Phthalide derivatives

Solberg isolated 5,7-dihydroxy-6-methylphthalide (113) from extracts of Alectoria nigricans (303) where it co-occurs with the benzyl ester, alectorialic acid (115). 

comparisons indicated that both the phthalide (113) and 5,7-dihydroxy-6-formylphthalide (114) occur in extracts of Alectoria capillaris together with the cogeneric benzyl esters, alectorialic acid (115) and barbatolic acid (116). It seems highly probable that these phthalides are artefacts of the isolation procedure rather than metabolites of the lichens (303). 

In addition to the known chromone siphulin (121), Shimada et al. 296) described the isolation of two new derivatives, oxysiphulin (122) and protosiphulin (123), from Siphula ceralites. The structures of these metabolites were determined by comparison of the H- and C-n.m.r. spectra with those of siphulin. Protosiphulin (123) is regarded as the biosynthetic precursor of siphulin (121). 

Huneck 174) isolated the new chromone 6-hydroxymethyleugenetin (124) from the lichen Roccella fuciformis. In addition the novel chromone glucosides galapagin (2), mollin (3) and roccellin (1) were isolated from Roccellaria mollis, Schismatomma accedens and Roccella galapagoensis while lobodirin (4) was isolated from Lobodirina cerebriformis 172, 175). The structure of these chromone glucosides have been discussed in Chapter 2. 

Seven new lichen xanthones have been isolated and identified in the past decade, and these are listed in Table 1. Six of these new compounds (125 —130) vary only in the degree of O-methylation and ring chlorination like all the previously identified lichen xanthones. However erythrommone (131), isolated from Haematomma erythromma, provides the first example of an O-acetylated lichen xanthone. 

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Phthalide derivatives are of pharmacological interest, as they show antitumor [294] and anticonvulsant [295] as well as antimicrobial activity [296] they have also been found to have useful herbicidal activity [297]. 

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 phthalide derivatives cnidilide, (.Z)-ligustilide, (3>S )-butylphtha-lide, neocnidilide, and Z-butyldienepthaHde and the furanocoumarins xanthotoxin and isopimpinellin have been reported as insecticides and... 

A new synthetic, low temperature approach to polyimides has recently been reported [112]. The synthetic scheme is based on dicyanomethylidene phthalide derivatives, which are synthetic analogs to the corresponding anhydrides. As shown in Scheme 33, pyromellitic dianhydride can be readily converted to the... 

Two promising herbicides, KIH-2031 250 and KIH-6127 251, were developed by Kumiai for the treatment of cotton and rice, respectively. Based on these structures, six new phthalide derivatives (252-254 X = O, S) were prepared as potential herbicides. Of these, compound 252 (X = 0) was found to be very effective in combating Echinochloa, the largest weed problem affecting rice paddies. Under the trade name Pyriftalid, this compound was registered for use in 2001 by Syngenta. It is combined with cinosulfuron and marketed under the name APIRO Ace GR as a broad-spectrum herbicide <2001MI205>. 

Diaryl phthalides, particularly phenolphthalein 281 and several phthalides derived from it, are widely used for the preparation of cardo polymers. The term is derived from the latin word for hinge or pivot, which is an apt name given that the aryl substituents are hinged on the C-3 carbon of the phthalide. In one application, compound 281 was used to prepare phthalamide 282 and both bisphenols were copolymerized with terephthaloyl chloride 283 to form polyesters. These formed strong flexible fdms with improved thermal stability and solubility <1997PSA3227>. 

Oxazolines may be used as ortho directors in phthalide syntheses analogous to those shown in Schemes 11-14. The phthalides derived from oxazolines have been further transformed to polycyclic aromatics by a route that is analogous to, and perhaps more general dian, those shown in Scheme 12. An efficient synthesis of the lignin lactones chinensin and justicidin along such lines was reported by Meyers (Scheme 15). ... 

Main components Up to 0.8% essential oil in the fresh herb, which is partly lost during drying. Phthalide derivatives as well as diacetyl are aroma carriers [48]. The monoterpene fraction represents app. 95% of the herb oil and contains mainly limonene, myrcene and Z-ocimene [49], The essential oil produced from the fruits (they contain up to 2.5% oil) is considered more valuable (see also [50] for the corresponding oleoresins). 

Apart from acetone-dried G. candidum IFO 4597, intact whole cells of various strains of G. candidum have been found to be useful for asymmetric reduc-tions(75 78, 101, 120 167 171) For example, methyl 2-acetylbenzoate was reduced by G. candidum ATCC 34614, IFO 5767 or IFO 4597 as well as by other microorganisms such as Mucor javanicus, Mucor heimalis, Endomyces magnusii, Endomyces reessii and bakers yeast to afford phthalide derivatives (Fig. 15-26) which have various pharmacological profiles such as relaxant, antiproliferative or antiplatelet effects, etc.[171). 

