Facile, efficient, and enantiospecific syntheses of 1,1′-N-linked pseudodisaccharides as a new class of glycosidase inhibitors

Article abstract of DOI:10.1021/ja0470158

This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1′-N-linked pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first synthesis of 2 (consisting of two 2-epi-valienamines)

Full text of DOI:10.1021/ja0470158

Published on Web 11/19/2004
Facile, Efficient, and Enantiospecific Syntheses of
1,1′-N-Linked Pseudodisaccharides as a New Class of
Glycosidase Inhibitors
Tony K. M. Shing,*,† Connie S. K. Kwong,† Aries W. C. Cheung,†
Stanton H.-L. Kok,† Zhifeng Yu,‡ Jianmei Li,‡ and Christopher H. K. Cheng‡
Contribution from the Departments of Chemistry and Biochemistry,
The Chinese UniVersity of Hong Kong, Shatin, NT, Hong Kong
Received May 20, 2004; E-mail: tonyshing@cuhk.edu.hk
Abstract: This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1′-N-linked
pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first
synthesis of 2 (consisting of two 2-epi-valienamines) in 15 steps with an overall yield of 24% from (-)-
quinic acid. The synthesis involves a stereospecific palladium-catalyzed coupling reaction between an allylic
amine and an allylic chloride as the crucial step. The acetonide blocking groups were shown to be the best
hydroxyl protecting groups, compatible with the palladium-catalyzed allylic amination reaction that afforded
high yields of the 1,1′-N-linked pseudodisaccharides with a minimum amount of an elimination diene side
product.
Introduction
synthesis from (-)-quinic acid 3 have already produced
validamine,7 valiolamine and its diastereomers,8 valienamine,
The chemotherapeutic potential of sugar-mimic glycosidase
inhibitors1 as antidiabetic, anticancer, and antiviral agents has
been recognized and has stimulated demand for these com-
pounds.2 Valienamine3 is a natural amino pseudomonosaccharide
and an important component of the powerful R-D-glucosidase
inhibitor acarbose. Acarbose, an oral-active antidiabetic medi-
cine,4 contains three monosaccharides and one valienamine unit
linked together.5 In view of acarbose bioactivity, 1,1′-N-linked
pseudodisaccharides 1 (consisting of two valienamines) and 2
(consisting of two 2-epi-valienamines) are required for inves-
tigation as glycosidase inhibitors. Furthermore, these 1,1′-N-
linked pseudodisaccharides resemble trehalose (1,1-bis-R-D-
glucose) structurally and therefore are potential trehalase
inhibitors.1 Indeed, 1 was shown to be a strong inhibitor (IC50
3.85 × 10-8 M) against trehalase.6 The total synthesis of 1 had
been reported by Ogawa et al.,6 starting from a racemic Diels-
Alder (furan-acrylic acid) cycloadduct and involving an epoxide
opening with an amine as the key coupling step that proceeded
with poor regioselectivity. On the other hand, no synthesis of 2
has been published. Our endeavors in amino pseudosugar
and 2-epi-valienamine.9
The present article further demonstrates the versatility of this
avenue in the facile syntheses of 1,1′-N-linked pseudodisac-
charides 1 and 2, involving a stereospecific palladium-catalyzed
coupling reaction of an allylic chloride with an amine as the
key step.
† Department of Chemistry.
Results and Discussion
‡ Department of Biochemistry.
(1) (a) Ossork, A.; Elbein, A. D. Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, Germany,
2000; Part II, pp 513-531. (b) Bercecibar, A.; Grandjean, C.; Siriwardena,
A. Chem. ReV. 1999, 99, 779-844.
(2) (a) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R.
J. Phytochemistry 2001, 56, 265-295. (b) Asano, N.; Nash, R. J.; Molyneux,
R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645-1680.
(3) Horii, S.; Iwasa, T.; Mizuta, E.; Kameda, Y. J. Antibiot. 1971, 24, 59-63.
(4) British National Formulary, 2003, 46, 337.
(5) Junge, B.; Heiker, F. R.; Kurz, J.; Mu¨ller, L.; Hara, N.; Sugita, K.; Omura,
S. J. Antibiot. 1982, 35, 1234-1236.
(6) Ogawa, S.; Sato, K.; Miyamoto, Y. J. Chem. Soc., Perkin Trans. 1 1993,
691-696.
