Milbemycin analogs

Despite the considerable effort that synthetic chemists have expended on the synthesis of the avermectins only three partial or total syntheses have thus far been reported. In addition a number of syntheses of the less complex milbemy-cins or milbemycin analogs have been recorded [63, 149, 150]. Some of the milbemycin syntheses have been reviewed elsewhere [1, 2] and this section will focus on the synthesis of avermectins. 

In conclusion, convergent syntheses of four ivermectin analogs 40, and 45, 46 and two milbemycin analogs 50, 51 (mixture) from commerciallyavailable starting materials were achievid. 

The milbemycins are a family of 16 membered lactones produced by Streptomyces hygroscopicus. The structures are character zed By a b.b spiroketal unit, a side chain with eight carbon atoms, and a complex cyclohexene carboxylic acid. A synthetic route for the spiroketal and connecting chain, and an approach to a southern portion analog via Diels Alder Chemistry are described. 

On account of their interesting structure and the analogies to the spiroketal partial structures of, e.g., the milbemycins and avermectins, T. have been the target of numerous enantioselective syntheses. 

The critical three double bonds present in the anthelmintic ivermectin were introduced via the Wadsworth-Emmons or Julia reactions. The Mukaiyama procedure was used to construct 16-membered lactones. These analogs differ from ivermectin in lacking the diol system at C5 and C7, the alkyl substituents at C24 and C25, the oxymethylene fragment at Cs, and by replacement of the disaccharide at C13. A variation of this procedure was also successful in the synthesis of analogs of the miticidal milbemycin D. The biological activity of the synthetic analogs was inferior when compared to that of the naturally occurring compounds. 

The preparation of milbemycin H analogs is presented. The results of in vitro and in vivo biological evaluation of these compounds suggest that the strategy of molecular simplification to a minimum toxicophore is unlikely to yield a useful synthetic insecticide product in this field of chemistry. 

Milbemycin H analog HI was inactive in the in vitro assays, as well as in the whole animal tests. 

Ytterbium shift reagents also can promote cycloaddition reactions, in some cases more efficiently than the europium analogs (Danishefsky and Pearson, 1983). In chemistry apphcable to the synthesis of milbemycin/avermectin targets, <5% Yb(fod)j catalyzed the diene-acetaldehyde cyclocondaisation [eq. (9)], whereas one equivalent of zinc chloride was required to effect similar conversions in like yields. 

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