Enzymatic dihydroxylation of aromatic compounds: Nature's unique reaction and its impact on the synthesis of natural products

Bedard, Korey; Hudlický, Tomáš

doi:10.1016/b978-0-12-822212-6.00006-0

Cited by 3 publications

(3 citation statements)

References 206 publications

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“…The more elaborate synthesis of the C-ring coupling precursor, which contains all the necessary chiral centers of the final product, begins with the enzymatic dihydroxylation of ortho-dibromobenzene (13, Scheme 3). This is accomplished by a whole-cell fermentation process [20] with a recombinant strain of E. coli JM109 (pDTG601A [21]) that over-expresses toluene dioxygenase and was successfully used for the oxidative de-aromatization of various aromatic substrates [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] employed in the synthesis of natural products. Once dibromodiene diol 12 was obtained, it was subjected to acetonide protection and a nitroso Diels-Alder reaction in a one-pot procedure to form the bicyclic oxazine 21.…”

Section: Enzymatic Dihydroxylation Of Ortho-dibromobenzene and Nitros...mentioning

confidence: 99%

“…21: R f = 0.6 [EtOAc:Hex (1:3)]; [α] 23 D = −5.4 (c = 0.36, CHCl 3 ); IR (neat, cm −1 ) 3030, 2997, 1755, 1725, 1598, 1442, 1377, 1268, 1225, 1074; 1 H NMR (300 MHz, CDCl 3 ) δ 7.39-7.30 (m, 5H), 6.69 (d, J = 6.1 Hz, 1H), 5.21 (s, 2H), 5.08 (dd, J = 6.4, 4.1 Hz, 1H), 4.79 J = 6.9 Hz, 1H), 4.56 (dd, J = 6.9, 4.0 Hz, 1H), 1.39 (s, 3H), 1.33 (s, 3H); 13 [1,3]dioxol-4-yl)carbamate (22) Aluminum amalgam (prepared from 20 mg, 0.72 mmol, 8 equivalents of aluminum turnings after treatment with 1 M aq. KOH and 0.5% aq.…”

Section: Preparation and Characterization Of Compoundsmentioning

confidence: 99%

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Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

Habaz

Bedard²,

Smith³

et al. 2022

Molecules

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A 15-step chemoenzymatic total synthesis of C-1 methoxycarbonyl narciclasine (10) was accomplished. The synthesis began with the toluene dioxygenase-mediated dihydroxylation of ortho-dibromobenzene to provide the corresponding cis-dihydrodiol (12) as a single enantiomer. Further key steps included a nitroso Diels–Alder reaction and an intramolecular Heck cyclization. The C-1 homolog 10 was tested and evaluated for antiproliferative activity against natural narciclasine (1) as the positive control. Experimental and spectral data are reported for all novel compounds.

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Section: Enzymatic Dihydroxylation Of Ortho-dibromobenzene and Nitros...mentioning

confidence: 99%

Section: Preparation and Characterization Of Compoundsmentioning

confidence: 99%

Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

Habaz

Bedard²,

Smith³

et al. 2022

Molecules

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“…Rieske oxygenases (ROs) are nonheme iron-containing enzymes that catalyze a remarkably expansive range of reactions and act upon a diverse group of substrate chemical types. − Found widely across nature, − the ROs are increasingly appreciated for their roles and applications in human health, ,− environmental biotechnology, − agriculture, and chemoenzymatic synthesis. − Collectively, the catalytic repertoire of the RO family exceeds even those of other well-studied oxygenases, including cytochrome P450, dinuclear iron-containing hydrocarbon monooxygenases, flavin oxygenases, and α-ketoacid-linked monooxygenases. ,− …”

Section: Introductionmentioning

confidence: 99%

Contrasting Mechanisms of Aromatic and Aryl-Methyl Substituent Hydroxylation by the Rieske Monooxygenase Salicylate 5-Hydroxylase

et al. 2022

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The hydroxylase component (S5HH) of salicylate-5-hydroxylase catalyzes C5 ring hydroxylation of salicylate but switches to methyl hydroxylation when a C5 methyl substituent is present. The use of 18 O 2 reveals that both aromatic and aryl-methyl hydroxylations result from monooxygenase chemistry. The functional unit of S5HH comprises a nonheme Fe(II) site located 12 Å across a subunit boundary from a one-electron reduced Riesketype iron−sulfur cluster. Past studies determined that substrates bind near the Fe(II), followed by O 2 binding to the iron to initiate catalysis. Stopped-flow-single-turnover reactions (STOs) demonstrated that the Rieske cluster transfers an electron to the iron site during catalysis. It is shown here that fluorine ring substituents decrease the rate constant for Rieske electron transfer, implying a prior reaction of an Fe(III)-superoxo intermediate with a substrate. We propose that the iron becomes fully oxidized in the resulting Fe(III)-peroxo-substrate-radical intermediate, allowing Rieske electron transfer to occur. STO using 5-CD 3 -salicylate-d 8 occurs with an inverse kinetic isotope effect (KIE). In contrast, STO of a 1:1 mixture of unlabeled and 5-CD 3 -salicylate-d 8 yields a normal product isotope effect. It is proposed that aromatic and aryl-methyl hydroxylation reactions both begin with the Fe(III)-superoxo reaction with a ring carbon, yielding the inverse KIE due to sp 2 → sp 3 carbon hybridization. After Rieske electron transfer, the resulting Fe(III)-peroxo-salicylate intermediate can continue to aromatic hydroxylation, whereas the equivalent aryl-methyl intermediate formation must be reversible to allow the substrate exchange necessary to yield a normal product isotope effect. The resulting Fe(III)-(hydro)peroxo intermediate may be reactive or evolve through a high-valent iron intermediate to complete the arylmethyl hydroxylation.

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Synthesis and biological evaluation of 10-benzyloxy-Narciclasine

Ticli

Zhao

et al. 2021

Tetrahedron

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Enzymatic dihydroxylation of aromatic compounds: Nature's unique reaction and its impact on the synthesis of natural products

Cited by 3 publications

References 206 publications

Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

Contrasting Mechanisms of Aromatic and Aryl-Methyl Substituent Hydroxylation by the Rieske Monooxygenase Salicylate 5-Hydroxylase

Synthesis and biological evaluation of 10-benzyloxy-Narciclasine

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