Polyhydroxylated alkaloids

The same principle of sequential cyclopentene-opening RCM resulting in the formation of a dihydropyrrole ring was the key step in Blechert s novel approach to the polyhydroxylated indolizine alkaloid (-)-swainsonine (378) via RRM of 375 (Scheme 73) [157]. 

Cycloaddition reaction of nitrone (—)-(394) with dimethyl maleate D14 has been used for the synthesis of two new polyhydroxyl pyrrolizidines (687) and (688) (Schemes 2.293, 2.294). These compounds are analogs of alkaloids ros-marinecine and crotanecine, which were assayed for their inhibitory activities toward 22 commercially available glycosidase enzymes. One of them ((-)- a-epi-crotanecine) (—)-(688) is a potent and selective inhibitor of a-mannosidases (310). The reaction of (—)-(394) with dimethyl maleate gave a 9.6 6 1 mixture of cycloadducts (—)-(680), (+ )-(680), and (—)-(681), which arise from anti-exo,... 

Several fully saturated derivatives that can be viewed as aza analogues of polyhydroxylated indolizidine alkaloids have also been prepared for their biological evaluation <2000JOC136, 2000T1005>. 

Asano N, Yamashita T, Yasuda K, Ikeda K, Kizu H, Kameda Y, kato A, Nash RJ, Lee HS, Ryu KS. (2001) Polyhydroxylated alkaloids isolated from mulberry trees Moms alba L.) and silkworms Bombyx mori L.). J Agric Food Chem 49 4208-4213. 

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. 

The formation of thiocarbonyl ylids by the reaction of metallocarbenoids with thiocarbonyl compounds has not been extensively studied, as noted by Padwa and Weingarten in a review [167]. However, formation of rings by interaction of these compounds has recently received some attention. A key step in the synthesis of a polyhydroxylated indolizidine alkaloid related to castanospermine is the reaction of diazoketone with a thioamide, in the presence of rhodium acetate [135]. After desulfurisation an enaminone was obtained. 

Because of the availability of NeuAc aldolase and its unique stereochemical features, many biologically interesting molecules have been prepared. This method has been exploited, for example, in the synthesis of d- and L-sialic acid analogues (Scheme 5.31),54 in the synthesis of the polyhydroxylated alkaloid 3-(hydroxymethyl)-6-epi-castanospermine (Scheme 5.32),55 and in the synthesis of the melanoma antigen 9-0-acetyl GD3 from GD3 (Scheme 5.33).56... 

Glycosidase-inhibiting alkaloids from plants are classified into five structural classes polyhydroxylated pyrrolidines, piperidines, indolizidines, pyrrolizidines, and nortropanes. Furthermore, they also occur as the glycosides. This review describes recent studies on isolation, characterization, glycosidase inhibitory activity, and therapeutic application of the sugar-mimicking alkaloids from plants. 

Hyacinthus orientalis (Hyacinthaceae) is a plant native to North Africa and Eurasia, and commonly known as hyacinth. A search for polyhydroxylated alkaloids in species of the Hyacinthaceae family by GC-MS led to isolation and characterization of eleven... 

In the course of a search for a-glucosidase inhibitors, Kitaoka et al. found that such inhibitors are present in some Thai traditional crude dmgs [39]. For example, a-HNJ occurs in Non tai yak at a level of 0.1 % (dry weight). The Non tai yak sample is known to be Stemona tuberosa (Stemonaceae), which has been used in China and Japan for various medicinal purposes. In particndar, an extract from the fresh tuberous roots of S. tuberosa is used to treat respiratory disorders, including pulmonary tuberculosis and bronciiitis, and is also recommended as an insecticide [27,40,41]. In 2005, re-examination of polyhydroxylated alkaloids in S. tuberosa led to the isolation of thirteen alkaloids, 1, 24,25,31,36,37 (0.1 % of dry weight), 38,40,41,... 

In 1988, alexine (65), a polyhydroxylated pyrrolizidine alkaloid, was isolated from the pods of legume Alexa Idopetala [56]. Although the broad class of pyrrolizidine alkaloids bear a carbon substituent at C-1 [57,58], alexine is the first example of a pyrrolizidine alkaloid with a carbon substituent at C-3. At about the same time, australine (66) was isolated from the seeds of C. australe and found to be 7a-epi-alexine by X-ray crystallographic analysis [59]. The isolation of 1-epi-australine (67),... 

Tab. 5.1 Distribution of polyhydroxylated nortropane and indolizidine alkaloids in the Convolvulaceae. 

Iminosugars are naturally occurring polyhydroxylated alkaloids,[5] many of them are potent inhibitors of glycosidases and glycosyltransferases (Figure 19.1) [6]. Because of that they have attracted much interest with respect to potential therapeuhc applications [2, 7]. Furthermore, they are useful probes in fundamental biochemical studies of glycosidases mechanism [8]. 

An efficient new methodological pathway for the preparation of the polyhydroxylated alkaloids, indolizidines, and quinolizidines was developed through (4a) catalyzed RCM/allylic amination or, alternatively, RCM/haloamination strategies (equations), starting from a methyl ftiranoside precursor ... 

At the outset of the structure investigation it was hoped that single-crystal X-ray methods might be successful, particularly with the large alkaloids however, as a number of trials were not promising, the approaches to structures have relied on spectroscopic and chemical methods. Spectroscopic examination involved electron impact, chemical ionization, and field desorption mass spectrometry, H- and C-nuclear magnetic resonance study (sometimes NOE and correlation spectroscopy), and this was followed by isolation of the polyhydroxylated core by alcoholysis or hydrolysis. Core 30 was novel and its structure established spectroscopically 48), whereas euonyminol was characterized as its octaacetate and compared with an authentic sample. 

Figure 1. Diagram illustrating the common nomenclature for polyhydroxylated piperidine alkaloids, (a) 5-Amino-5-deoxy-D-glucopyranose has the trivial name nojirimycin, (b) 1-deoxynojirimycin (DNJ) is the trivial name for l,5-dideoxy-l,5-imino-D-glucitol and similarly (c) 1-deoxymannojirimycin (DMJ) is the common name for l,5-dideoxy-l,5-imino-D-mannitol.

While there may be phylogenetic reasons for particular distributions of the polyhydroxylated alkaloids in plants, caution should nevertheless be exercised in using the presence of these compounds as taxonomic markers. One reason is that these alkaloids can be released into the soil by producer plants and micro-organisms from where some, such as DMDP and castanospermine can be readily taken up and accumulated in plant tissues of completely unrelated neighbouring species. It may also be the case that micro-organisms (Rhizobium, other rhizosphere organisms, or endophytes) closely associated with specific plants may also produce polyhydroxylated alkaloids which could then be mistakenly considered of plant origin. 

From Table 1 it can be seen that the majority of naturally-occurring polyhydroxylated alkaloids have been isolated from plants. Although the first alkaloid of this type to be discovered (nojirimycin) was isolated from the fermentation broth of a species of Streptomyces, only a limited number of bacteria (principally actinomycetes)... 

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