Studies toward a total synthesis of digitoxigenin from thujone

This thesis concerns studies directed towards a total synthesis of digitoxigenin 3c from thujone 1. The steroidal analog 85 had previously⁵ been synthesized from thujone and the strategy envisaged for the completion of the synthesis involved alkylation of 85 to produce 86a which, after deoxygenation of the Cl6-ketone followed by reduction of the nitrile, would produce the aldehyde 86b. Aldol condensation of the aldehyde 86b and glyoxylic acid (or an ester thereof) would result in the butenolide 87 which could be converted to the known digitoxigenin synthon 43 by hydrolysis of the C3-ethylene ketal. The steroid analog 85 was synthesized from the commercially available androst-4-ene-3,17-dione 6 by catalytic hydrogenation of the C4,5-double bond, to produce a mixture of the C5α-H and C5β-H diastereomers 88a and 88b, respectively. Separation by preparative liquid chromatography and protection of the C3-ketone of 88b as the ethylene ketal derivative resulted in the Cl7-ketone 89. Wittig reaction of 89 with methyltriphenylphosphonium bromide produced the C17-methylene derivative 91 which was oxidized with selenium dioxide to produce the allylic alcohol 92 and small amounts of the α,β-unsaturated ketone 93. Oxidation of 92 to the required α,β -unsaturated ketone 93 was achieved via the Swern methodology or, alternatively, by treatment with pyridinium dichlorochromate. Oxidation of the trimethylsilylenolether of 93 with DDQ resulted in the cross-conjugated dienone 85. A model study was conducted at this time utilizing the α,β -unsaturated ketone 93 in order to develop the necessary chemistry for elaboration of the butenolide ring. Thus akylation of 93 produced the nitrile 94, the C16-ketone of which was subsequently protected as the corresponding ethylene ketal derivative to provide the required C17β-nitrile 95a. Nuclear Overhauser difference experiments on both 94 and 95a confirmed that both compounds had the required 17β-configuration. Reduction of the nitrile with diisobutylaluminum hydride resulted in the aldehyde 95b which was alkylated with mentholglyoxylate, followed by reduction to produce the butenolide 98 and the trans ester 99. The approach to the synthesis of digitoxigenin was pursued by alkylation of the cross-conjugated diene 85 with diethylaluminum cyanide to produce 86a as a mixture of Cl7-epimers (ratio 2:1, on the basis of NMR). Separation of these isomers proved to be impractical and NOE-difference experiments on this mixture are consistent with the major isomer having the C17β-configuration.Science, Faculty ofChemistry, Department ofGraduat