Natural avermectins

In applying mutasynthesis to the production of novel avermectins, the elimination of branched-chain a-keto acid dehydrogenase (BCDH) was targeted. This multienzyme complex is responsible for supplying the 2-methylbutyryl- and iso-butyryl-CoA starter units that initiate natural avermectin biosynthesis [21,29],... 

These results confirmed that branched-chain amino acid catabolism via the BCDH reaction provides the fatty acid precursors for natural avermectin biosynthesis in S. avermitilis. In contrast, B. subtilis appears to possess two mechanisms for branched-chain precursor supply. The dual substrate pyruvate/branched-chain a-keto acid dehydrogenase (aceA) and an a-keto acid dehydrogenase (bfmB), which also has some ability to metabolize pyruvate, appears to be primarily involved in supplying the branched-chain initiators of long, branched-chain fatty acid biosynthesis [32,42], Two mutations are therefore required to generate the bkd phenotype in B. subtilis [31,42],... 

A similar strategy has been developed in the avermectin system, using an S. avermi-tilis strain that lacks a branched-chain a-keto acid dehydrogenase (BCDH) activity. This dehydrogenase activity is required to produce the acyl-CoAs that are required for avermectin biosynthesis, and thus the BCDH mutant is unable to produce avermectin without the addition of exogenous fatty acids to the fermentation media. The addition of isobutyric acid or isovaleric acid allows the production of the natural avermectins, while the addition of non-natural carboxyhc acids results in the production of novel avermectins [92-94]. 

Invermectin is usually extracted from the soil of actinomycete Streptomyces avermitilis, the natural avermectins are 16-membered macrocyclic lactones and is found to be a mixture of 22, 23-dihydro structural analogues of avermectins and B, prepared by catalytic hydrogenation (reduction). In reality, avermectins are members of a family of rather structurally complex antibiotics obtained by fermentative process with the pure isolated strain of S. avermitilis. An intensive screening of cultures for the anthelmintic drugs exclusively from the natural products ultimately gave birth to this wonderful drug. 

It has been amply demonstrated that the natural avermectins invariably exhibit minimal biologic profile of activity, whereas invermectin has proven to be extermely useful and hence recognized for the management and treatment of good number of nematode infections. Besides, it is found to be active against arthropods that usually parasitize the animal folks. ... 

Extracted from the soil actinomycete Streptomyces avermitilis, the natural avermectins are 16-membered macrocyclic lactones that, on reduction of the C22-23 double bond, give rise to ivermectin (IVM), which is an 80 20 mixture of dihydroavermectin Bia and Bip, respectively. The natural avermectins have minimal biological activity, but IVM has proven to be quite beneficial in the treatment of various nematode infections. 

The previous discussion clearly shows that total synthesis provides a viable approach to the avermectin disaccharide for use in the synthesis of avermectins. An alternative source of the disaccharide unit is chemical degradation of a natural avermectin. It is worth noting that the chemical degradation approach to the avermectin disaccharide unit could in principle use any natural avermectin or mixture of avermectins as a starting material. The ready availability of several natural avermectins from fermentation makes this approach particularly advantageous when a large amount of material is needed in a short period of time. The first example of this route to an avermectin disaccharide was reported by Albers-Schonberg et al. in 1981 [5]. As part of the structure determination of the avermectins they subjected avermectin A2a 123 to ozonolysis followed by... 

It is clear from the examples described above that there are a number of viable approaches to derivatives of the avermectin disaccharide unit. The availability of these procedures has allowed the synthesis of two natural avermectins and one unnatural analog. In addition, it can be expected that the availability of the disaccharide unit will result in the synthesis of numerous additional avermectins in the near future. 

The resulting seco-acid methyl ester 131 was treated with nBu4NF( ) to remove the silyl ethers then saponified to afford the deprotected seco-acid. Macrolactonization with DCC followed by selective silylation of the C-5 hydroxl group afforded aglycone 132. Disaccharide 133 (derived from natural avermectin Bi, see disaccharide section) was then attached to the aglycone to afford penultimate intermediate 134. The crucial deconjugation of the C-2,3... 

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