Avermectin allylations

A mild procedure for the appendage of MOM groups to acid-sensitive substrates is illustrated by the protection of the allylic alcohol in Avermectin derivative 259.1 using [(methoxymethyl)thio]-2-pyridine (259 2) sitver(I) Inflate and sodium acetate in THF at room temperature [Scheme 4.259],479 Primary secondary and tertiary alcohols and phenols are methoxymethylated in good yield though phenols are slower to react. Reagent 259.2 (bp 66 °C/0.088 kPa) is easily prepared in 75% yield by the reaction of pyridine-2-thiol with dimethoxy-methane activated by trifluoroborane etherate. 

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. 

Emamectin is prepared from abamectin in four chemical steps [14-17]. Therefore, it is also a mixture of the two homologs Bia and Bib. The allylic hydroxy group at C5 of avermectins is the most reactive in the molecule. It has to be protected before reactions on the C4" hydroxy group can be performed. Reaction with t-butyl-dimethylchlorosilane and imidazole in N,N-dimethylformamide gives the 5-0-t-butyldimethylsilyl ether (Scheme 29.6.1). 

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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