Synthesis of a sulfonium ion analogue of the glycosidase inhibitor swainsonine

Article abstract of DOI:10.1021/jo052111s

The synthesis of a bicyclic sulfonium ion analogue of a naturally occurring indolizidine alkaloid, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multistep synthesis starting from (2S,3S,4R)-2,3-d

Full text of DOI:10.1021/jo052111s

enzyme-catalyzed hydrolysis reaction, thus making them good
glycosidase inhibitors.11,12 It is proposed that such inhibitors
carry a positive charge at physiological pH, thus providing the
stabilizing electrostatic interactions between the inhibitor and
the carboxylate residues in the enzyme active site.13
Synthesis of a Sulfonium Ion Analogue of the
Glycosidase Inhibitor Swainsonine
Nag S. Kumar and B. Mario Pinto*
An alternative means of achieving the required charge state
to provide such electrostatic interactions would be with com-
pounds that bear a permanent positive charge at a suitable
position, for example, with compounds that bear a positively
charged sulfur atom. Thus, we have described the synthesis,
free and enzyme-bound conformations, and glycosidase inhibi-
tory activity (albeit weak) of a sulfonium ion analogue (3) of
castanospermine (2).14,15 This concept was also exploited by
Siriwardena and co-workers,16-18 who have recently reported
the synthesis of the sulfonium salt 4, a potent inhibitor of several
mannosidases with selectivity greater than that of swainsonine
(1).18
Department of Chemistry, Simon Fraser UniVersity,
Burnaby, British Columbia, Canada V5A 1S6
bpinto@sfu.ca
ReceiVed October 9, 2005
The synthesis of a bicyclic sulfonium ion analogue of a
naturally occurring indolizidine alkaloid, swainsonine, in
which the bridgehead nitrogen atom is replaced by a
sulfonium ion, has been achieved by a multistep synthesis
starting from (2S,3S,4R)-2,3-dibenzyloxy-4-formaldehyde-
thiolane. The synthetic strategy relies on the intramolecular
displacement of a leaving group on a pendant acyclic chain
by a cyclic thioether. This bicyclic sulfonium salt provides
a candidate with which to further probe the hypothesis that
a sulfonium salt carrying a permanent positive charge would
be an effective glycosidase inhibitor.
In addition, the discovery of a new class of glycosidase
inhibitors, namely, salacinol (5) and kotalanol (6) from Salacia
reticulata, with intriguing inner-salt sulfonium sulfate struc-
tures19-21 has led to significant synthetic efforts to derive
Cell surface oligosaccharides play an important role in
intercellular recognition processes, and their modification has
been implicated in disease states such as cancer.1-7 Inhibition
of the glycosidase enzymes involved in oligosaccharide process-
ing of glycoproteins by natural or synthetic inhibitors might
lead to therapeutic strategies for the treatment of viral infections,
cancer, and other disorders.3,4 For instance, swainsonine (1), a
plant-derived indolizidine alkaloid, is an inhibitor of Golgi
R-mannosidase II (GMII), a key enzyme in the N-glycosylation
pathway, has been shown to reduce tumor mass in human
patients with advanced malignancies, and is a potential drug
therapy for patients suffering from breast, liver, and lung cancer
and other malignancies.8-10 Naturally occurring glycosidase
inhibitors of the indolizidine alkaloid class, such as swainsonine
(1) and castanospermine (2), are postulated to mimic the shape
and charge of the oxacarbenium-like transition state for the
(8) Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin. Cancer Res.
1997, 3, 1077-1086.
(9) Mohla, S.; White, S.; Grzegorzewski, K.; Nielsen, D.; Dunston, G.;
Dickson, L.; Cha, J. K.; Asseffa, A.; Olden, K. Anticancer Res. 1990, 10,
1515-1522.
(10) Goss, P. E.; Baptiste, J.; Fernandes, B.; Baker, M.; Dennis, J. W.
Cancer Res. 1994, 54, 450-1457.
(11) McCarter, J. D.; Withers, S. G. Curr. Opin. Struct. Biol. 1994, 4,
885-892.
(12) Ly, H. D.; Withers, S. G. Annu. ReV. Biochem. 1999, 68, 487-
522.
