Synthesis of the Azaphilones Using Copper‐Mediated Enantioselective Oxidative Dearomatization.

Zhu, Jianglong; Grigoriadis, Nicholas P.; Lee, Jonathan P.; Porco, John A.

doi:10.1002/chin.200546022

Cited by 5 publications

(5 citation statements)

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“…31 Racemic syntheses of azaphilones have been reported using these reagents; however, achieving high levels of enantioselectivity can be a challenge. Enantioenriched azaphilones have been accessed using Porco and co-workers' copper-oxo (−)-sparteine dearomatization strategy, 36 achieving the total synthesis of (−)-mitorubrin with 97% ee, 37 as well as that of (+)-sclerotiorin and (+)-8-O-methylsclerotiorinamine from a common precursor obtained in 98% ee. 29 This method requires superstoichiometric quantities of both the oxidant and the chiral ligand.…”

Section: ■ Introductionmentioning

confidence: 99%

Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products

et al. 2019

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Selective access to a targeted isomer is often critical in the synthesis of biologically active molecules. Whereas small-molecule reagents and catalysts often act with anticipated site- and stereoselectivity, this predictability does not extend to enzymes. Further, the lack of access to catalysts that provide complementary selectivity creates a challenge in the application of biocatalysis in synthesis. Here, we report an approach for accessing biocatalysts with complementary selectivity that is orthogonal to protein engineering. Through the use of a sequence similarity network (SSN), a number of sequences were selected, and the corresponding biocatalysts were evaluated for reactivity and selectivity. With a number of biocatalysts identified that operate with complementary site- and stereoselectivity, these catalysts were employed in the stereodivergent, chemoenzymatic synthesis of azaphilone natural products. Specifically, the first syntheses of trichoflectin, deflectin-1a, and lunatoic acid A were achieved. In addition, chemoenzymatic syntheses of these azaphilones supplied enantioenriched material for reassignment of the absolute configuration of trichoflectin and deflectin-1a based on optical rotation, CD spectra, and X-ray crystallography.

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Section: ■ Introductionmentioning

confidence: 99%

Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products

et al. 2019

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“…Chemistry Although various studies on the synthesis of azaphilones have been reported, some with stereoselective chemistry (26)(27)(28) and others focused on racemic analogues (13,(29)(30)(31)(32)(33), this deceptively simplelooking bicyclic structure still presents significant challenges, especially when the requirement is to prepare analogues with diverse substituents at the 3-position. Recently, Porco's (34) group reported an efficient gold-catalysed cycloisomerization of 2-alkynylbenzaldehydes to give 2-benzopyrylium salts that can subsequently be oxidized with IBX to form the azaphilone ring system.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Fungicidal Activity of Novel Sclerotiorin Derivatives

et al. 2012

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Sclerotiorin, a chlorine-containing azaphilone-type natural product, was first isolated from Penicillium sclerotiorum and has been reported to exhibit weak fungicidal activity. Optimization of the substituents at the 3-and 5-positions of the sclerotiorin framework was investigated with the aim of discovering novel fungicides with improved activity. The design of sclerotiorin analogues involved replacing the diene side chain with a phenyl group or an aromatic-or heteroaromatic-containing aliphatic side chain. The designed compounds were synthesized by cycloisomerization and subsequent oxidation of suitable 2-alkynylbenzaldehydes, in which a variety of substituents were introduced using a Sonogashira coupling reaction. The structures of these newly prepared compounds were confirmed by 1 H and 13 C NMR spectroscopy, HRMS and single-crystal X-ray analysis. The antifungal activity of the synthesized compounds was evaluated against seven phytopathogenic species. Compounds 3, 9g and 9h were found to have a broad spectrum of fungicidal activity, and these structurally simpler products can be recognized as lead compounds for further optimization.Key words: antifungal activity, azaphilone, natural product, sclerotiorin, structural modification Received 3 March 2012, revised 28 June 2012 and accepted for publication 3 July 2012Sclerotiorin was first isolated in 1940 from Penicillium sclerotiorum as a chlorine-containing fungal pigment (1). It belongs to the class of natural products known as azaphilones, which have been isolated from a variety of fungal species (2-5) and feature a highly oxygenated bicyclic core and a chiral quaternary centre that breaks the aromaticity of the ring system (6-10). To date, over 170 different natural azaphilones have been identified (11). They have been reported to exhibit a wide range of biological activities, such as inhibition of monoamine oxidase (12), inhibition of the formation of the P53-MDM2 complex (13), inhibition of the gp120-CD4 binding reaction (14), inhibition of fatty acid synthase (15), inhibition of lipooxygenase (16), as well as having antifungal activity (17,18). Although various potentially beneficial biological activities have been discovered, the relationship between structure and activity amongst the azaphilones, as well as their mechanism of action, remains unclear. Furthermore, most of the azaphilones have been isolated as secondary metabolites of fungal species, and little attention has been paid to the modification of structure for the optimization of antifungal activity. As we know, natural product leads offer an efficient approach for the discovery and optimization of new agrochemicals for the control of plant diseases. As part of our programme for developing fungicides with novel scaffolds (19-22), we envisioned that sclerotiorin, which had shown weak antifungal activity in Syngenta's screens, might be a useful lead for the discovery of novel agricultural fungicides.Although the nine-carbon aliphatic diene side chain on the bicyclic core containing a chiral quat...

