt, 72 h (85%); (c) 50% aq. TFA, 50 °C,
1.5 h; (d) H2, 10%Pd–C, 80% aq. AcOH, 50 °C, 48 h; (e) IRA 400J(Cl– form), CH3OH, rt, 3 h; (f) NaBH4, H2O, 0 °C, 20 min (50% from 25).
the protecting group on C3 hydroxyl moiety, the yield of the
key coupling reaction was improved from previously reported
37% to 87% in the present study, which clearly confirmed our
former assumption that locking hydroxy group on C3 position
would effectively prevent the intramolecular cyclisation of
the corresponding triflate as side reaction. Sulfonium salt
(20) was then converted to the target compound 5ʹ‑epi‑7 by
hydrogenolysis over Pd–C under acidic condition followed by
ion exchange reaction using IRA 400J (Cl– form) and finally by
NaBH4 reduction in 51% overall yield from 20.
derived trial) and from 64% to 85% (in D‑glucose derived trial),
respectively, indicating that isopropylidene protection of C3 and
its adjacent hydroxy group on monosaccharide moiety could
effectively prevent the side reaction which was encountered
in our previous investigation. It is highly commented that the
present findings would greatly facilitate the further structure
modification of this group of natural products, which is now
underway in our laboratory.
Experimental
Melting points were taken on XT‑4 micro melting point apparatus
and are uncorrected. NMR spectra were recorded for 1H NMR at
300, 500or 700 MHz and for 13C NMR at 75, 125 or 175 MHz. For 1H
NMR, tetramethylsilane (TMS) served as internal standard (δ=0)
for CDCl3 and no internal standard was added for D2O. 1H NMR data
are reported as follows: chemical shift, integration, multiplicity
(s = si nglet, d = doublet, t = t r iplet, q = qua r tet, m = multiplet, br = broad),
and coupling constant in Hz. For 13C NMR, TMS (δ=0) or CDCl3
(δ=77.25) was used as internal standard for CDCl3 and no internal
standard was used for D2O. Mass spectra were obtained using Agilent
1100‑LCMSD‑Trap/SL and HRMS were obtained using Agilent QTOF
6520. Low‑resolution MS and HRMS data were obtained using ESI
ionisation. Column chromatography was carried out over Fuji Silysia
silica gel BW‑200. All the organic extracts were dried over anhydrous
sodium sulfate prior to evaporation.
Benzyl-2,3-O-isopropylidene-4-benzyl-6-O-tert-butyldimethylsilyl-
β-D-mannopyranoside (17): A solution of 1623 (1.2 g, 2.8 mmol) in
dry DMF (5 mL) was added to a mixture of sodium hydride (NaH,
240 mg, 6 mmol, 60% in liquid paraffin) and benzyl bromide (BnBr,
0.5 mL, 4.1 mmol) in dry DMF (10 mL) at 0 °C. After stirring at room
temperature for 2 h, the resulting mixture was poured into ice‑water,
then extracted with ether. The extract was washed with brine, and
condensed under reduced pressure to give a yellow oil (1.68 g), which on
column chromatography (hexane/AcOEt, 40/1) gave the title compound
(17, 1.4 g, 97%) as a pale yellow oil. [α]D25 =+47.4 (c= 1, CH3OH) 1Η ΝΜR
(500 MHz, CDCl3) δ 7.27–7.12 (m, 10H), 5.00 (s, 1H), 4.80 (d, J= 11.5 H z,
1H), 4.65 (d, J=11.5 Hz, 1H), 4.52 (d, J=11.5 Hz, 1H), 4.41 (d, J= 11.5 H z,
1H), 4.25 (t, J=6.5 Hz, 1H), 4.09 (d, J=5.5 Hz, 1H), 3.80 (dd, J= 11.0 H z,
