Antibiotics, sugar-derived

This tool has been of great value in the elucidation of the structures of some important biologically-derived amino (14) and deoxy (13) sugars in the form of their dialkyl dithioacetals. Tedious degradation reactions which would require both time and valuable material could be avoided in many cases by resorting to mass spectrometry. The antibiotic sugars (22) paramose (1), mycinose (2) and chalcose (3) were, for example, studied by mass spectrometry (13, 14). 

Among the carba-sugar derivatives, the most important and attractive members are amino carba-sugars, particularly 5a-carba- -D-glucopyran-osylamlne (validamine) and its unsaturated derivative (valienamine). These amino carba-sugars have been synthesized successfully, as well as validamycin antibiotics and some of the aforedescribed enzyme inhibitors. 

Among other carba-sugar derivatives, the most important compounds are amino carba-sugars having an amino group at C-1. They are known as validamine, valiolamine, hydroxyvalidamine, and valienamine, and are found in validamycin antibiotics as unique components they have been synthesized in dl forms and also in optically active forms. 

The Mukaiyama condensation method was also utilized in the synthesis of several antibiotics and related bioactive substances. These syntheses include apramycin, using 4-azido-2,3,6-tri-(P-benzyl-4-deoxy-) -D-glucopyranosyl fluoride (prepared from the corresponding a-D-glucopyranosyl chloride by the AgF method ) avermectin B , using protected sugar derivatives of oleandrosyl fluoride (a-L-Ole-F) and 0-(a-L-01e)-(1 4)-a-L-0le-F (both... 

Figure 2.3 Sugar-derived high-value-added products antibiotics, vitamins, and pharmaceuticals.

Debono, M. and Molloy, R.M., Isolation and structure of the novel branched-chain amino sugar derived from antibiotic A35512B, J. Org. Chem., 45, 4685, 1980. 

From his time at the Squibb research laboratories, he was interested in the chemistry of antibiotics, and in this area, he elucidated the partial structure of curamycin, an antibiotic produced by Streptomyces curacoi. From curamycin, he isolated and characterized the new natural sugar derivatives D-curacose (4-O-methyl-D-fucose), curacin [4-0-(dichlo-roisoeveminyl)-2,6-dideoxy-D-araW/io-hexose], and curamycose (2,6-di-O-methyl-D-mannose). 

Reduction of the nitro group of 545-547 in the presence of Raney nickel catalyst respectively afforded the corresponding 4-amino-pento-, -hexo-, and -hepto-pyranosides 548-550. Methyl 4-amino-2,3,4,6-tetradeoxy-a- and -/3-DL-en/t/iro-hexopyranoside (549), characterized as the A -benzoyl derivative, was identical in its H-n.m.r.-speetral data with the analogous derivative of the natural, antibiotic sugar tolyposamine. On the other hand, reductive demethyl-ation of 549 with formaldehyde-Raney nickel (under 3.5 kg/cm2 pressure of hydrogen) was effected, to yield another antibiotic sugar, methyl DL-forosaminide (551). 

Dutcher, James D., Chemistry of tlie Amino Sugars Derived from Antibiotic Substances, 18, 259-308... 

Ab initio molecular orbital calculations on these systems have been confined to the 1,2,3-triazolo[4,5-d]pyrimidines (7), the so-called 8-azapurines , and references to this subject may be found in the previously mentioned review <86AHC(39)ii7>. In 1989, quantum mechanical perturbation methods have been used to study the activity of 8-azapurine nucleoside antibiotics in transcription processes <89Mi 7i3-oi>. The l,2,3-thiadiazolo[5,4-d]pyrimidine derivative (51), a rearrangement product of 8-aza-6-thioinosine, has been used in a molecular modeling study of the antitumor activity of sugar derivatives of pyrimidopyrimidines <89PNA(86)8242>. 

Durette, Philippe L., and Horton, D Conformational Analysis of Sugars and Their Derivatives, 26,49-125 Dutcher, James D., Chemistry of the Amino Sugars Derived from Antibiotic Substances, 18, 259-308... 

P. Herczegh, M. Zsdby, L. Szil gyi, 1. Bajza, A. Kovacs, G. Batta, and R. Bogndr, Inter- and intramolecular Diels-Alder reactions of sugar derivatives, ACS Symp. Sen 494 112 (1992). N. Chida, M. Ohtsuka, K. Nakazawa, and S. Ogawa, Total synthesis of antibiotic hygromycin A, J. Org. Chem. 56 2976 (1991). 

The 4,5-unsaturated pyranoses or 3,4-unsaturated furanoses are usually prepared by a base-catalyzed elimination of a leaving group such as halogen, sulfonyloxy etc. from appropriate sugar derivatives. The classical example is represented by the synthesis of compound 19 from l,2 5,6-di-0-isopropylidene-a-D-glucofuranose 18 [1]. Analogous elimination performed for 20 led to derivative 21 from which capuramycin—a complex nucleoside antibiotic could be prepared readily (O Scheme 14) [30]. 

The antibiotic thiolactomycin (43), a fermentation product from a Nocardia species containing an unusual thiolactone moiety was patented as antibiotic no. 2-200 and subsequently reported in the literature in 1982 [73,74]. It resembles a sugar-derived a,/3-unsaturated 4-thioglycono-1,4-lactone and was found to be a broad-spectmm antibiotic [75] by interference with the fatty acid metabolism of bacteria and also inhibited inducible /3-lactamases [76]. A de novo synthesis of the racemate was reported by a Du Pont group in 1984 [77]. Chambers and Thomas [78] reported the synthesis of the (55j-enantiomer in 1989 and concluded from its optical rotation that the natural product is the (5i )-enantiomer. 

The majority of these substances may be considered unique polypeptides which contain unusual amino acids or amino acids joined in some unusual manner. Antibiotics now definitely known to be in this class are the penicillins (2), gramicidin (2), tyrocidine (1), gramicidin-S 3), bacitracin (4), subtilin (-5), polymyxin (6), aerosporin (7) and others. The penicillins are produced by a mold. The others listed here are produced by related bacteria. Streptomycin is a very important antibiotic therapeutically but it does not belong to the polypeptide class, being a complex amino-sugar derivative. 

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