Efficient synthesis of the glucosidase inhibitor blintol, the selenium analogue of the naturally occurring glycosidase inhibitor salacinol

Article abstract of DOI:10.1021/jo048058+

(Chemical Equation Presented) An efficient synthesis of blintol, the selenium congener of the naturally occurring glycosidase inhibitor salacinol, and a potent glucosidase inhibitor itself, is described. Unlike our previously reported synthesis, this impr

Full text of DOI:10.1021/jo048058+

In the search for novel glycosidase inhibitors, we have
also reported the synthesis and glycosidase inhibitory
properties of the heteroatom congeners of salacinol in
which the ring sulfur atom has been substituted by the
cognate atoms nitrogen and selenium.5,6 The structure-
activity studies revealed different inhibitory activities of
these compounds against different glycosidase enzymes.5,6
Significantly, the selenium analogue, blintol, has been
shown to be very effective in controlling blood glucose
levels in rats after a carbohydrate meal, thus providing
a lead candidate for the treatment of Type 2 diabetes.7
This agent acts by inhibiting the membrane-bound glu-
cosidase enzymes in the small intestine that break down
oligosaccharides to glucose.7 The extended study of the
effectiveness and toxicities of these types of compounds
in animal models demands more efficient and economical
synthetic routes. Toward this end, we have already
reported an optimized synthesis of salacinol (1).8 We now
report an efficient method for the synthesis of the
selenium congener, blintol (2). Unlike our previously
reported synthesis,6 the present route makes use of
p-methoxybenzyl ether protecting groups on the selenium
heterocycle and D-glucose instead of L-glucose for the
synthesis of the other reacting partner, a cyclic sulfate.
Retrosynthetic analysis indicated that blintol (2) could
be obtained by alkylation of anhydroseleno-D-arabinitol
(3) at the ring heteroatom using an appropriately pro-
tected cyclic sulfate (4) (Scheme 1).3
The previously reported synthesis of blintol (2) used
benzyl ethers as the protecting groups for the hydroxyl
groups on the anhydroseleno-D-arabinitol 3.6 However,
the deprotection of the benzyl-protected blintol (2) by
hydrogenolysis was problematic due to the poisoning of
the palladium catalyst by small amounts of the seleno-
ether 3 formed in the reaction mixture.
Efficient Synthesis of the Glucosidase
Inhibitor Blintol, the Selenium Analogue of
the Naturally Occurring Glycosidase
Inhibitor Salacinol
Hui Liu and B. Mario Pinto*
Department of Chemistry, Simon Fraser University,
Burnaby, B.C., Canada V5A 1S6
bpinto@sfu.ca
Received November 1, 2004
An efficient synthesis of blintol, the selenium congener of
the naturally occurring glycosidase inhibitor salacinol, and
a potent glucosidase inhibitor itself, is described. Unlike our
previously reported synthesis, this improved route makes
use of p-methoxybenzyl ether protecting groups in the
synthesis of one of the two key intermediates, 2,3,5-tri-O-
p-methoxybenzyl-1,4-anhydro-4-seleno-D-arabinitol, from L-
xylose. The other key intermediate, 2,4-O-benzylidene-L-
erythritol-1,3-cyclic sulfate, was successfully prepared from
D-glucose instead of the expensive L-glucose. All protecting
groups in the resulting adducts were removed with trifluo-
roacetic acid to yield a mixture of stereoisomers, thereby
obviating the problematic deprotection of benzyl ethers by
hydrogenolysis. The major stereoisomer, blintol, was then
obtained by fractional crystallization.
To eliminate the problematic hydrogenolysis step, the
use of p-methoxybenzyl (PMB) protecting groups on the
seleno-D-arabinitol, as in our optimized synthesis of
salacinol (1) and the synthesis of 1,4-anhydro-4-thio-D-
ribitol,8 was considered. Thus, the reaction of the p-
methoxybenzyl-protected selenoether 4 with the ben-
zylidene-protected L-erythritol-1,3-cyclic sulfate (5; R )
