Enzyme-Based Organic Synthesis. Cheanyeh Cheng
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Название: Enzyme-Based Organic Synthesis
Автор: Cheanyeh Cheng
Издательство: John Wiley & Sons Limited
Жанр: Химия
isbn: 9781118995150
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One of the well‐known industrial applications with hydroxylase for the hydroxylation of aromatic ring is the catalytic production of tyrosine from phenylalanine by phenylalanine hydroxylase and the subsequent hydroxylation of tyrosine yielding the catecholamine neurotransmitter L‐dihydroxyphenylalanine (L‐DOPA), as in Scheme 2.10 [53, 55].
Scheme 2.10 The catalytic hydroxylation of L‐phenylalanine and L-tyrosine by phenyl hydroxylase and tyrosine hydroxylase, respectively, to produce corresponding L‐tyrosine and L‐DOPA.
Recently, a microsomal P450 designated as PcCYP65a2 that was derived from the white rot fungus Phanerochaete chrysosporium can catalyze 3′‐hydroxylation of naringenin to yield eriodictyol in the culture of the recombinant S. cerevisiae AH22/pG65a2 cells (Scheme 2.11) [56].
Isoliquiritigenin (2′,4′,4‐trihydroxychalcone) is a chalcone found in licorice root and other plants, which has shown potent antioxidant, anti‐inflammatory, phytoestrogenic, tyrosinase inhibitory, and antitumor activity in vitro. However, when prepared in vivo, aromatic hydroxylation of isoliquiritigenin on the A or B ring was found by the metabolism of human liver microsomes to produce 2′,4′4′,5′‐tetrahydroxychalcone or butein, respectively (Scheme 2.12) [57]. The enzyme involved in the formation of the hydroxylated metabolites of isoliquiritigenin was cytochrome P450.
Amphetamine was once extensively used for weight reduction, and it has been employed in treating mild depression and narcolepsy as well. The administration of amphetamine may cause excitability, restlessness, tremors, insomnia, dilated pupils, increased pulse rate and blood pressure, hallucinations, and psychoses. Since amphetamine is inexpensive, it has been a drug of abuse. The biotransformation of d‐amphetamine into p‐hydroxyamphetamine (HA) by cytochrome P450 occurs in human and mouse (Scheme 2.13) [58]. The urinary excretion of HA not only is a biomarker of exposure but also gives an insight into d‐amphetamine reactivity.
Scheme 2.11 Hydroxylation of naringenin in the culture of the recombinant S. cerevisiae expressing P. chrysosporium PcCYP65a2 to produce eriodictyol.
Scheme 2.12 Hydroxylation of isoliquiritigenin in human liver by cytochrome P450.
Scheme 2.13 Hydroxylation of d‐amphetamine by cytochrome P450 to give p‐hydroxyamphetamine.
2.1.4 Dihydroxylation of Aromatic Compounds
The initial degradation of aromatic compounds by bacteria often involves the cis‐dihydroxylation, which is catalyzed by Rieske non‐heme iron dioxygenases to yield cis‐dihydrodiol derivatives. This type of reaction leads to a permanent disruption of aromaticity and offers a strategy for regio‐ and stereoselectivity in organic syntheses to a variety of useful natural and unnatural compounds [59]. The first report in literature for the arene cis‐dihydroxylation to produce cis‐dihydrodiol metabolite was with the use of bacterium Pseudomonas putida F1 and the substrate was benzene [60]. Later developments of this synthetic strategy extend the use of monosubstituted arenes such as toluene, chlorobenzene, phenol, etc.; polycyclic arene such as naphthalene; and biphenyl as the starting material to produce various kinds of cis‐1,2‐dihydrodiols that in turn have been used as chiral synthons for the generation of valuable biologically active products through sequential chemoenzymatic steps. The following examples show the wide applications of this synthetic strategy.
It is noted that the hybrid toluene/biphenyl dioxygenase (TDO/BPDO) in Escherichia coli encoded by the todC1 gene of P. putida F1 and the bphA2A3A4 genes of Pseudomonas pseudoalcaligenes KF707 was able to biotransform monocyclic aromatic compounds including benzene, toluene, styrene, p‐xylene, acetophenone, propiophenone, butyrophenone, and trifluoroacetophenone to their corresponding cis‐dihydrodiols (Scheme 2.14). Subsequently, these cis‐dihydrodiols were bioconverted by the bphB (dihydrodiol dehydrogenase) expressed in E. coli cells in addition to todC1‐bphA2A3A4 to produce their monocyclic arene‐diols [61].
Scheme 2.14 Catabolic pathways of monosubstituted benzene to diol via cis‐dihydrodiol.
Alkaloid pancratistatin is tested as anticancer, antiviral, and antiparasitic agents. The cis‐dihydroxylation of bromobenzene by TDO from the bacterium strain P. putida 39/D to produce cis‐bromocyclohexadienediol was utilized to chemically synthesize the key intermediate bromoazide (Scheme 2.15) for the preparation of pancratistatin analogs [62]. (−)‐Conduramine C‐4 was also synthesized in six steps from the whole‐cell fermentation of bromobenzene with P. putida 39/D in 23% overall yield [63].
The same chemoenzymatic method has been used for the synthesis of certain alkaloids and terpenoids by starting with the whole‐cell biotransformation of a variety of monosubstituted benzene to form the corresponding cis‐1,2‐dihydrocatechol using TDO expressing P. putida 39‐D or E. coli JM109 (pDTG601) [64, 65]. E. coli JM109 (pDTG601) was also used for the dihydroxylation of methyl 2‐iodobenzoate to give two cis‐dihydrodiol metabolites in a molar ratio of 4:1 (Scheme 2.16) [66]. The minor product in the diol mixture was further chemically transformed to an alcohol intermediate for the asymmetric preparation of kibdelone C and its congeners.
Ten 1,4‐disubstituted benzene substrates using P. putida UV4 as a source of TDO have been biotransformed to yield the corresponding cis‐dihydrodiol metabolites [67]. The yields of these cis‐dihydrodiols СКАЧАТЬ