3-methyl-3,4-dihydroisocoumarins

DC037 Sarkar, S. K., and Phan Chon Ton. Biosynthesis of 6-hdroxy-8-methoxy-3-methyl-3,4-dihydroisocoumarin and 5-hydroxy-7-methoxy-2-methylchromone in carrot root tissues... 

An alternate synthesis from chloroindanone is also known. The key intermediate here is 5-chloro-8-hydroxy-3-methyl-3,4-dihydroisocoumarin 38 The key inter-... 

A stereospecific synthesis of both enantiomers of 8-hydroxy-3-methyl-3,4-dihydroisocoumarin, mellein, from propylene oxide has been described <97TA2153>. 

Mangas-Sanchez, f., Busto, E., Gotor-Fernandez, V., and Gotor, V. (2012) Enantiopure 3-methyl-3,4-dihydroisocoumarins and 3-methyl-l,2,3,4-tetrahydroisoquinolines via chemoenzymatic asymmetric transformations. Catal. Sci. Technol., 2 (8), 1590-1595. 

Anderson, J.R., R.L. Edwards and A.J.S. Whalley Metabolites of the Higher Fungi - Part 21. 3-Methyl-3,4-dihydroisocoumarins and Related Compounds from the Ascomycete Family Xylariaceae. J. Chem. Soc. Perkin Trans. I 1983, 2185. 

A simple one-pot dynamic kinetic resolution using recombinant Escherichia coli cells that overejqrressed ADH-A from R. ruber provided an enantioselective route to 4-alkyl-3-methyl-3,4-dihydroisocoumarins 80 as shown in Scheme 6.30. Key to the reaction was the introduction of anion exchange resin or triethylamine to promote the desired racemization of the ketone during reduction to yield en-antiopure alcohols with excellent selertivities. The reactions were performed in pH 7.5 buffer with hexane cosolvent. The reductant was supplied via isopropyl alcohol cofactor regeneration with excellent conversions [44]. 

Artemidinal 4<5 can be readily synthesised from homophthalic anhydride (vide infra). Its syntheses from 3-methyl dihydroisocoumarin and 3-methyI isocoumarin are given below... 

The (E)- and (Z)-regioisomers of 6-ethylidenedioxadisilacyclohexane 1134 undergo palladium catalyzed-cross coupling with methyl-2-iodobenzoate to furnish dihydroisocoumarins with excellent (E)- or (Z)- selectivity (Scheme 282) <20030L1119>. 

Enzymic kinetic resolution of racemic l-arylpropan-2-ols preceded their ZnCl2-catalysed cyclisation to optically pure 3-methylisochromans by treatment with chloromethyl methyl ether (Scheme 20). Conversion to dihydroisocoumarins has been achieved through C-l oxidation. A detailed CD study of these O-hctcrocycles has allowed the determination of their absolute configurations <07EJO296>. 

The isocoumarin and the dihydroisocoumarin ring systems occur widely in nature Their synthesis by lithiation method is according to type C and involves ortho metalation of N-methyl arylcarboxamides. The organometallic compounds on treatment with electrophilic reagents such as an epoxide or allylbromide followed by hydrolysis and cyclisation furnish the dihydroisocoumarins. Bromination at benzylic position followed by dehydrobromination then gives the isocoumarins themselves. 

The lithiation of isophthalic acid can be achieved either at 2- or 4- position after conversion of the carboxylic acid groups to oxazole derivatives or N,N -butylamide derivatives respectively. Conversion to N-methyl amide derivative leads to the precipitation of the N-lithio salt on treatment with BuLi which fails to lithiate further. The N-lithio salt of the N-butylamide, however, remains in solution under the experimental conditions. It may be noted that the two lithiation reactions furnish two different carboxydihydroisocoumarins. The 5-carboxy dihydroisocoumarin can be converted to erythrocentaurine, which is naturally occurring... 

