2-Deoxy-2-iodo derivatives

In view of the efficient inhibition of a particular crystalline glycan hydrolase by the epoxylbutyl -cellobioside 7 (n = 2), we decided to prepare the deoxy iodo derivative 21 to aid in the X-ray crystallographic analysis. We soon found that, although the alkene 22 was easily available as a direct precursor to our target, the epoxide functionality had to be introduced indirectly using bromo-hydrin 23 technology any direct oxidation of 22 invariably led to some loss of the iodine atom [23]. 

Methyl a-D-mannopyranoside was treated in succession with p-toluene-sulfonyl chloride, carbonyl chloride, and benzoyl chloride, and, without isolating the intermediates, there was obtained in 37% yield methyl 4-0-l enzoyl-2,3-O-carbony 1-6-0-(p-tolylsulfonyl ) -D-mannoside. The tos-yloxyl group of the latter was replaced by iodine, and hydrogenation of the 6-iodo derivative in the presence of a nickel boride catalyst gave methyl 4-0-benzoyl-2,3-0-carbonyl-6-deoxy- -D-mannoside. Treatment of the latter with hydrogen bromide in acetic acid gave crystalline 4-0-benzoyl-2,3-0-carbonyl-6-deoxy-a-D-mannosyl bromide (8) (16). The... 

Attempted selective displacement (96) of the primary tosylate function in 34 with sodium iodide in refluxing 2-butanone led to the 6-deoxy-6-iodo derivative 35 in 32% yield only, while the di-iodo derivative 36 was formed in 45% yield. These results are to be compared with those reported by Owen and Ragg (85) who observed no reaction with either potassium thiolacetate or potassium thiocyanate in the corresponding / -series. 

The D-gluco analog 37 reacted with sodium iodide in refluxing 2-butanone to give the crystalline 6-deoxy-6-iodo derivative 38 in 82% yield (97). Only 11% of the mixed di-iodo derivative 39 was formed in this case, which reflects on the higher order of reactivity at C-4 in 34 compared to 37. 

The reaction is quite susceptible to steric effects since hindered secondary hydroxyl groups were found to be unreactive. The method can therefore be used to selectively replace a primary hydroxyl group by halogen in the presence of more hindered secondary hydroxyl groups in the same molecule. An example (70) is the reaction of 52 with triphenylphosphite methiodide which affords the 6-deoxy-6-iodo derivative 53 (60%) in which the C-2 hydroxyl group remains intact. 

Whereas l,2-0-isopropylidene-5,6-di-0-methyl-D-glucofuranose was found to be unreactive towards triphenylphosphite dibromide, triphenylphosphite methiodide or phosphorus pentachloride, the related methyl 2,5,6-tri-0-methyl-/ -D-glucofuranoside (59), in which the hindrance caused by the ketal group is absent, reacted with triphenylphosphite methiodide to give the 3-deoxy-3-iodo derivative 60 in 31% yield. 

The reaction was found to be adaptable to dithioacetal derivatives also (70). Thus the product from the treatment of 61 with triphenylphos-phite methiodide was the expected 6-deoxy-6-iodo derivative 62 with no noticeable migration of ketal groups. 

In a similar way, 5-O-acetylthymidine was converted into the 3-deoxy-3-iodo derivative 72 in 55% yield. In this case, the replacement of the hydroxyl group by iodine was presumed to have taken place by retention of the configuration at C-3. The first intermediate in the reaction was proposed to be the phosphonate (70) which rapidly collapses to an O-3-cyclonucleoside (71) and the latter is subsequently attacked by iodide ion to give the product 72. It was also observed (106) that treatment of nucleosides containing a cis vicinal diol grouping such as 5-0-acetyluridine with triphenylphosphite methiodide failed to provide iodinated products but gave phosphonate derivatives instead. 

Selective replacement of primary hydroxyl groups in carbohydrates by iodine atoms has been achieved by using the Rydon reagent, namely, methyltriphenoxyphosphonium iodide.368 Treatment of methyl 3,4-O-isopropylidene-jS-D-galactopyranoside with the phosphonium salt in benzene for 48 hours at room temperature yielded 60% of the 6-deoxy-6-iodo derivative,369 and reaction of thymidine, uridine, and 2,2 -anhydrouridine in N,N-dimethylformamide afforded 5 -deoxy-5 -iodo derivatives in yields of 63, 65, and 31%, respectively.370... 

