Total synthesis of lactarane and marasmane sesquiterpenes

Lactarane and marasmane sesquiterpenes are mostly found in nature as metabolites from mushrooms of the genera Lactarius and Russula . Because a considerable number of these compounds possesses a variety of interesting biological activities, they are assumed to take part in the mushroom's chemical defense mechanism. The total synthesis of these natural products via extension of the base-induced rearrangement of perhydronaphthalene 1,4-diol monosulfonate esters, initially designed for the synthesis of cis -hydroazulenes, is the key subject of this thesis.The first synthetic challenge was the total synthesis of the lactarane furanether B (Scheme 1). Upon exposure to Li(O t -Bu) 3 AlH in refluxing toluene mesylate 2 , prepared from the readily available ketone 1 , underwent rearrangement to the cis -fused cation intermediate 3 . Intramolecular trapping of the positive charge in 3 by the proximate alcoholate provided tricyclic ether 4 . Completion of the synthesis of the natural product was accomplished by an annulation method based on a Pummerer-induced cyclization reaction of compound 6 .Scheme 1As a second objective the synthesis of the marasmane skeleton via a tandem rearrangement-cyclopropanation reaction was investigated. Initial studies on model system 9 lacking the methyl group at C(8) demonstrated that this tandem reaction could be applied successfully for the synthesis of the tricylic core of marasmanes as followed from the formation of ketone 11 (Scheme 2). However, poor results were obtained with the fully substituted system 12 probably due to severe steric hindrance (Pitzer strain) in the cyclopropanation step ( 13 →14 ).In contrast the silyl enol ether 16 , prepared form the easily available dione 15 , rearranged readily to the normarasmane compound 18 upon treatment with the Lewis-acid MgI 2 . In this case, the better stabilized cyclopropylcarbinyl cation 17 compensated for the increased steric hindrance caused by Pitzer strain. Compound 18 was then further converted to the two 'simple' marasmanes 19 and 20 .Scheme 2Optically pure (+)- 21 , needed for the preparation of (+)-isovelleral via the tandem rearrangement-cyclopropanation reaction, was obtained via an enzymatic resolution of racemic 21 with Candida rugosa lipase (Scheme 3). The enantiomericaly pure building block (+)- 21 might also be used for the synthesis of optically pure lactaranes via the sequence developed for furanether B.Scheme 3The methodology developed for the synthesis of the marasmane skeleton was successfully applied in the synthesis of (+)-isovelleral. When mesylate 23 possessing an allyl group was treated with MgI 2 , ketone ()- 24 was obtained in high yield (Scheme 4). The best route to synthesize both aldehydes groups, present in (+)-isovelleral, proved to be the following. Isomerization of the double bond present in ()- 24 and enolization of the ketone followed by treatment with Tf 2 NPh gave ()- 25 . Selective ozonolysis of the allyl moiety in ()- 25 and subsequent treatment with NaBH 4 afforded enol triflate ()- 26 , which via palladium-catalyzed methoxycarbonylation, reduction and Swern oxidation gave (+)-isovelleral. When a different sequence was applied, the ozonolysis of the allyl group or the synthesis of the enol triflate moiety turned out to be troublesome.Scheme 4