1.5 Hz, 1H), 3.69 (dd, J=11.0 Hz, 5.5 Hz, 1H), 3.61 (ddd, J= 10.0 H z,
5.5 Hz, 1.5 Hz, 1H), 3.46 (dd, J=10.0 Hz, 6.5 Hz, 1H), 1.40 (s, 3H), 1.26
(s, 3H), 0.83 (s, 9H), 0.001 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 138.4,
137.1, 128.4, 128.23, 128.19, 127.9, 127.8, 127.5, 109.1, 96.1, 78.9, 75.9,
75.7, 72.9, 69.8, 68.6, 62.7, 27.8, 26.3, 25.9, 18.3. HRMS(ESI M+H) m/z
In view of this result, a similar strategy was used for the
synthesis of natural product neoponkoranol (7). Hence,
1,2:3,5‑di‑O‑isopropylidene‑α‑D‑glucofuranose
(23)24,
which could be easily prepared from commercially available
1,2‑O‑isopropylidene‑α‑D‑glucofuranose (22) through three
steps with the overall yield of 85% was subjected to sulfonation
reaction to give the corresponding triflate (24) in 91% yield
(Scheme 2). Coupling reaction between 24 and thiosugar 9 was
then immediately conducted in dry THF at room temperature
for 3 days to afford the desired coupled product (S)‑2,3,5‑
tri‑O‑benzyl‑1‑deoxy‑S‑(1,2:3,5‑di‑O‑isopropylidene‑6‑
deoxy‑α‑D‑glucofuranos‑6‑yl)‑4‑thio‑D‑arabinofuranose
trifluoromethanesulfonate (25) with the yield of 85%. Acid
catalysed hydrolysis of 25 was then performed through
treatment with 50% trifluoroacetic acid leading to the almost
quantitative formation of intermediate (26) as a mixture of both
furanose and pyranose form anomers24. Finally, compound 26
was converted to the target compound neoponkoranol (7) in
50% overall yield in a similar procedure as discussed above for
the preparation of 5ʹ‑epi‑7.
Conclusions
Based on our former synthetic studies on a naturally occurring
potent α‑glucosidase inhibitor neoponkoranol (7), we have
developed an efficient strategy to optimise the coupling reaction
as the key protocol to synthesise this series of sulfonium salts.
Compared with the previously reported route, triflates (19)
and (24) selected in the present study as coupling precursors
could be more easily and economically prepared from
commercially available materials. In addition, coupling yields
were dramatically improved from 37% to 87% (in D‑mannose
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718 JOURNAL OF CHEMICAL RESEARCH 2013
calcd for C29H43O6Si: 515.2829; found:515.2841.
which on column chromatography (CHCl3/MeOH, 10/1 → 4/1) gave the
title compound (5ʹ-epi-7, 89 mg, 51%). 1H NMR (700 MHz, D2O): 3.67
(1H, dd, J=11.8, 6.0 Hz, H‑6’a), 3.74 (1H, ddd, J=ca 8.8, 6.0, 2.7 Hz,
H‑5ʹ), 3.77 (1H, dd, J=8.8, 1.2 Hz, H‑4’), 3.80 (1H, dd, J= 13.2, 9.0 H z,
H‑1’a), 3.85 (1H, dd, J=ca 11.8, 2.7 Hz, H‑6’b), 3.88 (1H, dd, J=8.2,
1.2 Hz, H‑3’), 3.90 (1H, dd, J=13.0, 4.0 Hz, H‑1a), 3.93 (1H, dd, J=13.0,
3.0 Hz, H‑1b), 3.95 (1H, dd, J=11.2, 8.2 Hz, H‑5a), 3.98 (1H, dd, J=ca
13.2, 3.2 Hz, H‑1’b), 4.13 (1H, ddd, J=ca 8.2, 5.0, 2.6 Hz, H‑4), 4.15 (1H,
dd, J=11.2, 5.0 Hz, H‑5b), 4.23 (1H, ddd, J=9.0, 8.2, 3.2 Hz, H‑2’), 4.45
(1H, dd, J=ca 2.9, 2.6 Hz, H‑3), 4.76 (1H, ddd, J=ca 4.0, 2.9, 2.9 Hz,
H‑2);13C NMR (175 MHz, D2O) δ: 50.8 (C‑1), 53.1 (C‑1’), 61.9 (C‑5), 65.7
(C‑6’), 70.0 (C‑2’), 71.6 (C‑4’), 72.7 (C‑4), 73.3 (C‑5ʹ), 74.3 (C‑3’), 79.7
(C‑2), 80.2 (C‑3). HRMS(ESI) m/z calcd for C11H23O8S+: 315.1114; found:
315.1134.
