Castanospermines

1 Castanospermines (+)-Castanospermine [(lS,65, 7i, 87 ,8a7 )-l,6,7,8-tetrah-ydroxyindolizidine, 1] was isolated from the seeds of the Australian legume Cas-tanospermum australe and the dried pod of Alexa leiopetala The analogues (+)- 

Syntheses of castanospermine from noncarbohydrates and its unnatural analogues from both carbohydrates and noncarbohydrates have been reported.  

A good stereocontrol was also exhibited in the Sakurai allylation of the manno analogue of 12, whereby (- -)-6-cp/-castanospermine (2) was synthesized in 42% yield. 

The olefin 31, ° obtained from D-glucose, was converted into the azido diene 32 in 56% overall yield. Intramolecular cycloaddition of 32 produced the indolizine 33, which could 

Another methodology for preparing 1 and 2 has also been developed from D-glncono- 

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Castanospermine [79831-76-8] (78) contains four secondary hydroxyl groups and therefore represents a significant challenge for regioselective... 

Castanospermine (6), isolated from Castanospermum australe by Ho-henschutz and coworkers and characterized as a strong inhibitor for )S-d-... 

The importance of a basic nitrogen atom for strong inhibition by the indolizine type of inhibitor is demonstrated by the finding that I for inhibition by castanospermine A -oxide of the ) -D-glucosidase from almonds is 500-fold larger than of castanospermine itself (760 fiM V5. 1.5 /lA/at pH... 

The pH-dependence of the inhibition also indicated that unprotonated castanospermine is a better inhibitor than the protonated form. However, as essential carboxyl groups of the enzyme ionize in the same range of pH as castanospermine (pK, 6.09), it was not possible to estimate the inhibitory potency of protonated castanospermine. 

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. 

Schols D, Pauwels R, Witvrouw M, Desmyter J, De Clercq E. Differential activity of polyanionic compounds and castanospermine against HIV replication and HIV-induced syncytium formation depending on virus strain and cell type. Antiviral Chem Chemother 1992 3 23-29. 

The total syntheses of the potent glycosidase inhibitors (+)-castanospermine, (+)-6-epicas-tanosperimine, (+)-australine, and (+)-3-epiaustraline have been reported. These four natural products are derived from a single common intermediate, the nitroso acetal (as shown in Scheme 8.43), which is created in the key step by the asymmetric tandem [4+2]/[3+2] cycloaddition between silaketal nitroolefin and chiral vinyl ether.182 The strategy of the synthesis is outlined in Scheme 8.43. Scheme 8.44 presents a total synthesis of (+)-castanosperimine and (+)-6-epi-castanosperimine from the common intermediate prepared by tandem [4+2]/[3+2] cycloaddition. 

The synthesis of a bridgehead sulfonium salt analogue 59, of the naturally occurring glycosidase inhibitor castanospermine, proceeded by a multistep procedure starting from 5-thio-d-glucopyranose pentaacetate <2000JA10769>. The desired bicyclic sulfonium salt 57 could not be obtained from the key bromide precursor... 

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

Stereoselective allylation of aldehydes is another preferred strategy for the synthesis of appropriate intermediates for the total synthesis and introduction of hydroxy functionalities. Park and co-workers <2003S2473> proposed a synthesis of castanospermine 228 through a key indium-mediated allylation in the presence of (+)-cinchonine of an a-amino aldehyde 247 derived from D-glucono-O-lactone (Scheme 53). 

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). 

Indolizidine alkaloids. The key step in a new stereocontrolled synthesis of these alkaloids, such as castanospermine (5), depends upon the diastereoselective reaction of an azagluco aldehyde with allylmetal reagents catalyzed by Lewis acids (12, 21-22). Thus reaction of allyltrimethylsilane with the aldehyde 1 and TiCL, (excess) in CH2C12 at - 85° results in the product 2, formed by selective chelation of the ot-amino aldehydo group with TiCl4. The product can be converted into 5... 

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

As a matter of fact, the second cycle increases the conformational rigidity of the molecule sometime increasing the activity and selectivity of the inhibitor. In the case of castanospermine for example, it has been postulated that the increase of inhibitory activity on a-glucosidase with respect to nojirimicin, is due to the orientation of the hydroxyl group at C-6 (referred to glucose) that in the case of castanospermine is restricted (Fig. 45).76... 

Fig. 45 Restricted conformation of castanospermine with respect to deoxynojirimicin.

Castanospermine is a plant alkaloid isolated from the seeds of the Australian chestnut tree, Castanospermium australe. As with most anti-HIV inhibitors, the discovery of the compound predates the time of isolation of HIV-1. The compound inhibits a-glucosidase-1, and therefore normal processing of the glycopro-... 

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