Synthetic investigations in sesquiterpenoids

Abstract

Synthetic approaches to pinguisane sesquiterpenes, containing a cis?1,2,6,7?tetramethylbicyclo[4.3.0]nonane skeleton incorporating two vicinal quaternary carbon atoms and four cis?oriented methyl groups on four contiguous carbon atoms, isolated from liverworts, are described in this chapter. To begin with, a stereoselective formal total synthesis of ??pinguisene (13) and pinguisenol (12) starting from Hagemann’s ester (36) has been achieved. Thus, Hagemann’s ester 36 was converted into the allyl alcohol 35 via regioselective alkylation, ketalisation, and reduction. The ortho?ester Claisen rearrangement of allyl alcohol 35 afforded the ene ester 42, thereby creating the first quaternary carbon atom. Hydrolysis of the ketal and ester moieties transformed ene ester 42 into keto acid 52. Intramolecular cyclopropanation of the diazo ketone 53, derived from keto acid 52, afforded a 3:2 mixture of chromatographically separable tricyclic diones 55 and 56. Simultaneous regiospecific reductive cyclopropane ring cleavage and reduction of cyclohexanone in dione 55 with lithium in liquid ammonia furnished keto alcohol 57, which on deoxygenation followed by oxidation afforded the bicyclic ketone 30 (Schinzer’s precursor of pinguisenol 12 and ??pinguisene 13), constituting a formal total synthesis of these sesquiterpenes.

An enantiospecific total synthesis of pinguisenol (+)?12 and several other pinguisanes starting from trans?6?methylcarvone (70a) is described in the next section. trans?6?Methylcarvone (70a), obtained from (R)?carvone (65), was converted into trans?3,4?dimethylcarvone (71) using a 1,3?alkylative enone transposition strategy. Stereospecific reduction of ketone 71 followed by ortho?ester Claisen rearrangement of the resulting allyl alcohol 69 furnished ene ester 68. Intramolecular cyclopropanation of the diazo ketone 78, derived from ene ester 68, yielded the tricyclic ketone 67. Regiospecific reductive cleavage of the cyclopropane ring in 67 furnished the bicyclic ketone 80, which on deoxygenation afforded 10?methylene?pinguisane (66). Ozonolysis of 10?methylene?pinguisane 66 generated pinguisan?10?one (88). Alternatively, ozonation and Criegee rearrangement of the tricyclic ketone 67 yielded a 3:2 mixture of keto alcohol 92 and keto acetate 91. Reductive cleavage of the cyclopropane in keto alcohol 92 yielded pinguisane?8,10?dione (94). Keto acetate 91, on treatment with lithium in liquid ammonia, furnished keto alcohol (–)?57, which was converted into Schinzer’s ketone (–)?30 via deoxygenation and oxidation. Stereoselective 1,2?addition of vinylmagnesium bromide to ketone (–)?30 afforded pinguisenol (+)?12, the optical antipode of naturally occurring pinguisenol.

During exploratory studies toward chiral pinguisanes, a novel 1,4?homo elimination–based approach to chiral bicyclo[3.3.1]nonenes was discovered. Thus, treatment of the tricyclic alcohol 100, obtained from (R)?carvone 65 in seven steps, with methanesulfonyl chloride and pyridine furnished the bicyclo[3.3.1]nonene derivative 101, instead of the expected mesylate 96. To test the scope and generality of this reaction, various chiral bicyclo[3.3.1]nonenes were prepared from the corresponding tricyclic alcohols, including both optical antipodes of the bicyclic structural units (101, 152, and 151) of the sesquiterpenes upial (153) and trifarienols (154–158)