An asymmetric synthesis of febrifugine, halofuginone and their hemiketal isomers

Smullen, Shaun; Evans, Paul

doi:10.1016/j.tet.2017.07.041

Cited by 15 publications

(23 citation statements)

References 42 publications

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“…Treatment of 10 with TMSOTf in the presence of N,N ‐diisopropylethylamine (DIPEA) and subsequent bromination with NBS afforded α ‐bromoketone 11 in 76% yield. Finally, compound 11 was smoothly converted to the desired (+)‐Febrifugine ( 1 ) {mp 124–126 °C; lit . mp 133–136 °C; [ α ] D 25 =+20.4 ( c 0.25, EtOH), lit .…”

Section: Resultsmentioning

confidence: 99%

“…Finally, compound 11 was smoothly converted to the desired (+)‐Febrifugine ( 1 ) {mp 124–126 °C; lit . mp 133–136 °C; [ α ] D 25 =+20.4 ( c 0.25, EtOH), lit . [ α ] D 20 =+14.0 ( c 0.50, EtOH); lit .…”

Section: Resultsmentioning

confidence: 99%

“…The combined organic layers were dried over anhydrous Na 2 SO 4 and K 2 CO 3 , filtered and concentrated. The crude product was purified by silica gel flash chromatography (DCM/CH 3 OH=10:1) to afford the compound 1 as a white solid (104 mg, 68%), {mp 124–126 °C; lit . mp 133–136 °C; [ α ] D 25 =+20.4 ( c 0.25, EtOH), lit .…”

Section: Methodsmentioning

confidence: 99%

“…The crude product was purified by silica gel flash chromatography (DCM/CH 3 OH=10:1) to afford the compound 1 as a white solid (104 mg, 68%), {mp 124–126 °C; lit . mp 133–136 °C; [ α ] D 25 =+20.4 ( c 0.25, EtOH), lit . [ α ] D 20 =+14.0 ( c 0.50, EtOH); lit .…”

Section: Methodsmentioning

confidence: 99%

“…[9] Very recently, (+)-Halofuginone (3) has also been selected for further investigation as the candidate for treatment of knee arthritis in pre-clinical research. [10] Owing to the existence of β-amino ketone moiety in the structure, (+)-Febrifugine (1) ing hemiketal forms (+)-Iso-febrifugine (2) and (+)-Iso-halofuginone under acidic conditions, [11] causing great difficulties in their preparation, especially for the scalable synthesis. During the past 30 years, asymmetric synthesis of (+)-Febrifugine (1) or (+)-Halofuginone (3) has attracted wide attention and a number of powerful approaches have been reported.…”

Section: Introductionmentioning

confidence: 99%

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Stereoselective Intermolecular [4+2] Process of N,O‐acetals with Terminal Alkynes for Construction of Functional cis‐Pyrido and Pyrrolo[1,2‐c][1,3]oxazin‐1‐ones

et al. 2019

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stereoselective Intermolecular [4+2] Process of N,O‐acetals with Terminal Alkynes for Construction of Functional cis‐Pyrido and Pyrrolo[1,2‐c][1,3]oxazin‐1‐ones

et al. 2019

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Metathesis Reactions in Natural Product Fragments and Total Syntheses

et al. 2022

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The passion of total‐ and fragments syntheses of natural products always remained one of the top priorities among the synthetic chemists worldwide. Due their curiosity toward the complexity of molecules of living nature and their endeavour to imitate them in laboratory; limitless arrays of natural products have been extracted, architecturally‐elucidated, synthesized, and chronicled by utilizing various synthetic methodologies in different fashions. Frequently, the synthesis of complex natural products proceed with inscrutable synthetic challenges, which can be circumvented either by modification of previously developed synthetic methods or by formulating a new one. In this way, a myriad of powerful synthetic reactions have been developed since the genesis of the logic of chemical synthesis. Amongst them, metathesis tactics discovered unexpectedly in the 1950s (Nobel Prize in 2005), have incredibly influenced and changed the landscape of the art of the total and formal synthesis in the last three A. H. Hoveyda, A. R. Zhugralin, me abruptly as compared to other developed transformations or their modified forms. In this particular review article, we envisioned to report a comprehensive detail of the metathetic tools involved in both total and fragments synthesis of natural products in the years 2018 and 2019 along with an overview of 2017.

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Synthesis of the cis‐ and trans‐3‐Fluoro Analogues of Febrifugine and Halofuginone

Alkhathami,

Chieng,

Ortin

et al. 2024

Eur J Org Chem

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The novel synthesis of racemic cis‐ and trans‐3‐fluorofebrifugine and halofuginone is described. This straight‐forward seven‐step process relies on an electrophilic fluorination‐allylation sequence generating a mixture of N‐Cbz protected, diastereomeric 2‐allyl‐3‐fluoropiperidines. On separation, a Wacker oxidation‐methyl functionalisation sequence enabled introduction of the required quinazolinone portion. Finally, removal of the N‐Cbz protecting group lead to isolation of the 3‐fluorofebrifugine dihydrobromide analogues that are of potentially pharmacological use. Analysis of the NMR spectra for each stereoisomer provides information concerning the preferred conformers of the different diastereomers. Evidence indicates that the cis‐diastereomer favours a conformation where the F‐atom occupies an axial orientation. In contrast, for its trans‐stereoisomeric counterpart, the 2‐substituent overrides any F‐atom effect and it preferentially occupies a conformer where both substituents occupy equatorial positions. Finally, interconversion between the cis‐ and trans‐diastereomers was studied. In DMSO‐d6 and as their free‐bases, isomerisation of each diastereomer gave a common 65:35 ratio of trans‐ to cis‐3‐fluorofebrifugine. Determination of the reaction rate constants for the isomerisation process at different temperatures enabled calculation of the activation energy barriers, for each process, using an Arrhenius plot. The activation energy barrier for the isomerisation of the trans‐isomer was 94.3 kJ mol‐1, whereas for the cis‐isomer it was 84.5 kJ mol‐1

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An asymmetric synthesis of febrifugine, halofuginone and their hemiketal isomers

Cited by 15 publications

References 42 publications

Stereoselective Intermolecular [4+2] Process of N,O‐acetals with Terminal Alkynes for Construction of Functional cis‐Pyrido and Pyrrolo[1,2‐c][1,3]oxazin‐1‐ones

Stereoselective Intermolecular [4+2] Process of N,O‐acetals with Terminal Alkynes for Construction of Functional cis‐Pyrido and Pyrrolo[1,2‐c][1,3]oxazin‐1‐ones

Metathesis Reactions in Natural Product Fragments and Total Syntheses

Synthesis of the cis‐ and trans‐3‐Fluoro Analogues of Febrifugine and Halofuginone

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