Carbohydrate, 2,3-epoxides

Coxon, B., Reynolds, R. C. Synthesis of nitrogen-15-labeled amino sugar derivatives by addition of phthalimide-15N to a carbohydrate epoxide. Carbohydr. Res. 1982, 110, 43-54. 

Compound 47 has been generated and used in the synthesis of a variety of 2-substituted indoles 48. Unlike lithiation of 77-(phenylsulfonyl)indole 3 [9,14], hthia-tion reactions of 4 have not been studied systematically. Nonetheless, selected examples including the corresponding reaction conditions used are given below (Table 7). Silanol 48g has been generated and exploited by Denmark in cross-coupling reactions [192, 193]. Kline used this chemistry to prepare 48b en route to a synthesis of 2-iodotryptamine [194]. Additional electrophiles used in reactions with 47 include epoxides (carbohydrates) [166], allyUc pivalates [195], and chlorodialkylphosphines [196]. 

Scheme 8.41 Utilization of glycals and a-glycal epoxides in carbohydrate chemistry.

Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

Examples for straightforward epoxide preparation from natural sources can be found in carbohydrate chemistry [28,29]. Deoxygenations of such compounds are shown in Scheme 4. 

Microwave-assisted epoxide ring-openings of l,5 2,3-dianhydro-4,6-0-benzyl-idene-D-allitol with nucleobases have been reported [218], Various rapid microwave-assisted protection and deprotection methods in the area of carbohydrate chemistry are known [210], and two general review articles on microwave-assisted carbohydrate chemistry were published in 2004 [219, 220]. 

The importance of reactions with complex, metal hydrides in carbohydrate chemistry is well documented by a vast number of publications that deal mainly with reduction of carbonyl groups, N- and O-acyl functions, lactones, azides, and epoxides, as well as with reactions of sulfonic esters. With rare exceptions, lithium aluminum hydride and lithium, sodium, or potassium borohydride are the... 

This approach provides a new method for carbohydrate synthesis. In the synthesis of tetritols, pentitols, and hexitols, for example, titanium-catalyzed asymmetric epoxidation and the subsequent ring opening of the thus formed 2,3-epoxy alcohols can play an essential role. 

Chiral Ketone from Carbohydrate. Tu et al.100 reported a dioxir-ane-mediated asymmetric epoxidation based on the ketones derived from the low cost material D-fructose (Scheme 4-47). 

The observation of a stereoconvergent cyclization by Roy et al. [18], as shown in the third example, is of special interest from a synthetic point of view because it exploits the configurational lability of radicals in a favorable manner. The other examples, i. e. Nugent and RajanBabu s cyclization of a carbohydrate-derived epoxide [5d] and Clive s quinane synthesis [19], amply demonstrate the usefulness of the titanocene-initiated epoxide opening. 

The epoxidation of nonfunctionalized alkenes may also be effected by chiral dioxiranes. These species, formed in situ using the appropriate ketone and potassium caroate (Oxone), can be formed from C-2 symmetric chiral ketones (29)[93], functionalized carbohydrates (30)[94] or alkaloid derivatives (31)[95]. One example from the laboratories of Shi and co-workers is given in Scheme 19. 

The purpose of this study was to explore the introduction of an OZT moiety onto the specific C-3 site of both l,2 5,6-di-0-isopropylidene-a-D-glucofuranose and 1,2 4,5-di-0-isopropylidene-p-D-fructopyranose, taking advantage of the well-defined frame of both carbohydrate structures to generate all possible OZT-isomers. These spiroheterocyclic structures could be constructed according to a simplified sequence based on a key stereoselective approach from uloses via epoxides or aziridines (Scheme 16). 

Epoxidations of chiral allenylsilanes are also highly stereoselective, especially if the silyl group is spatially demanding (Eq. 9.54) [60]. A bis-epoxide intermediate is formed which rearranges to an a,/8-unsaturated a -hydroxy ketone. Such products are of interest as branched carbohydrate analogues. 

In polymer applications derivatives of oils and fats, such as epoxides, polyols and dimerizations products based on unsaturated fatty acids, are used as plastic additives or components for composites or polymers like polyamides and polyurethanes. In the lubricant sector oleochemically-based fatty acid esters have proved to be powerful alternatives to conventional mineral oil products. For home and personal care applications a wide range of products, such as surfactants, emulsifiers, emollients and waxes, based on vegetable oil derivatives has provided extraordinary performance benefits to the end-customer. Selected products, such as the anionic surfactant fatty alcohol sulfate have been investigated thoroughly with regard to their environmental impact compared with petrochemical based products by life-cycle analysis. Other product examples include carbohydrate-based surfactants as well as oleochemical based emulsifiers, waxes and emollients. 

There are data from animal studies in mice, rats, and pigs that indicate that both carbohydrate metabolism and lipid metabolism may be affected by exposure to heptachlor or heptachlor epoxide (Enan et al. 1982 Halacka et al. 1974 Kacew and Singhal 1973 Pelikan 1971). Alterations in gluconeogenic enzymes and an increase in cellular steatosis in the liver have been reported. Granulomas and fibrotic liver have also been observed. In addition, hepatocellular carcinoma was identified as causally related to heptachlor in the diet in a mouse study conducted by the National Cancer Institute (NCI 1977). The existing evidence suggests that heptachlor and heptachlor epoxide are hepatic toxicants. 

Hydroxylation may also take place at nitrogen atoms, resulting in hydroxyl-amines (e.g., acetaminophen). Benzene, polycyclic aromatic compounds (e.g., benzopyrene), and unsaturated cyclic carbohydrates can be converted by mono-oxygenases to epoxides, highly reactive electrophiles that are hepato-toxic and possibly carcinogenic. 

A useful application of the chemistry shown in Scheme 83 is the synthesis of branched-chain functionalized carbohydrates. For this purpose two epoxides 261 and 262 derived from D-glucose and 263 derived from D-fructose were prepared following reported methodologies, and were submitted to a DTBB-catalyzed lithiation as described above in Scheme 83. The expected intermediates 264-266 and final products 267-269 were prepared in a regio- and stereoselective manner in 15- 95% yield" Also here, the use of a prochiral electrophile gave equimolecular amounts of both diastereomers. 

Z)-awh-4-Hydroxy-l-aIkenyl carbamates 363, when subjected to substrate-directed, vanadyl-catalysed epoxidation , lead to diastereomerically pure epoxides of type 364 (equation 99)247,252,269 qqjggg epoxides are highly reactive in the presence of Lewis or Brpnsted acids to form -hydroxylactol ethers 366 in some cases the intermediate lactol carbamates 365 could be isolated . However, most epoxides 364 survive purification by silica gel chromatography . The asymmetric homoaldol reaction, coupled with directed epoxidation, and solvolysis rapidly leads to high stereochemical complexity. Some examples are collected in equation 99. The furanosides 368 and 370, readily available from (/f)-0-benzyl lactaldehyde via the corresponding enol carbamates 367 and 369, respectively, have been employed in a short synthesis of the key intermediates of the Kinoshita rifamycin S synthesis . 1,5-Dienyl carbamates such as 371, obtained from 2-substituted enals, provide a facile access to branched carbohydrate analogues . 

Richardson s interest in these trehalose epoxides stemmed from his desire to prepare a wide range of modified trehalose analogues for evaluation as inhibitors of the trehalase of insects, as trehalose is known to be the storage carbohydrate of many insects and good inhibitors of this processing enzyme could potentially function as green insecticides. 

Fig. 9. A model for diastereoselectivity in epoxidation of carbohydrate-based oxepines.

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