Perhydroazulene synthesis

These procedures should be widely applicable to perhydroazulene synthesis. 

The "acyl effect" proves crucial in the formation of the perhydroazulene systems cyclization can only take place with the presence of an acyl group on the TMM portion whereas the parent hydrocarbon fails. For example, treatment of substrate (51) with the palladium catalyst gave a mixture of the bicyclic compounds (52) and (53) in 51% yield. The formation of endocyclic olefin (52) is presumed to occur when the first formed (53) was exposed to silica gel during purification [22]. This intramolecular cycloaddition strategy was utilized in a highly diastereoselec-tive preparation of a key intermediate (54) in the total synthesis of (-)-isoclavuker-in A (55) (Scheme 2.16) [21]. 

Hudlicky, T., Reddy, D.B., Govindan, S.V., Kulp, T., Still, B. and Sheth, J.P., Intramolecular cyclopentene annulation. 3. Synthesis and carhon-13 nuclear magnetic resonance spectroscopy of bicyclic cyclopentene lactones as potential perhydroazulene and/or monoterpene synthons. J. Org. Chem., 1983, 48, 3422. 

The biological activity displayed by the perhydroazulenes, ranging from diuretic and anti-inflammatory to antitumor, combined with the unique bicyclo [6-3-0] system make them very attractive synthetic targets. The approach of Trost and Higushi to this class of compounds, exemplified by the total synthesis of isoclavu-kerin 65 (Scheme 12.12) [34], has the distinctive feature that it allows the simultaneous formation of both the five- and seven-membered rings through a palladium-catalyzed formal [3+2] cyclization as its key step [35]. 

When the inner C-C bonds of the cyclopropane, adjacent to the olefinic bond of the cycloadducts 38 and 39, are cleaved, Q bridged tricyclic compounds 100 (compare [74]) like cedrene 101 (Sch. 19) [19,61] are readily available. If both inner bonds of the cyclopropane ring are cleaved during the synthesis, the perhydroazulen skeleton can be obtained easily like in the synthesis of rudmollin 102 [77]. 

Thermolysis of these yields the diketones (95) which are useful compounds for the synthesis of the perhydroazulenes This specific example (95) was converted into the natural product daucene (96). Others have also described the photocycloaddition of the enone (92) to the cyclobutene (93) to afford the (2+2)-adduct (94) in 24 % yield. The adduct was transformed into the natural product balanitol (97). The triplet state of conjugated enones can be photochemically reduced by sodium borohydride. ... 

Tosylate rearrangement. Mazur devised an ingenious scheme for the synthesis of perhydroazulenes and first explored the stereochemistry by applying the reaction in the steroid series. Cholestane-5a,6a-diol 6-tosylate (1) is converted quantitatively into the A-homo-B-nor-5-ketosteroid (2) when refluxed with finely divided calcium carbonate-dimethylformumide for 6-8 hrs. or heated with potassium i-butoxide in f-butanol at 100°, C holeNtune-4( ..5 -diol 4-tosylate (3) gave A-nor-B-homo-.5-... 

This methodology was featured in the synthesis of perhydroazulene sesquiterpenes such as damsinic aid (66) and confertin (67). The rearrangement of divinylcyclopropanes 63 is more effective under combined thermal and photochemical conditions, which also minimizes the competing production of 65. 

The 1,3-cycloaddition of ethylenes to benzene and its derivatives, giving rise to dihydrosemibullvalenes, has been known for a number of years and the reaction has recently been reviewed.84 The reaction with cyclopentene as olefin has been the subject of several earlier reports.10 Its light-induced addition to anisole can be used as a stereospecific synthesis of perhydroazulenes 35 the adduct (18) is formed in 85% yield. Its consumption of only one mole of hydrogen on catalytic hydrogenation and its failure to undergo photosensitized decomposition have been... 

Okuno, T., and T. Matsumoto Synthesis of a cw-Perhydroazulene Derivative Related to Grayanotoxin. Tetrahedron Letters 1969, 4077. 

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