Chemistry and synthesis of the lignan (–)-cubebin

Abstract

Contrary to the established literature, ' isocubebinic ether *, ' cubebinic ether ', and ' cubebinol ' are acid-catalysed cyclisation products, (IV), ( V I I ; R = OAc), and (VII: R = H), respectively. Their formation from (-)-cubebin (I) is discussed.The first synthesis of cubebin is described. (-+) -a-(3,4-Methylenedioxybenzyl)-~-(3,4-methylenedioxybenzylidene)succinic acid (XIII) is prepared by a double Stobbe approach and resolved with quinine. Reduction to the diol ( X X I ) and oxidation with manganese dioxide gives (+)-, (-)-, and (*)-hibalactone (XXII) [the first synthesis of the natural (-)-form] ; selective oxidation with this reagent gives dehydrocubebin (XXIII). (+)-, (-)-, and(+) -1sohinokinin (XXV) are obtained by hydrogenation of the corresponding hibalactones ; epimerisation of (+)and (-) -isohinokinin gives (-) and (+)-hinokinin (XXVI) respectively. By selective reduction with sodium aluminium hydride the lactone (-) -hinokinin is converted into the hemiacetal (-) -cubebin (I).THE structure and absolute stereochemistry of the lignan cubebin (I), a constituent of cubeb fruits (Piper cuubeba) was elucidated by the work of Haworth,l Mameli,2 and I~higuro.~ The accepted chemistry 495 of cubebin contains certain unusual features. Treatment of cubebin with halogen acids in acetic acid is said to give ' cubebinic ether ' (11), which is reported to be reduced to an alcohol, cubebinol (111), with sodium and alcohol. Further, a compound of unknown structure, ' isocubebinic ether ', is obtained from cubebin by reaction with sulphuric-acetic acid; this gives ' cubebinol ' with methanolic hydrochloric acid. In this paper the three named compounds are shown to be cyclisation products and their chemistry is rationalised. Later, the complete synthesis of natural (-)-cubebin is described. A r (11) -fCH20H + Ar (111) Ar = Lo O PN.m.r. and other spectral data (Experimental section) for natural (-)-cubebin are in agreement with structure (I), and show that it exists, in chloroform solution, as the hemiacetal. Although Jz.3 (4 Hz) can be measured, this value is not decisive in determining the orientation of the hydroxy-function. Treatment of (-)-cubebin with acetic and sulphuric acids, as described by Mameli,2c

Chemical constituents of peppers (Piper spp.) and application to food preservation: naturally occurring antioxidative compounds.

“…We identified this compound as (-)-cubebin [12] (20,21). On the basis of its spectral data we determined the other compound (mp 85.0-85.5°C) to be a 2,3-seco-7, 11-dehydrogermacranolide sesquiterpene lactone.…”

“…After separation of compound [1], the neutral fraction was subjected to column chromatography on silica gel, using a mixture of benzene-acetone (98:2) as eluant. Methyl piperate [7b] was obtained from samples 14-18, compounds [10] and [11] were obtained from samples [21][22][23][24][25][26], and compounds [8] and [9] were obtained from samples 32- …”

Melanogenesis Stimulation in Murine B16 Melanoma Cells by Piper nigrum Leaf Extract and Its Lignan Constituents

“…Table 2]. On the basis of comparison of the physicochemical data of 1 and 2 with those of the reported data, [7][8][9][10][11][12][13][14] 1 and 2 were identified as (Ϫ)-cubebin and (Ϫ)-3,4-dimethoxy-3,4-desmethylenedioxycubebin, respectively. The comparisons of 1 H-and 13 C-NMR spectral data of 1 with the reported data 11,13,14) are shown in Tables 1 and 2, respectively.…”

“…10) In fact, a fragment ion produced by C 7 -C 8 fission was observed at m/z 203 [corresponding to M ϩ (m/z 372)Ϫ18 (H 2 O)Ϫ151 (3,4-dimethoxybenzyl ion)] with 16% relative intensity in the EI-MS spectra of 2, whereas a fragment ion produced by C 7Ј -C 8Ј fission observed at m/z 219 [corresponding to M ϩ Ϫ18Ϫ135 (3,4-methylenedioxybenzyl ion)] had 5% relative intensity. In the EI-MS spectra of 3, a fragment ion produced by C 7 -C 8 Stimulation of Melanogenesis in Cultured B16 Melanoma Cells Melanogenesis activity in the cultured murine B16 melanoma cells is closely related to the amount of produced melanin which is estimated from the sum of the amount of melanin retained in the cells (intracellular melanin) and that excreted into the cultured medium (extracellular melanin). Thus, we evaluated melanogenesis activity on the basis of the sum of the amount of intracellular and extracellular melanin.…”

“…Fractions (hexane/EtOAc, 1 : 1, 106 mg) that showed a single spot of Rf-value 0.6 on TLC were collected and evaporated. The residue was recrystallized from benzene-hexane to afford 1 [7][8][9] [colorless needles, mp 125-128°C, Table 1, 13 C-NMR: Table 2, isolation yield, 62 mg, 0.07% from leaves]. The EtOAc soluble fraction (3.83 g) was submitted to chromatography over 240 g of silica gel column (4.5ϫ30 cm).…”