On the Chemistry of Ingenol, IV [1]

Abstract

A simple and fast procedure was worked out to prepare from the commercially available seeds of Euphorbia lathyris L. substantial amounts of the polyfunctional tetracyclic diterpene ingenol (la). Ingenol-3,4:5,20-diacetonide (1d) was treated with five different bases at two different temperatures to achieve epimerization to 8-epiingenol. In any case unchanged 1 d was obtained. By reduction of ingenol-3,4: 5,20-diacetonide (1d) with sodium in ether/2-propanol (9 R)-9-deoxo-9-hydroxyingenol-3,4:5,20-diacetonide (2b) was obtained and converted to the corresponding 5,20-monoacetonide 2e. Reduction of ingenol-5,20-acetonide (le) with LiAlH4 in tetrahydrofuran furnished the epimeric (9 S)-9-deoxo-9-hydroxyingenol-5,20-acetonide (3c).The (9 R)-monoacetonide 2e was used to prepare the 3-tetradecanoate 2c of (9 R)-9-deoxo-9-hydroxyingenol (2a). From the (9 S)-monoacetonide 3 c four 3-esters [butyrate (3d), tetradecanoate (3e), eicosanoate (3f), benzoate (3g)] of (9S)-9-deoxo-9-hydroxyingenol (3 a) were synthesized. The 3,4 : 5,20-diacetonides of 2a and 3a, i.e. 2b/3b were used to provide the 9-hexadecanoates 2 f and 3j. The irritant activities of the 3-esters of the (9 S)-series depend strongly on the nature of the acyl group, thus furnishing, e. g. the moderately irritant tetradecanoate 3e [compared to corresponding 3-esters lb of ingenol (la)] as well as the highly active benzoate 3g of 3 a. The (9 R)-3-tetradecanoate 2c exhibits comparable activity as its (9 S)-analogue 3e. Thus, the spatial orientation (R or S) of the 9-hydroxy function plays a significant but not a crucial role for irritant activity. Both epimeric (9 R)/(9 S)-hexadecanoates 2f/3j were non-irritant.

An Expeditious Procedure for the Isolation of Ingenol from the Seeds of Euphorbia lathyris

“…This plant has received worldwide attention as a renewable source of industrial raw materials (hydrocarbons and oleic acid), and mass cultivation has been attempted in westernEurope and the United States. In 1991, Hecker published a detailed procedure for the isolation of ingenol from the seeds of E. lathyris . This procedure is labor-intensive and relies on a series of solvent partitions and selective adsorption on Si gel to separate a fraction containing ingenol esters.…”

“…12 Ingenol (1a) is widely distributed within spurges, 9 but the seeds of the caper spurge (E. lathyris L., mole plant) are the only commercial source of this compound. 13 This plant has received worldwide attention as a renewable source of industrial raw materials (hydrocarbons and oleic acid), 14 and mass cultivation has been attempted in western Europe and the United States. In 1991, Hecker published a detailed procedure for the isolation of ingenol from the seeds of E. lathyris.…”

“…In 1991, Hecker published a detailed procedure for the isolation of ingenol from the seeds of E. lathyris. 13 This procedure is labor-intensive and relies on a series of solvent partitions and selective adsorption on Si gel to separate a fraction containing ingenol esters. This is then subjected to hydrolysis, and the parent alcohol is eventually purified by column chromatography.…”

On the Chemistry of Ingenol, Va. Preparation of Tritium-Labeled 3-O-Tetradecanoylingenol ([20-3Η]-3-TI)

“…Rotiszint 44 was purchased from R oth, Karlsruhe, FRG . Ingenol was prepared from the seed oil of Euphorbia lathyris [1], To m onitor the reactions, silica gel 60 F 254 pre coated TLC aluminium sheets from Merck, D arm stadt, FR G , were used. Spots were visual ized under UV light (254 nm) and by spraying with vanillin/sulfuric acid followed by brief heating at 100 °C.…”

“…A wide range of skin irritant ingenol-3-esters has been isolated from many species of the botanical family of Euphorbiaceae especially from the genus Euphorbia or were prepared by partial syntheses from ingenol [1][2][3][4]. M any o f them turned out to be tum or prom oters in the two-stage model o f tumorigenesis on mouse skin [5][6][7], In addition, in current efforts to develop certain Euphorbia spe cies as renewable oleochemical resources, 3-0-hexadecanoylingenol (3-HI) may be considered a potential risk factor o f occupational cancer [8,9].…”