Convenient synthesis of D-talose from D-galactose

Article abstract of DOI:10.1002/cjoc.201090213

The rare and expensive D-talose was conveniently synthesized from readily available D-galactose in four steps with an overall yield of 58%. The key step was the inversion of equatorial 2-OH of galactose to the axial one by S _N2 reaction under the modified Lattrell-Dax reaction conditions.

Full text of DOI:10.1002/cjoc.201090213

FULL PAPER
Convenient Synthesis of D-Talose from D-Galactose
Xiao, Hualinga(肖华玲)
Wang, Guangfaa(王广法)
Wang, Penga(王鹏)
,
Li, Yingxia b(李英霞)
*
a School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China
b School of Pharmacy, Fudan University, Shanghai 201203, China
The rare and expensive D-talose was conveniently synthesized from readily available D-galactose in four steps
with an overall yield of 58%. The key step was the inversion of equatorial 2-OH of galactose to the axial one by SN2
reaction under the modified Lattrell-Dax reaction conditions.
Keywords rare sugar, carbohydrate, D-talose, SN2 reaction, synthesis
Introduction
was formed with Bu2SnO in benzene. The equilibrium
shifted largely in favor of talose-1,2-cis-O-stannylene
acetal at reflux temperature, which was subsequently
hydrolysized by treatment with 15∶1 (V/V) DMF-H2O
at 50 ℃ to give 6-O-trityl-D-talose in yield of 60%—
70% along with comparative 6-O-trityl-D-galactose re-
covery. The intermediate was detritylated smoothly to
afford D-talose in 90% yield.
Rare sugars are defined as a class of monosaccha-
rides and derivatives which exist in nature with a few
amount.1 Over the past few years there has been
growing interest in the role of rare sugars for a variety
of uses, such as potential inhibitors of various glycosi-
dases,2 low-calorie carbohydrate sweeteners and bulking
agents,3,4 and improving the clinical effect as an immu-
nosuppressant.5 In addition, many results have demon-
strated that rare sugar structures in many anticancer and
antimicrobial natural products provide an important
function. For example, rare sugar moieties in some
antineoplastic drugs, such as daunorubicin,6 rebeccamy-
cin,7 anthracycline antibiotics adriamycin8 and tallyso-
mycin9 are critical in forming the anthracycline-DNA
binary and anthracycline-DNA-topoisomerase ternary
complexes ultimately leading to DNA damage and cell
death.10 The unique disaccharide appendage in glyco-
peptide antibiotic vancomycin has been shown to be
important for promoting dimerization,11 which appears
to be beneficial due to cooperative binding of the target
ligands.12,13 Talose, a rare sugar existing in certain
plants and bacteria, its derivatives and talose-contain-
ning glycoconjugates have been reported to present
some important biological and pharmacological activi-
ties, including anti-tumor,14,15 antimicrobial,16-18 inhibi-
tion of the galactose-binding galectin-419 and recrystal-
lization-inhibition (RI) activity.20 Talose is also a
marker of the O-antigens.21 Therefore, development of
mass production method of the expensive sugar for fur-
ther applications has become very attractive. In the past
years, generous chemical methods were used to prepare
talose, notably by Masamune and Sharpless,22 Traut-
wein,23 O’Doherty24,25 and Kovac.26,27 Among the varies
procedures, the synthetic strategy reported by Kovac
and co-workers was most efficient (Scheme 1). Starting
from 6-O-trityl-D-galactose, 1,2-O-stannylene complex
Scheme 1
Due to the impalpable Rf value difference, isolation
of 6-O-trityl-D-talose from 6-O-trityl-D-galactose was
formidable. Moreover, in this procedure large amount of
expensive Bu2SnO was needed and could not be recy-
cled. Therefore it is unsuitable for the mass production.
Fortunately, during our synthesis of N-glycan octasac-
*
E-mail: liyx417@fudan.edu.cn; Tel.: 0086-021-51980127; Fax: 0086-021-51980127
Received October 22, 2009; revised February 24, 2010; accepted March 12, 2010.
Chin. J. Chem. 2010, 28, 1229— 1232
