Synthesis avermectin

Diols were converted to lactols by TPAP/NMO/PMS/CHjCN [352] or TPAP/NMO/ PMS/CH Clj-CHjCN [353] oxidation of a keto hemi-ketal by TPAP/NMO/PMS/ CH Cl in an avermectin synthesis yielded a lactol, via an intermediate retro-aldol [354], The 1,4-diols in Fig. 2.19 (R=C3H, Ph) produced lactones with TPAP/ NMO/PMS/CHjClj as did the 1,5-diol HO(CH3) C(OH)C5H, [46]. 

Alkenyl and aryl radicals are also useful for expedient synthesis of oxacyclic natural products. For example, the hexahydrobenzofuran subunit 12 for avermectin synthesis was obtained from the bromopropenyl ether 11 [13] (Scheme 6). A formal synthesis of morphine (15) was reported by Parker utilizing tandem radical cyclizations initiated by the aryl radical from the bromoaryl ether 13 [14] (Scheme 7). A closely related example for the morphine skeleton synthesis also employed aryl radical cyclization [15]. 

An important consideration in the planning of an avermectin synthesis is the source of the optically active disaccharide (L-oleandrosyl-L-oleandrose) unit 98. In principle there are two reasonable solutions to this problem. The first is to prepare L-oleandrose 99 by total synthesis (oleandrose is not commercially available) either from chiral precursors or by asymmetric synthesis then couple two oleandrose units to form disaccharide 98. An alternative approach is to prepare 98 by chemical degradation of a naturally occurring avermectin. In practice there are advantages to both approaches and both have been used for the synthesis of derivatives of oleandrose and disaccharide 98. 

The difficulty of effecting deconjugation of the C-2,3 double bond and the propensity for a C-3,4 double bond to move into conjugation with the C-1 ester have prompted Fraser-Reid and coworkers [58] to develope an alternative strategy for avermectin synthesis. Their strategy, which involves the use of intermediates with an exo double bond at C-4 rather than the more traditional endo double bond approaches, has not yet led to an avermectin synthesis but does provide an interesting alternative. Of course the ideal solution would be a... 

The Mukaiyama condensation method was also utilized in the synthesis of several antibiotics and related bioactive substances. These syntheses include apramycin, using 4-azido-2,3,6-tri-(P-benzyl-4-deoxy-) -D-glucopyranosyl fluoride (prepared from the corresponding a-D-glucopyranosyl chloride by the AgF method ) avermectin B , using protected sugar derivatives of oleandrosyl fluoride (a-L-Ole-F) and 0-(a-L-01e)-(1 4)-a-L-0le-F (both... 

SCHEME 15. Synthesis of an Avermectin B1 analogue by glycosidation of a trichloroacetimidate donor catalyzed by HC104-Si02. 

In the synthesis of avermectin Bla, the disaccharide fluoride 48 is prepared and coupled with avermectin aglycon 49 in the presence of SnCl2-AgC104 in dry ether to give protected avermectin Bla50 in 62% yield (Scheme 2.16) [23]. 

C-6,209,214 anhydro sugars,branched monosaccharides, fluori-nated amino sugars,difluorinated monosaccharides, and fluorinated monosaccharide phosphates,and phosphonates have been described. Further progress has been achieved in the synthesis and n.m.r.-spectral analysis of fluorinated avermectin Bu, tylono-lide, and neuraminic acid derivatives. " ... 

The title of this session. Guided and Serendipitous Discovery (within the symposium. Approaches to Rational Synthesis of Pesticides) focuses attention on the nature of the discovery, rather than the outcome. The discovery of the avermectin family of compounds was by no means serendipitous those who were seeking found what they sought. It is the purpose of this paper to record the manner of the seeking and the manner... 

Cross-cyclization of epoxides with homoallylic amines is an easy way to access tetrahydropyran moieties, which form the core structure of many biologically important natural products such as avermectins, aplysiatoxin, oscillatoxins, latrunculins, talaromycins, acutiphycins, and apicularens. Even though many methods are available for the synthesis of this moiety [14—24], its importance and wide applicability demands further methods. 

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 ... 

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