Glycals, bromination

The determination of the lifetime of the ionic intermediates using the azide-clock method has been however useful in showing that electrophilic addition of Br2 can occur, even through a fully concerted mechanism, definable as SN2-like. Bromination of cyclic enol ethers (glycals) 8-10 in methanol in the presence of... 

The most attractive approach for the 2-deoxy-p-glycosides starts with 2-bromo-2,6-dideoxyhexopyranosyl bromides (2 ) such as These are available regio- and stereo-specifically from readily accessible and simple precursors by reaction with dibromomethyl methyl ether (DBE) (22, 2 ). In principle, the formation of related compounds may be anticipated by the addition of bromine to glycal precursors. Previous studies (24-27). however, proved these processes to yield several isomers which renders this approach of little preparative value. 

It was envisaged that the enones were produced following abstraction of H-1 (a process facilitated by the ability of sulfur atoms to stabilize radicals on bonded carbon centers), radical bromination, elimination of hydrogen bromide to give substituted glycals, allylic bromination at C-3, and loss of acetyl bromide. In the formation of compound 6, hydrogen abstraction from C-5 was deemed to compete with that from C-1, and to lead to substitution at the former site with the formation of a relatively stable product. 

Phenylselenyl chloride adds to the double bond of the glycal 26 to give a phenyl-selenoxonium ion which is tra/w-opened by an approaching nucleophile to the glycoside 27. Other electrophiles have also been used likep-toluenesulfonic acid, bromine, or iodine. Acid conditions, however, may cause destruction of labile 2-deoxy sugar products and the value of such reagents will be diminished by this evident disadvantage. 

Bromine adds to hexaacetylcellobial to yield a dibromide, and chlorine yields similarly a dichloride.65 Deacetylation produces free cellobial (LXV). As with lactal, cellobial also gives no pine splinter reaction, in contrast to the glycals with a free hydroxyl at carbon 4.64 Otherwise it displays the well known reactions of the glycals. Hydrogenation of... 

The composition of reaction mixtures obtained under classical Fischer-Zach conditions was determined by capillary gas chromatography [53] of per-O-silylated and per-O-acetylated components of the crude reaction mixtures, and some progress was made in explaining the mechanism behind typical side-product formation. The compounds identified included products of solvolytic displacement of an anomeric bromine by acetic acid and water as well as 2,3-unsaturated derivatives. Interestingly, there was a difference in the reaction outcome of pentopyranosyl versus hexopyranosyl substrates. In the former case, glycals were accompanied by acetylated 1,5-anhydropentitols in the latter, hex-l-enitols contained admixtures of peracetylated 2-deoxyhexopyranosides. 

Surprisingly, the allylic radical bromination of the nonfluorinated glycal 10 had not been reported, although the allyl bromide could obviously provide a shorter route to 16-substituted derivatives than the previously described approaches from artemisitene or artemisinic acid [28, 29, 59a, 65, 66], Conversely, reactivity of 10 toward electrophilic brominating agents was well documented. Dibromides [44,67] and bromohydrins [68,69] have been used for the introduction of ionizable functions in artemisinin at C-10 and C-9. 

Allylic bromination of glycals 10 and 18 was investigated under the usual Wohl-Ziegler conditions with /V-bromosuccinimide (NBS/CCLt/reflux) in the presence of azobi-sisobutyronitrile (AIBN) as initiator. Although both bromides were easily formed in this reaction, the nonfluorinated one appeared to be unstable and could not be isolated [70], The parent 10-CF3-16-bromo derivative 22 was also obtained in good yield (72%) (see Scheme 6.12). The compound could be purified by crystallization and stored for several weeks at 0°C. Clearly, the electron-withdrawing character of the CF3 group makes the allyl bromide less labile. 

The presence of an initiator (AIBN) was not necessary in the bromination reaction of glycal 18 and yield was even improved to 90% when the reaction was performed without... 

AIBN. The ease of the allylic bromination of 18 has been attributed to the presence of the endoperoxide, which can initiate the radical reaction [44], Similar results were obtained with Br2 without initiator, whereas Br2 reacts with glycal 10 through an electrophilic addition on the double bond [44, 67],... 

Glycosyl fluorides Glycals are transformed into glycosyl fluorides with a combination of Sip4 and an oxidant such as l,3-dibromo-5,5-dimethylhydantoin, phenyliodine(III) acetate (H2O). In such cases, a bromine atom or a hydroxyl group is also introduced. 

Glycals. Substituted glycosyl bromides undergo the elimination of bromine and a group at the adjacent carbon on brief treatment with (Cp2TiCl)2 in THF at room temperature. Glycals are obtained in good yields. 

A useful variant of the Ramberg-BScklund reaction involves in situ halogena-tion and alkene formation. The reagent combination KOH or t-BuOK in CCI4 or Cp2Br2 permits chlorination or bromination followed by direct deprotonation, episulfone and hence alkene formation. A route to exo-glycals uses this chemistry, with bromination a- to the sulfone, followed by in situ Ramberg-BScklund reaction (2.98). 

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