Natural phthalides

Zheng G-Q, Kenney PM, Zhang J, et al. 1993. Chemoprevention of benzo[a]pyrene-induced forestomach cancer in mice by natural phthalides from celery seed oil. Nutr Cancer 19 77-86. 

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. 

PLANT Sources, chemical structures and classifications of natural phthalides Chemical Structure of Phthalide... 

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. 

In this review, the natural phthalides of plant origin are classified into four types based on chemical structure (Fig. (2-6)) 1) 3-substituted phthalides 2) non-3-substituted phthalides 3) phthalide dimers and 4) phthalide isoquinolines. The 3-substituted phthalide derivatives are further classified into two subtypes, namely non-alkaloid phthalides (Fig. (2 and alkaloid phthalides (Fig. (3 . Phthalide alkaloids without the isoquinoline structure are always 3-substituted and are accordingly subclassified as the... 

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. 

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>. 

Introduction of two diaminophenylethylene moieties at the 3-position of the phthalide ring naturally also produces color formers exhibiting infrared absorption. As in Section 4.6.1, the first report93 encompasses a vast number of compounds such as 22 which was prepared by treating phthalic anhydride with 2 mol of 1,1-bisdimethylaminophenylethylene in acetic anhydride. 

Phthalides constitute a relatively minor class of natural products.25-30 However, their value as synthetic intermediates is shown by an extensive list of applications. The use of phthalides derived from metalation of N,N-diethylbenzamides in the... 

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. 

Kinetic and mechanistic investigations on the o-xylene oxidation over V205—Ti02 catalysts were carried out by Vanhove and Blanchard [335, 336] using a flow reactor at 450°C. Possible intermediates like o-methyl-benzyl alcohol, o-xylene-a,a -diol, toluic acid and phthalaldehyde were studied by comparing their oxidation product distribution with that of toluene. Moreover, a competitive oxidation of o-methylbenzyl alcohol and l4C-labelled o-xylene was carried out. The compounds investigated are all very rapidly oxidized, compared with o-xylene, and essentially yield the same products. It is concluded, therefore, that these compounds, or their adsorbed forms may very well be intermediates in the oxidation of o-xylene to phthalic anhydride. The ratio in which the partial oxidation products are formed appears to depend on the nature of the oxidized compounds, i.e. o-methylbenzyl alcohol yields relatively more phthalide, whereas o-xylene-diol produces detectable amounts of phthalan. This... 

However, the ketone VI/63 did not undergo transamidation reaction either under acidic or under basic conditions5 When the primary amino function in VI/63 was protected (as a phthalide by Nefkens reagent [49] [50]), the planned transformation of VI/64 to VI/1 via VI/66, VI/68, VI/69, outlined above and in Scheme VI/14, was realized in an overall yield of 56 % [10]. The behavior of the ketone VI/63 suggest an aminoacetal formation of type VI/73 [51]. Such a compound can be of interest for metallion transport phenomena in plants, because isomers of VI/63 are natural products and may have some functions in nature. A detailed analysis of this abnormal behavior is in progress [51]. 

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. 

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. 

Phthalides are valuable synthons for obtaining several biologically active compounds and natural products. Naphthols, anthraquinones and anthraquinone antibiotics, isoquinolones, phthalide isoquinolines, indolizidine and quinolizidine alkaloids, and berbine alkaloids have been synthesised with phthalides as the starting compounds. Some of the syntheses, which have interesting chemistry, are described below. The required phthalides, in some cases, have been synthesised through aromatic lithiation reactions, while in others by more conventional methods. 

CHEMISTRY AND BIOLOGICAL ACTIVITIES OF NATURALLY OCCURRING PHTHALIDES... 

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