Total synthesis, stereochemistry, and lithium–ammonia reduction of (±)-4-demethylaristolone and (±)-5-epi-4-demethylaristolone

Abstract

The total synthesis of (f-)-4-demethylaristolone (14) and its epimer, (2)-5-epi-4-demethylaristolone (15) is described. The key step of this synthesis involves the intramolecular cyclization of the olefinic diazoketone 12, which produces the two epimers, 14 and 15, in a ratio of approximately 2:1, respectively. The stereochemistry of the two epimers is unambiguously determined. It is observed that the lithium-ammonia reduction of 14 gives a dihydro derivative 16 containing trans-fused six-membered rings, while, interestingly, a similar reduction of 15 affords the corresponding cis-fused decalone system 26.Canadian Journal of Chemistry, 47.4299 (1969) Very recently, we reported (1) the total synthesis of the racemic form of the sesquiterpenoid aristolone (1) (2-4). This synthesis, in which the key step involved the cupric sulfate catalyzed intramolecular cyclization-of the diazoketone 2, was based on a model study involving the preparation of (*)-4-demethylaristolone. The model study, which has already been reported in preliminary form (5), was undertaken primarily with the aim of determining whether or not the crucial cyclization of the type 2 --> 1 would take place. That is, in order to initially avoid some of the stereochemical problems involved in the synthesis of aristolone itself, we first decided to prepare a diazoketone of the type 3. Successful intramolecular cvclization of the latter would then eventually lead to aristolone-type compounds lacking the C-4 secondary methyl group. We r e~o r t here the details of this model studv which, in addition to demonstrating the feasibility of the proposed synthetic approach, also produced some interesting results regarding the lithium-ammonia reduction of the final products, (_+ )-4-demethylaristolone and (&)-5-epi-4-demethylaristolone.Alkylation of 2-methyl-6-n-butylthiomethylenecyclohexanone (4) (6) with methallyl chloride in t-butyl alcohol in the presence of potassium t-butoxide gave, after removal (6) of the 11-butylthiomethylene blocking group from the product 5, a 56% overall yield of 2-methyl-2-methallylcyclohexanone (6). Conversion of the latter into the desired 2-methyl-2-methylpropenylcyclohexanone (7) required isomerization of the olefinic double bond from the terminal position to the more highly substituted internal position. Although a number of different methods were attempted in order to carry out this transformation, it was eventually found that simple acid catalyzed isomerization was the most convenient. Thus, treatment of the methallyl compound 6 with p-toluenesulfonic acid in refluxing benzene for 3 days produced, in 77 % yield, a mixture of compounds which, by gas-liquid chromatographic analysis, was shown to consist of approximately 80 % of the desired isomerized ketone 7, 17 % of the starting material 6 , and 3 % of an unidentified component. Careful fractionation of this mixture through a spinning band column allowed the isolation of nearly pure desired ketone 7. The fact that simple double bond isomerization had taken place was shown cle...

Structure relation of conjugated cycloalkenones and their ketals

“…In bulb-to-bulb distillation of 0.56 g of the crude oil at 50 °C (0.02 mm). 0.45 g was collected containing 55% of 8 according to VPC; the total yield was 57%: IR 1715 (C=0; COO), 1635 cm'1 (C=C); NMR (CDCla) 6.03 (t, 1 H, J = 1.5 Hz, vinylic), 4.18 (q, 2 H, J = 7 Hz, -OCH2CH3), 2.89, 2.31 (AB, 2 H, J = 17 Hz, COCH2), 1.25 (t, 3 H, J = 7 Hz, CH3CH2-); MS M+ 194, 2-(2-Methylallyl)-2,5-dimethylcyclopentanone (31). To 4.37 g (0.039 mol) of potassium tert-butoxide in 80 mL of dry benzene in a 250 mL three-neck flask equipped with a mechanical stirrer, an addition funnel, and a condenser was added 3.56 g (0.31 mol, 4 mL) of 2,5-dimethylcyclopentanone in 10 mL of dry benzene during 10 min.…”

“…The product was short-path distilled at 78-80 °C (10 mm); the first fraction of 1.4 g was pure 31 as shown by VPC and the second fraction of 7.49 g contained 43% of 31 (total yield 46%): IR 1730 (C(=0)C), 1640 cm"1 (C=C); NMR (CDC13) 4.87 (m, 1 H, vinylic), 4.73 (m, 1 H, vinylic), 1.7 (br s, 3 H, CH3C=C), 0.97 (s, 3 H, -CCHS); MS M+ 2-Acetonyl-2,5-dimethylcyclopentanone (32). 31 (1.99 g, 0.012 mol) was ozonolyzed in 150 mL of methylene dichloride at -78 °C. The excess of ozone was removed by a stream of nitrogen and the solvent was removed at 0 °C under reduced pressure on a rotary evaporator.…”