Isocoumarins acids

The biosynthesis of ochratoxin A has been studied using both and C-labeled precursors. In preliminary studies, Ferreira and Pitout (1969) showed that DL-[l- C]-jS-phenylalanine was incorporated into ochratoxin A by cultures of A. ochraceus. Hydrolysis of the labeled ochratoxin A with 6 N hydrochloric acid gave the isocoumarin acid 7 and L-jS-phenylalanine. The amino acid was found to contain all the activity. These results were confirmed by Steyn et al. (1970) and Maebayashi et al. (1972) using L-[f/- C]- -phenylalanine, as well as by Searcy et al. (1969) using [1- " C]-jS-phenylalanine. 

The origin of the carboxy group at C(8) was established by Steyn et al. (1970) through addition of DL-[m /zj /- C]methionine to a resting culture of A. ochraceus. The resulting radioactive ochratoxin A was hydrolyzed and the isocoumarin acid, 7, was converted into the acid azide, 10. Schmidt decarboxylation of 10 yielded active carbon dioxide, whereas the amine (11) contained no activity. 

The isocoumarin 151 is prepared by the intramolecular reaction of 2-(2-propenyDbenzoic acid (149) with one equivalent of PdCbjMeCN) . However, the (Z)-phthalide 150 is obtained from the same acid with a catalytic amount of PdjOAc) under 1 atm of Oi in DMSO, alone is remarkably efficient in reoxidizing Pd(0) in DMSO. The isocoumarin 151 is obtained by the reaction of 2-(l-propenyl)benzoic acid (152) under the same conditions[4], 2-Vinylbenzoic acid (153) is also converted into the isocoumarin 154, but not to the five-membered lactone) 167,170],... 

Aryl- or alkenylpalladium comple.xcs can be generated in situ by the trans-metallation of the aryl- or alkenylmercury compounds 386 or 389 with Pd(Il) (see Section 6). These species react with 1,3-cydohexadiene via the formation of the TT-allylpalladium intermediate 387, which is attacked intramolecularlv by the amide or carboxylate group, and the 1,2-difunctionalization takes place to give 388 and 390[322]. Similarly, the ort/trt-thallation of benzoic acid followed by transmetallation with Pd(II) forms the arylpalladium complex, which reacts with butadiene to afford the isocoumarin 391, achieving the 1,2-difunctionalization of butadiene[323]. 

Homofolic acid, 5,11-methenyl-tetrahydro-biological activity, 3, 327 Homofolic acid, tetrahydro-biological activity, 3, 327 Homoisoflavanones occurrence, 3, 722 thermoisomerization, 3, 722 thermolysis, 3, 728 Homolytic reactions heterocyclic compounds reviews, 1, 74 Homophthalic acid isocoumarins synthesis from, 3, 830 synthesis, 3, 830 Homophthalic anhydride isochroman-l-one synthesis from, 3, 860 20a-Homoporphyrin nomenclature, 1, 30 Homopterocarpin isolation, 4, 998 ( )- D- Homotestosterone synthesis, 1, 453 Homer-Emmons reaction chromene synthesis by, 3, 749 Hortiacine isolation, 3, 149 Hortiamine isolation, 3, 149... 

Isocoumarin-3-carboxyIic acid, 8-methoxy-synthesis, 3, 834 Isocoumarin-4-carboxylic acid methyl ester synthesis, 3, 832... 

Isocoumarin-3,4-dicarboxylic acid diethyl ester hydrolysis, 3, 691 Isocoumarins... 

Iso-crotonsaure, /. isocrotonic acid, -cumarin, n. isocoumarin, isocumarin. -cyansaure, /. isocyanic acid, -cyanursaure, /. isocyanuric add. 

Diels-Alder cycloaddition of 3,4-bis(trifluoromethyl)furan with ethyl propynoate involved addition of two a,/3-unsaturated esters followed by acid-catalyzed ring opening, rearrangement, and elimination of ethanol to give a 6,7-bis(trifluoromethyl)isocoumarin-3-carboxylate [92JFC(56)359]. 

Solid extracts of (1) alfalfa and (2) red clover (used in food flavorings) were examined by GC/MS. 389 of 450 detected components were identified in (1), vs. 210 of 309 components detected in (2). In both extracts, predominant compounds identified were esters (1) 105, (2) 55 acids (1) 42, (2) 31 alcohols (1) 34, (2) 31 and hydrocarbons (1) 28, (2) 14. Many other compounds were also found, including cannabinol, caffeine, scopolamine, isocoumarin, phenylpentadienal, phenylhexadiene, and nepetalactone.25... 

The choice of catalyst controls the intramolecular cyclisation of 2-(l-alkynyl)benzoic acids, with AgNCh effecting efficient formation of 3-substituted isocoumarins, but Ag powder favouring a 5-exo-dig-cyclisation to the phthalide (Scheme 45) <00T2533>. 

Lateral metallation is the key step in the synthesis of the pen-fused isocoumarin 69 from 5,6,7,8-tetrahydro-1 -naphthoic acid <00S 1113>. 

