Swainsonine derivatives

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. 

Swainsonine derivatives having nonnatural lipophilic substituents at C-5, such as compound 204, did not show increased inhibitory power but remained as powerful as the parent compound.292... 

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). 

A trail pheromone of the Pharaoh ant was identified as 3-butyl-5-methylindolizidine of the stereochemistry given in (219) (75JHC289). Slaframine (220) is a metabolite isolated from Rhizoctonia leguminicola responsible for producing excessive salivation in cattle. A stereoselective synthesis was reported (73JOC3848). Swainsonine (221), a potent inhibitor of a-mannosidase, has been isolated from Swainsona caneszens. The stereochemistry was derived from the NMR spectrum (79AJC2257). 

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. 

Acylamino cyclization.l0 The indolizidine alkaloid (- )-swainsonine (3) has been synthesized by radical cyclization of the acylamine 1, derived from D-tartaric acid, to provide the indolizidinones 2 in 71% yield. Conversion to the alkaloid (3) included removal of the keto group by conversion to the thiolactam by Lawesson s reagent (97%) followed by desulfurization with Raney nickel (96% yield). 

In 1993 Dennis and co-workers synthesised derivatives of swainsonine with lipophilic groups attached to either position 2 or 8. The 2-carbonoyloxy esters of... 

The biosynthesis of swainsonine was studied in the fungus Rhizoctonia leguminicola The piperidine ring was shown to be derived from lysine via pipecolic acid. A noteworthy... 

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... 

Alternatively, methyl 6-0-benzoyl-2,3-0-isopropylidene-a-D-talopyranoside (57), derived from D-mannose, was utilized for the synthesis of swainsonine but in low yield (Scheme 6)P Mesylation of 57 followed by removal of the isopropylidene group with TEA, displacement of the mesylate group with azide ion, acetonation with DMP in acetone and... 

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). 

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