The synthesis of Lacrimin A

Takle, Andrew Kenneth (1989) The synthesis of Lacrimin A. University of Southampton, Doctoral Thesis.

Abstract

A review is given of the various methods used to synthesise the spiroacetal fragments of the Avermectins and Milbemycins. The successful, convergent synthesis of the title compound, Lacrimin A (124), is described via fragments (88) and (127). The C10-26 spiroacetal fragment (88), containing all of the chiral centres and the (E) C14-15 trisubstituted double bond, was synthesised via the substituted allenol ethers (167) and (168). Deprotection and acid catalysed cyclisation of (168) afforded the unsaturated spiroacetal (128), which could be readily elaborated to (88). The isochroman-1-one (127) was prepared by a palladium-catalysed cross coupling of aryl iodide (201) and the alkenyl tin (211). Formation of the remaining (E) C10-11 double bond was accomplished by a Horner-Wittig coupling between phosphonate (230) and aldehyde (233). Despite good control of the C10-11 double bond some scrambling of the C8-9 double bond was observed. Deprotection followed by separation of the double bond isomers, by hplc, completed the synthesis of (124). An alternative synthesis of the (E) C14-15 double bond is also reported. This makes use of a recently discovered reaction which allows the stereoselective generation of di- or trisubstituted double bonds, but the Cu (l) assisted reaction of metallated cyclic enol ethers with organolithiums.(DX86224)

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