The dihydroisocoumarin can also be formed from N-methyl-o-toluamides or esters of o-toluic acids on treatment with BuLi followed by an aldehyde or ketone. It should be noted that the syntheses do not involve aromatic lithiation reaction. 

Dihydrocoumarins and Dihydroisocoumarins. - The potential of thalHum compounds in organic synthesis continues to be developed in a variety of reactions. One of these was the synthesis of dihydrocoumarins by oxidative cyclization of 3-arylpropionic acids, e.g. (177), by thallium(in) trifluoro-acetate-trifluoracetic acid (TTFA). The coumarin was accompanied by methyl 3-(2-hydroxyphenyl)propionate (178), which was formed by ring-... 

Reduced Isocoumarins.- Kigelin (143 R=H) is a natural di-hydroisocoumarin its methyl ether (143 R=Me) has been synthesized in two steps from another natural compound called elemicin (allylbenzene). Cyclization with mercury(II) acetate gave the 1-isochromanol which was oxidized to (143 R=Me) with pyridinium chlorochromate.153 Isomeric with dihydroisocoumarins are the isochroman-3-ones one such compound has been synthesized by the action of hot mineral acid on 2-methoxymethylbenzyl cyanides such... 

Baciphelacin is toxic to HeLa cells and a study of its mechanism of action revealed that it was a potent inhibitor of protein synthesis (ref.121). A 50% inhibition of protein synthesis in HeLa cells was found at a concentration around 10" M (0.042 ig/ml). This compound is unusual and interesting because it blocks translation only in animal cells and not in plant, yeast or Escherichia coli systems. Translation inhibitors are usually blockers of eukaryotic and/or prokaryotic systems not animal cells only. In a study of related compounds 4-acetyl-6,8-dihydroxy-5-methyl-3,4-dihydroisocoumarin was found to block translation in HeLa cells but not in yeast cells. Interestingly, the saturated... 

Some ant species (Formicidae) use nitrogen heterocycles as trail pheromones others however use hydrocarbons or alcohols (Fig. 8.62). In the rectal glands of a few Lasius and Formica species, 3,4-dihydroisocoumarins have been identified. The scents are emitted by exocrine glands like the poison apparatus or the sternal gland. The trail pheromone of the leafcutter ant (Atta texana) is effective at extremely low concentrations of 80 fg/cm (If = 10" ). One milligram of methyl 3-methylpyrrole-2-carboxylate is sufficient to lay a trail three times around the Earth. 

C11H10O4, Methyl 3,4-dihydroisocoumarin-3-carboxylate, 42B, 238 C11H10O4, a-Benzyloxy-7-butyrolactone, 46B, 310... 

Dihydroisocoumarins. LiBH4 added to a soln. of methyl 2-carboxy-4,5-di-methoxyphenylacetate in anhydrous tetrahydrofuran, refluxed 4 hrs., and the product isolated the next day 3,4-dihydro-6,7-dimethoxyisocoumarin. Y 87.5%. F. e., also with isolation of the intermediate hydroxycarboxylic acid, s. N. K. Bose and D. N. Chaudhury, Tetrahedron 20, 49 (1964). 

Bhide, B.H., and K.K. Sham Isocoumarins Part III. Synthesis of Methyl and Methy-lenedioxy-dihydroisocoumarins and a New Synthesis of ( )-5-Methylmellein. Indian J. Chem. 19B, 9 (1980). 

Condon, P., J. Kuc., and H.N. Draudt Production of 3-Methyl-6-methoxy-8-hydroxy-3,4-dihydroisocoumarin by Carrot Root Tissue. Phytopathology 53, 1244 (1963). 

ScHROEDER, H.W., and R.D. Stipanovic Production of 3-Methyl-6-methoxy-8-hy-droxy-3,4-dihydroisocoumarin by Aspergillus caespitosus. Appl. Microbiol. 29, 706 (1975). 

Dynamic kinetic bioreduction to access 4-alkyl-3-methyl-3 -dihydroisocoumarins. 

---