Phthalide naturally occurring

Two syntheses of hongconin (18), a naturally occurring isochroman-4-one which exhibits antianginal activity, have been described. One utilises the annulation of phthalide unit to optically pure dihydropyran-3-ones <96JOC455>, whilst a similar Michael addition to the bicyclic pyranone levo ucosenone and subsequent enolate methylation are essentials of the second route <96JOC459>. 

The lactones are the intramolecular esters of the corresponding hydroxy fatty acids. They contribute to the aroma of butter and various fruits. 15-Pentadeca-nolide is responsible for the musk-like odor of angelica root oil. Of the naturally occurring bicyclic lactones, phthalides are responsible for the odor of celery root oil, and coumarin for woodruff. 

The naturally occurring phthalides have been recently reviewed by Dean and others In this chapter only those obtained recently, and which have been synthesised through lithiation reactions are given. 

The naturally occurring Z-butylidene phthalide also can be synthesised from the phthalaldehydic acid using Wittig reaction. 

CHEMISTRY AND BIOLOGICAL ACTIVITIES OF NATURALLY OCCURRING PHTHALIDES... 

In this article, we review the chemical structures and sources of the currently known naturally occurring phthalides of plant. Recent advances related to the biological activities of the extensively investigated natural phthalides are also described. As examples, we focus on the phthalide ingredients and medical uses of three commonly used phthalide-containing TCM herbs. 

The basic core structure of phthalide is l(3H)-isobenzofuranone, which contains a benzene ring (ring A) fused with a y-lactone (ring B) between carbon atoms 1 and 3 (Fig. (1)). To date, all known natural phthalide compounds have been identified as derivatives of l(3H)-isobenzofiiranone. The structures of these derivatives either have the core structure substituted with one or more groups at different positions or contain a reduced form with one, two or no double bond(s) in ring A and various substitutions at different positions. The detailed structures of the naturally occurring phthalide derivatives identified from plants are discussed in the Classifications of Natural Phthalides Section below. 

Table I. Plant Sources of Naturally Occurring Phthalides...

The details of the classifications and chemical structures of four types of natural phthalides are illustrated in Figs. (2-6). Most of the isolated natural phthalides belong to the 3-substituted phthalide type, which accounts for about 61% of the total known naturally occurring phthalides, and of these, non-alkaloid phthalides constitute the most important subtype due not only to their abundance in nature (75 compounds identified) but also their extensively reported pharmacological activities. The pharmacological activities of individual phthalides are discussed in the following Biological Activity Section. 

Table 2. Summary of the Biological Activities of Naturally Occurring Phthalides of Plant Origin...

Two modifications which lead directly to anthraquinones without the need for the final oxidation step have been described. In one , the phthalide carries a phenylsulfonyl substituent in the 3-position, whereas in the other a 3-cyanophthalide is used. In this way the intermediate 535 formed by attack of the phthalide on the benzyne can collapse directly to an anthraquinone. A number of naturally occurring anthraquinones have been prepared this way h252... 

The phthalides and the important group of naturally occurring Cg-compounds, which can formally be considered as phenylpropane derivatives, are included after the hemiterpenes. 

Sargent MV (1987) Naturally occurring dibenzofurans. Part 9. A convenient synthesis of phthalides the synthesis of methyl di-O-methylporphyrilate. J Chem Soc Perkin Trans 1 231-235... 

Differently substituted allylsilanes, among them 1, have been used in the solid phase synthesis of naturally occurring phthalides (eq41). ... 

Knepper K, Ziegert RE, Brase S. Solid-phase synthesis of isoindolinones and naturally-occurring benzobutyrolactones (phthalides) using a cyclative-cleavage approach. Tetrahedron 2004 60 8591-8603. 

The phthalides occur in several natural products . They are also intermediates for the synthesis of a variety of natural products like naphthols, anthraquinone natural products, anthracyclic antibiotics, the phthalide isoquinolines, protoberberine alkaloids etc. 

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