Enantiospecific synthesis of pseudoacarviosin as a potential antidiabetic agent

Article abstract of DOI:10.1021/ol8010503

(Chemical Equation Presented) A pseudo-1,4′-N-linked disaccharide, pseudoacarviosin 5, was constructed via a key palladium-catalyzed coupling reaction of pseudoglycosyl chloride 8 (prepared from d-glucose via a novel direct intramolecular aldol addition i

Full text of DOI:10.1021/ol8010503

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3145-3148
Enantiospecific Synthesis of
Pseudoacarviosin as a Potential
Antidiabetic Agent
Tony K. M. Shing,*,†, Hau M. Cheng,† Wai F. Wong,† Connie S. K. Kwong,†
Jianmei Li,‡ Clara B. S. Lau,| Po Sing Leung,§ and Christopher H. K. Cheng*,‡,
Departments of Chemistry, Biochemistry, and Physiology, School of Pharmacy, and,
Center of NoVel Functional Molecules, The Chinese UniVersity of Hong Kong,
Shatin, Hong Kong, China
tonyshing@cuhk.edu.hk (synthesis); chkcheng@cuhk.edu.hk (bioeValuation)
Received May 7, 2008
ABSTRACT
A pseudo-1,4′-N-linked disaccharide, pseudoacarviosin 5, was constructed via a key palladium-catalyzed coupling reaction of pseudoglycosyl
chloride 8 (prepared from d-glucose via a novel direct intramolecular aldol addition in 12 steps) and pseudo-4-amino-4,6-dideoxy-r-d-glucose
9 (prepared from l-arabinose via an unusual trans-fused isoxazolidine-selective intramolecular nitrone-alkene cycloaddition in 11 steps).
Pseudoacarviosin 5 has been shown to be a potent inhibitor of r-glucosidases, particularly the intestinal mucosal enzymes sucrase and
glucoamylase of relevance to blood glucose control.
The therapeutic potential of sugar-mimetic glycosidase
inhibitors for the treatment of diabetes, obesity, lysosomal
storage diseases, cancer, and viral infections has stimulated
demand for these compounds.1 R-d-Glucosidase inhibitor
acarbose 1 is a natural product that contains the pseudoami-
nosugar valienamine 2 as an indispensable component2 for
its bioactivity (Figure 1). Acarbose 1 is an orally active agent
sold under the brand name Glucobay, Precose, or Prandase
for the treatment of type 2 diabetes either on its own or in
combination with other medications such as biguanides or
sulfonylureas.3 Hence, the design, synthesis, and bioevalu-
ation of new R-d-glucosidase inhibitors4 are highly warranted
in order to obtain improved and more potent compounds for
the treatment of hyperglycemia and related disorders.
Valienamine 2 itself is only a weak R-glucosidase inhibi-
tor.5 Its R-glucosidase inhibitory activity increases when it
is linked to a di- or trisaccharide moiety as in adiposin-1 3
and acarbose 1, respectively.6 On the other hand, methyl
acarviosin 4, obtained from the methanolysis of acarbose 1,
has been shown to exhibit stronger R-amylase inhibitory
activity than 1.7
† Department of Chemistry.
Methyl acarviosin 4 contains valienamine 2 linked to an
6-deoxy-R-d-glucoside residue. Replacing the latter with a
Center of Novel Functional Molecules.
‡ Department of Biochemistry.
| School of Pharmacy.
§ Department of Physiology.
(1) (a) de Melo, E. B; Gomes, A. da S.; Carvalho, I, Tetrahedron 2006,
62, 10277–10302. (b) Asano, N. Glycobiology 2003, 13, 93R–104R.
(2) Chen, X.; Zheng, Y.; Shen, Y. Biotechnol. Prog. 2005, 21, 1002–
1003.
(3) Br. Nat. Formulary 2007, 53, 365.
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(5) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y Chem. ReV. 2003, 103, 1955–
1978, and references cited therein.
10.1021/ol8010503 CCC: $40.75
Published on Web 06/17/2008
2008 American Chemical Society