benzylidene) was envisioned. Since both PMB and ben-
zylidene protecting groups are labile to acidic hydrolysis,
the removal of all protecting groups by acid hydrolysis
would be facile.8
Salacinol (1), a potent glycosidase inhibitor isolated
from the aqueous extracts of Salacia reticulata that are
used in Sri Lanka and India for the treatment of diabetes,
has generated a lot of attention recently.1-3 The unique
structure of salacinol is a sulfonium ion (1,4-anhydro-4-
thio-D-pentitol cation) stabilized by an internal sulfate
counterion (1-deoxy-L-erythroxyl-3-sulfate anion). This
glycosidase inhibitor is presumably a mimic of the
oxacarbenium-ion intermediate in glycosidase-mediated
hydrolysis reactions. We and others have previously
reported the synthesis of salacinol and its stereoisomers.2-4
The synthesis of the PMB-protected anhydroseleno-D-
arabinitol (3) from L-xylose (6) required the judicious
choice of aglycon. Initial attempts to use the allyl
glycosides yielded an inseparable mixture of the desired
* To whom correspondence should be addressed. Tel: (604) 291-
4327. Fax: (604) 291-3765.
(1) (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.;
Yamahara, J. Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38,
8367-8370. (b) Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda,
H. Chem. Pharm. Bull. 1998, 46, 1339-1340. (c) Muraoka, O.; Ying,
S.; Yoshikai, K.; Matsuura, Y.; Yamada, E.; Minematsu, T.; Tanabe,
H.; Matsuda, H.; Yoshikawa, M. Chem. Pharm. Bull. 2001, 49, 1503-
1505. (d) Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.;
Muraoka, O. Bioog Med. Chem. 2002, 10, 1547-1554.
(2) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000,
41, 6615-6618.
(5) Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2001, 123, 6268-6271.
(6) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2002, 124, 8245-8250.
(7) (a) Pinto, B. M.; Johnston, B. D.; Ghavami, A.; Szczepina, M. G.
US Provisional Patent, filed June 25, 2003. (b) Pinto, B. M.; Johnston,
B. D.; Ghavami, A.; Szczepina, M. G.; Liu, H.; Sadalapure, K. US
Patent, filed June 25, 2004.
(8) (a) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.;
Snider, B. B.; Pinto, B. M. Synlett 2003, 1259-1262. (b) Minakawa,
N.; Kato, Y.; Uetake, K.; Kaga, D.; Matsuda, A. Tetrahedron 2003,
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(3) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001,
66, 2312-2317.
(4) Ghavami, A.; Johnston, B. D.; Maddess, M. D. Chinapoo, S. M.;
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942.
10.1021/jo048058+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/23/2004
J. Org. Chem. 2005, 70, 753-755
753

SCHEME 1
SCHEME 3
SCHEME 2
SCHEME 4
allyl xylofuranosides and undesired allyl xylopyranosides.7a
Furthermore, the cleavage of the allyl group was judged
to be too expensive a process for large-scale synthesis.
Nevertheless, the mixture of furanosides and pyranosides
was used in the successful synthesis of blintol (2), their
separation being effected at a later stage in the synthetic
scheme.8
These concerns led us to explore the following strat-
egy: (1) The use of n-pentenyl glycosides, first exploited
by Fraser-Reid and co-workers:9 this group was also
reported to be cleaved by NBS without affecting the PMB
groups.10 (2) The use of boric acid in the acid-catalyzed
acetylation of L-xylose (6) to improve the furanoside-to-
pyranoside ratio.11 The latter procedure led to the
conversion of L-xylose (6) to 1,2,3,5-tetra-O-acetyl-D-
xylofuranose (7) in a two-step, one-pot procedure. Analy-
Another problem in the synthesis of blintol (2) (and
the optimized synthesis of salacinol7) is the availability
of 2,4-O-benzylidene-L-erythritol-1,3-cyclic sulfate (15).
This compound was previously prepared from L-glucose.3
However, due to the high cost of L-glucose and the fact
that it was the starting material in a six-step synthetic
route, it was critical to prepare the cyclic sulfate 15 from
a less expensive material. We report here the preparation
of compound 15 from D-glucose (16).
1
sis of the H and 13C NMR spectra indicated that the
furanosides 7 were formed exclusively without formation
of the undesired pyranoside side products (Scheme 2).
Compound 7 was then treated with 4-penten-1-ol and
BF3‚OEt2 to give the 4-pentenyl 2,3,5-tri-O-acetyl-L-
xylofuranosides (8).12 This compound underwent acidic
hydrolysis to cleave the acetyl groups, followed by the
reprotection of the three hydroxyl groups with PMB
groups, to afford the 4-pentenyl 2,3,5-tri-O-p-methoxy-
benzyl-L-xylofuranosides (10). The anomeric hydroxyl
group of 10 was then released using NBS in acetonitrile-
water to yield the corresponding 2,3,5-tri-O-p-methoxy-
benzyl-L-xylofuranose (11). The 2,3,5-tri-O-p-methoxy-
benzyl-L-xylofuranose 11 was reduced to the corresponding
xylitol 12 by NaBH4; mesylation of the hydroxyl groups
then gave the dimesylate 13. Compound 13 was then
converted to the 1,4-anhydro-2,3,5-tri-O-p-methoxyben-
zyl-4-seleno-D-arabinitol (14) in 83% yield, using sodium
selenide, generated in situ, from selenium metal and
sodium borohydride in ethanol (Scheme 3).
