Synthetic approaches towards the synthesis of the milbemycin and avermectin family of antibiotics

Abstract

A Study directed towards the total synthesis of the simplest member
of the milbemycin/avermectin family of antibiotics, milbemycin 63
is described. The approach to the spiroacetal fragment of milbemycin
@3 involved the coupling of a lithium anion of 2R,3^-20-tetrahydropyranyl-
3-methyl-pent-4-yn-2-ol with a protected form of 4S,6S-4-
hydroxy-6-methanol-tetrahydropyran-2-one.
The synthesis of two such lactones, 4S,6S-4-hydroxy-40-(1'tert
butyl-1',1'-diphenyl-silyl)-6-(1'0-phenyl methyl)methanoltetrahydropyran-
2-one and 4Sy6Sp4-hydroxy-40-(phenyl methyl)-6-(l'Ophenyl
methyl)-methanol-tetrahydropyran-2-ohe from 1,6-anhydro-6,Dgluco
pyranose(levoglucosan) is described. The application of the
dibenzyl lactone to the construction of the milbemycin/avermectin
family of antibiotics is shown by the synthesis of 2^,4^,6^,8^,9R-
2-methanol-4-hydroxy-8,9-dimethyl-l,7 dioxaspiro-(5,5)-undecane,a
key intermediate required for a proposed synthesis of milbemycin 83.
The reaction of two organometallic reagents derived from ethyl-2-
bromomethyl-prop-2-enoic acid with phenyl oxirane to form ==-
methylene-'S' -lactones was attempted. It was found that the treatment
of phenyl oxirane with 3^-2-carboethoxy-allyl zinc bromide afforded
+-3-methylene-5-(phenyl methyl)dihydrofuran-2-one and not the
isomeric “^emethylene-'S’ -lactone.

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