An efficient synthesis of 3,5‐dimethoxyhomophthalic acid, a key intermediate for synthesis of natural isocoumarins

Saeed, Aamer; Rama, Nasim Hasan; Arfan, Muhammad

doi:10.1002/jhet.5570400317

Cited by 16 publications

(6 citation statements)

References 30 publications

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“…Synthesis of the polyketide fragment began with Friedel–Crafts acylation of methyl 3,5‐dimethoxyphenyl acetate 10 12 to give 11 13 (Scheme ). Ketone 11 was then aromatized under basic conditions to give 1,3‐dihydroxy‐6,8‐dimethoxynaphthalene ( 12 )14 in high yield.…”

Section: Methodsmentioning

confidence: 99%

Biomimetic Total Synthesis of (±)‐Merochlorin A

Pepper

George

2013

Angew Chem Int Ed

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Dedicated to Professor Sir Jack E. Baldwin on the occasion of his 75th birthday Merochlorins A (1) and B (2) are isomeric chlorinated meroterpenoids with unique polycyclic ring systems, and were recently isolated from the marine bacterium Streptomyces sp. strain CNH-189. [1] Merochlorin A has a compact bicyclo[3.2.1]octanone [2] core with four contiguous stereocenters, three of which are quaternary. The structure of 1 was initially elucidated using 2D NMR studies. [1b] However, later X-ray studies [1a] and our synthetic work indicate that its structure should be represented as shown in Scheme 1 (the configurations of the stereocenters at C9 and C10 of 1 were originally misassigned). Further to its structural interest, 1 is a potent antibiotic against Clostridium difficile (MIC = 0.15 mg mL À1 ) and various multi-drug resistant Staphylococcus aureus strains (MIC = 2-4 mg mL À1 ). [1b] It is therefore an excellent lead candidate for the development of novel antibiotics. However, the mechanism of action of 1 is unknown, and given its scarcity in nature a chemical synthesis is desirable.Merochlorin B has a 6-5-5-fused ring system with three contiguous stereocenters and an a-chloroenone motif. The unprecedented structures of 1 and 2 suggest an unusual biosynthesis. This was investigated by Moore et al., [1a] who partially sequenced the genome of the CNH-189 bacterium to reveal a merochlorin gene cluster containing 41 genes (mcl1-mcl41). The key genes implicated in the biosynthesis of the merochlorins were found to encode a 1,3,6,8-tetrahydroxynaphthalene synthase (mcl17), an aromatic prenyl transferase (mcl23), a vanadium-dependent haloperoxidase [3] (VHPO; mcl24), and a protein containing an iron-sulfur cluster (mcl30). On the basis of their bioinformatic analysis, Moore and co-workers proposed a biosynthesis of 1 and 2 involving VHPO-dependent chlorination or oxidation of an alkene as the prelude to a cyclization cascade to form the polycyclic ring systems. [1a] However, their proposed cyclization mechanism is (by their own admission) highly speculative, and we herein propose an alternative biosynthetic mechanism (Scheme 1). In common with the biosynthesis described by Moore et al., we suggest that the starting point for the biosynthesis of 1 and 2 is the formation of 1,3,6,8-tetrahydroxynaphthalene (4) by aromatization of the acyclic polyketide 3, catalyzed by the mcl17 polyketide synthase. We then propose that 4 undergoes alkylation (mcl23) to give 5 and chlorination (mcl24) to give 6. Oxidative dearomatization of 6 (perhaps catalyzed by the putative protein that contains the Fe-S cluster and is encoded by mcl30) would then generate phenoxonium ion 7 which could cyclize through a [5+2] cycloaddition to give 1 or a [3+2] cycloaddition to give 2. These cycloadditions are presumably stepwise in mechanism. Previously, intramolecular [5+2] cycloadditions have been proposed to occur between para-quinones and alkenes in the biosynthesis of aand b-pipitzol [4] and elisapterosin B, [5] which has inspired elegant biom...

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Section: Methodsmentioning

confidence: 99%

Biomimetic Total Synthesis of (±)‐Merochlorin A

Pepper

George

2013

Angew Chem Int Ed

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“…3,5-Dimethoxyhomophthalic acid [15] was efficiently converted into corresponding anhydride (2) by refluxing with acetic anhydride in dry toluene. The anhydride 2 in acetonitrile was added to a solution of 1,1,3,3-tetramethyl guanidine (TMG) in the same solvent at 0 °C followed by addition of triethylamine [16].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one from Tessmannia densiflora

Saeed

2011

Eur. J. Chem.

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“…3,5-Dimethoxy-4-methylbenzoic acid was prepared from 4-methylbenzoic acid according to the literature procedure 17 and was converted to 3,5-dimethoxy-4methylphenylacetic acid by the standard homologation sequence. 18 These are the key starting materials for the synthesis of fungal metabolites of sclerotiorin and rotiorin groups. 19 3-Methoxybenzoic acid, 3-methoxyphenylacetic acid, 3,4-dimethoxy phenylacetic acid, 3-methoxycinnamic acid and 3,4,5-trimethoxyphenylpropionic acid were commercial products from Aldrich.…”

Section: Resultsmentioning

confidence: 99%

Sodium borohydride reduction of aromatic carboxylic acids via methyl esters

Saeed

Ashraf

2006

J Chem Sci

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A number of important aromatic carboxylic acids precursors, or intermediates in the syntheses of natural products, are converted into methyl esters and reduced to the corresponding primary alcohols using a sodium borohydride-THF-methanol system. The alcohols are obtained in 70-92% yields in 2-5 hours, in a pure state. This two-step procedure not only provides a better alternative to aluminum hydride reduction of acids but also allows the selective reduction of esters in presence of acids, amides, nitriles or nitro functions which are not affected under these conditions.

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An efficient synthesis of 3,5‐dimethoxyhomophthalic acid, a key intermediate for synthesis of natural isocoumarins

Cited by 16 publications

References 30 publications

Biomimetic Total Synthesis of (±)‐Merochlorin A

Biomimetic Total Synthesis of (±)‐Merochlorin A

Synthesis of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one from Tessmannia densiflora

Sodium borohydride reduction of aromatic carboxylic acids via methyl esters

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