Studies directed towards the total synthesis of tedanolide: Synthesis of the C(5)-C(21) segment via a highly stereoselective fragment assembly methyl ketone aldol reaction

Tedanolide and 13-deoxytedanolide are structurally complex, potent antitumor macrolides of marine origin which have attracted considerable attention in the synthetic organic community. This dissertation describes our synthesis of the C(5)-C(21) segement of tedanolide via a stereoselective aldol coupling of a C(5)-C(12) methyl ketone and a C(13)-C(21) aldehyde fragment. In Chapters I and II, we describe previously published research including the biological activities of tedanolide and 13-deoxytedanolide and ongoing efforts by other research groups to synthesize these molecules. Prior research in the Roush group had demonstrated that the stereoselectivity of aldol reactions between structurally complex aldehydes and methyl ketones is dependent upon the metal enolate employed, the α,β-stereochemistry of the aldehyde component and the β-alkoxy protecting group of the aldehyde component. The use of a lithium enolate and an anti substituted, α-methyl,β-alkoxy aldehyde was shown to give optimal selectivity for the syn- or Felkin diastereomer when the β-alkoxy group of the aldehyde was protected as a sterically less demanding methoxymethyl ether. The correct stereochemistry at C(13) of tedanolide requires a Felkin-selective aldol addition. In Chapters II, III and IV, we describe original research focusing on our attempts to design Felkin-selective aldehyde substrates which were then coupled with lithium, sodium, titanium and boron enolates of 3-methyl-2-butanone. Contrary to previously published research with similarly substituted aldehydes, we found that the β-alkoxy group of the aldehyde component could also be protected as a triethylsilyl ether and give high Felkin selectivity in the subsequent methyl ketone aldol reaction. In Chapter V, we argue that the global conformation of the aldehyde substrate along with the relative orientation of alkoxy protecting groups along the entire chain of a structurally complex aldehyde contributes significantly to the reactive transition state leading to the Felkin diastereomer. Last, in Chapter VI, we describe our synthesis of a C(5)-C(12) methyl ketone and the stereoselective aldol coupling with a C(13)-C(21) aldehyde fragment to comprise the C(5)-C(21) segment of tedanolide.