Pummerer ketone

Recently, mention has also been made of lunaridine (96), which differs from lunarine (91) in that the incorporation of the spermidine part takes place in the opposite way (see Section V). The tetrahydro derivative 97 has been synthesized in the racemic form (cf. Scheme 14). By oxidative coupling of 4-hydroxycinnamic acid the Pummerer ketone-like intermediate 98 is formed, which is then converted to the A./V -diacetylhydroxylamine (99) in the manner depicted. Heating the latter with spermidine in boiling THF gives 12% yield of a macrocyclic substance that can be converted to... 

The total syntheses of both lunarine (91) and lunaridine (96) have been published (93). Starting material was the same Pummerer ketone-like compound 98 (see Scheme 14) that was converted by standard procedures to 101 (see Scheme 15). In order to introduce the two double bonds conjugated with the ester, 101 was oxidized to 102 by the reaction sequence depicted in... 

Ortho,ortho -coupling of the phenoxy radical produces V, its further oxidation forms via an arene oxide the benzofuran VI, and the ortho, para -coupling leads after a subsequent Michael addition to the Pummerer ketone VII. 

As previously described, the function of the enzyme is to produce the phe-noxy radicals under mild reaction conditions. The resulting phenoxy radicals are able to form polymers via recombination processes if a suitable reaction medium (solvent mixture composition), pH value (buffer systems), and kind of substrate are chosen. Some phenols, for example, are known to react preferentially via oxidation to form orfho-diketones [68] or Pummerer ketones [52], and are therefore not suitable for polymerization. Other phenols are known to prefer dimerization reactions, for instance caffeic acid [71]. 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

Parallel oxidations either electrochemically [117] or with iron([Il) salts [119] in water have also been made using l-alkyl-7-hydroxy-6-methoxytetrahydroisoquinO line salts as substrates. 4-Methy phenol is oxidised at a carbon anode in alkaline solution to give Pummerer s ketone 25 by the ortho-para coupling of two phenoxy radicals [120],... 

New examples of application appear regularly. In the following one [248] phenylsulfenylation of nopinone (4) was followed by oxidation to the sulfoxide. Pummerer rearrangement of the latter led directly to the a-phenylthio substituted a-unsaturated ketone (6) (overall yield 94%), starting material for further elaboration of natural sesquiterpene synthesis via 4,4-disubstituted nopinones (7). 

As a typical example of coupling reactions the oxidation of p-cresol (VII) to Pummerer s ketone (VIII) is presented in Figure 5, showing the mesomeric nature of the phenoxyl radical. According to Barton et al. 2) the ketone is formed by coupling at one 0-carbon atom and at one p-carbon atom and subsequent formation of an ether linkage. 

Figure 5. Formation of Pummerer s ketone VIII) from p-cresol VII)...

The aryl ketones 8 arise from an initially formed thietane followed by photochemical fission of the C-S bond and then by hydrolysis of an imine during chromatographic work-up <95JCS(P1)2931>. A 2-alkylation of a furan was effected by a vinylogous Pummerer reaction of the amido-substituted sulfoxide 9 <95JOC7082>. 

The photo-[4+2] cycloaddition of furan with Pummerer s ketone 102 [70,71] gives evidence for the intermediacy of the highly twisted enone intermediate 103, and a biradical cycloaddition pathway (Sch. 23). The structures of the endo and exo products 104 were confirmed by X-ray crystallography [72,73]. In a related comparison of cyclohexenone and cyclopentenone photochemistry, conditions that gave [4+2] adducts for the cyclohexenone produced only [2+2] adducts from cyclopentenone [74]. 

The pioneer in phenolate radical coupling was Pummerer. In 1925 he showed1 that one electron oxidation of />-cresol using potassium ferricyanide afforded a nicely crystalline ketonic dimer of the radical in up to 25 % yield. Pummerer s ketone, as it became known, was considered to result from the coupling of two p-cresol radicals to give the dienone 1. This then underwent spontaneous cyclization to furnish 2. As proof of the structure... 

Precursors such as reticuline 10 were synthesized labelled with 14C (O and N methyl groups) and with 3H in the aromatic nuclei. Labelling could also be done in the two 2-carbon bridges. We also synthesized from thebaine the key alkaloid 11 for the first time. Unlike the situation with Pummerer s ketone 11 did not close to 12 spontaneously. Later on, alkaloid 11 was isolated from a Brazilian plant. From correspondence with Prof. R. A. Barnes, we realized that the two were probably identical, which was confirmed by an exchange of specimens. So, we used thereafter the name salutaridine, given by our Brazilian colleagues. 

I was pleased with this result because the plant had clearly indicated to us that the original, and chemically available, pathway was not correct. Further thought then gave the real pathway. I was also pleased that so much beautiful chemistry (by nature) came from reflections on the erroneous formula of Pummerer s ketone. 

Valenti P, Recanatini M, Magistretti M, DaReP (2006) Some basic derivatives of Pummer-er s ketone. Archives der pharmazie 314 740-743... 

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