Pristinamycin oxidation

Natural pristinamycin II is a mixture of two polyunsaturated macrolactones which differ in the level of oxidation of the proline residue. The major component, pristinamycin 11 (33), possesses a dehydroproline ring, which is replaced by a (i )-proline residue in the minor component, pristinamycin Ilg (34). The ratio of these two compounds in the natural mixture varies from 90 10 to 97 3 depending on the fermentation conditions and the strain of Streptomyces. The pristinamycin II components also contain an oxazole nucleus incorporated into the macrolactone structure, which is relatively uncommon in naturally occurring compounds. 

Treatment of pristinamycin IIa with meta-chloroperbenzoic acid afforded a compound to which the structure (79) was initially assigned, resulting from epoxidation of the more substituted double bond (12,13-C). This material did not display chemical properties characteristic of an epoxide as the assumed epoxide moiety remaining after treatment with nucleophilic reagents. Michael-type addition products on the dehydroproline ring were observed after treatment with thiols or amines (see Sect. 5.4.5). 2D-NMR analysis of the product from reaction of pristinamycin IIa with mCPBA showed that a transannular oxidative cyclization had taken place leading to formation of (80). The reaction can be considered to involve initial epoxidation of the 12,13-double bond followed by an intramolecular nucleophilic attack by the 37-hydroxy of the enol ether (Scheme 19). A similar transannular oxidative cyclization reaction has been reported for the reaction of l,5-dimethylcyclooct-4-en-l-ol with meta-chloroperbenzoic acid [125]. 

In oxidized pristinamycin (80) the activated double bond of the dehydro-proline residue displayed the same reactivity towards thiols. Some water soluble derivatives of (80) were prepared by this route, but they were devoid of antibacterial activity. 

In view of the relative ease of stereocontrolled formation of the 26-di-alkylaminoalkylthio derivatives obtained from pristinamycin 11 which were active in vivo in association with pristinamycin I, the chemistry of these compounds was explored further. Their in vivo activity in association with pristinamycin 1 might be explained by oxidative metabolism of these thioethers in the animal model to the corresponding sulfoxides and/or sulfones. Due to the presence of different oxidizable functionalities including the hydroxy group (see Sect. 5.4.1), the conjugated double bonds (see Sect. 5.4.4), the amino function of... 

The use of different oxidizing agents for the conversion of the 26-dialkylamino-ethylthio derivatives of pristinamycin Ilg to the corresponding sulfoxides was investigated. The results of these investigations into the oxidation of 26-diethylaminoethyl thioether (94a=94, = R2 = Et) with m ta-chloroper-... 

Other classical oxidizing reagents for the sulfur-sulfoxide oxidation [132] were tested, and they nearly all gave the expected products but often without any control of the stereochemistry. Only Oxone which has been used for the formation of sulfoxides from sulfides [133, 134] gave an interesting result. Oxone is acidic and formed a water soluble salt with 26-diethylaminoethylthio pristinamycin Ilg (94a) and the oxidation, which could be carried out in water or aqueous ethanol between —20° and 5°, afforded in good yield a 95 5 mixture of the corresponding diastereomeric sulfoxides [135]. 

A first examination of the complexity of 26-dialkylaminoethylthio derivatives obtained from pristinamycin 11 (or the corresponding sulfoxides) would lead one to assume that reaction with ruthenium tetroxide could be expected to give products arising from oxidation taking place at any one of the centers indicated in Scheme 25. 

However, oxidation of the 26-diethylaminoethylthio derivative of pristinamycin IIb (94a), or the corresponding sulfinyl analog (97), using ruthenium tetroxide generated in situ from a catalytic amount of ruthenium dioxide with sodium metaperiodate as the co-oxidant, afforded the desired 26-diethylamino-sulfonyl derivative (98) in good yield. Alternative ruthenium catalysts included ruthenium trichloride or tris(triphenylphosphine)ruthenium(II) chloride. 

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