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Synthetic studies towards the tetracyclic diterpenoids aphidicolin and stemodin Herbert, David John

Abstract

The work described in this thesis is concerned with the development of a general synthetic approach to the tetracyclic diterpenoids aphidicolin 8 and stemodin 9. This novel class of diterpenoids has to date been represented by aphidicolin 8 and stemodin 9. Although these materials contain different substituents, they do possess remarkably similar carbon skeletons. This work began with the transformation of the Wieland-Miescher ketone 46, using a six-step sequence, into the bicyclic ketal ketone 45. The conversion of this material into the next key intermediate, the tricyclic ketal enone 44 was accomplished in two manners. The first approach made use of, as the key reaction, the internal Wittig-Horner cyclization of the β,Є-diketo phosphonate 108 to the desired enone 44 while the second proposal involved the aldol condensation of the bicyclic diketone 131 to the desired enone 44. This second pathway was initially explored by means of a model system. The β,Є -diketo phosphonate 108 was prepared in the following manner. Alkylation of the enolate of 45 with methyl iodoacetate gave the keto ester 105. Saponification of the ester 105 gave the acid 123 which was converted into the corresponding acyl chloride and treatment of this material with the anion of dimethyl methylphosphonate gave the desired β,Є -diketo phosphonate 108. The bicyclic diketone 131 was prepared as follows. Alkylation of the enolate of the bicyclic ketone 45 with methallyl iodide gave the keto olefin 130 and oxidative cleavage of the olefinic double bond in 130 using osmium tetraoxide and sodium meta-periodate gave the bicyclic diketone 131. The next phase of this work dealt with the construction of the tetracyclic ketones 55 and 60, possessing the basic tetracyclic carbon skeletons of aphidicolin 8 and stemodin 9 respectively. The proposed synthetic pathway to these materials is discussed but only partially realized during the scope of this work. The photochemically induced addition of allene to the enone 44 gave the photoadducts 56 and 57. The keto olefins 56 and 57 were transformed into the keto esters 59 and 133, obvious precursors to the tetracyclic ketones 55 and 60.

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