Studies towards the total synthesis of manoalide

Abstract

Two different synthetic approaches to the terpenoid natural product Manoalide are described. The first of these approaches was based upon a novel copper (I)-catalysed coupling reaction between Grignard reagents and -metallated cyclic enol-ethers. 4-Methyl-3-pentenyl magnesium bromide and 5-lithio-2,3-dihydrofuran were coupled in the presence of copper (I) cyanide to produce a vinylmetallic intermediate. The intermediate was reacted with a number of electrophiles to form trans-geometry homoallylic alkenol products with a very high degree of stereocontrol. Attempts to further elaborate the products of the coupling reaction to bring about the synthesis of manoalide were unsuccessful. The second approach to Manoalide was based upon the use of a carbo-magnesiation reaction between 4-di-butylamino-2-butyn-1-ol and a homoallylic Grignard reagent. In this fashion the trisubstituted C6-C7 double bond of the manoalide skeleton was constructed with a very high degree of stereocontrol. The product of the carbomagnesiation reaction was then further manipulated to prepare 2-trimethylsilyl-4-[(3'E,7'E)-10'-(2",6",6"-trimethyl-1"-cyclohexen-1"-yl)-8'-methyl-4'-formyl-1'-hydroxy-3',7'-decadien-1'-yl]-furan. Since Garst and co-workers have reported the conversion of this compound to Manoalide in two steps, its preparation constitutes a formal synthesis of the natural product.

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