A facUe synthesis of 3,4-disubstituted isocoumarins and their benzologues is based on the Pd-catalysed annulation of internal alkynes by 2-iodobenzoate esters (Scheme 27). Tri- and tetra- substituted pyran-2-ones are also available by this route <99JOC8770>. 3-Substituted isocoumarins result from the Pd-catalysed 6-endo-dig cyclisation of 2-ethynylbenzoic acids. The 5-exo-dig products, phthalides, are also formed when there is a terminal bulky group on the alkyne moiety <99S1145>. 

The cumulation reactions, which start from carboxylic acids and esters usually lead to the formation of pyrone derivatives. Methyl (Z)-3-iodoacrylate and 3-hexyne gave, for example, 5,6-diethyl-2-pyrone in acceptable yield (4.38.). Inclusion of the acrylate into a six membered ring starting from ethyl 2-bromocyclohexen-l-carboxylate, led to a condensed ring system, giving a partially reduced isocoumarin derivative.50... 

The coupling of 2-iodobenzoic acid and phenylacetylene under Sonogashira coupling conditions was found to give a mixture of an isocoumarin derivative and a phthalide (4.40.), The proper choice of the catalyst system led to the preferential formation of the latter compound.53 The process might also be diverted towards the formation of the isocoumarin derivative by isolation of the intermediate o-cthynyl-benzoic acid and its subjection to carefully selected cyclization conditions54... 

Fusion of isocoumarins (299) with strong alkali gives a benzoic acid (57JGU2342). 

The two ester groups of diethyl isocoumarin-3,4-dicarboxylate (334) exhibit a curious lability to treatment with hydrochloric acid in that the 4-carboxyl group is lost on refluxing with 10% aqueous acid while 37% acid at 70 °C hydrolyzes the 3-carboxylate group only (Scheme 20) (57JGU2342). 

A number of approaches to the isocoumarin ring system are based on the facile ring closure of homophthalic acid and its derivatives and hence a major synthetic task lies in the preparation of these compounds. 

The synthesis of homophthalic acids has been achieved by carboxylation of the dianion derived from o-methylbenzoic acids (82JCS(Pl)llll). Acetylation is hindered by substitution at the 5-position of the isochroman-l,3-dione and yields of the isocoumarins are reduced in these cases. Deuteration at C-4 can be achieved by deuterating the 4-carboxylic acid, followed by decarboxylation. 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

The use of ethyl oxalate in the Claisen synthesis affords 3,4-disubstituted isocoumarins. It appears that hydrolysis of the 3-ethoxycarbonyl group is easier than that of the 4-substituent, but the 4-carboxylic acid is more readily decarboxylated than the 3-isomer (54JCS3617). 

The cyclization of 2-carboxybenzyl ketones to isocoumarins has been achieved under acidic conditions (59JCS923). 

The naphthalene derivative (501) may be regarded as a special case of these ketones and on heating it forms the naphthoisocoumarin (503) (56JCS4535). The same isocoumarin results when the dicarboxylic acid (502) is treated with polyphosphoric acid (Scheme 180). 

Carboxybenzyl aryl ketones are formed together with the isocoumarin when homophthalic anhydride (isochroman-l,3-dione) is used to acylate aromatic molecules under Friedel-Crafts conditions (51JOC1064) and the 7-methoxy derivative behaves in a similar fashion (66JIC615). Some care in the choice of Lewis acid is necessary in view of the formation of the tropone derivative (504) in the acylation of hydroquinone (Scheme 181) (55JCS2244). 

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

There are several other examples of the use of indene derivatives as a source of isocoumarins. Alkaline decomposition of the cyclic peroxide (507), produced by ozonolysis of indene itself, yields a phenylacetaldehyde (57JA3165). Treatment of these aldehydes with acid gives access to isocoumarins which are unsubstituted in the pyranone ring (65JIC211). 

Esters of 2-acetonylbenzoic acid are formed when methyl 2-bromobenzoates are treated with 7r-(2-methoxyallyl)nickel bromide (77JOC1329). Cyclization to the isocoumarin occurs on treatment with sodium hydride in benzene with a trace of t-butanol (Scheme 183). A... 

A greater variety of substituted isocoumarins is available from the reaction of 7r-allylnickel halides with the sodium salts of 2-bromobenzoic acids. Use of the sodium salt is necessary to prevent debromination through an intramolecular proton transfer from the carboxyl group. The initial products, 2-allylbenzoic acids, undergo a palladium-assisted ring closure to isocoumarins. 

The acids have also been obtained from isocoumarins through alkaline ring opening to the ketone and subsequent reduction. Ring closure occurs directly on acidification (71JIC707). 

In a related manner, sodium 2-bromobenzoates have been converted into 2-allylbenzoic acids. A palladium-catalyzed cyclization involving nucleophilic attack of the carboxylate on the palladium-complexed alkene yielded an isocoumarin. However, in situ catalytic hydrogenation results in the formation of an isochroman-l-one. 

Coumarins and isocoumarins appear to be of varied origins. Simple coumarins, such as umbelliferone, are formed by the shikimic acid pathway in which hydroxylation of p-hydroxycinnamic acid occurs. Other coumarins, for example alternariol (690), are derived from a polyketide unit, as are a number of chromanones, chromones, pyranones and isocoumarins (B-78MI22400). The biosynthesis of 5-hydroxy-2-methylchromone has been shown to involve the chromanone (60JCS654). However, isocoumarins are also derived from the mixed acetate-shikimate route, through initial cyclization of the polyketide and subsequent lactonization. 

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