Emergence of 2,3,5-trisubstituted tetrahydrofuran natural products and their synthesis

Fernandes, Rodney A.; Gorve, Dnyaneshwar A; Pathare, Ramdas S.

doi:10.1039/d0ob01542c

Cited by 15 publications

(11 citation statements)

References 148 publications

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“…The catalysis is particularly effective in the synthesis of spiro and fused bi-and tricyclic ethers commonly found in agrochemical, pharmaceutical, and natural products. [1][2][3][4][5][6]9 With the wide functional group tolerance and the generation of enolester motifs, 16 we envision the methodology presented here would provide rapid access to a variety of highly functionalized cyclic, structurally complex ether precursors for elaborated downstream organic synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Our mechanistic investigation suggested a novel, stereospecific C–H functionalization pathway via the in situ formation of a vinyl C-based radical to generate the kinetically stable ( Z )-2-alkylidene dihydrofurans with high entropic selectivity for five-membered rings and heightened reactivity toward electron-rich C–H bonds. The catalysis is particularly effective in the synthesis of spiro and fused bi- and tricyclic ethers commonly found in agrochemical, pharmaceutical, and natural products. − , With the wide functional group tolerance and the generation of enolester motifs, we envision the methodology presented here would provide rapid access to a variety of highly functionalized cyclic, structurally complex ether precursors for elaborated downstream organic synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Tetrahydrofuran (THF) structures, among other oxygen-containing heterocycles, are fundamental structural units often encountered in a wide range of pharmaceuticals, agrochemicals, and natural products. − Indeed, THF-containing drugs such as darunavir are among the top 200 pharmaceuticals by retail sales in 2019, while thousands of marine products such as macrolides with oxacyclic building blocks are isolated each year, providing candidates for future pharmacological developments . The high cation affinity and potency as hydrogen bond acceptors make the cyclic ethers potential candidates to alter membrane ion permeability to function as antibiotics and to replace peptidic features of protease inhibitors for antiviral HIV treatments, respectively .…”

Section: Introductionmentioning

confidence: 99%

“…The high cation affinity and potency as hydrogen bond acceptors make the cyclic ethers potential candidates to alter membrane ion permeability to function as antibiotics and to replace peptidic features of protease inhibitors for antiviral HIV treatments, respectively . Although a variety of methodologies have been developed to synthesize functionalized THF motifs, ,− most show limited functional group tolerance and are ill-suited for preparing spiro or fused bi- and tricyclic structural units prevalent in most of the applications listed above. , Recently, Trost and co-workers published their Pd-catalyzed method to drive a [3 + 2] cycloaddition employing an oxyallyl cation to prepare a range of bi- and tricyclic fused structures (Figure a) . However, the catalysis is limited by the necessity of a conjugated diene, while it is also less effective toward the formation of spiro constructs.…”

Section: Introductionmentioning

confidence: 99%

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O-Heterocycle Synthesis via Intramolecular C–H Alkoxylation Catalyzed by Iron Acetylacetonate

et al. 2021

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Intramolecular alkoxylation of C–H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C–H alkoxylation to furnish oxacycles from easily prepared α-diazo-β-ketoesters using commercially available iron acetylacetonate (Fe(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N2 extrusion, which mediates a proximal H–atom abstraction followed by a rapid C–O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C–D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C–H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C–H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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O-Heterocycle Synthesis via Intramolecular C–H Alkoxylation Catalyzed by Iron Acetylacetonate

et al. 2021

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“…Oxepanecontaining marine compounds were recently reviewed by our group [7]. Total syntheses of marine and non-marine products containing 2,3,5-trisubstituted tetrahydrofurans (such as kumausallene or petromyroxol) have been recently reviewed by Fernandes [8,9].…”

Section: Introductionmentioning

confidence: 99%

The Tetrahydrofuran Motif in Polyketide Marine Drugs

et al. 2022

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Oxygen heterocycles are units that are abundant in a great number of marine natural products. Among them, marine polyketides containing tetrahydrofuran rings have attracted great attention within the scientific community due to their challenging structures and promising biological activities. An overview of the most important marine tetrahydrofuran polyketides, with a focused discussion on their isolation, structure determination, approaches to their total synthesis, and biological studies is provided.

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Enantioselective (3+2) Annulation of Donor‐Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases

Obregón,

Rost,

Kocemba

et al. 2024

Angewandte Chemie

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The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted‐base catalyzed enantioselective (3+2) annulation of donor‐acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5‐substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β‐cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99% ee. Surprisingly, aromatic aldehydes afforded the cis‐2,5‐substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans‐cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99% ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

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Emergence of 2,3,5-trisubstituted tetrahydrofuran natural products and their synthesis

Abstract: The emergence of various 2,3,5-trisubstituted tetrahydrofuran natural products in recent literature and their syntheses has been the focus of this review. These molecules exhibit varied bioactivities and have garnered the...

Cited by 15 publications

References 148 publications

O-Heterocycle Synthesis via Intramolecular C–H Alkoxylation Catalyzed by Iron Acetylacetonate

O-Heterocycle Synthesis via Intramolecular C–H Alkoxylation Catalyzed by Iron Acetylacetonate

The Tetrahydrofuran Motif in Polyketide Marine Drugs

Enantioselective (3+2) Annulation of Donor‐Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases

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