The total synthesis of 3b-hydroxynagilactone F

The investigations described in this thesis deal with the total synthesis of physiologically active nor- and bisnorditerpenoid dilactones (fig.1).<img src="/wda/abstracts/i1033_1.gif"/>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.<img src="/wda/abstracts/i1033_2.gif" height="375" width="600"/>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, e.g. drimane type sequiterpenes.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.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.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.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.<img src="/wda/abstracts/i1033_3.gif" height="209" width="600"/>Treatment with base gave lactone opening to a diene carboxylic acid which upon irradiation stereoselectively afforded theδ-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.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 theγ-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.<img src="/wda/abstracts/i1033_4.gif" height="244" width="600"/>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