Avermectins total synthesis

P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermectin disaccharide, benzyl a-L-oIeandrosyl-a-L-4-acetoxyoleandrolide, J. Org. Chem. 48 3489 (1983). 

This method of forming the oxahydrindene ring system was later applied to an elegant total synthesis of avermectin Ai,.96 ... 

Finally, oxidative cyclization (HgO, I2, hiA of tqjpropriately substituted alcoholic ethers formed the basis of Kay s stereoselective syntheses of both 4-hydroxy-l,7-dioxaspiro[S.S]undecane, an olive fly pheromone component, and ( )-talaromycin B (equations 4 and 5). More recently, Danishefsky et at have further extended the scope of this spiroketal-forming reactitm in their elegant total synthesis of avermectin Ai (equation 6). ... 

Isopropenyl carbonates 236 were introduced by Sinay [363] and were used with TMSOTf as a promoter. Reactions of imidazole carbonate derivatives 237 were assisted by ZnBr2 [522], whereas for imidazole thiocarbonate derivatives 238, AgC104 was used as the promoter [523, 524]. These methods were used in the total synthesis of avermectin Bla 245 by Ley [523,524] (Scheme 4.47). 

Ford, M J, Knigbt, J G, Ley, S V, Vile, S, Total synthesis of avermectin Bla. S3mtbesis of tbe carbobydrate bis-oleandrose fragment and coupling to the avermectin Bla aglycone, Synlett, 331-332, 1990. 

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... 

S. Hanessian, A. Ugolini and M. Therien, J. Org. Chem., 1983, 48, 4427. Later reports on the total synthesis of avermectin B, indicated that the yield of this transformation had been improved to 82% by using the lithium salt of the alkyne. No further comment was made by the authors. S. Hanessian, A. Ugolini, P. J. Hodges, P. Beaulieu, D. Dube and C. Andre, Pure Appl. Chem., 1987, 59, 299 S. Hanessian, A. Ugolini, D. Dube, P. J. Hodges and C. Andre, J. Am. Chem. Soc., 1986, 108, 2776 and references cited therein. 

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). 

The preparation of avermectins has been carried out by fermentation, microsomal oxidation of early fermentation compounds and by semi-synthetic methods [57,113]. Approaches to synthesize some avermectins such as abamectin [114] and ivermectin [115-117] have also been published. Recently the total synthesis of aver-mectin [118], avermectin A g [119] and the aglycones of avermectin A g and B g [120,121] have been reported. 

The synthetic plan to achieve the total synthesis of avermectin involves the preparation of the aldehyde fragment (A) from D-glucal tripivalate (114), and the ketone fragment (B) from D-ribose aldehyde(125). Coupling of (A) and (B) gives the macrolactone (C). The resulting lactone is reacted with disaccharide (D) to form avermectin A [119]. 

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