Using our previously reported method,3,6 the benzyl-
protected cyclic sulfate 20 was prepared from D-glucose
(16). It is interesting to note that cleavage of the
benzylidene protecting group in compound 17 was
achieved with 60% TFA at room temperature for 30 min
to afford the corresponding diol 18 in a comparable yield
to that obtained with aqueous acetic acid. Since the
original method involved refluxing compound 17 in 80%
HOAc for 48 h, this modification proved to be more
efficient. Compound 20 underwent hydrogenolysis to
afford the unprotected cyclic sulfate 21. Installation of
the benzylidene acetal using pyridinium p-toluene-
sulfonate (PPTS) as the catalyst was the critical step
since, under these conditions, the cyclic sulfate was not
cleaved. The desired benzylidene-protected cyclic sulfate
15 was obtained in 71% yield (Scheme 4).
The coupling reaction of the anhydroseleno-D-arabinitol
14 with the cyclic sulfate 15 in 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) at 60-65 °C proceeded smoothly in 7 h
to give a mixture of the 2,3,5-tri-O-p-methoxybenzylse-
lenonium salts 22 in 95% yield (Scheme 5). The choice of
HFIP as a solvent was based on our previous work.6,8a
(9) Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Chem. Soc., Chem.
Commun. 1987, 1462-1463.
(10) Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988,
110, 2662-2663.
(11) Furneaux, R. H.; Rendle, P. M.; Sims, I. M. J. Chem. Soc.,
Perkin Trans. 1 2000, 2011-2014.
(12) Gurjar, M. K.; Reddy, L. K.; Hotha, S. J. Org. Chem. 2001, 66,
4657-4660.
1
Analysis of the H and 13C NMR spectra indicated that
754 J. Org. Chem., Vol. 70, No. 2, 2005

pound 22 was produced as a 7:1 mixture of isomers at the
stereogenic selenium center. The major isomer was assigned to
be the isomer with a trans relationship between C-5 and C-1′
by analogy to the results obtained previously for the correspond-
ing benzyl-protected selenonium salt. For trans-22: 1H NMR
(600 MHz, CD2Cl2) δ 7.45-6.80 (17H, m, Ar), 5.58 (1H, s,
C6H5CH), 4.51 (1H, dd, J2′,3 ) J3′,4′ax ) 9.7, J3′,4′eq ) 5.3 Hz, H-3′),
4.48 (1H, br s, H-2), 4.46 (1H, dd, J4′ax,4′eq ) 10.5 Hz, H-4′eq),
SCHEME 5
4.41, 4.33 (2H, 2d, JA,B ) 11.1 Hz, CH2Ph), 4.57 (2H, 2d, JA,B
)
