Avermectin Bia

Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin Bia and avermectin Bib. It... 

Analogous sequences have been used in the synthesis of the ansa chain of rifamycin [100,101] and in the synthesis of the avermectin Bia spiroketal unit 52 [102]. The retrosynthetic plan used is described in Scheme 11.30 and leads to the same intermediate, 118. 

The glycosylation chemistry in White s total synthesis of avermectin Bia [13] is similar to Hanessian s synthesis of avermectin Bia (Scheme 12.9). Thus, the glycosidation of the... 

The two-stage activation procedure for oligosaccharide synthesis, which was developed by Nicolaou and applied to his synthesis of avermectin Bia [10]> was also employed in his total synthesis of efrotomycin [15] (Scheme 12.11). The chemo- and stereoselective glycosidation of the... 

AW 300) [44], and Naflon -SAC resin [19] (see above) are highly valuable solid-supported acid catalysts. This is nicely demonstrated in an avermectin Bia analog synthesis [43] Rham-nosylation of intermediate 5b with donor 5a gave target molecule 5c in quantitative yield (O Scheme 5). 

This class of macrolide antibiotic has mostly antiparasitic activity. Avermectin Bia (45) and ivermectin (46) (O Scheme 18) are used mostly in veterinary medicine, however, some semisynthetic derivatives are also used for treatment of onchocerciasis in humans [59]. The action of avermectin is believed to stimulate specific chloride ion transport systems increasing the membrane permeability to Cl ions via GABA (y-butyrate) receptors and non-GABA receptors [60]. 

These 3-dimensional structures are shown in Figure 4. The top panel shows avermectin Bia and 22, 23 dihydroavermectin Bia, from which we can see some general features of abamectin and ivermectin that are not obvious from the 2-dimensional representation. These include the rigid, corrugated planar form of... 

Figure 4. Molecular models of avermectins used in the specificity studies of Table I. Top panel avermectin Bia (left) and 22,23,dihydroavermectin Bia (right). Middle panel avermectins Bia (left) and B2a (right). Note differences in the C22 — C23 bonding, and its effect on orientation of the R2 ethyl group (arrows) in these free energy-minimized structures. Bottom panel avermectins A2a (left) and B2a (right), oriented to show the OCH3 or OH groups at R3 (arrows).

The 3-dimensional molecular models of the avermectins helped us to define the subtle structural differences recognized by the MAbs, but these models must be viewed and interpreted with caution. Since we could not invoke solvent interactions, we have no way to know what the differences may be between these gas-phase representations and the conformations assumed in solution. On the other hand, data for other hydrophobic compounds, including some macrolide antibiotics, suggests that their gas-phase and solution structures are very similar, and the major differences we observed in Figure 4 were in hydrophobic parts of the molecule. For this reason, we did not attempt to model the last analog in Table I, the 4" deoxy-4"epimethylamino avermectin Bi hydrochloride, even though it was the best competitor in the EIAs, because it is far more water soluble than the others. Another concern is that the samples compared in the competition EIAs were mixtures of isomers, e.g., abamectin is actually avermectin Bia Bib 80 20. Because it is virtually impossible to obtain the purified individual isomers for the EIA or other tests of antibody specificity, we can only assume that the competition EIA results primarily reflected how each MAb bound to the maior isomer. 

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