Perhydroazulenes

Base catalyzed pinacol rearrangement of vicinal m-glycol monotosylates is a simple and useful general method for preparing perhydroazulenes. Thus, treatment of cholestane-5a,6a-diol 6-tosylate (115a) with either one mole-equivalent of potassium t-butoxide in f-butanol at 25° or with calcium carbonate in dimethylformamide at 100° gives a quantitative yield of 10(5 6/5H)... 

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]. 

A slight modification of the cyclopropyl conjunctive reagent transforms a cyclopentannulation into a cycloheptannulation. Thus, the 2-vinylcyclopropyllithium reagent 3, converted to its cuprate 4, generates a 1,2-divinylcyclopropane. Heating to only 180 °C leads to smooth Cope type rearrangement, driven by the release of the cyclopropyl strain, to create a perhydroazulene ring systerh of many sesquiterpenoids (Eq. 19) 20>. 

Danise B, Minale L, Riccio R, Amico V, Oriente G, Piattelli M, Tringali C, Fattorusso E, Magno S, Mayol L (1977) Further perhydroazulene diterpenes from marine organisms. Experientia 33 413 115... 

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. 

Thermolysis of the pyranyl acetate (228) gave rise to the isomeric perhydroazulenes (229a-b), presumably via intramolecular cycloaddition of an intermediate oxidopyrylium ylide.127 A similar cyclization occurred for the pyran-4-one (230), leading to (231a), which was isolated as the acetate (231b).128 No evidence was presented for an oxidopyrylium intermediate and the timing of carbonyl-enol tauto-merization is unknown. Thus, another mechanism may apply. 

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]. 

Portulal (Figure 8) is a novel diterpene containing a perhydroazulene nucleus and was isolated from Portulaca grandi-flora Hook. It inhibits the elongation of Avena coleoptile sections induced by IAA. It also accelerates adventitious root formation of Azukia epicotyl cuttings. 

Linear, as well as angular, benzannulated perhydroazulenes 88 and 89, which are related to some important classes of diterpenes, have been synthesized (Scheme 8.26) [34] by the intramolecular cydoaddition of the carbonyl ylide generated by the irradiation of a, 3-epoxyketone 86 and 87, respectively. 

Feldman, K.S. (1983) Photochemical activation of a-p-Epoxyketones. Formation of benzannelated perhydroazulenes by intramolecular trapping of a reactive intermediate. Tetrahedron Letters, 24, 5585—5586. 

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. ... 

Perchloropropylene, 938 Perchlorotoluene, 1131 Perchlorylbenzene, 803 Perchloryl fluoride, 802-808 Perfluorocyclobutanone, 171 Perfluorocyclopropane, 1237 Perfluoropropene, 117 Pefformic acid, 457-458, 759 Perhydroanthracene, 579, 580 Perhydroazulenes, 103,104 Perhydrosqualene, 1165 Perillyl alcohol, 568 Perinaphthanones, 1257 Perinaphthenones, 1257 Periodates, 809-815 Periodic acid, 815-819 Periplogenin, 614 Permaleic acid, 819 Permutit resins, 512 Peroxybenzoic acid, 458 Peropyrene, 1272... 

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 5 -perhydroazulene structure (524) is accessible by solvolysis of a la-mesylate (523)." The comparable reaction in the 5a-series requires solvolysis of a 1 -substituted steroid. In each case the migrating C jj-C o) bond has an onti-periplanar relationship to the leaving group. Related perhydroazulenes (526) are obtained by transannular cyclisation of the 5,10-seco-steroid (525). ... 

Crich and Batty [39] further extended the studies with cis and tram 4,5-dioxygen-substituted (as acetonide) hept-6-enoyl radicals and found that in the tram isomer 154 the 1-endo mode was suppressed when compared to that in the cis isomer 150 for conformational reasons. It was further extended to a tandem 1-endo trig - 5-exo dig radical cyclization sequence starting from the selenoester 158 to generate the perhydroazulenes 159. 

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... 

C-C Bond Construction. The addition of l,3-bis(silyl)pro-penes to a variety of electrophiles can be accomplished under Lewis acid catalysis or by using the corresponding 1,3-disilylallyl anion and this represents an important method for C-C bond construction. A single case of the addition to an a, 8-unsaturated ketone is reported in the context of the perhydroazulenes and photoaddition of l,3-bis(trimethylsilyl)propene to phenyl pyrroli-dinium perchlorate has been disclosed, though these examples will not be discussed in detail. 

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