Synthesis of ( ± )-Kigelin

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-trimetóxihomoftálico 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.


Introduction
Kigelia 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][10][11][12][13][14] The aim of present study was to devise an efficient synthesis of commercially important and bioactive dihydroisocoumarin 1.

Results and Discussion
We envisaged the synthesis of 1 using 3,4,5trimethoxyhomophthalic acid (4) as a key starting material.Saeed and Ehsan J. Braz.Chem.Soc.
Reduction of 5 with sodium borohydride gave the racemic hydroxy acid (6) which was cyclodehydrated using refluxing acetic anhydride to furnish 6,7,8trimethoxy-3-methyl-3,4-dihydroisocoumarin (7).In the IR spectrum of 7, the lactonic carbonyl absorption was observed at 1725 cm -1 .The protons of the C-4 methylene group adjacent to the stereogenic centre (C3) exhibited the diastereotopic effect characteristic of an ABX system. 17The hydrogen cis to side chain methyl resonated slightly upfield at δ 2.81 and the trans hydrogen slightly downfield, at δ 2.95 respectively.The H-3 (X) showed a multiplet at δ 4.56.The carbon signals for C-3 and C-4 appeared at δ 80.2 and 68.1.
Regioselective demethylation of trimethoxydihydroisocoumarin 7 was attained using boron tribromide under mild conditions (-78 °C, 20 min) to furnish kigelin 1.The presence of phenolic hydroxyl was confirmed by purple ferric chloride test and solubility in dilute aqueous sodium hydroxide.The lactonic carbonyl absorption was lowered to 1665 cm -1 due to chelation with 8-hydroxyl which appeared at 3440 cm -1 .
In summary, an efficient synthesis of racemic kigelin, a natural bioactive dihydroisocoumarin has been accomplished.

Experimental
Melting points were recorded using a MEL TEMP MP-D apparatus and are uncorrected. 1H NMR and the 13 C NMR spectra were determined as CDCl 3 or CD 3 OCD 3 solutions at 400 MHz (Bruker AM-400) and 100 MHz (Bruker AM-100), respectively.FT-IR spectra were recorded on an FTS 3000 MX spectrophotometer; mass spectra (EI, 70 eV) on a MAT 312 instrument and elemental analyses were conducted using a CHN-Rapid Heräus apparatus.All compounds were purified by thin layer chromatography using silica gel from Merck having a fluorescent indicator F254 (Merck) and the spots were detected under ultraviolet light.

( ± ) -8 -H y d ro x y -6 , 7 -d i m e t h o x y -3 -m e t h y l -3 , 4dihydroisocoumarin (1)
A 1 mol L -1 solution of boron tribromide in dry dichloromethane (0.55 mL) was injected into a stirred solution of (7) (0.1 g, 0.4 mmol) in dry dichloromethane (4 mL) at -78 ºC under argon.After stirring for 20 min., the mixture was poured into ice water (20 mL) and stirred for