(13) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH: Weinheim, New York, 1999.
(14) Svansson, L.; Johnston, B. D.; Gu, J.-H.; Patrick, B.; Pinto, B. M.
J. Am. Chem. Soc. 2000, 122, 10769-10775.
(15) Johnson, M. A.; Jensen, M. T.; Svensson, B.; Pinto, B. M. J. Am.
Chem. Soc. 2003, 125, 5663-5670.
(16) Siriwardena, A. H.; Chiaroni, A.; Riche, C.; El-Daher, S.; Win-
chester, B.; Greirson, D. S. J. Chem. Soc., Chem. Commun. 1992, 1531-
1533.
* To whom correspondence should be addressed. Tel: (604) 291-4152. Fax:
(604) 291-4860.
(1) Holman, R. R.; Cull, C. A.; Turner, R. C. Diabetes Care 1999, 22,
960-964.
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J. Am. Chem. Soc. 2004, 126, 6866-6867.
(2) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605-611.
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Eds. Essentials of Glycobiology; Cold Spring Harbor Laboratory Press: Cold
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10.1021/jo052111s CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/27/2005
1262
J. Org. Chem. 2006, 71, 1262-1264

SCHEME 1
SCHEME 2
sulfonium salts with potential glycosidase inhibitory activities.22-29
The 1,4-anhydro-4-thio-D-arabinitol moiety with the positive
charge at the sulfur atom is postulated to bind to glycosidase
enzymes by mimicry of the shape and charge of the oxacarbe-
nium ion transition state in the glycosidase-mediated hydrolysis
reaction.30 It thus appears that even Nature has exploited
sulfonium ions for glycosidase inhibition, and it is therefore of
interest to examine sulfonium ion analogues of the known
nitrogen-based glycosidase inhibitors as candidates with in-
creased potency and selectivity. Accordingly, we have recently
reported the synthesis of a sulfonium ion analogue (7)31 of
australine, and we report herein the synthesis of the sulfonium
ion analogue (8) of swainsonine (1) as a potential glycosidase
inhibitor. We note that compound 8 also differs from swain-
sonine (1) in the stereochemistry at C-3.
SCHEME 3
aldehyde 931 (corresponding to C). Treatment of 9 with a freshly
prepared Grignard reagent from the reaction of 2-(2-bromo-
ethyl)-1,3-dioxane and magnesium furnished compound 10 as
a 7:1 mixture of diastereomers. Compound 10 was isolated by
crystallization, and after cyclization, it was deduced that
compound 10 had the R configuration at C-5. The secondary
hydroxyl group at C-5 was protected as a benzyl ether to give
compound 11. Finally, the 1,3-dioxane protecting group was
hydrolyzed to give the corresponding aldehyde that was
subsequently reduced using NaBH4 to give 12.
Retrosynthetic analysis of the bicyclic sulfonium salt A
indicates that it could be synthesized by an intramolecular
displacement of a suitable leaving group on a pendant side chain
by a cyclic thioether (Scheme 1). The key intermediate B could,
in turn, be synthesized from C.
Scheme 2 outlines the synthesis of the alcohol 12, corre-
sponding to B, which was synthesized, in turn, from the
Initially, we anticipated that compound 15 could be synthe-
sized directly from 12 by converting the hydroxyl group at C-8
to a triflate moiety, which could be displaced by the cyclic
thioether. The reaction did not proceed as planned, and
compound 13 was the only sulfonium salt that was isolated
(Scheme 3). Presumably, the primary hydroxyl group at C-8 of
compound 12 was converted to the corresponding triflate and
then the oxygen atom at C-5 attacked C-8 faster than the
thioether. Subsequent attack by the thioether on the benzyl group
at C-5 would then yield 13. The stereochemistry at the sulfonium
ion center of compound 13 was assigned with the aid of 1D-
NOESY experiments, which showed a correlation between H-4
and +SCH2Ph, suggesting that the benzyl group at the S+ center
and the C-4 substituent were trans to each other. Treatment of
12 with methanesulfonyl chloride furnished the corresponding
sulfonate ester, which was subsequently treated with LiBr to
(22) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000, 41,
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(23) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001,
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(24) Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka,
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Jensen, M. T.; Svensson, B.; Pinto, B. M. Can. J. Chem. 2002, 80, 937-
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B. B.; Pinto, B. M. Synlett 2003, 9, 1259-1262.
