Of hydroxylated indolizidines

Although more rare, the ring opening of A-acyl (3-lactams has also been realized by using hydrides, giving rise to the corresponding reduction products. In this context, Scheme 40, Lee and Pak [107] have described the treatment of A-Boc (3-lactam 119 with lithium aluminium hydride to give A-protected amino alcohol 120. Compound 120 could serve as potential intermediate for the synthesis of various hydroxylated indolizidine alkaloids. 

Swainsonine, the enantiomer of the naturally occurring swainsonine, was enantiospecifically synthesised and proved to be a very potent inhibitor of naranginase, a (+)-ramannosidase, while (-)-swainsonine does not inhibit the same enzyme. Some other more highly hydroxylated indolizidines were also synthesised but proved to be less efficient as glycosidase inhibitors [113]. 

Cyclizations. Cyclization of hydroxylated propargyl sulfones may involve isomerization to the corresponding allenyl sulfones which should behave as Michael acceptors. Access to the indolizidine skeleton by an intramolecular Michael reaction of 5-tosyl-4-pentenamide and subsequent alkylation at nitrogen and carbon is quite efficient. A synthesis of resorcinols from dimethyl acetonedicarboxylate and alkyl alkynoates involves a Michael reaction-Dieckmann cyclization sequence. 

A USDA group was struck by the similarity in structure between the two hydroxylated indolizidines 95 and 96, and was led to examine the effect of castanospermine on hydrolytic enzymes. The American workers found it was a powerful inhibitor of both a- and [3-glucosidases [1151 it was further shown to inhibit glycoprotein processing [116], which in... 

Alternatively, the diastereomeric mixture of aldol adducts undergoes lithium aluminum hydride reduction, primary alcohol silylation, and chromatographic separation to afford 291. Subsequent Mitsunobu inversion at C-3 to furnish the j -alcohol 292 followed by a depro-tective sequence and ring closure provides (+ )-castanospermine (293). This poly-hydroxylated indolizidine alkaloid isolated from Castanospermum australe and Alexa leipetala is a potent inhibitor of various a- and j8-glucosidases [98] (Scheme 68). 

Rao and coworkers have reported formal syntheses of (—)-2-ep -lentigi-nosine (128) and several other hydroxylated indolizidines from the D-ribose derivative 166 (Scheme 21). This precursor was converted by treatment... 

A potentially general route to unusual hydroxylated indolizidines, e.g. 158 (sugar numbering shown), has been developed using L-arabinose, and nitrone 159 (from either D- or L-arabinose) has been applied to the synthesis of racemic hydroxylated p)OToIizidines and indolizidines. ... 

The enantiomerically pure indolizidine (—)-422 has been synthesized starting from L-malic acid diethyl ester 407. The hydroxyl function of L-malic acid diethyl ester 407 has been protected as dihydropyranyl ether 408 with 2/7-dihydropyran and Amberlyst 15 in pentane at room temperature. The diethyl ester 408 was then reduced with lithium aluminium hydride in diethyl ether under reflux and the newly generated hydroxyl functions then protected with mesyl chloride in the presence of triethylamine in dichloromethane at 0°C. This was converted into newly protected pyrroline nitrone 409 in 44% overall yield through a well-established method (Scheme 90). The regio-isomeric 5-pyrroline-iV-oxide 410 formed in 4% overall yield was easily separated by column chromatography <20000L2475>. 

Hydroxylated nitrones 321 and 322 afford, by subsequent thermal rearrangement of the adducts, a straightforward approach to polyhydroxylated indolizidines, inhibitors of glycosidases. The total synthesis of (+ )-Len-tiginosine is representative of the process (Scheme 47) [82]. 

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