11.3 Hz, CH2Ph), 4.43 and 4.40 (2H, 2d, JA,B ) 12.0 Hz, CH2-
Ph), 4.39 and 4.26 (2H, 2d, JA,B ) 11.4 Hz, CH2Ph), 4.32 (1H,
dd, J1′a,2 ) 2.2 Hz, H-1′a), 4.27 (1H, br d, J2,3 ) 2.0 Hz, H-3),
4.25 and 4.19 (2H, 2d, JA,B ) 10.8 Hz, CH2Ph), 4.21 (1H, ddd,
H-2′), 4.04 (1H, br d, J1,2 < 1 Hz, H-1a), 4.03 (1H, br dd, J3,4
<
1 Hz, H-4), 3.90 (1H, dd, J1′a,1′ ) 12.2, J1′b,2 ) 3.6 Hz, H-4), 3.78
(3H, s, OCH3), 3.77 (1H, dd, H-4′ax), 3.77 (3H, s, OCH3), 3.76
(3H, s, OCH3), 3.55 (1H, dd, J1a,1b ) 12.8, J1b,2 ) 2.9 Hz, H-1b),
3.54(1H, dd, J5a,5b ) 9.7, J4,5a ) 6.7 Hz, H-5a), 3.48 (1H, dd, J4,5b
) 9.4 Hz, H-5b); 13C NMR (150 MHz, CDCl2): δ 160.34, 160.09,
136.58 and 130.14-126.51 (21 CAr), 114.56, 114.47 and 114.70
(3 × Cipso, OMBn), 102.17 (PHCH), 84.31 (C-3), 83.00 (C-2), 77.30
(C-2), 73.37, 72.49, and 72.10 (3 × CH2Ph), 69.67 (C-4′), 67.75
(C-3′), 66.80 (2 × C, C-4, C-5), 55.67 (3 × C, 3 × OCH3), 48.73
(C-1′), 46.69 (C-1). Anal. Calcd for C40H46O12SSe: C, 57.90; H,
5.59. Found: C, 57.87; H, 5.57.
Procedure for the Synthesis of 1,4-Dideoxy-1,4-[[(2S,3S)-
2,4-dihydroxy-3-(sulfooxy)butyl]episelenoniumylidene]-D-
arabinitol Inner Salt (Blintol, 2). The selenonium salts 22
(3.80 g, 4.58 mmol) were dissolved in cold trifluoroacetic acid
(40 mL) to give a purple solution. Water (4.0 mL) was added,
and the reaction mixture was kept at room temperature for 0.5
h. The solvents were removed on a rotary evaporator, and the
residue was triturated with CH2Cl2 (4 × 50 mL), with each
portion of solvent being decanted from the insoluble gummy
product. The crude product was dissolved in water (50 mL) and
filtered to remove a small amount of insoluble material. The
aqueous filtrate was concentrated to a syrupy residue (1.84 g).
Analysis by NMR spectroscopy indicated that the product was
an isomeric mixture (7:1) of 2 with its stereoisomer at the
selenium center. Recrystallization from MeOH gave pure 2 (1.09
g, 62%) in two crops. This material was identical in all respects
to that obtained previously6 using hydrogenolysis to remove the
benzyl protecting groups. Purification of the mother liquor
fractions by column chromatography (EtOAc/MeOH/H2O, 6:3:
1) gave a 3:2 mixture of 2 with its isomer (0.25 g, 14%) as a
syrup.
compound 22 was a 7:1 mixture of isomers at the
stereogenic selenium center. The major isomer was
assigned to that with a trans relationship between C-5
and C-1′, as described previously.6
The selenonium salts 22 were subsequently depro-
tected by treatment with trifluoroacetic acid (TFA) and
purified by recrystallization to afford pure blintol (2) in
62% yield (Scheme 5). The isomers were configurationally
stable.6
In conclusion, an improved synthesis of p-methoxy-
benzyl-protected 1,4-anhydro-4-seleno-D-arabinitol (14)
was achieved. Another key intermediate in the synthesis
of blintol (2), namely 2,4-O-benzylidene-L-erythritol-1,3-
cyclic sulfate (15), was successfully prepared from D-
glucose instead of expensive L-glucose. The coupling of
14 and 15 in HFIP was extremely efficient and amenable
to the large-scale synthesis of blintol (2).
Experimental Section
Procedure for the Synthesis of 2,3,5-Tri-O-p-methoxy-
benzyl-1,4-dideoxy-1,4-[[(2S,3S)-2,4-benzylidenedioxy-3-
(sulfooxy)butyl]episelenoniumylidene]-D-arabinitol Inner
Salt (22). The seleno-D-arabinitol 14 (3.11 g, 5.59 mmol), the
cyclic sulfate 15 (1.33 g, 4.88 mmol), and K2CO3 (160 mg, 1.16
mmol) were added to 1,1,1,3,3,3-hexafluoro-2-propanol (8.0 mL),
and the mixture was stirred in a sealed tube with heating at
60-65 °C for 7 h. Periodic analysis by TLC (EtOAc/MeOH, 10:
1) showed that the reaction proceeded smoothly until the
selenoether had been consumed leaving some cyclic sulfate
unreacted. The mixture was cooled and filtered through Celite
with the aid of CH2Cl2. The solvents were removed, and the
residue was purified by column chromatography (gradient of
EtOAc to EtOAc/MeOH, 10:1). The selenonium salt 22 (3.85 g,
95% based on selenoether 14) was obtained as a colorless foam.
Analysis of the 1H and 13C NMR spectra indicated that com-
Acknowledgment. We are grateful to University
Medical Discoveries, Inc., for financial support.
Supporting Information Available: Complete experi-
mental details for the synthesis of 14 from 6 and of 15 from
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO048058+
J. Org. Chem, Vol. 70, No. 2, 2005 755