Milbemycins

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Interestingly, the latter was subsequently also obtained from a milbemycin fermentation and given the name milbemycin B41-D (see Fig. 2 for stmcture Bib)-... 

In several cases of syntheses of highly functionalized molecules, use of CH3Li-LiBr for ylide formation has been found to be advantageous. For example, in the synthesis of milbemycin D, Crimmins and co-workers obtained an 84% yield with 10 1 Z E selectivity.251 In this case, the more stable E-isomer was required and it was obtained by I2-catalyzed isomerization. 

Phosphine oxide-based olefination has been increasingly used as a synthetic method. The phosphine oxide (62). required for a synthesis of 3-milbemycin (64). has been prepared as a mixture of... 

Martin, R.J. (1995) An electrophysiological preparation of Ascaris suum pharyngeal muscle reveals a glutamate-gated chloride channel sensitive to the avermectin analogue milbemycin D. Parasitology 112, 252. 

When one of the reacting partners in the Wittig-Horner reaction, either the phosphine oxide or the carbonyl compound, has a double bond, the product is a diene. The Wittig-Horner reaction was utilized by Smith and coworkers in the total synthesis of milbemycin (equation 98)170. They found that when sodium hexamethyldisilazide was employed as a base, the desired E-diene selectivity is high (85%). Some examples from the literature where the Wittig-Horner reaction has been utilized for the construction of E-double bonds present in dienes and polyenes are given in Table 19171. 

Another incentive to this screening may have arisen from the discovery of two remarkably potent families of fermentation products with insecticidal and acaricidal activity, the milbemycins and the avermectins. Abamectin (a mixture of not less than 80% avermectin and not more than 20% avermectin is already... 

Structure Determination. The structures of a new group of pesticidal sixteen-membered lactones named milbemycin B, B2, and B were described in 1975 (4) on the basis of X-ray analysis. A later publication (5) gave details of isolation and structures of thirteen milbemycins, with spectral data. 

More recently, the new insecticide, fipronil (Figure 3.11), has been shown to act as a potent blocker of the GABA-regulated chloride channel. It is being used to control both foliar and soil insects9 whilst the avermectins and milbemycins can only be used against foliar pests. 

Included in this group are avermectins and milbemycins, which are fermentation products possessing a 16-member cyclic lactone, a spirochetal moiety, and a disaccharide unit. Abamycin, ivermectin, doramectin, and eprinomectin are major avermectins available for anthelminthic treatment of livestock, whereas moxidectin is a milbemycin with worldwide acclaim as a cattle anthelminthic (Fig. 4.7). 

Moxidectin is a semisynthetic milbemycin intended for treatment of endec-toparasites in cattle, sheep, and horses. It is administered by oral or subcutaneous routes at a dosage of 0.2 mg/kg bw in cattle and sheep, and 0.4 mg/kg bw in horses. 

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