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Xiao et al.
FULL PAPER
charide,28 we found that the equatorial 2-OH of gluco-
side could be completely inverted to the axial one by
SN2 reaction and the 2-O-acetyl group of penta-O-ace-
tyl-β-D-galactopyranose could be selectively removed
in the presence of 90% TFA without destroying other
acetyl groups.29,30 Taking the two points into account,
here we would like to report a new route to conveniently
prepare D-talose from D-galactose.
Scheme 2
Results and discussion
Following our method, D-talose would be prepared
from D-galactose in four steps, as outlined in Scheme 2.
D-galactose was firstly converted to known 1,2,3,4,6-
penta-O-acetyl-β-D-galacotose 531 in 94% yield. Then
selective cleavage of 2-O-acetyl group of 5 with 90%
TFA prepared the key intermediate 1,3,4,6-tetra-O-
acetyl-β-D-galactopyranose 6 in yield of 40%—50%
(Lit.29 in 70% yield) and by-product 2,3,4,6-tetra-O-ace-
tyl-β-D-galactopyranose. We observed that the ratio of
the by-product increased during the working up when
the reaction mixture was concentrated at high tempera-
ture to remove the TFA. We presumed that part of 6 was
converted to the by-product under the conditions.
Therefore in order to inhibit the transformation, we im-
proved the working up by washing out the TFA with
water and saturated aqueous Na2CO3. As a result, the
key 6 was obtained in a good yield of 66% through re-
crystallization and the by-product was reduced greatly
as expected. Subsequent estification of the 2-OH of
tetra-O-acetate 6 was carried out by treatment with
trifluoromethanesulfonic anhydride to provide 1,3,4,6-
tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-galact-
opyranose, without separation purification, followed by
treatment with 10∶1 (V/V) DMF-H2O at 70 ℃ to af-
ford a mixture of 1,3,4,6-tetra-O-acetyl-α-D-talose (7)
and 1,2,4,6-tetra-O-acetyl-α-D-talose (8) in 94% yield
in a 1∶0.7 ratio. Compound 7 (54%) and 8 (40%) could
be separated by column chromatography on silical gel.
The relative configurations of 7 and 8 were determined
by examining relevant coupling constants and NOEs
from 1H NMR, and 1H,1H-COSY experiments.
Reagents and conditions: (a) NaOAc, Ac2O, 120 ℃, 94%; (b) 90%TFA,
66%; (c) (i) Tf2O, pyr, CH2Cl2; (ii) H2O/DMF, 70 ℃, 7 (54%), 8 (40%).
Scheme 3
Reagents and conditions: (a) Ac2O, pyr, quantitive; (b) CH3ONa, CH3OH,
quantitive.
pounds. It also has an important guiding significance for
the synthesis of other rare sugar compounds.
The structures of 7 and 8 were further confirmed by
acteylation with Ac2O in pyridine, both giving com-
pound 9 with the same NMR data. Zemplén deacetyla-
tion of 7 and 8 afforded D-talose as a mixture of ano-
mers (α,β-pyranoses and α,β-furanoses) in quantitive
yield (Scheme 3). The observed 13C NMR spectral data
were in agreement with standard substance of talose.
Experimental protocols
General methods
Solvents were purified in a conventional manner.
Thin layer chromatography (TLC) was performed on
pre-coated E. Merck silica gel 60 F254 plates. Flash
column chromatography was performed on silica gel
(200—300 mesh). Optical rotations were determined
1
with a Perkin-Elmer Model 241 MC polarimeter. H
Conclusion
NMR and 13C NMR spectra were taken on a JEOL
JNM-ECP 600 spectrometer with tetramethylsilane as
an internal standard. Mass spectra were recorded on a
Q-TOF Global mass spectrometer.
In summary, we developed a simple and efficient
method for the synthesis of D-talose from cheap and
readily available D-galactose (58% overall yield) in four
steps. This route also provided a method for the prepa-
ration of two intermediate compounds tetra-O-acetyl-D-
taloses 5 and 6 which could be converted to talose or as
a raw material for the synthesis of various chiral com-
Synthesis
1,3,4,6-Tetra-O-acetyl-α-D-galacotose (6) A so-
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Chin. J. Chem. 2010, 28, 1229—1232

