Descreve-se a síntese da 8-hidróxi-6,7-dimetóxi-3-metil-3,4-diidroisocumarina (±) kigelina, um metabólito bioativo encontrado em Aspergillus terreus e Kigelia pinnata. O ácido 3,4,5-trimetóxi-homoftálico após tratamento com nidrido acético na presença de piridina, sob refluxo, forneceu o ácido 2,3,4-trimetóxi-6-(2-oxopropril)benzóico. Redução deste último, seguido de ciclodesidratação resultou na formação da 6,7,8-trimetóxi-3-metil-3,4-diidroisocumarina, que sofreu desmetilação regiosseletiva fornecendo a (±) kigelina.A simple synthesis of racemic 8-hydroxy-6,7-dimethoxy-3-methyl-3,4-dihydroisocoumarin or kigelin, a metabolite of Aspergillus terreus and Kigelia pinnata, exhibiting several bioactivities, is described. 3,4,5-Trimethoxyhomophthalic acid was refluxed with acetic anhydride in dry pyridine to afford 2,3,4-trimethoxy-6-(2-oxopropyl)benzoic acid. Reduction of the latter followed by cyclodehydration yielded 6,7,8-trimethoxy-3-methyl-3,4-dihydroisocoumarin which on regioselective demethylation furnished the (±)-kigelin.
Keywords: dihydroisocoumarin, Kigelia pinnata, Aspergillus terreus
IntroductionKigelia pinnata (Syn. Kigelia africana) is a highly variable mono-specific genus of the family Bignoniaceae. K. pinnata (also known as the 'sausage tree' or Worsboom due to its large fruits) is cultivated in many parts of India as an ornamental and roadside tree 1 and in Africa where it grows as an endemic species in many areas and finds a variety of medicinal uses. 2 The plant has deep chocolate red flowers and gourd like fruit.Govindachari et al. isolated kigelin 3 as the major constituent of plant from the root heartwood of Kigelia pinnata DC. The structure of kigelin was established by chemical methods and spectroscopic techniques as 8-hydroxy-6,7-dimethoxy-3-methyl-3,4-dihydroisocoumarin (1) and it was concluded that the absolute configuration at C-3 was R on the basis of CD spectral analysis (Figure 1).Chaudary et al. have recently reported 4 the isolation of (3R)-kigelin from the extract of fungus Aspergillus terreus culture medium. Kigelin was shown to display significant activity against human pathogenic dermatophytes, Microsporum canis and Trichophyton longifusus and also exhibited potent xanthine oxidase (XO) inhibitor activity even better than those of 3-t-butyl-4-hydroxyanisole (BHA) and propylgallate (PG).Kigelin is an active ingredient of cosmetics and skin lotions and is likely to be responsible for skin healing properties. It is used in the removal of solar keratosis lesions on the skin, particularly the face, neck, hands and arms. 2,5,6. Kigelia cream containing kigelin as major constituent is used successfully against melanoma. Kigelin is known to cure certain types of eczemas and is also an active constituent of Bust Force Multi Toner Serum. 7 The great biological and commercial importance of kigelin together with its simple structure has made kigelin an attractive target for synthesis. [8][9][10][11][12][13][14] The aim of present study was to devise an efficient synthesis of commercially im...