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... 

Table 3. The Anti-Proliferative Activity of Different Phthalide Derivatives in the Primary Culture of Mouse Aorta Smooth Muscle Cells...

In the same chemical series, a new phthalide derivative, corollosporine A (26), was identified by spectroscopic data and chemical reactions from the filtrate culture of Corollospora maritima Werderm (Halosphaeriaceae) collected in the North Sea. This Ascomycotina is an obligate marine fimgus that uses rotting algae and driftwood as substrates2. 

Phthalide derivatives are of major importance in the dye industry, particularly in the area of recording material color formers. Pressure-sensitive carbonless copy paper and thermal recording paper are typical applications. Five principal structural classes have been developed extensively the xanthene dyes (fluorans (208)), 3,3-diarylphthalides (209), spirofluorenes (210), 3,3-bis(di-arylethylene)phthalides (211), and 3-substituted phthalides <84Mi 208-03>. Some of these structures are common to many familiar acid/base indicators, dyes, biological stains, or laser dyes such as fluorescein (212) and phenolphthalein (213) ,... 

Phenolphthalein (213) and its derivatives have found application in the polymer area. Phenol-phthalein itself (213) and substituted derivatives were polymerized with 2,6-dichlorobenzonitrile to form heat-resistant polycyanoaryl ethers <89JAP(K)01225631). A tetrabromo derivative (256) was polymerized with epichlorohydrin to form flame-retardant epoxy resins. The phthalide-derived... 

Scheme 18). To overcome this situation we were left with only one solution i.e. to effect the isomerisation of 90 into 89 (Scheme 19) which was then elaborated to the benz-phthalide derivative 98. 

Tertiary benzamides can be efficiently metallated at the ortho position by Bu Li at -78 °C in the presence of TMEDA the aryl-lithium derivatives thus produced react well with a range of electrophiles. Of particular relevance to this section of the Report is their reaction with ketones leading to the phthalide derivatives (56). 3-Aryl-3-methylphthalides (57) are available from a Friedel-Crafts reaction between o-acetylbenzoyl chloride and arenes using stannic chloride as Lewis acid. ° A total synthesis of the phthalide derivative iso-ochracinic acid (58) has been reported. ... 

Lo, J. and Pearce, E. M. Flame-retardant epoxy resins based on phthalide derivative. /. Polym. Sci. Polym. Chem. Ed., 22, 1707 (1984)... 

Subsequently, a Pd-mediated cyclocarbonylation reaction of MBH adducts was developed and then applied in the synthesis of quinoline-phthalide derivatives containing the lactone structure. Adducts 229 are sequentially treated with Pd2(dba)3 and carbon monoxide to provide tetrasubstituted olefins 231 in 70-85% yield (Scheme 4.74). Phthalide 232 could be isolated as major... 

In 2004, Cheng and co-workers reported a nickel-catalyzed cyclization of 2-haloesters with aldehydes to phthalides. Here, hy using Ni(n) as the catalyst, phthalide derivatives were produced in excellent yields with high chemoselectivily under mild conditions (Scheme 2.162a). In addition to five-memhered products, this methodology can he further applied to the synthesis of six-memhered lactones. The reaction of methyl 2-(2-bromophenyl)-acetate with henzaldehyde under similar reaction conditions afforded a six-membered lactone in a 68% yield. A possible catalytic mechanism for this cyclization was also proposed. Reduction of nickel(ii) to nickel(O) hy using zinc powder is likely to initiate the catalytic reaction. Oxidative addition of atyl iodide to the nickel(O) species yields the nickel(ii) intermediate. 

These monomers could be readily converted to phthalimidines by reaction with NH3 or aniline where the oxygen of the phthalide ring became either an -NH or -N( >, respectively No appreciable enhancement of char or oxygen index was noted when compared to the phthalide derivatives. 

The mononuclear phenol compounds isolated from lichens can be subdivided into three major categories, namely the orsellinic acid, the phloroacetophenone and the phthalide derivatives. These are discussed in turn. 

The resulting dialdehyde was converted to derivatives. The reaction between phthalic anhydride and TNT is reported to form a phthalide derivative as shown in figure 8-58. However the reaction could not be duplicated. When TNT couples with diazonium... 

In 2014, Yang and Yoshikai reported enantioselective intramolecular hydroacylation reactions of ketones and olefins using cobalt-chiral diphosphine catalysts (Scheme 10.7) [21]. A cobalt catalyst generated by the reduction of CoBr2 with indium powder in the presence of l,2-bis((2R,5R)-2,5-diphenylphospholano)ethane ((R,R)-Ph-BPE) promotes cyclization of a variety of 2-acylbenzaldehydes to afford phthalide derivatives in moderate... 

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