(S)-2,3,5-Tri-O-benzyl-1-deoxy-S-(1,2:3,5-di-O-isopropylidene-
6-deoxy-α-D-glucofuranos-6-yl)-4-thio-D-arabinofuranose
trifluoromethanesulfonate (25): In a manner similar to that used for
the synthesis of triflate (19), diacetonide (2324, 390 mg, 1.5 mmol)
was subjected to sulfonation reaction to afford 24 (536 mg, 91%) as
a colourless oil, which was directly coupled with thiosugar (9). A
solution of thiosugar (9, 630 mg, 1.5 mmol) in THF (1.5 mL) at room
temperature under argon atmosphere was added to a solution of 24
(392 mg, 1.0 mmol) in THF (1.5 mL). The resultant mixture was then
stirred at room temperature for 72 h. After the total consumption of the
triflates, the reaction mixture was condensed under reduced pressure
to give a pale yellow oil (1.05 g), which on column chromatography
(CHCl3/MeOH, 200/1) gave the title compound (25, 690 mg, 85%) as a
pale yellow oil. [α]D25 =+28.6 (c= 1, CH3OH) 1H NMR (300 MHz, CDCl3)
δ 7.34–7.15 (m, 15H), 5.98 (d, J=3.6 Hz, 1H), 4.67–4,45 (m, 7H), 4.36 (dd,
J=6.3, 3.6 Hz, 2H), 4.30 (s‑like, 1H), 4.25–4.17 (m, 2H), 4.08 (dd, J= 9.3,
6.3 1H), 3.92–3.72 (m, 5H), 3.41 (m, 1H), 1.48 (s, 3H), 1.313 (s, 3H), 1.307
(s, 3H), 1.28(s, 3H); 13C NMR (75 MHz, CDCl3) δ 136.5, 135.97, 135.94,
128.8, 128.7, 128.63, 128.60, 128.52, 128.5, 128.4, 128.31, 128.27, 128.10,
128.07, 112.9, 106.5, 102.0, 83.8, 82.9, 82.6, 80.9, 74.8, 73.6, 72.6, 72.2,
68.8, 67.1, 66.5, 48.9, 48.7, 27.1, 26.6, 24.2, 23.4. HRMS(ESI) m/z calcd
for C38H47O8S+: 663.2992; found: 663.2979.
(R)-1-Deoxy-R-(6-deoxy-D-glucitol-6-yl)-4-thio-D-arabinofuranose
chloride (neoponkoranol 7): A solution of sulfonium salt 25 (406mg,
0.5 mmol) in 50% aqueous TFA solution (5 mL) was stirred at room
temperature for 2 h. Concentration of the mixture gave compound 26
(329 mg) as a mixture of both furanose and pyranose form anomers.12
Without purification, the mixture was then subjected to hydrogenolysis
over 10% Pd–C followed by ion exchange reactions using IRA 400J (Cl–
form) and finally by NaBH4 reduction in a similar procedure discussed
above to give the title compound (neoponkoranol 710, 78 mg) with the
overall yield of 50% from 25. [α]D23 +4.3 (c= 0.6, H 2O), lit10 [α]D23 +4.1
(c= 0.7, H 2O). 1H NMR (700 MHz, D2O): 3.61 (1H, dd, J=ca 11.8, 5.6 Hz,
H‑6’a), 3.71 (1H, dd, J=11.8, 3.6 Hz, H‑6’b), 3.73 (1H, dd, J= 7.8, 1.8 H z,
H‑3’), 3.78 (1H, dd, J=13.2, 9.2 Hz, H‑1’a), 3.80 (1H, ddd, J=ca 5.6, 5.6,
3.6 Hz, H‑5ʹ), 3.82 (1H, dd, J=ca 5.6, 1.8 Hz, H‑4’), 3.88 (1H, dd, J=13.0,
4.0 Hz, H‑1a), 3.92 (1H, dd, J=13.0, 3.0 Hz, H‑1b), 3.95 (1H, dd, J= 11.0,
8.2 Hz, H‑5a), 3.97 (1H, dd, J=13.2, 3.2 Hz, H‑1’b), 4.12 (1H, ddd, J=ca
8.2, 4.8, 3.0 Hz, H‑4), 4.14 (1H, dd, J=11.0, 4.8 Hz, H‑5b), 4.25 (1H, ddd,
J=9.2, 7.8, 3.2 Hz, H‑2’), 4.45 (1H, dd, J=ca 3.0, 3.0 Hz, H‑3), 4.76 (1H,
ddd, J=ca 4.0, 3.0, 3.0 Hz, H‑2); 13C NMR (175 MHz, D2O): 50.9 (C‑1),
52.8 (C‑1’), 62.0 (C‑5), 65.0 (C‑6’), 70.2 (C‑2’), 72.0 (C‑4’), 72.6 (C‑4),
75.5 (C‑5ʹ), 75.8 (C‑3’), 79.7 (C‑2), 80.3 (C‑3). HRMS(ESI) m/z calcd for
C11H23O8S+: 315.1114; found: 315.1128.