Figure 2. Retrosynthesis of pseudoacarviosin 5.
4-amino-4,6-dideoxy sugars, the right-hand portion of the
target molecule.6b This paper discloses a novel approach
toward 9 via an unusual trans-fused isoxazolidine-selective
intramolecular nitrone-alkene cycloaddition (INAC)12 as the
key step (Scheme 1). Thus, trans-diacetal 10 was readily
Figure 1. Structural relationship among acarbose, R-d-glucose,
acarviosins, and pseudo-1,4′-N-linked disaccharides.
pseudoglucose moiety provides pseudoacarviosin 5, a pseudo-
1,4′-N-linked disaccharide with an R-d-gluco-configuration
(except for the alkene C-5 carbon, carbohydrate numbering).
Pseudoacarviosin 5 is a novel molecule that has not been
considered or exploited as a glucosidase inhibitor. We
postulated that 5 would be a more stable R-d-glucosidase
inhibitor than 4 because the C-1′ in 5 is no longer an
anomeric center and the OH-1′ configuration is therefore
fixed and does not epimerize; hence, 5 is permanently locked
in an R-d-glucosyl configuration. In contrast, the C-1′
glucosidic bond in 4 (and in acarbose) is prone to acid
hydrolysis in the stomach, affording acarviosin 6. It is not
stable in its pyranose form and readily generates tricyclic
compound 7,7 which does not produce the desired inhibitory
effect.8 The stability of 5 toward acid hydrolysis would
produce a more sustained enzyme inhibition profile than 4.
Indeed, the newly synthesized pseudoacarviosin 5, with half
the molecular weight of acarbose, is shown in the present
study to be a potent inhibitor of R-d-glucosidases of relevance
to blood glucose level control, particularly toward the
intestinal mucosal enzyme sucrase and glucoamylase.
The key step in the retrosynthesis of the target pseudoac-
arviosin 5 is the palladium-catalyzed coupling reaction9
between the protected pseudoglycosyl chloride 8 and pseudo-
4-amino-4,6-dideoxy-R-d-glucopyranose 9, leading to the
formation of the N-linkage (Figure 2). We have previously
synthesized pseudosugars on the basis of transformation from
(-)-quinic acid.9,10 In the present investigation, we reveal
efficient and innovative synthetic avenues for pseudosugar
derivatives 8 and 9 from d-glucose and l-arabinose, respec-
tively, the supply of which is inexpensive and virtually
unlimited.11
Scheme 1
obtained from l-arabinose in four steps with 56% overall
yield according to our recent endeavor.13 Oxidative Vic-diol
cleavage14 of 10 followed by reaction with BnNHOH
generated nitrone 11 quantitatively. INAC of nitrone 11 gave,
inter alia, the desired trans-fused isoxazolidine 12 in 43%
isolated yield. The stereoselective formation of the trans-
fused isoxazolidine 12 along with lesser amounts of three
other stereoisomers, controlled by the trans-diacetal blocking
group of the nitrone,12 is noteworthy because nitrones with
cis-acetonides and with benzyl protecting groups generally
afford cis-fused isoxazolidines.15 The structure of 12 was
confirmed by X-ray crystallography. Silylation of 12 pro-
vided silyl ether 13 that underwent hydrogenolysis of the
(10) (a) Kok, S. H.-L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem. 2001,
66, 7184–7190. (b) Shing, T. K. M.; Li, T. Y.; Kok, S. H. L. J. Org. Chem.
1999, 64, 1941–1946. (c) Shing, T. K. M.; Wan, L. H. J. Org. Chem. 1996,
61, 8468–8479. (d) Shing, T. K. M.; Tai, V. W.-F. J. Org. Chem. 1995,
60, 5332–5334.
The synthesis of the coupling precursor 9 is presented first.
There has been no report on synthetic studies toward pseudo-
(11) (-)-Quinic acid is in short supply for the synthesis of Tamiflu;
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3146
Org. Lett., Vol. 10, No. 14, 2008

