The Chemistry of the Natural Order Cupressales. 46. The Structure of Nootkatone.

Abstract

A new sesquiterpene ketone, nootkatone, has been isolated from the neutral fraction of the acetone ext. of Chamaecyparis nootkatensis by two methods. The neutral fraction from 28 kg. heartwood (370 g.) was distd. through a fractionating column and the fractions b. 156-8°/5 mm. were redistd. through a spinning band column. Series of fractions boiling between 154 and 155° were obtained, the optical rotation of which varied from [α]D 91° to 148°. They were dissolved in 6 times their vol. of EtOH and treated with NaOAc and semicarbazide-HCl to give 25 g. crystals, which gave 15 g. pure nootkatone semicarbazone. A mixt. of the latter with 15 g. Bz2O and 45 ml. H2O was steam distd. and the distillate extd. with ether to give 5 g. nootkatone (I) as an oil, m. 36-7°, [α]D 195.5° (c 1.5, CHCl3), λ 238 mμ (ε 15,000), ν 1680 cm.-1, and the formula C15H22O. In the second method, the fraction b5 155-180° (105 g.) and 16 g. Girard P reagent were dissolved in 300 ml. EtOH contg. 30 g. HOAc and refluxed 40 min. After cooling it was poured into 2 1. H2O contg. 27 g. Na2CO3 and the mixt. extd. with ether to give 10 g. of a brownish oil which crystd. from petr. ether to give pure I; I semicarbazone m. 195-7°; 2,4-dinitrophenylhydrazone m. 157.5°. The ultraviolet and infrared spectra of I clearly showed that I is an α,β-unsatd. ketone and is thought to have the structure given. The ozonization of 118 mg. I in 20 ml. CH2Cl2 gave only HCHO isolated as its dimedon deriv. but no acetone was isolated. I (51.9 mg.) in EtOH in the presence of Pd-C was hydrogenated to give tetrahydronootkatone (II) as a viscous oil; its semicarbazone m. 210-11° (decompn)., [α]D 66.5° (c 0.09, CHCl3). In the presence of Adams catalyst 120 mg. I was hydrogenated to give a product, which after chromatography gave 30% oil and 70% crystals. The latter, tetrahydronootkatol (III), m. 76.5-77°, [α]D 13.9° (c 2.2, CHCl3). Oxidn. of 320 mg. III in 5 ml. pyridine with 400 mg. CrO3 in 5 ml. pyridine overnight gave a liquid, b6 152°, nD 1.4886, [α]D 54.1° (c 2.4, CHCl3), whose semicarbazone was identical with that of II. A sample of II prepd. by oxidn. of III was purified by ozonizing the unsatd. impurities and had [α]D 19.2°. Redn. of 300 mg. I in 5 ml. MeOH with 300 mg. KBH4 overnight gave 300 mg. of a viscous, uncrystallizable oil. The latter was heated with 300 mg. Se 12 hrs. to give eudalene isolated as its picrate. To locate the CO group, 1.3 g. II in 5 ml. ether was treated with MeMgBr prepd. from 0.2 g. Mg and 1.5 g. MeI in 5 ml. ether. After keeping overnight, it gave 0.9 g. of a pale yellow alc., ν 3620 cm.-1, with no CO band. On heating this alc. with Se at 330° 30 hrs. it gave 0.4 g. liquid; picrate m. 104-6°; trinitrobenzene adduct m. 121-2°. These were identical with the corresponding derivs. of 1,3-dimethyl-7-isopropylnaphthalene. The proton magnetic resonance spectrum of I in CCl4 showed a signal at 62 cycles/sec. due to a single proton on a double bond. The low frequency is due to the proton being next to a CO group. A signal at 103 cycles/sec. was due to 2 H atoms on terminal methylene group of isopropenyl group. Three sharp lines at 250, 223, and 207 cycles/sec. corresponded to three Me groups of which the last is due to a Me group in the system of the type COCH: CMe. All these facts favor structure I. The configuration at C7 is not known with certainty. It is present as β in eudesmol and the phys. properties of I suggest it to be similarly oriented in I. If it is correct, the Me group at C4 and the OH at C2 in III should be β-oriented, hydrogenation occurring at the least hindered side. [on SciFinder(R)]