Isocoumarins derivatives

Bihel, F. Quelever, G. Lelouard, H. Petit, A. Alves de Costa, C. Pourqie, O. Checler, F. Thellend, A. Pierre, P Kraus, J.-L. Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new beta-amyloid peptide production inhibitors and their activities on various classes of protease. Bioorg. Med. Chem. 2003, 11, 3141-3152. 

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... 

Based on 13C-NMR analyses, it has been assumed [62] that 6-methoxymellein, a polyketide compound, is synthesized by head-to-tail condensation of one acetyl-CoA and four malonyl-CoA to form 3,4-dehydro-6-hydroxymellein as an intermediate. This isocoumarin derivative is then reduced to its dihydro-form, 6-hydroxymellein, which then accepts a methyl-unit via Omethyltransferase. We have shown [63] that cell extracts prepared from elicitor-treated carrot root disks catalyzes... 

The germination of the monocotyle Setaria italica and the dicotyle Lepidium sativum is inhibited by the mycorrhizins, e.g. 123, lachnumon (124), and halogenated isocoumarin derivatives, like 125, which have been isolated from the ascomycete Lachnum papyraceum [98]. 

Several examples of intramolecular solvomercuration of arylalkynes have been reported (equations 81 to 83).200 The mercury moiety can be removed by protiodemetallation or converted to a variety of other functional groups. The use of a methyl ether as the nucleophilic functionality is noteworthy, as is the change in the regioselectivity (equation 82 versus equation 83). A bromocyclization related to equation (83) using a phenylethynylbenzoate ester also gives an isocoumarin derivative via 6-endo cyclization.201 Palladium-catalyzed cyclizations of 3,y-alkynic ketones or 2-methyl-3-alkyn-l-ols to form substituted furans are discussed in Chapter 1.4, Section 3.1.3 in this volume. 

Benzoic acid and its derivatives orthothallate. Reaction of o-carboxyphenylthallium bis(trifluoroace-tate) with palladium chloride and alkenes followed by base treatment yields isocoumarin derivatives (equation 15).41 Cyclization does not occur until base is added in the second step. 

The condensation of the 1-methyl group in 2-benzopyrylium salts 92 with carbonyl derivatives such as aromatic aldehydes (70KGS1308) in acetic acid gives rise to 1-styryl-substituted salts 94. The reaction proceeds similarly with orthoesters (74KGS37), isocoumarin derivatives, and di-methylformamide (DMF) (80KGS193) or azomethines (82KGS465). The... 

Stadler M, Anke H, Sterner O (1995) New Metabolites with Nematicidal and Antimicrobial Activities from the Ascomycete Lachnum papyraceum (Karst.) Karst IV. Structural Elucidation of Novel Isocoumarin Derivatives. J Antibiot 48 267... 

Utility High Yielding Method for Preparing Isocoumarin Derivatives... 

Phosphorous pentachloride catalyzed cyclization of 2-bromoethyl-2-carboxyphenyl acetate as a route for preparing isocoumarin derivatives is described (2). 

Using primary aliphatic amines, ring opening of isocoumarin-derived thiolactones (3) according to equation (2) offers a convenient access to o-(2-oxoalkyl)thiobenzamides (4) with yields in the 80% range aromatic amines give side reactions. ... 

Ochratoxin A (OTA) is dangerous to human health, and its legal limits in grape and wine are fixed. The molecule consists of an isocoumarin derivative linked to phenylalanine through a carboxyl group (structure reported in Fig. 8.1). 

Figure 4, Preparation of isocoumarin derivatives mellein and 8-methoxyisocoumarin...

Methoxybenzamide after o-lithiation in tetrahydrofuran with sec-butyllithium containing tetra(N-methyl)ethylenediamine, methylation with excess iodomethane at -90°C, removal of excess reagent, followed by re-cooling of the mixture to -60°C to form the carbanion of the intermediate product with lithium diisopropylamide, and finally reaction with 4-methoxybenzaldehyde, afforded the isocoumarin derivative shown in 45% yield (ref. 169) after work-up with aqueous ethanolic sodium hydroxide. 

In an alternative approach [89], the known compound 110 and dimethyl acetone dicarboxylate were condensed in the presence of a base and the resulting isocoumarin derivative 111 was taken to 112 (Scheme 23). 

These compounds were found to be important mycotoxin constituents of Aspergillus species shortly after the discovery of the aflatoxins (see Chap. 2.). The ochratoxins are isocoumarin derivatives coupled with p-phenylalanine. The major representatives of this class of pentaketides are shown in Fig. 6.2. Ochratoxin B (324) is the dechloro analog of ochratoxin A (323), which is the most important member of this group with respect to its toxicity. The corresponding methyl and ethyl esters of ochratoxin A (323) and B (324) were found also in Aspergillus species and the ethyl ester of ochratoxin A (323) has been named ochratoxin C (325). Ochratoxin a (326) is a free carboxylic acid that represents the dihydroi-socoumarin nucleus of ochratoxin A (323). 