N-O linkage and the N-benzyl group to give amino alcohol
14 efficiently. Regioselective mesylation16 of the hydroxyl
group in 14 followed by hydride displacement of the resultant
mesylate gave 9 in 90% overall yield from 14. Hence, the
coupling precursor 9 was made from l-arabinose in 11 steps
with an overall yield of 21%.
Synthesis of pseudoglycosyl chloride 8, the left-hand
portion of the target molecule, was accomplished by a novel
carbocyclization of d-glucose involving a direct intramo-
lecular aldol addition as the key step. Glycosidation of
d-glucose produced a mixture of R- and ꢀ-d-allyl pyranosides
that were trans-2,3-O-acetalized17 and then 4,6-O-isopro-
pylidenated to give the fully protected glycosides 15 in 43%
overall yield (Scheme 2). Palladium-catalyzed deallylation18
in fact the first report of a direct intramolecular aldol addition
of a ketone(acceptor)-ketone(donor) derived from d-glucose.
The structure of 19 was confirmed by X-ray crystallography.
21
Elimination of the tertiary alcohol in 19 with POCl3
afforded enone 20 almost quantitatively. Luche reduction22
of enone 20 provided a mixture of diastereomeric allylic
alcohols which were acetylated to give a mixture of acetates,
separable on chromatography. Thus, ꢀ-acetate 21 was
isolated pure in 82% overall yield from enone 20. Deacety-
lation of 21 gave ꢀ-alcohol 22 in excellent yield. Mesylation
of 22 followed by nucleophilic displacement with tetrabu-
tylammonium chloride provided the desired R-allylic chloride
8 smoothly. The protected pseudoglycosyl chloride 8 was
thus synthesized from d-glucose in 12 steps with an overall
yield of 16.9%.
Palladium-catalyzed coupling reaction23 of allylic chloride
8 and amine 9 produced a pseudo-1,4-aminodisaccharide in
84% yield. Three equivalents of amine 9 were required in
order to give good yields of the adduct, and fortunately, most
of the excess amine 9 was recovered. Our previous work9
has already optimized the reaction conditions on similar
substrates and reported that acetal blocking groups were ideal
Scheme 2
for this type of reaction that proceeded with retention23 of
1
configuration. The H NMR spectrum of 23 displays J1,2
)
5.1 Hz and J2,3 ) 10.8 Hz, indicating that H1 and H2 are
still cis-disposed after the coupling reaction and the structure
is therefore assigned as protected pseudoacarviosin 23.
Complete deprotection of 23 was achieved in one step under
mild acid hydrolysis to give the target compound 5 which
was characterized as its corresponding heptaacetate 24.
Pseudoacarviosin 5 was thus made from d-glucose in 14 steps
with 12.7% overall yield.
Pseudoacarviosin 5 was demonstrated to exhibit strong
inhibitory actions against various R-glucosidases including
R-amylase from human saliva and R-glucosidases (maltase,
sucrase, isomaltase, glucoamylase) from the small intestine
of rat. Enzyme inhibition by 5 was in a dose-dependent
manner, and the order of inhibition on the enzymes was
glucoamylase > sucrase > maltase > R-amylase > isoma-
ltase. Inhibition toward sucrase and glucoamylase was
particularly potent, with IC50 values of 3.9 × 10-7 M and
1.2 × 10-7 M, respectively (Table 1). Compared with
acarbose 1, pseudoacarviosin 5 is a better sucrase inhibitor.
Inhibition of sucrase by pseudoacarviosin 5 was demonstrated
to be reversible by simple dilution and dialysis. Preliminary
in vivo studies on diabetic rats indicates that 5 is an orally
active specific inhibitor of R-glucosidases and exhibits more
potent effect than acarbose in sucrose loading test and could
significantly lower increase in blood glucose level of diabetic
of glycosides 15 furnished lactols 16 that were subjected to
Grignard methyl addition to give the diols 17 efficiently.
Oxidation of 17 furnished 1,5-diketone 18 that underwent
l-proline-catalyzed intramolecular aldol addition19,20 to gen-
erate ꢀ-hydroxyl ketone 19 smoothly in 82% yield. This is
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Org. Lett., Vol. 10, No. 14, 2008
3147

novel transformation of carbohydrates into carbocycles,
especially the ketone-ketone intramolecular direct aldol
addition, could be exploited for a wide range of function-
alized cyclohexenoid or cyclohexanoid targets and intermedi-
ates of pharmaceutical importance, including a new synthesis
of Tamiflu,11 which is a functionalized cyclohexene used in
the treatment of avian flu.
Table 1. IC50 Values (Expressed in M) of the Inhibition of
Digestive Enzymes by Pseudoacarviosin 5 As Compared with
Acarbose 1
enzyme
pseudoacarviosin 5
acarbose 1
R-amylase
maltase
sucrase
trehalase
isomaltase
glucoamylase
5.1 × 10-5
1.6 × 10-5
3.9 × 10-7
no inhibition
1.3 × 10-4
1.2 × 10-7
2.5 × 10-6
2.7 × 10-6
0.9 × 10-6
no inhibition
1.0 × 10-4
1.6 × 10-7
Acknowledgment. This work was supported by a Strategic
Investments Scheme administered by the Center of Novel
Functional Molecules of The Chinese University of Hong
Kong. The provision of direct grants and graduate student-
ships from The Chinese University of Hong Kong is also
acknowledged.
rats even at 0.02 mg/kg. Investigation is still underway and
the results will be published in a full paper.
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
In conclusion, the results suggest that 5 could be used in
the treatment of type 2 diabetes by lowering postprandial
blood glucose level. It is particularly useful in inhibiting the
digestion of table sugar, and provides an important lead for
the design of antidiabetic drugs in view of the importance
of postprandial glycemic control in the pathological develop-
ment of diabetes.24 The synthetic chemistry that involves
OL8010503
(24) (a) Blondel, O.; Bailbe, D.; Portha, B. Diabetes 1989, 38, 610–
617. (b) Li, J. M.; Che, C. T.; Lau, C. B. S.; Leung, P. S.; Cheng, C. H. K.
J. Pharmacol. Exp. Ther. 2007, 320, 38–46.
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