Dithioacetal derivatives have also been employed56 in reactions with 23. The primary hydroxyl group in 2,3 4,5-di-0-isopropylidene-D-galactose diethyl and dibenzyl dithioacetals is readily replaced by iodine, to give the expected 6-deoxy-6-iodo derivatives in almost quantitative yields. The secondary hydroxyl group in 5-0-benzoyl-2,3-0-isopropylidene-L-arabinose diethyl dithioacetal (32) was similarly replaced by iodine to give 5-0-benzoyl-4-deoxy-4-iodo-2,3-O-isopropylidene-D-xylose diethyl dithioacetal (33) however, a rearranged product, namely, 4-0-benzoyl-5-deoxy-5-iodo-2,3-0-iso-propylidene-L-arabinose diethyl dithioacetal (34) was also produced. 

The formation of 34 was explained by a rearrangement of 33 by way of a benzoxonium intermediate the ion is attacked at the less-hindered, C-5 position, to give a 5-deoxy-5-iodo derivative. The structure of 34 was confirmed by its reduction to 4-0-benzoyl-l,5-dideoxy-2,3-0-iso-propylidene-L-arabinitol. 

The reactions of 23 with 2, 3 -0-isopropylidene derivatives of purine nucleosides, or with free adenosine, give the corresponding N3,5 -anhydronucleosides in high yield a 5 -deoxy-5 -iodo deriv-... 

There are many examples of the reaction of carbohydrates with Rydon reagents [16] the reaction is controlled by steric factors. Thus, no reaction occurred between 1,2-0-isopropylidene-5,6-di-0-methyl-a-D-glucofuranose and either 6 or bromotriphenoxyphos-phonium bromide, presumably because of the steric hindrance caused by the trioxabicyclo [3.3.0]octane ring-system, whereas methyl 2,5,6-tri-O-methyl-p-D-glucofuranoside reacted with 6 to give a 3-deoxy-3-iodo derivative in 31% yield. 

Treatment of methyl 4,6-0-benzylidene-2-benzyloxycarbonylamino-2-deoxy-3-0-(imidazole-l-sulfonyl)-a-D-glucopyranoside with tetrabutylammonium iodide in refluxing toluene (3 h) gave the corresponding iodo derivative in 90% yield [68] (Scheme 13). When... 

The method employing triphenyl phosphite methiodide, as adapted to carbohydrates,130 has been used for the synthesis of protected 4-deoxy sugars. From methyl 2,3-di-0-methyl-6-0-p-tolylsulfonyl-a-D-glucoside and the corresponding D-galactoside, epimeric 4-iodo derivatives were obtained these were both reduced to methyl 4-deoxy-2,3-di-0-methyl-b-0-p-tolyl-sulfonyl-a-D-zj/Zo-hexoside. 

The synthesis of a member of this class of deoxy sugars was accomplished in 1950. The then well-known ethyl 2,3-dideoxy-a-D-en/l/iro-hex-2-enopyranoside was reduced and the product was converted into ethyl 2,3,0-trideoxy-4-O- (methylsulfonyl) -a-D-eryfAro-hexopyranoside by way of the 4,6-dimethanesulfonate. During this work, it was found that, when the dimethanesulfonate of the unsaturated derivative is treated with sodium iodide in the cold, a selective displacement at C-4 occurs, no doubt due to the activated allylic system. The resulting 4-iodo derivative could... 

O-p-tolylsulfonyl-a-D-mannoside (39) in 37% yield. Treatment of (39) with sodium iodide in acetone gave the 6-iodo derivative (40), which underwent reduction with hydrogen in the presence of a nickel boride" catalyst" to give methyl 4-0-benzoyl-2,3-0 carbonyl-6-deoxy-o>-D-manno-side (41) in 95% yield. Reaction of (41) with hydrogen bromide in acetic acid effected replacement of the methoxyl group at C-l, affording crystalline... 

The iodo derivative is a useful intermediate for the preparation of a wide variety of different types of compounds. Primary mesyl esters also react with sodium iodide in acetone, but the selectivity of this cleavage is less because of the greater reactivity of secondary mesyl esters. oa( ) Methyl 2,3,4-tri-0-acetyl-6-0-mesyl-a-D-glucopyranoside is converted into methyl 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside with acetic anhydride and potassium acetate. Replacements of a primary mesyloxy group with fluorine by use of potassium fluoride in methanol,106 with chlorine by use of lithium chloride,102 and with pyridine to form a pyri-dinium deoxy derivative,106 have been reported. Primary tosyloxy groups have been replaced by hydrogen,106 by thiocyanate,107 and by... 

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