Organic Process Research & Development 2008, 12, 831–836
Scale-Up Synthesis of Swainsonine: A Potent r-Mannosidase II Inhibitor†
Pradeep K. Sharma,* Rajan N. Shah, and Jeremy P. Carver
GLYCO Design Inc., 480 UniVersity AVenue, Toronto, Ontario, Canada
Abstract:
The large-scale synthesis of Swainsonine 1, a potent r-mannosidase
II inhibitor, has been achieved with several improvements. The
key modifications were (a) performing the Wittig olefination under
Figure 1.
mild conditions and isolation of the product 4 with modified
workup conditions, (b) introduction of the azido group on a large
scale under Mitsunobu conditions to produce 12, (c) performing
the 1, 3-dipolar cycloaddition of an unactivated azide 12 to afford
the imino carboxylic ester 7, (d) formation of amide 10 from 7
under mild acidic conditions, and (e) isolation of the final
compound 1 as a stable hydrochloride salt. In addition, synthesis
of 11 was accomplished from 12 by telescoping the four steps.
5
Various syntheses reported in the literature have described
the preparation of 1 in milligram quantities, which were
sufficient for the initial structure-activity relationships. How-
ever, to fully develop the potential clinical applications of 1
and address initial pharmacological and toxicological require-
ments, 100 g to kilogram levels of 1 as the hydrochloride salt
were required. To this end we report process conditions required
for the large-scale synthesis of 1·HCl salt.
Introduction
Results and Discussions
Polyhydroxy indolizidine alkaloids possess a wide range of
biological activities such as immunoregulatory activity, anti-
HIV activity and anticancer activity. Swainsonine 1 is an
indolizidine alkaloid isolated from the Australian plant Swain-
sona canescens, North American plants of genera Astragalus
and Oxytropis,
leguminocola. Compound 1 (Figure 1.) is a potent inhibitor
of the Golgi enzyme R-mannosidase II, an enzyme required
for maturation of N-linked oligosaccharides of newly synthe-
sized glycoproteins. Compound 1 also blocks lysosomal R-
mannosidase resulting in the accumulation of oligomannoside
The medicinal chemistry route used to prepare 1 is based
on the synthesis described by Cha et al. as depicted in Scheme
1
,2
6
1
. Treatment of lactol 3 with the ylide of 3-(carbethoxypro-
pyl)triphenylphosphonium bromide, generated in situ by treat-
ment with KN(TMS) at -78 °C, produced the olefinic alcohol
in 58% yield after purification by silica gel chromatography.
Conversion of alcohol 4 with TsCl/Et N/CH Cl gave 5.
Subsequent treatment of 5 with excess NaN in DMF at elevated
temperature gave 7 in 72% yield. It is believed that triazole 6
was the intermediate, which upon loss of a mole of N gave 7.
3
a
2
3
b
and from the fungus Rhizoctonia
4
3c
3
2
2
3
2
The alkaline hydrolysis of the ester group of 7 resulted in 8,
which upon heating in a solution of toluene using a Dean-Stark
apparatus produced the enamide 10 Via the intermediate 9.
Hydroboration of 10 followed by oxidation resulted in a single
diastereomer 11. The removal of the acetonide linkage under
acidic conditions using HCl followed by treatment with Dowex
4
chains in cells exposed to the drug.
†
Part of this work has been incorporated in the patent application (U.S. Patent
6
,051,711, WO992185, CAN 130:338281 AN 1999: 297421).
Author for correspondence. E-mail: sharmap76@yahoo.com.
*
(
1) (a) For selected reviews see: deMelo, E. B.; de Silveria Gomes, A.;
Carvalho, I. Tetrahedron 2006, 62, 10277. (b) Lillelund, V. H.; Jensen,
H. H.; Liang, X. F.; Bols, M. Chem. ReV. 2002, 102, 515. (c) Heihtman,
T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750. (d) deMelo,
E. B.; de Silveria Gomes, A.; Carvalho, I. Tetrahedron 2006, 62,
-
OH afforded the desired compound 1 as an off-white solid.
The medicinal chemistry route is elegant, but a number of
factors (such as the use of multiple column chromatography
steps for purifications, excess NaN at elevated temperature,
3
basic resins, etc.) rendered the medicinal chemistry approach
unsuitable for scale-up conditions to deliver the quantities
required for development activities. In addition, 1 was isolated
as a free base from its corresponding hydrochloride salt. As a
consequence, we report a newly developed process for the large-
scale synthesis of 1·HCl with several modifications.
1
0277.
(
(
(
2) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (b) Asano, N. Glycobiology
2
003, 13, 93R. (c) Watson, A.; Fleet, G. W. J.; Asano, N.; Molyneux,
R. J.; Nash, R. J. Phytochemistry 2001, 56, 265. (d) Gerber-Lemaire,
S.; Juillerat-Jeanneret, L. Mini-ReV. Med.Chem. 2006, 6, 1043.
3) (a) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem.
1
979, 32, 2257. (b) Molyneux, R. J.; James, L. F. Science (Washington,
D.C.) 1982, 216, 190. (c) Davis, D.; Schwarz, P.; Hernandez, T.;
Mitchell, M.; Warnock, B.; Elbein, A. D. Plant Physiol. 1984, 76,
9
72. (d) Skelton, B. W.; White, A. H. Aust. J. Chem. 1980, 33, 435.
4) (a) Taylor, P. C.; Winchester, B. G. Iminosugars as Glycosidase
Inhibitors 1999, 125. (b) Burgess, K.; Henderson, I. Tetrahedron 1992,
Synthesis of 4. Wittig reaction between lactol 3 with
3-(carbethoxypropyl)triphenylphosphonium bromide in the pres-
4
8, 4045. (c) Fellow, L. E.; Kite, G. C.; Nash, R. J.; Simmonds,
M. S. J.; Scofield, A. M. Rec. AdV. Phytochem. 1989, 23, 395. (d)
Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin. Cancer Res.
(5) (a) Nemr, A. E. Tetrahedron 2000, 56, 8579. (b) Martin, R.; Murruzzu,
C. A; Riera, M. A. J. Org. Chem. 2005, 70, 2325, and references
cited there-in. (c) Heimgaertner, G.; Raatz, D.; Reiser, O. Tetrahedron
2005, 61, 643. (d) Pearson, W. H.; Ren, Y.; Powers, J. D. Heterocycles
2002, 58, 421. (e) Lindsay, K. B.; Pyne, S. G. Aust. J. Chem. 2004,
57, 669. (f) Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609.
(6) Bennett, R. B.; Choi, J. R.; Montgomery, W. D.; Cha, J. K. J. Am.
Chem. Soc. 1989, 111, 2580.
1
997, 3, 11077. (e) Elbein, A. D. FASEB J. 1991, 5, 3055. (f)
Galustian, C.; Foulds, S.; Dye, J. F.; Guillou, P. J. Immunopharma-
cology 1994, 27, 165. (g) Grzegorzewski, K.; Newton, S. A.; Akiyama,
S. K.; Sharrow, S.; Olden, K.; White, S. L. Cancer Commun. 1989,
1
, 373. (h) Elbein, A. D. Annu. ReV. Biochem. 1987, 56, 497. (i) Di
Bello Cenci, I.; Fleet, G.; Tadano, S. K.; Winchester, B. Biochem. J.
989, 259, 855.
1
1
0.1021/op800059y CCC: $40.75
2008 American Chemical Society
Vol. 12, No. 5, 2008 / Organic Process Research & Development
•
831
Published on Web 07/26/2008