Diterpenoids from halimium viscosum

Urones, L.G.; Teresa, J. De Pascual; Marcos, L.Sánchez; Díez, David; Garrido, Narciso M.; Guerra, Richard

doi:10.1016/s0031-9422(00)82353-5

Cited by 50 publications

(26 citation statements)

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“…Physical and spectroscopic data of the synthetic product 3 were in good agreement with those reported for the natural product 16-hydroxy-ent-halima-5(10), 13-dien-15,16-olide. 10 In conclusion ent-halimic acid, a diterpene of known absolute configuration, 28 has been transformed into natural ent-halimanolides 1, 2, and 3, confirming their structure and establishing their absolute configuration. …”

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Synthesis ofent-Halimanolides froment-Halimic Acid

Marcos¹,

Pedrero²,

Sexmero³

et al. 2005

Synthesis

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Three natural ent-halimanolides have been synthesized from ent-halimic acid. Their structures have been confirmed as well as their absolute configurations established. Bestmann methodology has been used for the synthesis of butenolides and for the synthesis of g-hydroxybutenolides the Boukouvalas method has been employed.Annonaceae plants are a rich source of bioactive substances such as acetogenins. 1-4 The occurrence of natural diterpenes possessing hydroxybutenolide units has been reported frequently in plants of the genera Polyalthia, Acritopappus, Premna, and Cyathocalux (Annonaceae). [5][6][7] It is interesting to note that many species of these genera are widely used in folk medicine. 8 Genus Polyalthia has been widely studied, 9 in particular several alkaloids 11 and a large number of clerodane and ent-halimane diterpenes were isolated from Polyalthia longifolia. 10 In 1995 Hara et al. reported the isolation of three ent-halimanolides 1, 2, and 3. These compounds are the first ent-halimane diterpenes which have been isolated from Annonaceae plants. Their structures were elucidated by spectroscopic methods. Recently, the synthesis of the enantiomer 12 of 3 from (+)-hardwickiic acid (clerodane diterpene) was reported. In the present work, we report the synthesis of 1, 2, and 3, starting from ent-halimic acid, confirming the structure and establishing the absolute configuration of these natural products. ent-Halimic acid is the main component of Halimium viscosum (Villarino de los Aires) and has been used as the starting material in the synthesis of ent-halimanolides 13 and sesterterpenolides 14 similar to dysidiolide, 15 that show high anti-tumor activity, and chettaphanin I and II. 16 The synthesis of 1-3 is carried out in three parts:1. Reduction of C-18 and side chain degradation; 2. Functionalization of C-16; and 3. Synthesis of the butenolides and g-hydroxybutenolides.In the first part (reduction of C-18 and degradation of the side chain), the objective is the synthesis of methylketone 20. Several conditions and even strategies were developed in order to achieve this objective, first reduction and then degradation (Scheme 1) or vice versa (Scheme 2).For the transformation of the ester at C-18 several routes were attempted. The first employed a Huang-Minlon 17 reduction as the key step (Scheme 1). The hydroxyl group at C-15 was protected satisfactorily as methyl ether 5 or as the OTHP derivative 6; the subsequent reduction of C-18 with LiAlH 4 gave 7 and 8, respectively. tetra-n-Propylammonium perruthenate (TPAP) oxidation of these alcohols gave unstable aldehydes 9 and 10, respectively. These aldehydes were treated under Huang-Minlon conditions to produce 11 and 12 in 85% and 81%, respectively.The hydroxy derivatives 7 and 8 were subjected to other reduction procedures. The hydroxy derivative 8 was transformed into the xantogenate 13 by treatment with CS 2 and MeI. Reduction of 13 with n-Bu 3 SnH 18 gave 12 in a low 31% yield (Scheme 1). Reaction of 7 with N,N-dimethylphosphoramidic chloride and n-BuLi...