The route to 1,1′-bis-valienamine 1 is shown in Schemes 1
and 2. The enone 4 was readily obtained from (-)-quinic acid
3 in three steps.10 Regio- and stereoselective reduction of the
(7) Shing, T. K. M.; Tai, V. W.-F. J. Org. Chem. 1995, 60, 5332-5334.
(8) (a) Shing, T. K. M.; Wan, L. H. J. Org. Chem. 1996, 61, 8468-8479. (b)
Shing, T. K. M.; Wan, L. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1643-
1644.
(9) (a) Shing, T. K. M.; Li, T. Y.; Kok, S. H.-L. J. Org. Chem. 1999, 64,
1941-1946. (b) Kok, S. H.-L.; Lee, C. C.; Shing, T. K. M.; Li, T. Y. J.
Org. Chem. 2001, 66, 7184-7190.
9
15990
J. AM. CHEM. SOC. 2004, 126, 15990-15992
10.1021/ja0470158 CCC: $27.50 © 2004 American Chemical Society

Syntheses of 1,1
′
-N-Linked Pseudodisaccharides
A R T I C L E S
Scheme 1. Syntheses of Allylic Chloride 13 and Protected
Valienamine 15a
Table 1. Coupling Reactions Using Allylic Chlorides and Amine
with Other Protecting Groups
(%) yielda
allylic chloride
product
diene
i R ) Ac
ii R ) CONMe2
iii R ) MOM
v (42)
vi (50)
vii (57)
viii (38)
ix (30)
x (24)
a Reagents and conditions: Pd(dba)2, TMPP, CH3CN, 50 °C.
Palladium-catalyzed coupling reaction14 of allylic choride 13
with amine 15 using TMPP15 as the ligand proceeded smoothly
at room temperature, affording the desired pseudodisaccharide
16 in 78% yield and the undesired diene 17 in 15% yield. Other
protecting groups (acetate, carbamate, and MOM) at C-2, which
are shown in Table 1, were examined but gave inferior yields
(42-57%) of the disaccharides with increased amounts of the
corresponding diene (24-38%). The acetonide group in 15
induced the least steric hindrance and hence gave the best yield
of pseudodisaccharide 16. The formation of the diene side
a Reagents and conditions: (a) Three steps, 62%, see ref 10; (b) DIBALH,
THF, 0 °C, 78%; (c) 2 equiv of BzCl, pyridine, DMAP, room temperature,
95%; (d) RuCl3, NaIO4, EtOAc/CH3CN/H2O (3:3:1, v/v/v), 3 min, 0 °C,
94%; (e) 1 equiv of BzCl, pyridine, DMAP, room temperature, 99%; (f)
SOCl2, pyridine, CH2Cl2, 0 °C to room temperature, 85%; (g) TFA, CH2Cl2,
H2O, room temperature, 93%; (h) TBSOTf, Et3N, CH2Cl2, -78 °C; (i)
K2CO3, MeOH, room temperature; (j) 2,2-dimethoxypropane, p-TsOH,
CH2Cl2, room temperature, 65% from step h; (k) TBAF, THF, room
temperature, 90%; (l) PPh3, CCl4, reflux, 83%; (m) MsCl, Et3N, CH2Cl2, 0
°C to room temperature; (n) LiN3, DMF, reflux, 80% from step m; (o)
PPh3, NH3(aq), pyridine, room temperature, 90%.
product 17 is attributable to â-hydride syn-elimination,14
a
Scheme 2. Synthesis of 1,1′-bis-Valienamine 1a
rationalization supported by the absence of diene in the coupling
reaction of 28 (no syn-hydride). The (R)-configuration of the
N-linkage in 16 was confirmed by an X-ray analysis, and thus
the allylic substitution reaction occurred with retention of
configuration of the allylic chloride 13. Acidic hydrolysis then
afforded the target molecule 1,1′-N-linked pseudodisaccharide
1,6,16 which was also characterized as its octaacetate 18. The
a Reagents and conditions: (a) Pd(dba)2, TMPP, Et3N, CH3CN, room
temperature, 78%; (b) TFA, CH2Cl2, H2O, room temperature, 93%; (c)
Ac2O, pyridine, DMAP, room temperature, 89%.
