Summer, Edward M.O. (2001) An approach to the synthesis of ingenane diterpenes. Doctoral thesis, Durham University.
Ingenol is the parent compound of the ingenane diterpenes. Certain C-3 fatty acid derivatives of these compounds are potent tumour promoters. Their mode of action is thought to occur through binding to and activation of the cell regulatory enzyme, protein kinase C. Central to the ingenane skeleton is a bicylo[4.4.1]undecanone-ll- one unit which is a rare example of //-a/M-intrabridgehead or inside-outside stereochemistry and is very strained. The structures are also highly oxygenated, ingenol itself is host to a cis-triol motif. To date ingenol has yet to succumb to total synthesis. Access to this system was envisaged via a tandem Birch reduction-divinylcyclopropyl (Cope) rearrangement of a phenylcyclopropane followed by a biomimetic pinacol-pinacolone skeletal shift. A model study in to the Birch reduction chemistry of phenylcyclopropanes is discussed and involves the preparation of phenylcyclopropanes substituted with methoxymethyl, vinyl and carboxylate groups. The reductive cleavage of the cyclopropane ring is observed with any functionality able to stabilise intermediate radical or anionic species or that can act as a leaving group. In the case of methoxymethyl substitution, reductive cleavage can be avoided by using proton sources; thus dihydro derivatives are readily available. The ring opening mechanism associated with vinyl substituted phenylcyclopropanes such as 2-phenyl vinylcyclopropane and 2-methoxymethyl-3-phenyl vinylcyclopropane has been shown to be particularly facile and is probably radical in nature. The possible utility of this methodology in the preparation of indenyl-type structures via 5-exo-trig cyclisation of radical intermediates has been investigated and led to the synthesis of 3-(2'-vinylcyclopropyl)-N,N, diethyl benzamide by way of Suzuki cross-coupling of the cyclopropyl boronate, ethyl 2-(4,4,5,5-tetramethyl[l,3,2]dioxaborolane)cyclopropanecarboxylate. In this case the presence of benzamide functionality allows a degree of reaction tuning (even in the presence of a vinyl group) so as to provide products of either reductive cyclopropane cleavage or those of aromatic reduction and related Cope rearrangement. The key Birch reduction substrate for ingenol synthesis, 1-(1,'2'- dihydroxycyclopentyl)-2-(2"methoxyphenyl)cyclopropane, was prepared from the cM-diene, Z-I-(cyciopent-l-ene)-2-(2'-methoxyphenyl)ethene, by dihydroxylation followed by cyclopropanation. Unfortunately the 2,5 rather than the desired 1,4- regioisomer was obtained from the Birch reduction step. Installation of electron withdrawing functionality such as an amide on the aromatic ring should overcome any such problem in the future. The 2,5 isomer forms an interesting hexacyclo acetal when heated or on contact with protic or Lewis acids.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||26 Jun 2012 15:23|