Benzyl 2,3-O-isopropylidene-4-benzyl-β-D-mannopyranoside
(18): A mixture of compound 17 (1.03 mg, 2 mmol), 1 M solution
of tetrabutylammonium fluoride in THF (2.1 mL, 2.1 mmol), THF
(10 mL) was stirred at room temperature for 12 h. After the total
consumption of the starting material, the mixture was poured into ice‑
water (50 mL) and extracted with AcOEt. The extract was washed with
brine and condensed to give a pale yellow oil (852 mg), which on column
chromatography (n‑hexane/ethyl acetate, 20/1) gave the title compound
(18, 761 mg, 95%) as a white solid, m.p. 126–128 °C, [α]D25 =+63.3 (c=1,
CH3OH) 1H NMR (500 MHz, CDCl3) δ 7.35–7.22 (m, 10H), 5.12 (s, 1H),
4.88 (d, J=11.5 Hz, 1H), 4.70 (d, J=11.5 Hz, 1H), 4.63 (d, J= 11.5 H z,
1H), 4.49 (d, J=11.5 Hz, 1H), 4.35 (t, J=6.5 Hz, 1H), 4.19 (d, J= 5.5 H z,
1H), 3.83 (dd, J=11.5 Hz,2.5 Hz, 1H), 3.73–3.70 (m, 2H), 3.56 (dd,
J=10.0 Hz,6.5 Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 138.1, 136.8, 128.4, 128.3, 128.1, 128.0, 127.7, 109.3, 96.4, 78.6,
75.9, 75.8, 72.8, 69.2, 68.7, 62.4, 27.9, 26.3.HRMS(ESIM+H) m/z calcd
for C23H29O6: 401.1964; found:401.1953.
(S)-2,3,5-Tri-O-benzyl-1-deoxy-S-(1,4-di-O-benzyl-2,3-O-
isopropylidene-6-deoxy-α-D-mannopyrananos-6-yl)-4-thio-D-
arabinofuranose trifluoromethanesulfonate (20): Under argon
atmosphere, to a solution of 2,6‑lutidine (200 µL, 2.25 mmol) in
12 mL dry dichloromethane was added trifluoromethanesulfonic
anhydride (Tf2O, 430 µL, 2.25 mmol) at –20 °C. After 5 min, a solution
of 18 (600 mg, 1.5 mmol) in dry dichloromethane (12 mL) was added
dropwise to the solution at –20 °C. The resulting mixture was stirred
at –20 °C for 5 min, and then at 0 °C for another 30 min. The mixture
was poured into ice‑cooled water and extracted with dichloromethane.