The highly potent biological activity of aflatoxins stimulated considerable effort to trace these compounds in various feeds. One group of related toxins are isocoumarin derivatives called ochratoxins. Ochratoxin A (37) and B (38) have been isolated from a variety of agricultural products, stored corn, wheat, rice, and rye, infected with Aspergillus ochraceus [290—297]. A Penicillium species was reported to also produce ochratoxin [298]. 

Since aikenes and aikynes can be prepared via Heck and Sonogashira reactions, respectively, tandem processes are also possible for lactone synthesis [71-77]. Appropriately, o-iodobenzoic acids can generate both phthalide and isocoumarin derivatives under Pd catalysis, with a Cul co-catalyst favoring the former and... 

The asymmetric total synthesis of fusarentin 6-methyl ether, a natural isocoumarin derivative, is achieved in nine steps with 20.5% overall yield. This compound is also the key intermediate in the total synthesis of fusarentin 6,7-dimethyl ether, 7-O-demethylmonocerin and monocerin with 16.5,12.9% and 12.5% overall yields, respectively (13JOC6338). 

Scheme 3.47 Cu-catal zed synthesis of isocoumarin derivatives from 2-iodobenzoic acids.

Reactions with alkynes may lead to the formation of cyclized products. The reaction of iodobenzenes with two equivalents of an alkyne has been shown to give naphthalene derivatives in the presence of cobalt catalyst with a manganese reduc-tant. The process, shown in Scheme 15, is thought to involve oxidative addition of the aryliodide to cobalt followed by double alkyne insertion. The cobalt-catalysed annulation step probably involves an pathway. The cyclopentadienyl-rhodium-catalysed annulation of benzoic acids with alkynes has been used to form isocoumarin derivatives, such as (126). The process is thought to involve cyclorhodation at the ortho-position of a rhodium benzoate intermediate, followed by alkyne insertion to form a seven-membered rhodacycle and reductive elimination The silver-catalysed annulations of diphenylphosphine oxides with alkynes proceed in the absence of rhodium. Benzophosphole oxides such as (127), formed with diphenylethyne, are produced. Here, the proposed mechanism involves homolytic cleavage of the phosphorus-hydrogen bond to give a radical which can add to the alkyne and subsequently cyclize. ... 

The taste perception builds relatively slowly and also fades away slowly. The sweetening strength is /sac (5) = 250. A study of a number of related isocoumarin derivatives shows that taste quality and strength are very much dependent on the substitution pattern of the molecule (cf. Table 8.7). 

The range of spectroscopic techniques now available means that it is often a straightforward matter to arrive at a possible structure for a new isocoumarin. Key references are given in the Tables relating to the structure elucidation of the natural isocoumarins. Carbon-13 nuclear magnetic resonance spectroscopy has proved to be of use in determination of the structures of the more complex isocoumarins 139). The C-NMR data for some simple isocoumarin derivatives have been listed (227, 265). 

Most of the natural isocoumarins are derived biosynthetically from acetate via the acetate-polymalonate pathway 293, 294). Mellein (19) is formed from acetate and malonate, as in Scheme 3 140). The early reduction of two of the carbonyl groups in the polyketone chain has been indicated by results of CD3COOH feedings ). Loss of the oxygen function at C-6 of an isocoumarin is quite common but loss of the hydroxyl group at C-8 never occurs in those isocoumarins derived from acetate, presumably as a consequence of the cyclization mechanism 293). 

Synthesis of Some Isocoumarin Derivatives. Agric. Biol. Chem. 36, 506 (1972). 

Yamatodani, S., T. Yamano, Y. Kozu, and M. Abe Isolation of a New Isocoumarin Derivative, K-1, from the Saprophytic Culture of Oospora astringens. Nippon Nogei Kagaku Kaishi 37, 240 (1963) Chem. Abstr. 63, 570 (1965). 

Ochratoxins (Table 6.2, Figure 6.4) are another important group of mycotoxins mainly produced by Aspergillus ochraceus, or in some instances by Penicillium ver-rucosum. Ochratoxicosis produces the Balkan endemic nephropathy first described in Bulgaria. Chemically, ochratoxins are isocoumarin derivatives bound to phenylalanine. The most common and relevant is ochratoxin A or OTA. Most ochratoxicosis is related to field-contaminated maize dne to excess rainfall before harvesting or... 

---