L- -swainsonine

G.W.J. Fleet and co-workers synthesized L-(+)-swainsonine and other more highly oxygenated monocyclic structures that exhibited inhibitory activity toward naringinase (L-rhamnosidase). In order to remove a c/s-vicinal diol moiety in the endgame of the synthesis, the Corey-Winter olefination was utilized. 

Davis, B., Bell, A. A., Nash, R. J., Watson, A. A., Griffiths, R. C., Jones, M. G., Smith, C., Eleet, G. W. J. L-(+)-Swainsonine and other pyrrolidine inhibitors of naringinase through an enzymic looking glass from D-mannosidase to L-rhamnosidase Tetrahedron Lett. 1996,... 

Radical deoxygenation was used for conversion of 283 to 287, (7R)-7-hydroxy-L-swainsonine. The former was also elaborated to L-(+)-swainsonine 286 via 284 and 285 (Scheme 54), and also to the dehydrogenated analogue 288. L-Swainso-nine has Ki of 0.45 pM as an inhibitor of L-rhamnosidase (naringinase). ... 

The nitroso functionality is a powerful dienophile and N-alkyl- and N-acylnitroso compounds give inter- and intrahetero Diels-Alder reactions easily. The cycloadditions also occur in aqueous medium although some nitroso compounds (i.e. N-acylnitroso derivative) are short-lived in the presence of water. The NO functionality is generated in situ by periodate oxidation of the hydroxylamine group and the cycloaddition with butadienes gives a 1,2-oxazine ring. Scheme 5.16 illustrates the utility of the nitroso Diels-Alder cycloaddition for the synthesis of (—l-swainsonine/ (—)-pumiliotoxin and BCX-1812... 

This synthesis of (-)-swainsonine involves 21 steps and proceeds with an overall yield of 6.6% from tran5-l,4-dichloro-2-butene. It is not only the first reported noncarbohydrate route to this natural product, but it allows the stereoselective access to all 16 epimers and/or enantiomers of swainsonine as well. 

Dennis, J.W., White, S.L., Freer, A.M. and Dime, D. (1993). Carbonoyloxy analogs of the anitmetastatic drug swainsonine. Activation in tumor cells by esterases, Biochem. Pharmacol., 46, 1459-1466. 

Molyneux, R.J., James, L.F., Panter, K.E. and Ralphs, M.H. (1991b). Analysis and distribution of swainsonine and related polyhydroxyindolizidine alkaloids by thin layer chromatography, Phytochem. Anal., 2, 125-129. 

Dreyer, D. L., Jones, . C. and Molyneux, R. L. (1985). Feeding deterrency of some pyrrolizidine, indolizidine, and quinolizidine alkaloids towards pea aphid (Acryrthosiphon pisum) and evidence of phloem transport of indolizidine alkaloid swainsonine. Journal of Chemical Ecology 11 1045-1051. 

This method was adapted towards the synthesis of the natural product swainsonine which closely resembles l,2,3,5,6,8a-hexahydroindolizine (1). 

Despite the similarity between compound 1 and (-)-swainsonine, a different retrosynthetic strategy was devised for the synthesis of (-)-swainsonine (Scheme 3).19 The ring rearrangement yielded the hydropyrrolidine 5, which was prepared from the precursor 6. The enantiometrically pure oxazolidine derivative 7 was a suitable chiral starting material, as it was efficiently synthesised from the diol 8. As with the synthesis of 1, a palladium (0) catalysed allylic amination was carried out in the presence of ligand L (Scheme 2)14 to give 7 with an ee of 97%, which was increased to >99% on recrystallisation with dichloromethane/hexane. 

The syntheses of l,2,3,5,6,8a-hexahydroindolizine (1) and (-)-swainsonine were successfully carried out via a ROM-RCM strategy, and final CM with ethylene to free the ruthenium. Two different synthetic routes were implemented to achieve a similar compound. In the case of l,2,3,5,6,8a-hexahydroindolizine 1, the six-membered ring was established first using RRM and in the case of (-)-swainsonine, the five-membered ring was established first. In both cases, the ring rearrangement precursors were enantiomerically pure five-membered carbocycles, which can be synthesised efficiently from racemic starting materials. 

Ralphs, M.H., Creamer, R., Baucom, D., Gardner, D.R., Welsh, S.L., Graham, J.D., Hart, C., Cook, D. and Stegelmeier, B.L. (2008) Relationship between the endophyte Em-bellisia spp. and the toxic alkalod swainsonine in major locoweed species (Astragalus and Oxytropis). ]. Chem. EcoL, 34, 32-8. 

Trost has reported enhanced enantioselectivity in the desymmetrization of mero-biscarbamates in the presence of triethylamine. Under these conditions, high yields (>80%) and enantiomeric excesses (93-99% ee) are obtained. This methodology has been applied to the synthesis of (—)-swainsonine. a-Amino esters have been used as nucleophiles in the reaction with acyclic allylic esters and isoprene monoepoxide, providing access to diastereoselective N-alkylated a-amino esters. By employing the feature ligand, asymmetric palladium(0)-catalyzed cychzation of 2-(tosylamino)phenol with ( -l,4-bis[(methoxycarbonyl)oxy]but-2-ene provides 2-vinylbenzomorpholine in 79% ee. A number of alternative diphosphine ligands were studied and found to be inferior. 

A.D. Elbein. Swainsonine and Related Glycosidase Inhibitors , Eds. L.F. James, A.D. Elbein, R.J. Molyneux and C.D. Warren, Iowa State University Press, Ames, Iowa, U.S.A. 1989, Chapter 14, p. 155. 

Humphries, M. J., Matsumoto, K., White, S. L. and Olden, K. (1986a). Ohgosac-charide modification by swainsonine treatment inhibits pulmonary colonization by B16-F10 murine melanoma cells. Proc. Natl. Acad. Sci. USA 83, 1752-1756. 

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