Reid, Alison M. (1996) Approaches to the core structure of the squalestatins. Doctoral thesis, Durham University.
The squalestatins are a new family of natural products which display potent cholesterol lowering effects. Common to all these natural products is the highly oxidised bicyclic core and the aim of this project was to achieve a concise synthetic route to this core unit. Initial studies were carried out using 2-benzyloxycyclohexanone as a model template. Following conversion to the 2-oxa-3-oxo-spiro<4.5>decan-6-one via addition of the dianion of 3-(para- tolylsulphonyl)propionic acid, coupling of a C(2) fragment was explored. Addition of carboethoxymethylenetriphenylphosphorane, followed by oxidation to the diol and protection as the acetonide led to the formation of 4- Ethoxycarbonyl-(2,2-dimethyl-5"-oxodispiro[perhydro[l,3]dioxolane-4,r- cyclohexane-2',2"-(5"-H-furan)]-5-yl. The alternative order of addition of the C(4) and C(2) units has also been undertaken. Manipulation of the ester group to a silyl ether afforded a less reactive functionality and C(4) was manipulated to allow for the coupling of the next fragment to form the spiro lactone. The addition of the dianion of 3-(parc-tolylsulphonyl)propionic acid to4-((^t)butyldimethylsilyloxymethyl)-2,2-dimethyl-l,3-dioxa-spiro<4.5>decan-6-one failed and another route to the spiro lactone was explored. Formation of 4 - ((^t)butyldimethy Isilyloxymethy l)-2,2-dimethyl-1,3,7-trioxa- dispiro<220.127.116.11>tetradecan-8-one (I) was achieved by allylation at C(4) followed by hydroboration of the double bond and subsequent oxidation. The C(l) side chain could be added to the spiro lactone using allyl magnesium bromide without compromising the other functionality present. Acid treatment of 4-((^t)butyldimethylsilyloxymethyl)-8-methoxy-2,2-dimethyl-8- propyl-l,3,7-trioxa-dispiro<18.104.22.168>tetradecane (II) promoted deprotection of the acetonide followed by concomitant cyclisation to the desired 6-hydroxy-9-propyl- 8,12-dioxatricyclo<7.2.1,0>dodec-7-yl-l-methanol (III). This showed the viability of the retrosynthetic analysis as a route to core analogues of the squalestatins. Studies to the fully substituted core were commenced using cis-cyclohexadiene diol. The diol was protected as its p-anisaldehyde acetal before the formation of the Diels Alder adduct (IV) using 4-phenyl-l,3,5-triazolinone. However a lack of time prevented its manipulation to the a-alkoxy ketone species through Lewis Acid mediated cleavage of the acetal. In a second retrosynthetic plan 2-benzyloxycyclohexanone was coupled with methyl tetronate prepared following the procedure of Pelter. Preliminary studies towards the addition of the C(l) side chain have been undertaken and initial results seem promising
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||24 Oct 2012 15:06|