Swainsonine, azide 1,3-dipolar cycloadditions

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. 

A commoner way to make heterocycles by pericyclic reactions is to use 1,3-dipolar cycloadditions. These often occur without catalysis and so are compatible with many other reactions. The starting material 182 for this asymmetric synthesis of swainsonine was derived from a natural sugar (chiral pool strategy, chapter 23). An exceptionally stereoselective Wittig reaction gave the Z-alkene 183 (chapter 15) and the alcohol was converted into the azide 184 with diphenylphos-phoryl azide.24... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

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