Pristinamycin acylation

Acylations of the hydroxy function of the picolinic acid residue occurred readily using standard acylation procedures reaction of pristinamycin with acid chlorides or anhydrides in the presence of pyridine or triethylamine afforded the corresponding esters (15) and the use of N or 0-chlorocarbonyl reagents afforded carbamates or carbonates. 

Hydrolysis of the enaminone (23) in acidic aqueous medium gave, in good yield, 58-hydroxymethylene pristinamycin (26). This compound was readily acylated, sulfonated and phosphorylated, using standard conditions, affording the corresponding 0-acyl, 0-sulfonyl and 0-phosphonyl derivatives (27). 

Elimination is however greatly enhanced under conditions which transform this hydroxy group into a good leaving group (protonation, acylation, phosphorylation. . . ) or conditions which can result in a change of the conformation of the macrocycle (acidic medium, cations, heat.. . ). One of the mildest methods for generating the trienone (47) involved treatment of pristinamycin 11 with AT-methylanilinium trifluoroacetate in THF [111]. 

A limited number of semi-synthetic 36-0-acyl pristinamycin 11 derivatives were prepared by acylation of the 36-hydroxy group with acid anhydrides or acid chlorides under classical acylation conditions [114]. In all cases the trienone (47) was formed as a byproduct (a large number of the reactions afforded the trienone as the only identifiable product), and isolation of the 36-0-acyl pristinamycin 11 derivatives was often difficult reflecting their ease of transformation into the trienone. 

In contrast to the reaction of pristinamycin 11 with acid anhydrides, where acylation was only observed with acetic anhydride, the reaction of pristinamycin IIa with acid chlorides (Scheme 10) was demonstrated to be of greater synthetic utility. However, the course of acylation depended strongly on the reactivity of the acid chloride. For example, the reaction of pristinamycin 11 with ethyl malonyl chloride in the presence of triethylamine or pyridine resulted in a quantitative conversion by tic into the ester (50, R = CH2C02Et, 60% isolated yield) whereas the use of more reactive acyl chlorides, for example ethyl chloroformate resulted in acylation of the 37-ketone function as its enol ether (see Sect. 5.4.2). If the acylation reagents were used in excess, a diacylated derivative pf the enol form of pristinamycin 11 (51) was obtained. 

Borohydride reduction of pristinamycin 11 derivatives with the allylic alcohol protected followed by separation of the resulting isomeric alcohols, acylation and subsequent deprotection (Scheme 14) was investigated as an approach to the selective synthesis of the 37-0-acyl analogues of the diols (60) and (61). 

Treatment of pristinamycin 11 with 1.1 equivalent of ethyl chloroformate or benzoyl chloride in the presence of triethylamine resulted in acylation of the 37-ketone in the enolic form, forming (69, R = OEt or Ph). 

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