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(jo051560p).
J. Org. Chem, Vol. 71, No. 3, 2006 1263

give the bromide 14. In contrast to the tosylate analogue,32
compound 14 did not undergo spontaneous cyclization to form
the desired bicyclic sulfonium salt. Treatment of compound 14
with AgOTf in CH2Cl2 to promote cyclization gave the
undesired product 13 once again. However, when the same
reaction was carried out using CH3CN as solvent, the reaction
proceeded smoothly to give the desired sulfonium salt 15 as a
stable, colorless oil. Compound 15 was remarkably stable even
after long-term storage at room temperature. The ring junction
of this bicyclic compound 15 was cis as expected because of
the strain in the trans isomer, in agreement with the work of
Izquierdo and co-workers.32 The stereochemistry was further
confirmed with the aid of 1D-NOESY experiments, which
showed a correlation between H-3 and H-8ax, and the config-
uration at C-5 of compound 15 was also assigned by means of
a 1D-NOESY experiment, which showed a correlation between
H-3 and H-5; the stereochemistry of compound 10 was thus
assigned by inference. The benzyl protecting groups were
removed with boron trichloride at -78 °C to give the desired
bicyclic sulfonium salt 8. During the course of deprotection,
some of the triflate counterion was exchanged with the chloride
ion. Hence, the deprotected bicyclic sulfonium salt was treated
with Amberlyst A-26 (chloride form) to completely exchange
the triflate counterion with chloride ion.
Hz, H-1b), 3.61 (m, 1H, H-8eq), 3.29 (ddd, 1H, J7ax,8ax ) J8ax,8eq
)
12.8 Hz, J7eq,8ax ) 3.6 Hz, H-8ax), 1.92 (m, 1H, H-7ax), 1.74
(ddddd, 1H, J7ax7eq ) 15.3 Hz, J6eq,7eq ) J6ax,7eq ) J7eq,8eq ) 4.1
Hz, H-7eq), 1.60 (dddd, 1H, J6ax,6eq ) 13.9 Hz, J6eq,7ax ) 4.4 Hz,
H-6eq), 1.34 (dddd, 1H, J6ax,7ax ) 11.7 Hz, H-6ax). 13C NMR
(CDCl3): δ 137.0, 136.6, 136.4 (3Cipso), 130.0-128.2 (15CAr),
120.9 (q, 1C, JC,F ) 318.8 Hz, OTf), 84.8 (C-3), 83.6 (C-2), 72.9,
72.7, 71.0 (3CH2Ph), 69.0 (C-5), 55.4 (C-4), 43.9 (C-1), 35.4 (C-
8), 23.3 (C-6), 16.7 (C-7). MALDI-TOF MS: m/e 460.99 (M+
OTf). Anal. Calcd for C30H33F3O6S2: C, 59.00; H, 5.45. Found:
C, 58.92; H, 5.49.
