Avermectin allylic oxidation

That mercury(II) acetate allylic oxidation can be a useful reaction in the case of complex and sensitive substrates is demonstrated by the oxidation of avermectin A2a (38). The reaction, carried out in anhydrous toluene at 100 C for 40 min, was remarkably selective, allylic oxidation occurring exclusively at the 3,4-double bond with rearrangement to give (39) in up to 73% yield (equation 17). 

The avermectins also possess a number of allylic positions that are susceptible to oxidative modification. In particular the 8a-methylene group, which is both allylic and alpha to an ether oxygen, is susceptible to radical oxidation. The primary product is the 8a-hydroperoxide, which has been isolated occasionally as an impurity of an avermectin B1 reaction (such as the catalytic hydrogenation of avermectin B with Wilkinson s rhodium chloride-triphenylphosphine catalyst to obtain ivermectin). An 8a-hydroxy derivative can also be detected occasionally as a metabolite (42) or as an impurity arising presumably by air oxidation. An 8a-oxo-derivative can be obtained by oxidizing 5-O-protected avermectins with pyridinium dichromate (43). This also can arise by treating the 8a-hydroperoxide with base. 

Avermectins and milbemycins are produced by fermentation as mixtures containing either a C-5 hydroxy or methoxy group, of which the first are generally more potent antiparasitic agents. A procedure for the conversion of the allylic methyl ether to the desired alcohol involving oxidation by Hg(OAc)2, hydrolysis of the intermediate vinylether to the 5-ketone [37] and stereospecific reduction to the C-5-R-(p-) alcohol has been developed [38] (Fig. 6). 

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