Convenient Synthesis of D-Talose from D-Galactose
lution of 1,2,3,4,6-penta-O-acetyl-β-D-galacotose (5)31
(7.8 g, 20 mmol) in 90% trifluoroacetic acid aqueous
solution (50 mL) was stirred for 6 h. The reaction mix-
ture was diluted with CH2Cl2 (300 mL), washed with
H2O (100 mL×2), saturated aqueous NaHCO3 (100
mL×2), brine (100 mL×2), dried (Na2SO4) and con-
centrated. Isopropyl ether was added to the residue and
a white precipitate formed, the resultant solid was col-
lected by filtration and recrystallized with
EtOAc/petroleum ether to give 3 (4.6 g, 66.0%) as a
1 h at room temperature (r.t.). The solution was diluted
with CH2Cl2 (50 mL), washed with saturated NaHCO3
(20 mL×3), brine (20 mL×3), dried (Na2SO4), and
evaporated to give a residue, which was purified by sil-
ica gel column chromatography (3∶2, V∶V, petroleum
ether-EtOAc) to give 6 (330 mg, 100%) as a light yel-
low solid.
Starting from 1,2,4,6-tetra-O-acetyl-1-thio-α-D-
talose (8) (300 mg, 0.86 mmol) and using the same pro-
cedure as described above, compound 9 was also pre-
pared (330 mg, 100%). Rf＝0.38 [V(petroleum ether)∶
V(acetic ether)＝3∶2]; [α]2D5 ＋32.5 (c 0.1, CHCl3); 1H
NMR (CDCl3) δ: 6.16 (d, J＝1.9 Hz, 1H, H-1), 5.36 (t-
like, J＝1.9, 1.8 Hz, 1H, H-4), 5.32 (t-like, J＝3.7 Hz,
1H, H-3), 5.10 (t-like, J＝1.9 Hz, 1H, H-2), 4.34—4.31
(m, 1H, H-5), 4.19 (dd, J＝11.8, 6.9 Hz, 1H, H-6a),
4.16 (dd, J＝11.5, 6.9 Hz, 1H, H-6b), 2.16 (s, 6H,
CH3CO), 2.15, 2.05, 2.01 (s, 3H each, CH3CO); 13C
NMR (CDCl3) δ: 170.5, 169.8, 168.2, 91.5, 68.8, 66.4,
65.3, 65.2, 61.5, 21.0, 20.9, 20.7. HRESIMS calcd for
C16H22O11K 429.0799, found 429.0778.
1
white solid. [α]D25 ＋116.0 (c 0.1, CHCl3); H NMR
(CDCl3) δ: 6.31 (d, J＝3.7 Hz, 1H, H-1), 5.46 (t-like,
J＝1.8 Hz, 1H, H-4), 5.18 (dd, J＝10.5, 3.2 Hz, 1H,
H-3), 4.29—4.27 (m, 1H, H-5), 4.18 (dd, J＝10.6, 4.1
Hz, 1H, H-2), 4.12—4.06 (m, 2H, H-6a, H-6b), 2.19,
2.15, 2.07, 2.04 (s, 3H each, CH3CO). HRESIMS calcd
for C14H20O10Na 371.0954, found 371.0961.
1,3,4,6-Tetra-O-acetyl-α-D-talose (7) and 1,2,4,6-
tetra-O-acetyl-α-D-talose (8)
To a solution of
1,3,4,6-tetra-O-acetyl-α-D-galacotose (6) (3.5 g, 10
mmol) in distilled CH2Cl2 (60 mL) was added pyridine
(1.7 mL, 20 mmol). The reaction was cooled to －15
℃. Tf2O (1.8 mL, 11 mmol) was then added dropwise
over a 2 min period, and the reaction mixture was
stirred for 10 min. The reaction was concentrated under
high vacuum. The crude mixture was dissolved in 20
mL of DMF, then 2 mL of H2O was added, and the re-
action mixture was stirred for 24 h at 70 ℃. Then the
reaction mixture was concentrated under high vacuum
and purified by silica gel column chromatography (4∶1,
V∶V, petroleum ether-EtOAc) to give 7 (1.9 g, 54.3%)
and 8 (1.4 g, 40.0%) as white solid.
D-Talose
To a solution of 1,3,4,6-tetra-O-acetyl-α-D-talose (7)
and 1,2,4,6-tetra-O-acetyl-α-D-talose (8) (300 mg, 0.86
mmol) in DCM-MeOH (V∶V＝1∶3, 40 mL) was
added a catalytic amount of NaOMe (20 mg), the reac-
tion mixture was stirred at room temperature for 30 mi＋n,
then neutralized cautiously with Dowex 50×8 (H )
resin until pH＝7, filtered and concentrated under vac-
uum to give D-talose (158 mg, 100%). Crystallization
from EtOH gave material (a mixture of anomers) melt-
ing at 123—124 ℃ (Lit.26 mp. 126—127 ℃). 13C
NMR (D2O) δ: 103.4, 99.2, 97.4, 96.8, 85.2, 84.5, 78.4,
77.8, 74.5, 74.2, 73.9, 73.7, 73.5, 73.4, 73.3, 73.3, 72.3,
71.4, 71.1, 67.8, 65.4, 64.2, 63.9.
1
7: [α]2D5 ＋43.1 (c 0.1, CHCl3); H NMR (DMSO-d6)
δ: 5.90 (d, J＝2.2 Hz, 1H, H-1), 5.25 (d, J＝5.5 Hz, 1H,
2-OH), 5.23 (s, 1H, H-4), 5.02 (t, J＝3.8 Hz, 1H, H-3),
4.29 (td, J＝6.1, 1.1 Hz, 1H, H-5), 4.05 (dd, J＝6.6, 2.8
Hz, 2H, H-6a, H-6b), 3.76—3.75 (m, 1H, H-2), 2.10,
2.04, 1.99, 1.98 (s, 3H each, CH3CO×4); 13C NMR
(DMSO-d6) δ: 170.6, 170.5, 170.1, 169.3 (CH3CO×4),
94.3 (C-1), 69.2 (C-5), 67.7 (C-3), 66.4 (C-4), 65.7
(C-2), 62.0 (C-6), 21.4, 21.2, 21.1, 21.1 (CH3CO×4).
JH(1),C(1)＝175.6 Hz. HRESIMS calcd for C14H20O10Na
371.0954, found 371.0965.
Sample of D-talose 13C NMR (D2O) δ: 103.6, 99.2,
97.3, 96.8, 85.2, 84.6, 78.4, 77.9, 74.5, 74.2, 73.9, 73.7,
73.5, 73.4, 73.3, 73.3, 72.3, 71.4, 71.1, 67.8, 65.6, 65.4,
64.2, 63.9.
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8: [α]2D5 ＋28.9 (c 0.1, CHCl3); H NMR (DMSO-d6)
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