-
Procedure for the Synthesis of (2S,3S,4R,5R)-2,3,5-Tri-
hydroxy-cis-1-thioniabicyclo[4.3.0]nonane Triflate (8). BCl3 gas
was bubbled vigorously through a solution of 15 (100 mg, 0.16
mmol) in CH2Cl2 (6 mL) at -78 °C under N2 atmosphere for 10
min. The mixture was stirred at -78 °C for 2 h and a stream of
dry air was blown vigorously over the solution to remove excess
BCl3. The reaction was quenched with MeOH (2 mL) and the
solvent was removed. The residue was coevaporated with MeOH
(2 × 2 mL) and then washed with CH2Cl2 (2 × 2 mL) to give a
white solid. The solid was dissolved in MeOH (5 mL) and a freshly
washed ion-exchange resin (Amberlyst A-26 (chloride form), 100
mg) was added. The mixture was stirred at room temperature for
1 h and filtered. The filtrate was concentrated and recrystallized
from MeOH:CH2Cl2 to give compound 8 as white crystals (29 mg,
78%): mp 195-197 °C; [R]D - 38.00° (c 0.45, CH3OH). 1H NMR
(CD3OD): δ 4.49 (dd, 1H, J2,3 ) 6.0 Hz, J3,4 ) 8.6 Hz, H-3), 4.42
(m, 1H, H-5), 4.37 (ddd, 1H, J1a,2 ) 7.4 Hz, J1b,2 ) 5.9 Hz H-2),
3.86 (dd, 1H, J1a,1b ) 13.8 Hz, H-1a), 3.69 (dd, 1H, J4,5 ) 4.3 Hz,
H-4), 3.58 (ddd, 1H, J8ax,8eq ) 12.3 Hz, J7ax,8eq ) J7eq,8ax ) 4.0 Hz,
H-8eq), 3.52, (ddd, 1H, J7eq,8ax ) 3.6 Hz, J7ax,8ax ) 12.1 Hz, H-8ax),
In conclusion, the preparation of 8, a bicyclic sulfonium ion
analogue of the glycosidase inhibitor swainsonine (1), has been
achieved.
Experimental Section
3.18 (dd, 1H, H-1b), 2.19 (ddddd, 1H, J6ax,7ax ) 11.9 Hz, J7ax,7eq
)
15.4 Hz, J6eq,7ax ) 3.6 Hz, H-7ax), 2.06-1.81 (m, 3H, H-6ax, H-6eq,
H-7eq). 13C NMR (CD3OD): δ 78.0 (C-3), 77.2 (C-2), 62.4 (C-5),
59.3 (C-4), 44.1 (C-1), 36.7 (C-8), 25.7 (C-6), 16.2 (C-7). MALDI-
TOF MS: m/e 191.22 (M+ - Cl). Anal. Calcd for C8H15ClO3S:
C, 42.38; H, 6.67. Found: C, 42.31; H, 6.72.
Procedure for the Synthesis of (2S,3S,4R,5R)-2,3,5-Tribenz-
yloxy-cis-1-thioniabicyclo[4.3.0]nonane Triflate (15). A solution
of compound 14 (110 mg, 0.20 mmol) in CH3CN (4 mL) was
treated with AgOTf (104 mg, 2 equiv) for 20 h at ambient
temperature. The solvent was removed and the crude product was
purified by flash chromatography [CH2Cl2/MeOH, 1:0 to 20:1] to
give compound 15 as a colorless oil (88 mg, 71%): [R]D -14.40°
Acknowledgment. We thank Dr. B. D. Johnston for helpful
discussion. We also thank the Natural Sciences and Engineering
Research Council of Canada for financial support and the
Michael Smith Foundation for Health Research for a trainee
fellowship (to N.S.K.).
1
(c 0.75, CH2Cl2). H NMR (CDCl3): δ 7.29-7.03 (m, 15H, Ar),
4.53 and 4.34 (2d, each 1H, Ja,b ) 11.5 Hz, CH2Ph), 4.51 and 4.35
(2d, each 1H, Ja,b ) 12.1 Hz, CH2Ph), 4.49 (m, 1H, H-2), 4.47 and
4.43 (2d, each 1H, Ja,b ) 12.0 Hz, CH2Ph), 4.25 (dd, 1H, J2,3
)
3.8 Hz, J3,4 ) 7.8 Hz, H-3), 4.04 (dd, 1H, J4,5 ) 4.4 Hz, H-4),
3.89 (dd, 1H, J1a,1b )14.8 Hz, J1a,2 ) 6.6 Hz, H-1a), 3.76 (ddd,
1H, J5,6eq ) 4.9 Hz, J5,6ax ) 1.9 Hz, H-5), 3.66 (dd, 1H, J1b,2 ) 3.0
Supporting Information Available: Experimental procedures
and characterization data for compounds 10-14. This material is
available free of charge via the Internet at http://pubs.acs.org.
(32) Izquierdo, I.; Plaza, M. T.; Aragon, F. Tetrahedron: Asymmetry
1996, 7, 2567-2575.
JO052111S
1264 J. Org. Chem., Vol. 71, No. 3, 2006