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“…More recent reports extend the oxidative substrate scope of O species: ortho hydroxylation of phenolic substrates to catechols and quinones, the oxidative reactivity effected by the binuclear copper enzyme tyrosinase [6,8]; oxidation of weak O-H and C-H bonds [7,[35][36][37][38]; catalytic oxidation of cyclohexane to cyclohexanol and cyclohexanone using H 2 O 2 as the oxidant [9] and stoichiometric oxidation of THF to THF-OH and γ-butyrolactone [39], as well as oxidation of toluene to benzyl alcohol [40]. Regioselective and enantioselective oxidative dearomatization reactions (net O-atom transfer) are also possible, including the first asymmetric synthesis of the azaphilone natural products (+)-sclerotiorin and (+)-8-Omethylsclerotiorinamine and the preparation of several unnatural azaphilones, with asymmetric induction achieved using sparteine ligands [41][42][43]. The reactions of characterized O species are joined by numerous catalytic oxidations involving Cu(I) salts and O 2 in which the active oxidant species remain unclear [44].…”

Section: Exogenous Reactivitymentioning

confidence: 99%

Selective oxidation of exogenous substrates by a bis-Cu(III) bis-oxide complex: Mechanism and scope

Large

Mahadevan

Keown

et al. 2019

Inorganica Chimica Acta

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Cu(III) 2 (μ-O) 2 bis-oxides (O) form spontaneously by direct oxygenation of nitrogen-chelated Cu(I) species and constitute a diverse class of versatile 2e -/2H + oxidants, but while these species have attracted attention as biomimetic models for dinuclear Cu enzymes, reactivity is typically limited to intramolecular ligand oxidation, and systems exhibiting synthetically useful reactivity with exogenous substrates are limited. O TMPD (TMPD = N 1 , N 1 , N 3 , N 3 -tetramethylpropane-1,3diamine) presents an exception, readily oxidizing a diverse array of exogenous substrates, including primary alcohols and amines selectively over their secondary counterparts in good yields. Mechanistic and DFT analyses suggest substrate oxidation proceeds through initial axial coordination, followed by rate limiting rotation to position the substrate in the Cu(III) equatorial plane, whereupon rapid deprotonation and oxidation by net hydride transfer occurs. Together, the results suggest the selectivity and broad substrate scope unique to O TMPD are best attributed to the combination of ligand flexibility, limited steric demands, and ligand oxidative stability. In keeping with the absence of rate limiting C-H scission, O TMPD exhibits a marked insensitivity to the strength of the substrate C α -H bond, readily oxidizing benzyl alcohol and 1 octanol at near identical rates.

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Synthesis of the Azaphilones Using Copper‐Mediated Enantioselective Oxidative Dearomatization.

Cited by 5 publications

References 1 publication

Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products

Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products

Design, Synthesis and Fungicidal Activity of Novel Sclerotiorin Derivatives

Selective oxidation of exogenous substrates by a bis-Cu(III) bis-oxide complex: Mechanism and scope

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