Total Synthesis of Eremophilane-type Sesquiterpenoids: (±)-Eremophilenolide, (±)-Tetrahydroligularenolide, and (±)-Aristolochene

Abstract

The total synthesis of the racemic forms of the eremophilane-type sesquiterpenoids eremophilenolide (21, tetrahydroligularenolide (3). and aristolochene (4) is described. The octalone 7 was converted via an efficient, regioselective route into the keto ester 12, which served as a common synthetic intermediate for the preparation of the three sesquiterpenoids. Successive subjection of 12 t o alkylation, hydrolysis, and decarboxylation afforded the keto acid 14. Hydrogenation of the latter provided both the cis-fused keto acid 20, which was readily converted into (i)-eremophilenolide (2), and the trnr~s-fused keto acid 15, which was similarly transformed into (i)-tetrahydroligularenolide (3). Conversion of 12 into the dithioketal 23, followed by desulfurization and treatment of the resultant olefinic ester 2 5 with excess mcthyllithium, provided the olefinic alcohol 27. Dehydration of the latter yielded (i)-aristolochene (4).La synthese totale des formes rackmiques des sesquiterpCnoi'des erCmophilenolide (2) du type eremophilane, tCtrahydroligularenolide (3) et I'aristolochtne (4) est dCcrite. L'octalone 7 a CtC converti en passant par un chemin regiosklectif efficace en &to-ester 12, qui sert d'intermkdiaire synthktique commun pour la prCparation de trois sesquiterpenoi'des. Lorsque I'on soumet 12 successivement a une alcoylation,

Synthesis of Sesquiterpenes via Silicon-Guided Rearrangement of Epoxydecalins

“…Finally, removal of the hydroxyl group on C-4 was achieved as described in the synthesis of compounds 40a,b by treatment of 102 with acetic anhydride/pyridine and reduction of the resulting 3-acetoxy-2-butenoyl esters with potassium in tert-butylamine. During this reaction the inversion in the configuration of C-4 took place as a consequence of the preferential protonation from the less hindered side of the molecule, opposite to the angular methyl C-14, to give an almost quantitative yield of a product that showed spectral data coincident with those described in the literature for (−)-aristolochene (83) [42].…”

Rearrangement of 4,5-Epoxy-9-trimethylsilyldecalines. Application to the Synthesis of the Natural Eremophilane (−)-Aristolochene

“…The organic layer was washed with aqueous NH 4 Cl, 10% aqueous NaOH, and brine, dried, filtered, and concentrated under reduced pressure. Column chromatography (hexanes) gave 1.08 g (89%) of compound 6a: oil; [R] 22 D -88 (c 1.2, CHCl 3 ); EM m/z 264 (M + , 46), 191 (19), 190 (94), 175 (53), 147 (84), 91 (20) 1.95-1.86 (2H, m), 1.79 (1H, dt, J ) 12.9, 3.5 Hz), 1.71-1.62 (2H, m), 1.61-1.51 (2H, m), 1.34-1.19 (2H, m), 1.12 (3H, s), 0.88 (3H, d, J ) 6.3 Hz), 0.82 (3H, d, J ) 6.6 Hz), 0.05 (9H, s, (CH 3 ) 3 Si); 13 16), 237 (19), 207 (28), 147 (24), 145 (22), 129 (21), 105 (22), 73 (100); HRMS calcd for C 17 H 32 -OSi, 280.2222; found, 280.2233 (M + ); IR (NaCl) 1460, 1246, 860, 831 cm -1 ; 1 H NMR δ 2.93 (1H, br t, J ) 2.6 Hz), 2.05 (1H, dd, J ) 13.5,4.8 Hz),m),m),m), 1.08 (3H, s), 0.89 (3H, d, J ) 6.6 Hz), 0.86 (3H, d, J ) 6.6 Hz), 0.05 (9H, s, (CH 3 ) 3 Si); 13 1.80-1.57 (4H, m), 1.50-1.40 (1H, m), 1.34 (1H, t, J ) 12.5 Hz), 1.25 (1H, m), 1.14 (3H, s), 0.86 (3H, d, J ) 6.4 Hz), 0.79 (3H, d, J ) 6.8 Hz), 0.73 (1H, dd, J ) 4.0, 12.8 Hz), 0,02 (9H, s, (CH 3 ) 3 Si); 13 C NMR δ 145.5 (C), 124.5 (CH), 67.8 (CH), 43.1 (CH), 38.0 (C), 37.9 (CH 2 ), 35.6 (CH 2 ), 33.9 (CH), 29.4 (CH2), 26.8 (CH 2 ), 25.0 (CH), 22.3 (CH 3 ), 20.9 (CH 3 ), 20.5 (CH 3 ), 0.3 (3CH 3 , (CH 3 ) 3 Si).…”

“…As a continuation of our research on silicon-guided rearrangements of epoxy decalines, we report here the synthesis and acid-promoted rearrangement of several 4,5-epoxy-9trimethylsilyl-eudesmanes and 15-nor-eudesmanes and the application of such rearrangements in a total synthesis of (-)aristolochene, an eremophilane sesquiterpene that has been isolated from Aristolochia indica, 16 Bixa orellana, 17 and Dumortiera hirsuta 18 and which is a component of the defensive secretion of some termites. 19 (-)-Aristolochene has been synthesized in racemic form 20 and also in enantiomerically pure form starting from (+)-valencene. 21 Results and Discussion 1.…”