Of avermectin oxahydrindene

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

Additionally, in a carbohydrate-derived synthesis of the oxahydrindene portion of the avermectins, a Swem oxidation was performed on the alcohol (35), demonstrating further the range of functionality that can be accommodated under these conditions. ... 

A variant of this process was used to achieve a chain extension at C5 of a pentose derivative, allowing the construction of the oxahydrinden part of avermectins [59,156]. As shown in Scheme 11.49, the D-ribose derived aldehyde 217 was treated with ( )-trimethylcrotylsilane in the presence of BF3-Et20 [157]. This produced a mixture of three isomers in an 8.9 1.1 1.0 ratio, from which compound 218 was isolated in a yield of 78%. The subsequent steps allowed deoxygenation of the sugar ring to give the diol 219. This compound was, in turn, transformed into the... 

The nitrile oxide-olefin cycloaddition has been used to construct the oxahydrindene part of avermectins. The olefin was introduced at C3 of a glucofuranose unit, whereas the nitrile oxide was created by chain elongation at C5 [361]. 

The structural feature of avermectins (3) (Fig. 1) includes 6,6-spiroketal and a disaccharide unit in the northern part and an oxahydrindene unit in the southern part. Because of the sensitive hexahydrobenzofuran subunit, the C3-C4 double bond was incorporated at a late stage during the course of total synthesis. 

A powerful tandem 1,4-addition/cyclization was reported by Danishefsky in the total synthesis of avermectin A,., (15, Scheme 12.2) [53-55]. In the sequence, conjugate addition of thiophenoxide to enal 12 generates an intermediate enolate that is trapped by addition to the resident ketone. Subsequent oxidation of the sulfide in 13 to the corresponding sulfoxide and thermolysis provided the desired oxahydrindene 14 in 76% overall yield [54]. From advanced intermediate 14, only a few steps were required to complete the synthesis of the anthelmintic agent avermectin Aj (15) [54, 55], Fukumoto developed a stereoselective double Michael sequence for the construction of substituted bicyclo[2.2.2]octanes (Scheme 12.3) [56, 57]. The intramolecular transformation was conducted by treatment of 16 with base and afforded 17 as a single isomer in 58% yield. The sequence is no-... 

Both Fraser-Reid and Kozikowski have published details of their independent work using an intramolecular nitrile oxide cycloaddition approach to the oxahydrindene component (204) of the avermectins. 

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