Sequential cycloadditions for the synthesis of taxoid mimics and stereoselective synthesis of tamoxifen analogues via a new carbomagnesiation-palladium coupling reaction

Abstract

Studies towards the synthesis of TaxolRTM mimics 19 and 20 are described. The strategy involved two sequential Diels-Alder reactions to form the ABC ring system. The synthesis of aromatic analogue 19 was abandoned due to the lack of regioselectivity and low yields in the Diels-Alder reaction. More progress was made in the synthesis of norbornane analogue 20. In situ oxidation of methyl-2,5-dihydroxybenzoate, followed by cycloadditions with 2-triisopropylsilyl-1,3-butadiene and cyclopentadiene, respectively, gave the tetracyclic skeleton 56 in good yield. Further manipulations afforded compounds 69, 71, and 73, which were subsequently sent for biological testing with the hopes that they will display Taxol-like effects on microtubules. A sequential carbomagnesiation-palladium (0) coupling reaction was investigated. Treatment of a propargyl alcohol with vinyl magnesium chloride generated a magnesium-chelate intermediate, which was capable of undergoing a palladium-catalyzed cross coupling with aryl halides. The reaction was used in a stereoselective three-step synthesis of new analogues (99 and 100) of the breast cancer drug tamoxifen (74).