The total synthesis of 3Beta-hydroxynagilactone F

<p/>The investigations described in this thesis deal with the total synthesis of physiologically active nor- and bisnorditerpenoid dilactones (fig.1).<p/><img src="/wda/abstracts/i1033_1.gif"/><p/>The goal was to design a synthetic route for this class of natural products and its derivatives. From a retrosynthetic study of 3B-hydroxynagilactone F (42), which was chosen as target molecule, an approach, starting from ring B followed by annellation of ring A and ring C, seemed to offer good perspectives.<p/><img src="/wda/abstracts/i1033_2.gif" height="375" width="600"/><p/>Methylcyclohexanedione was used as starting material, representing ring B, and Robinson annellation with carbomethoxymethylinylketone yielded the AB ring system. This product could be stereoselectively transformed into the trans-fused bicyclic ketone 116, a crucial intermediate in the total synthesis. The method which was developed for this transformation was also applied in the synthesis of the trimethyl-analogue of 116, an intermediate, used in the synthesis of natural Products, <em>e.g.</em> drimane type sequiterpenes.<p/>Starting from 116 two possible routes were explored, which differed in the sequence of introduction of the two lactones varied. The first approach was the synthesis of the tricylic γ-lactone 117 and subsequent annellation of the δ-lactone. Different methods for the synthesis of 117 were investigated and ultimately introduction of a doubel bond, bromination, and cyclization resulted in the formation of the desired -lactone. The carbonyl function at C-9 can serve as handle for the annellation of 8-lactone.<p/>Initially the annellation was investigated using 2,2- dimethylcyclohexanone as a model compound for ring B. Aldolcondensation at C-8, followed by a dehydration, afforded an alkylideneketone. The carbonatomes 11 and 12 were introduced by an addition of dilithio acetate at the carbonyl at C-9. Cyclization of the adduct gave the - lactone. The choice of the aldehyde determines the side-chain at C 14 and the method therefore offers the Possibility to vary the diterpenoid dilactones at this position.<p/>This procedure was applied on the tricyclic γ-lactone 117. The results however were very disappointing. The introduction of the alkylidene side-chain could be nicely performed, but the addition of dilithio acetate failed. Once again it appeared that development of a method on a model compound is no guarantee for its applicability on more complicated compounds.<p/>The second approach started with the bicyclic ketone 116 to which the δ-lactone was annellated. Now, this reaction sequence could be performed without any particular problem and afforded the tricyclic product 119, which was however a mixture of the αand β-isomer at C-14.<p/><img src="/wda/abstracts/i1033_3.gif" height="209" width="600"/><p/>Treatment with base gave lactone opening to a diene carboxylic acid which upon irradiation stereoselectively afforded the<br/>δ-lactone 195 with the correct configuration at C-14. As the γ-lactone had to be introduced in a later stage of the synthesis it was necessary to activate the C-6 position. Regioselective transformation of 195 into the 7(8),9(11)-dienolide is therefore essential.<p/>Some methods have been investigated and the results are outlined in chapter 3. DDQ-dehydrogenation appeared to give the best results when applied on the tricyclic 7(8),9(11)-dienolide. A cyclization, analogous to that used in the synthesis of the<br/>γ-lactone 117, was performed on the intermediate 203 and this resulted in the formation of a small amount of the methyl ether of 3β-hydroxynagilactone F. The synthetic and racemic 3β-hydroxynagilactone F (42) could be isolated after treatment of the ether with boron tribromide at low temperature.<p/><img src="/wda/abstracts/i1033_4.gif" height="244" width="600"/><p/>The synthetic route, explored in this thesis leaves the possibility to vary the side chain C-14. Moreover, the substitution patern in ring A can be changed by functional group transformations, performed on the hydroxyl group Present in ring A