1
specific rotation and H- and 13C NMR spectral data of 18 are
in agreement with those in the literature.6
The route to 1,1′-bis-2-epi-valienamine 2 is shown in Schemes
3 and 4. Our previous work9b has indicated that (-)-quinic acid
3 could be converted into alkene 19 in five steps. Benzoylation
of 19 afforded diester 20, which was dihydroxylated to give
R-diol 21. Regioselective esterification of 21 furnished triben-
zoate 22, which underwent dehydration according to our
protocol9a to give alkene 23. Deacetalization of acetal 23
afforded diol 24, which reacted with Viehe’s salt17 to form
chlorocarbamate 25. Debenzoylation of 25 furnished triol 26,
in which the 4,6-diol was acetalized to give 4,6-O-acetonide
27. The carbamate group was removed with DIBALH, and the
resulting diol was acetalized to give diacetonide 28. The
carbonyl groups in 4 afforded diol 5, which was esterified to
dibenzoate 6. Stereoselective flash dihydroxylation11 of the
alkene in 6 was controlled by the allylic â-benzoate, affording
the R-diol 7.
Regioselective benzoylation of the more reactive secondary
alcohol in 8 according to our protocol9a produced alkene 9,
which was hydrolyzed to form diol 10. Selective silylation of
the allylic alcohol in 10 followed by debenzoylation and then
acetonation of the liberated tetraol afforded diacetal silyl ether
11 in good overall yield. The silyl group in 11 was removed to
give allyl alcohol 12, which was converted into allylic chloride
13. On the other hand, 12 was mesylated, and the resulting
mesylate was displaced with LiN3 to give allylic azide 14.12
Staudinger13 reduction of the azide functionality in 14 furnished
the desired coupling partner allylic amine 15.12
(14) (a) Trost, B. M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881-6882. (b)
Geneˆt, J. P.; Balabane, M. Tetrahedron Lett. 1983, 24, 2745-2748. (c)
Heumann, A.; Re´glier, M. Tetrahedron 1995, 51, 975-1015. (d) Kim, K.
S.; Choi, S. O.; Park, J. M.; Lee, Y. J.; Kim, J. H. Tetrahedron: Asymmetry
2001, 12, 2649-2655. (e) Tsuji, J. Palladium Reagents and Catalysts-
InnoVations in Organic Synthesis, 2nd ed.; John Wiley: Chicester, U.K.,
1995; p 9.
(15) Verkade, J. G.; Huttermann, T. J.; Fung, M. K.; King, R. W. Inorg. Chem.
1965, 4, 83-87.
(16) Compound 1 was reported, but was not characterized by the authors. It
was characterized as its octaacetate 18; see ref 6.
(10) Alves, C.; Barros, M. T.; Maycock, C. D.; Venturea, M. R. Tetrahedron
1999, 55, 8443-8456.
(11) (a) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H. F.; Jiang,
Q. Chem.-Eur. J. 1996, 2, 50-57. (b) Shing, T. K. M.; Tai, V. W.-F.;
Tam, E. K. W. Angew. Chem., Int. Ed. Engl. 1994, 33, 2312-2313.
(12) Ogawa, S.; Shibata, Y. Carbohydr. Res. 1989, 189, 309-322.
(13) Gololobov, Yu. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahaedron 1989,
37, 437-472.
(17) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis; John
Wiley: New York, 1995; Vol. 3, pp 1719-1721.
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A R T I C L E S
Shing et al.
Scheme 3. Syntheses of Allylic Chloride 28 and Protected
2-epi-Valienamine 31a
Table 2. Inhibitory Activities (IC50) of 1 and 2 against
R-Glucosidase (Baker’s Yeast) and Trehalase (Rat Intestine)a
R-glucosidase
trehalase
compound 1
compound 2
7.9 × 10-6
M
M
0.017 × 10-6
M
M
400 × 10-6
>1000 × 10-6
a Activity of R-glucosidase was assayed using p-nitrophenyl R-D-
glucoside (1 mM final concentration) as the substrate in 50 mM sodium
phosphate buffer pH 6.7 at 30 °C for 30 min. Enzyme activity was
quantitated by measuring the absorbance at 405 nm. Trehalase activity was
assayed using trehalose (40 mM final concentration) in 100 mM potassium
phosphate buffer pH 6.3 at 37 °C for 30 min. Glucose concentrations were
determined by the glucose oxidase/peroxidase method.
reaction occurred with retention of configuration of the allylic
chloride 28. Deprotection of 32 furnished the target molecule
2 for the first time in 92% yield. The structure and stereochem-
istry of 2 were assigned from the COSY and NOESY spectra
and the stereochemistry at C-1 and C-2 from the coupling
constants (J1,2 ) 7.3; J2,3 ) 2.4 Hz).