The extract was condensed under reduced pressure to give a pale
yellow oil (825 mg). After column chromatography (n‑hexane/AcOEt,
20/1), the target triflate benzyl 2,3‑O‑isopropyridene‑4‑benzyl‑6‑O‑
trifluoro‑methanesulfonyl‑α‑D‑mannopyranoside (19, 679mg, 85%)
was obtained as a pale yellow oil, which was then directly coupled with
thiosugar (9). A solution of thiosugar (9, 630 mg, 1.5 mmol) in THF
(1.5 mL) at room temperature was added under argon atmosphere to
a solution of 19 (533 mg, 1.0 mmol) in THF (1.5 mL). The resultant
mixture was then stirred at room temperature for 72 h. After the total
consumption of the triflates, the reaction mixture was condensed under
reduced pressure to give a pale yellow oil (1.1 g), which on column
chromatography (CHCl3/MeOH, 200/1) gave the title compound (20,
826 mg, 87%) as a pale yellow oil. [α]D25 =+70.5 (c= 1, CH3OH) 1H NMR
(500 MHz, CDCl3) δ 7.28–7.10 (m, 25H), 5.04 (s, 1H), 4.79 (d, J= 11.5 H z,
1H), 4.57–4.32 (m, 10H), 4.25 (t, J=6.5 Hz, 1H), 4.20 (s‑like, 1H), 4.13–
4.05 (m, 2H), 3.95 (m, 1H), 3.79–3.70 (m, 3H), 3.67–3.51 (m,3H), 3.34
(dd, J=9.5, 6.5 Hz, 1H), 1.42 (s, 3H), 1.28(s, 3H); 13C NMR (125 MHz,
CDCl3) δ 137.4, 136.7, 136.4, 136.1 (C×2), 128.9, 128.79, 128.75, 128.7,
128.64, 128.58, 128.52, 128.44, 128.43, 128.39, 128.34, 128.32, 128.28,
128.24, 128.21, 128.14, 128.10, 128.06, 128.00, 127.95, 127.9, 109.9, 96.9,
82.7, 77.7, 76.5, 75.5, 73.6, 72.6, 72.44, 72.35 (C×2), 70.4, 66.7, 66.5, 65.6,
48.3, 47.9, 27.9, 26.2. HRMS(ESI) m/z calcd for C49H55O8S+: 803.3618;
found:803.3626.
(R)-1-Deox y-R-(6 - deox y-D -mannitol- 6 -yl)- 4 -thio -D -
arabinofuranose chloride (5ʹ-epi-7): A suspension of 10% Pd–C
(500 mg) in 60% aqueous TFA solution (10 mL) was pre‑equilibrated
with hydrogen. A solution of compound 20 (476 mg, 0.5 mmol) in
1,4‑dioxane (2 mL) was added to the suspension and the mixture
was hydrogenated at 50 °C under atmospheric pressure until uptake
of hydrogen ceased. The catalyst was filtered off and washed with a
mixture of methanol and water. After the combined filtrate and the
washings were condensed under reduced pressure, the residue (245 mg)
was washed with dichloromethane to give a colourless oil (228 mg),
which was treated with IRA 400J (Cl– form, 2.50 g) in methanol (3 mL)
at room temperature for 3 h. The resins were filtered off and washed with
methanol. The filtrate and the washings were combined and condensed
under reduced pressure to give a colourless oil (200 mg), which was
treated with NaBH4 (130 mg, 3.4 mmol) in water (15 mL) at 0 °C for
20 min. The mixture was acidified with 2M hydrochloric acid to pH ca
4, and condensed under reduced pressure to give a white solid (320 mg),
This work was financially supported by Fundamental
Research Funds for the Central Universities (JKZ2011003),
the National Natural Science Foundation of China (Grant No.
81202409), Natural Science Foundation of Jiangsu Province
(SBK201240392), Scientific Research Foundation for the
Returned Overseas Chinese Scholars, Ministry of Education
(2013) and Technology Foundation for Selected Overseas
Chinese Scholar, Ministry of Personnel of China (2013).
JCR1302072_FINAL.indd 718
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JOURNAL OF CHEMICAL RESEARCH 2013 719
12 L. Sim, K. Jayakanthan, S. Mohan, R. Nasi, B.D. Johnston, B.M. Pinto and
D.R. Rose, Biochemistry, 2010, 49, 443.
13 S. Nakamura, K. Takahira, G. Tanabe, T. Morikawa, M. Sakano, K.
Ninomiya, M. Yoshikawa, O. Muraoka and I. Nakanishi, Bioorg. Med.
Chem. Lett., 2010, 20, 4420.
Received 19 July 2013; accepted 20 September 2013
Paper 1302072 doi: 10.3184/174751913X13823645011477
Published online: 6 December 2013
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