Synthesis castanospermine

Swansonine and castanospermine synthesis starts with the a-aminoacid, y-semialadehyde and, via piperidine-6-carhoxyhc acid synthetases, L-pipecolic acid. This compound is a substrate to HSCoA and acetyl-CoA. As a result of this activity, the second ring is established. Subsequently, it changes to 1 -indolizidinone and, by oxidation reaction, produces castanospermine or swansonine (Figure 50). 

FIGURE 2.30 Diagram of the swansonine and castanospermine synthesis pathway. 

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... 

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). 

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... 

D. Hendry, L. Hough, and A. C. Richardson, Enantiospecific synthesis of I-deoxy-castanospermine, (6S,7R,8R,8aR)-trihydroxyindolizidine, from D-glucose, Tetrahedron Lett., 28 (1987) 4597-4600. 

C.-K. Lee, K. Y. Sim, and J. Zhu, Enantiomeric synthesis of polyhydroxylated indolizidine analogues related to castanospermine l-Deoxy-7-epicastanospermine and l,7-dideoxy-7-fluorocastanosper-mine, Tetrahedron, 48 (1992) 8541—8544. 

P. C. Tyler and B. G. Winchester, Synthesis and biological activity of castanospermine and close analogs, in A. E. Stiitz, (Ed.), Iminosugars as Glycosidase Inhibitors, Wiley-VCH, Weinheim, New York, 1999, pp. 125-156. 

The synthesis of 8-epi-castanospermine (31), a bicyclic analogue of (5), was reported [48,73], but no biological data were given. 

The sialic acid aldolase-catalyzed condensation of D-mannose 8 and pyruvate led, in an excellent yield, to the synthesis of KDN 9 [33], a natural deaminated neuraminic acid first isolated from rainbow trout eggs [34] and then discovered in other species. The discovery that sialic acid aldolase accepts as substrates D-mannose substituted on the 2-position, even by bulky substituents such as phenyl, azido, or bromine, opened the route to novel unnatural sialic acid derivatives [35-39]. Pentoses also are substrates. N-Substituted neuraminic acids could be prepared either directly from the corresponding Af-substituted mannosamine, such as N-thioacyl derivatives [40], or after reduction and acylation of 5-azido-KDN [41]. Recently, AT-carbobenzyloxy-D-mannosamine was converted, in a good yield, into the N-carbobenzyloxy-neurarninic acid, further used as a precursor of a derivative of castanospermine [42]. 

Castanospermine is a polyhydroxylated alkaloid found in the plant Castanospermum australe.1 Its ability to function as a selective inhibitor of a and p glycosidases has made it the focal point of much synthetic activity in recent years.2 One particularly elegant synthesis of ( + )-castanospermine is that of Pandit and Overkleeft.3 It features a remarkable intramolecular olefin metathesis reaction for indolizidine ring assembly. We now analyse this interesting route, which showcases many important reagents and reactions used in contemporary organic synthesis. 

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