Swainsonin

The same principle of sequential cyclopentene-opening RCM resulting in the formation of a dihydropyrrole ring was the key step in Blechert s novel approach to the polyhydroxylated indolizine alkaloid (-)-swainsonine (378) via RRM of 375 (Scheme 73) [157]. 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

The acylnitroso approach has been used for the enantioselective syntheses of (—)-swainsonine and (—)-pumiliotoxin C [17d] (Scheme 6.5). 

Inhibition of D-Mannosidases and D-Glucosidases by Swainsonine and Castanospermine, Respectively... 

A case similar to the slow, practically irreversible inhibition of jack bean a-D-mannosidase by swainsonine is represented by the interaction of castanospermine with isomaltase and rat-intestinal sucrase. Whereas the association constants for the formation of the enzyme-inhibitor complex were similar to those of other slow-binding glycosidase inhibitors (6.5 10 and 0.3 10 M s for sucrase and isomaltase, respectively), the dissociation constant of the enzyme-inhibitor complex was extremely low (3.6 10 s for sucrase) or could not be measured at all (isomaltase), resulting in a virtually irreversible inhibition. Danzin and Ehrhard discussed the strong binding of castanospermine in terms of the similarity of the protonated inhibitor to a D-glucosyl oxocarbenium ion transition-state, but were unable to give an explanation for the extremely slow dissociation of the enzyme-inhibitor complex. 

Colgate, S. M., Dorling, P. R. and Huxtable, C. R. 1979. A spectroscopic investigation of swainsonine an a-mannosidase inhibitor isolated from Swainsona canescens. Austral. J. Chem. 32 2257-2264. 

A new noncarbohydrate-based enantioselective approach to (—)-swainsonine was developed in which the key step was an aqueous intramolecular asymmetric hetero-Diels-Alder reaction of an acylni-troso diene (Eq. 12.57).128 Under aqueous conditions there was significant enhancement of the trans stereoselectivity relative to the reaction under conventional nonaqueous conditions. 

Transannular cyclizations of nine-membered cyclic sulfides provided a novel route to thioanalogues of swainsonine derivatives. Treatment of the enantiopure polyhydroxylated thiacyclononane derivative 48a with trimethylsilyl iodide yielded the bicyclic sulfonium salt 49a as a single diastereomer, as shown in Equation (16) <2003JOC3311 >. The presence of a C2-axis and the complete regio- and stereoselectivity of the transannular substitution led to a single configurationally homogeneous product irrespective of the fact that the sulfur atom would attack C-5 or C-6. 

Pinto and co-workers have synthesized various thioniabicyclo[4.3.0]nonanes via a protocol that involves intramolecular displacement of a leaving group on a pendant acyclic chain by cyclic thioethers. A sulfonium ion analogue 54 of swainsonine <2006CAR1685> and an analogue 55 of epi-swainsonine <2006JOC1262>, which differs from swainsonine in the stereochemistry at C-3, were synthesized using this approach. 

The polyhydroxindolizidine alkaloids, whose most important examples are castanospermine, swainsonine, and lentiginosine, are noted for their potent glycosidase inhibitory activity <2000TA1645, 1998CC1161,... 

RCM, followed by dihydroxylation of the double bond, is one of the most used methods for the synthesis of these compounds. For two syntheses of (—)-swainsonine 230, the five-membered ring is formed by RCM, followed by cis-dihydroxylation. Blechert et al. <2002JOC4325> prepared the precursor 2,5-dihydropyrroline 234 by domino ring-opening/ring-closing metathesis of an amino cyclopentene derivative 233 (Scheme 49). 

Reductive amination is used in most of the syntheses as the method for the formation of a five- or six-membered aza heterocyclic ring. A triple reductive amination approach to castanospermine and swainsonine has been reported by Mootoo et al. <2001JOC1761> (Scheme 56). 

A variety of naturally occurring imino sugars presenting interesting biological activity, such as castanospermine, swainsonine or australine are bicyclic compounds (Fig. 44). 

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