Biomimetic oxidative dimerization

The architecturally interesting and biologically significant protein kinase C inhibitor calphostins (A-D), and their analogs were synthesized in the laboratory of C.A. Merlic. The key steps in their approach were a Dotz aminobenzannulation utilizing an enantiopure Fischer carbene complex to prepare a pentasubstituted naphthylamine, followed by a biomimetic oxidative dimerization to produce the perylenequinone skeleton. 

The elegant biomimetic synthesis of carpanone by Chapman and coworkers commences with the base-induced isomerization of 2-allyl-4,5-methylenedioxyphenol (4)3 to 2-(/ran.y-l-propenyl)-4,5-methylenedioxyphenol (3) (see Scheme 2). Compound 3, as simple as it is, is actually the key intermediate in this synthesis oxidative dimerization of 3 could result in the formation of carpanone (1) through the intermediacy of the C2-symmetric and highly reactive bis(quinodimethide) 2. 

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

Fig. 2.163. Oligomeric products arising from biomimetic DHICA oxidation dimers 4,4 -biindolyl, 4,7 -biindolyl, 7,7 -biindolyl and trimers. Reprinted with permission from A. Pezzella et al. [336].

Following on from their previous work on the biomimetic synthesis of marine natural products, Steglich et al. proposed a biomimetic lamellarin synthesis in which an oxidative dimerization of an arylpyruvic acid and condensation of the resulting 1,4-dicarbonyl compound with a suitable 2-arylethylamine would be the key steps of the synthesis. Thus, the synthesis of lamellarin G trimethyl ether was achieved by coupling two molecules of 3-(3,4-dimethoxyphenyl)pyruvic acid and the appropriate 2-phenylethylamine <9579941, 97AG(E)155>. The use of a mixture of two different arylpyruvic acids afforded the unsymmetrical lamellarin L <00MI1147>. 

An efficient asymmetric synthesis of substituted methyl 2-aryl-dihydrobenzo[h]furan-3-carlx)xylate was achieved by a rhodium-catalyzed C-H bond activation route in an excellent yield, and the generated product was an intermediate applicable to the total synthesis of (+)-lithospermic acid <0 A13496>. A similar type of framework existing in ( )-E-viniferin was m e through a biomimetic transformation by a T1(N03)3-mediated oxidative dimerization of resveratrol <05T10285>. 

A simplihed model has been developed to investigate the simplest complete OER reaction cycle. It is inspired by the biomimetic manganese dimers used for studying the water oxidation reaction in biological systems. The interest in these systems is twofold since they offer candidates for possible future water oxidation catalysts [61]. 

SCHEME 10A4 Biosynthesis of resveratrol-derived natural products and biomimetic dimerization strategy, (a) Biosynthetic pathway, (b) Direct but unconttolled dimerization under peroxidase, laccase, or inorganic oxidants, and (c) Biomimetic radical dimerization in vitro based on the stmctnraUy modified resveratrol [M +Mj,]. 

Li C, Johnson RP, Porco JA, Jr., Total synthesis of the quinone epoxide dimer (+)-torreyanic acid application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade. J. Am. Chem. Soc. 2003 125 5095-5106. 

A) (23), was obtained in an improved yield using the modified literature procedure (28) starting from benzene diazonium chloride (1054) and hydroxymethylene-5-methylcyclohexanone (1055). A biomimetic coupling of l-hydroxy-3-methylcarba-zole (O-demethylmurrayafoline A) (23) by reaction with di-ferf-butyl peroxide l(t-BuO)2] afforded the dimer of O-demethylmurrayafoline A (204). Finally, oxidation of 204 with PCC afforded (+ )-bismurrayaquinone-A (215). The resolution of atropo-enantiomers was achieved by chiral HPLC using Chiracel OF. The assignment of the absolute configuration of the two enantiomers (S)-215 and (f )-215 was achieved by comparison of their theoretical and experimental circular dichroism (CD) spectra (166,167,661) (Scheme 5.164). 

Iron porphyrin dimers, iron(III) /a-oxodimcr iron(III) porphyrin, for example, are used as biomimetic models of oxidation catalysts [98], It is shown that [Fe(TFPP)]20 and other modifications regioselectively oxidize adamantane and cyclohexane in the presence of iodosylbenzene (PhIO). Comparison of these results with corresponding monomeric analogs indicates the efficiency of the FeP dimer at the level of the monomeric one. 

The dimeric phenanthrenes agrostonin (421), agrostonidin (422) [193], reptanthrin and isoreptanthrin (418, 419) [194] have been regioselectively synthesized from their respective biomimetic methods involving oxidative coupling with PM A on a silica gel surface. 

A second disadvantage encountered with these biomimetic model systems, and with many other oxidations involving oxometal species, is deactivation via the formation of unreactive dimeric (or oligomeric) p-oxo complexes, e.g. 

Since the remarkable demonstration of the facility of an intramolecular Diels-Alder reaction (dimerization) of an o-quinone methide, generated by the oxidation of a substituted o-alkylphenol in the development of a biomimetic synthesis of carpanone [Eq. (44)],170... 

As mentioned in Section 3, oxidative phenolic coupling plays an important role in the biosynthesis of a wide range of natural products. This stimulated the application of this reaction to the biomimetic synthesis of natural biaryls. Unlike the in vivo processes, very probably following a radical dimerization pathway [91] yields of in vitro syntheses are generally moderate or low. Classical work in this field has been extensively reviewed [92], and important developments after the 70s will therefore be summarised here. 

The synthetic usefulness of this principle is well documented by numerous examples, even under biomimetic conditions. [6] In this way, using a similar synthetic sequence by co-oxidation of 7a and 7b, we have obtained not only the dimers, but also quinones 8a and 8b. [7] These are related to conocurvone la, but their antiviral properties have not yet been studied. 

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