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confidence: 86%

Synthesis ofent-Halimanolides froment-Halimic Acid

Marcos¹,

Pedrero²,

Sexmero³

et al. 2005

Synthesis

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“…

Compound 1 (d 5.84, dd, Jϭ11.0, 17.0 Hz; 5.18, dd, Jϭ1.5, 17.0 Hz; 5.06, dd, Jϭ1.5, 11.0 Hz), and two oxygenated methine protons (d 5.61, d, J=3.5 Hz; 4.86, dd, J =3.5, 13.0 Hz).

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confidence: 99%

“…The present paper describes the isolation and structure characterization of four new halimane-type (rearranged labdane-type) diterpenes (1)(2)(3)(4) 3) from the acetone extract of the fruit of V. trifolia. Repeated chromatography of the acetone extract led to the isolation of 1-4.…”

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confidence: 99%

“…In the electron impact (EI)-MS, 1 did not show a molecular ion peak but showed fragment ion peaks at m/z 346 [MϪCH 3 Tables 1 and 2, and the planar structure of 1 was determined as illustrated in Fig. 1.…”

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“…Both compounds showed an [MϩNa] ϩ ion peak at m/z 387, which was 42 mass units [CH 3 COϪH] smaller than that of 1 in the positive FAB-MS. The 1 H-NMR spectra of 2 and 3 were similar to that of 1, except that the signal due to an acetyl group disappeared and signals assignable to H-7 in 2 and H-6 in 3 were shifted upfield by 1.13 ppm and 1.40 ppm, respectively, in comparison with those of 1.…”

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Four New Halimane-Type Diterpenes, Vitetrifolins D-G, from the Fruit of Vitex trifolia.

2001

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In a previous paper, 1) we reported the isolation and structure elucidation of three new diterpenes, vitetrifolins A-C, along with three known diterpenes from the acetone extract of the fruit of Vitex trifolia L. (Verbenaceae), which are called "Viticis Fructus" and are used as folk medicine for headaches, colds, migraine, eye pain, etc.2)The present paper describes the isolation and structure characterization of four new halimane-type (rearranged labdane-type) diterpenes (1)(2)(3)(4) 3) from the acetone extract of the fruit of V. trifolia. Repeated chromatography of the acetone extract led to the isolation of 1-4.Compound 1 (d 5.84, dd, Jϭ11.0, 17.0 Hz; 5.18, dd, Jϭ1.5, 17.0 Hz; 5.06, dd, Jϭ1.5, 11.0 Hz), and two oxygenated methine protons (d 5.61, d, J=3.5 Hz; 4.86, dd, J =3.5, 13.0 Hz). The 13 C-NMR spectrum of 1 gave 24 carbon signals, including two carbonyl groups (d 170.8, 170.7), one tetra-substituted olefinic bond (d 141.5, 132.7), one vinylic group (d 144.5, 112.1), one oxygenated quaternary carbon (d 73.1), and two oxygenated methine carbons (d 72.8, 66.2), suggesting 1 to be a diterpene with a 3-hydroxy-3-methyl-1-propenyl group and two acetyl groups. These 1 H-and 13 C-NMR spectroscopic signals were assigned with the aid of 1 H-1 H correlation spectroscopy (COSY), heteronuclear multiple quantum coherence (HMQC), and heteronuclear multiple bond correlation (HMBC) techniques as shown in Tables 1 and 2, and the planar structure of 1 was determined as illustrated in Fig. 1. The relative stereostructure was defined on the basis of difference nuclear Overhauser effect (NOE) experiments and the coupling constant values of the signals due to H-6, H-7, and H-8 in the 1 H-NMR spectrum. In the difference NOE spectra of 1, which were mainly carried out in C 5 D 5 N, because the 1 H-NMR spectral signals were rather congested in CDCl 3 , NOEs were observed between the respective protons, as illustrated in Fig. 2. Moreover, when the configuration at C-13 was postulated to be S*, the stable conformation of 1 with minimum steric energy was simulated using CAChe Four new halimane-type (rearranged labdane-type) diterpenes, vitetrifolins D-G were isolated from the fruit of Vitex trifolia L. (Verbenaceae). Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence.

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