Swainsonine //-oxide

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. 

Pearson and Lin (52) developed an elegant approach to the synthesis of optically active ( )-swainsonine (247) from isopropylidene-D-erythrose (242) (Scheme 9.52). Wittig reaction of the acetonide 242 led to the (Z) alkene 252 in 86% yield. The chloro alcohol 252 was converted to the azide 253 in 76% yield, which subsequently underwent 1,3-dipolar cycloaddition, isomerization and hydroboration-oxidation to give the indolizidine 255 in 70% overall yield. Cleavage of the acetonide unit in 255 using 6 N HCl gave the target molecule 247 in 85% yield. 

Ring transformation of the mannopyranoside derivative 61, obtained from noncarbohydrate, to 1 has been developed (Scheme 7).225.226 Radical cyclization of the thiocarbonylim-idazolo derivative of 61 gave 62, which upon oxidation and reduction afforded 63 (30%) and 64 (55%). The latter was benzylated to give 65, which was converted into (fi)-oxime 67 via 66. Beckmann rearrangement of 67 followed by desilylation furnished 68. Cyclization of 68 to indolizidine skeleton followed by debenzylation, reduction of the lactam with BMS and hydrolysis afforded (-)-swainsonine (1). 

A synthesis of the intermediate 71, as aprecursor to (-)-swainsonine (1), has been reported (Scheme 8). Prolonged hydrogenation of the azide 69, obtained from D-mannose in eight steps, in methanol and then in acetic acid afforded the pyrrolidine 70 in 90% yield. Protection of the secondary amine in 70 with benzyl chloroformate followed by sodium periodate oxidation and subsequent sodium borohydride reduction gave 71. 

The discovery of the indolizidine alkaloid swainsonine (35) and its A-oxide (37) in the leguminous gtn tdi Astragalus, Oxytropis, and Swainsona suggests a biosynthetic route somewhat resembling those of pyrrolizidine and quinolizidine alkaloid biosynthesis (Harris et al, 1987 Kinghom and Balandrin, 1984). The similarity of certain indolizidine alkaloids to coniine-related compounds, such as 8-coniceine (not naturally occurring) has been observed. 

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... 

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