Microwave‐Assisted Generation and Capture by Azoles of <i>ortho</i>‐Quinone Methide Intermediates under Aqueous Conditions

González‐Pelayo, Silvia; López, Luís A.

doi:10.1002/ejoc.201701183

Cited by 11 publications

(6 citation statements)

References 47 publications

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“…This result suggests that the water in fact may help to stabilize the o -QM intermediate through intermolecular hydrogen bonding. 18 The positive effect of in situ generated water molecule on the stabilization of o -QM intermediate and the product yield is aligned with our observation on the phospha-Michael reaction. 17 In addition, various substituents on the phenol motif were examined for the substrate scope of the reaction.…”

Section: Resultssupporting

confidence: 87%

Catalyst-free thiophosphorylation of in situ formed ortho-quinone methides

Ash

Kang

2023

Org. Biomol. Chem.

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Section: Resultssupporting

confidence: 87%

Catalyst-free thiophosphorylation of in situ formed ortho-quinone methides

Ash

Kang

2023

Org. Biomol. Chem.

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“…Interception of o -QMs allows for rapid building of molecular complexity and has been employed in the total synthesis of several natural products. Conventional methods for generating o -QMs often require harsh conditions such as strongly acidic or basic conditions or photolysis using low wavelength (<300 nm) UV light, microwave, heat, or transition metal catalysts . In Nature, one approach to access o -QMs is benzylic hydroxylation of ortho -cresol compounds, followed by loss of water under mild physiological conditions .…”

Section: Chemoenzymatic Total Synthesis Of Xyloketal Natural Productsmentioning

confidence: 99%

Chemoenzymatic Total Synthesis of Natural Products

et al. 2021

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Metrics & MoreArticle Recommendations CONSPECTUS: The total synthesis of structurally complex natural products has challenged and inspired generations of chemists and remains an exciting area of active research. Despite their history as privileged bioactivity-rich scaffolds, the use of natural products in drug discovery has waned. This shift is driven by their relatively low abundance hindering isolation from natural sources and the challenges presented by their synthesis. Recent developments in biocatalysis have resulted in the application of enzymes for the construction of complex molecules. From the inception of the Narayan lab in 2015, we have focused on harnessing the exquisite selectivity of enzymes alongside contemporary small molecule-based approaches to enable concise chemoenzymatic routes to natural products.We have focused on enzymes from various families that perform selective oxidation reactions. For example, we have targeted xyloketal natural products through a strategy that relies on a chemo-and site-selective biocatalytic hydroxylation. Members of the xyloketal family are characterized by polycyclic ketal cores and demonstrate potent neurological activity. We envisioned assembling a representative xyloketal natural product (xyloketal D) involving a biocatalytically generated ortho-quinone methide intermediate.The non-heme iron (NHI) dependent monooxygenase ClaD was used to perform the benzylic hydroxylation of a resorcinol precursor, the product of which can undergo spontaneous loss of water to form an ortho-quinone methide under mild conditions. This intermediate was trapped using a chiral dienophile to complete the total synthesis of xyloketal D.A second class of biocatalytic oxidation that we have employed in synthesis is the hydroxylative dearomatization of resorcinol compounds using flavin-dependent monooxygenases (FDMOs). We anticipated that the catalyst-controlled site-and stereoselectivity of FDMOs would enable the total synthesis of azaphilone natural products. Azaphilones are bioactive compounds characterized by a pyranoquinone bicyclic core and a fully substituted chiral carbon atom. We leveraged the stereodivergent reactivity of FDMOs AzaH and AfoD to achieve the enantioselective synthesis of trichoflectin enantiomers, deflectin 1a, and lunatoic acid. We also leveraged FDMOs to construct tropolone and sorbicillinoid natural products. Tropolones are a structurally diverse class of bioactive molecules characterized by an aromatic cycloheptatriene core bearing an α-hydroxyketone moiety. We developed a two-step biocatalytic cascade to the tropolone natural product stipitatic aldehyde using the FDMO TropB and a NHI monooxygenase TropC. The FDMO SorbC obtained from the sorbicillin biosynthetic pathway was used in the concise total synthesis of a urea sorbicillinoid natural product.Our long-standing interest in using enzymes to carry out C−H hydroxylation reactions has also been channeled for the late-stage diversification of complex scaffolds. For example, we have used Rieske oxygenases to h...

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“…Lopez et al used microwaveassisted coupling of o-hydroxybenzyl alcohol and pyrazole, yielding N-alkylated pyrazoles (Scheme 1A). [17] In contrast, Jiang et al employed a chiral squaramide-catalyzed reaction with in situ generated o-QMs and pyrazolones, affording C4-alkylated 5-hydroxypyrazoles with excellent enantioselectivity (Scheme 1B). [18] Our research investigates the reactivity of 5aminopyrazoles with o-hydroxybenzyl alcohols for the synthesis of the alkylated pyrazole core commonly found in pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Organocatalytic Chemoselective C4‐Benzylation of 5‐Aminopyrazoles

Natarajan,

Kanchithalaivan,

Chatterjee

et al. 2024

Asian J Org Chem

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The first chemoselective C4‐benzylation of 5‐aminopyrazoles, utilizing a 3 mol% squaric acid catalyst, is disclosed. In this process, ortho‐quinone methides are efficiently generated from 2‐hydroxybenzyl alcohols in water under mild conditions. This method successfully delivers a wide range of C4‐benzylated 5‐aminopyrazoles, achieving moderate to excellent yields while demonstrating high chemoselectivity, which is further confirmed by mechanistic studies. Notably, the protocol uses water as an eco‐friendly solvent, requires a low organocatalyst loading, and eliminates the need for column chromatography.

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Microwave‐Assisted Generation and Capture by Azoles of ortho‐Quinone Methide Intermediates under Aqueous Conditions

Cited by 11 publications

References 47 publications

Catalyst-free thiophosphorylation of in situ formed ortho-quinone methides

Catalyst-free thiophosphorylation of in situ formed ortho-quinone methides

Chemoenzymatic Total Synthesis of Natural Products

Organocatalytic Chemoselective C4‐Benzylation of 5‐Aminopyrazoles

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