Preliminary biological evaluation of 1 and 2 afforded their
inhibitory activities against R-glucosidase and trehalase and are
shown in Table 2. 1,1′-bis-Valienamine 1 (with configurations
at C-1 to C-4 that resemble those in D-glucose) is demonstrated
to be a moderate R-glucosidase inhibitor but a potent trehalase
inhibitor, whereas 2 (with configurations at C-1 to C-4 that
resemble those in D-mannose) is demonstrated to be an
insignificant inhibitor, indicating not only the structural but the
subtle configurational importance of glycosidase inhibitors. The
detailed biological evaluation of 1 and 2 toward these and other
glycosidases are under investigation and will be reported
elsewhere.
a Reagents and conditions: (a) Five steps, 63%, see ref 8b; (b) 2 equiv
of BzCl, DMAP, pyridine, 0 °C to room temperature, 90%; (c) OsO4, NMO,
acetone/H2O (4:1), room temperature, 99%; (d) 1 equiv of BzCl, DMAP,
pyridine, 0 °C to room temperature, 98%; (e) SOCl2, pyridine, CH2Cl2, 0
°C to room temperature, 92%; (f) TFA, H2O, CH2Cl2, room temperature,
98%; (g) (CH3)2N+ ) CCl2Cl- (Viehe’s salt), Et3N, CH2Cl2, reflux, 88%;
(h) K2CO3, MeOH, room temperature, 85%; (i) 2,2-dimethoxypropane,
p-TsOH, acetone, room temperature, 89%; (j) DIBALH, THF, 0 °C to room
temperature; (k) 2,2-dimethoxypropane, p-TsOH, acetone, room temperature,
79% from step j; (l) SOCl2, Et3N, CH2Cl2, 0 °C; (m) LiN3, DMF, room
temperature, 64% from step l; (n) K2CO3, MeOH, room temperature; (o)
2,2-dimethoxypropane, p-TsOH, acetone, room temperature, 87% from step
n; (p) PPh3, NH3(aq), pyridine, 99%.
Scheme 4. Synthesis of 1,1′-bis-2-epi-Valienamine 2a
Conclusion
An enantiospecific synthesis of 1,1′-bis-valienamine 1 and a
first synthesis of 1,1′-bis-2-epi-valienamine 2 were achieved in
14 and 15 steps from (-)-quinic acid 3 with overall yields of
12 and 24%, respectively. Intense research for the production
of other 1,1′-N-linked pseudodisaccharides for biological evalu-
ation according to this avenue is in progress.
a Reagents and conditions: (a) Pd(dba)2, TMPP, CH3CN, Et3N, room
temperature, 94%; (b) TFA, H2O, CH2Cl2, room temperature, 92%.
structure and stereochemistry of 28 were confirmed by an X-ray
analysis.
Acknowledgment. This work was supported by a CUHK
Direct Grant.
Toward the construction of its coupling partner, diol 24 was
converted into the corresponding cyclic sulfite, which then was
ring-opened with lithium azide to form allylic azide 29.
Debenzoylation of 29 followed by acetonation gave diacetonide
30, which underwent Staudinger reaction13 to give amine 31.
Palladium-catalyzed coupling reaction14 of allylic choride 28
with amine 31 afforded 1,1′-N-linked pseudodisaccharide 32
in trans-orientation of NH-1, and OR-2 is evident from the
coupling constants (J1,2 ) 6.6; J2,3 ) 2.1 Hz). Thus, the coupling
Supporting Information Available: Experimental procedures,
1H and 13C NMR spectra of all compounds (PDF), and X-ray
crystallographic structure of 5, 16, 27, and 28 (PDF and CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0470158
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15992 J. AM. CHEM. SOC. VOL. 126, NO. 49, 2004