Origin of the <i>E</i>/<i>Z</i> Selectivity in the Synthesis of Tetrasubstituted Olefins by Wittig Reaction of α-Fluorophosphonium Ylides: An Explanation for the Low Stereoselectivity Observed in Reactions of α-Alkoxy Aldehydes

Depré, Dominique; Vermeulen, Wim A. A.; Lang, Yolande; Dubois, Jean; Vandevivere, Jan; Vandermeersch, Jeremy; Huang, Li-Hsin; Robiette, Raphaël

doi:10.1021/acs.orglett.7b00344

Cited by 10 publications

(5 citation statements)

References 14 publications

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“…Through this methodology, a series of Nprotected piperidin-3-ones and related compounds were converted into the corresponding fluoroalkenes with high E selectivity (Scheme 198). 200 Acyclic compounds behaved similarly under the reaction conditions. The presence of an…”

Section: Wittig Olefinationmentioning

confidence: 95%

Synthesis of Monofluoroalkenes: A Leap Forward

2018

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Monofluoroalkenes have found wide application in organic chemistry, medicinal chemistry, and materials science. This review summarizes the most recent advances made regarding the preparation of monofluoroalkenes, covering the period between October 2010 and September 2017. This review is divided in three main parts, one for each possible substitution pattern, namely di-, tri-, and tetrasubstituted. Then, for each class, further subclassification is made according to the reaction type.1 Introduction2 Disubstituted Monofluoroalkenes2.1 Disubstituted α-Monofluoroalkenes2.2 Disubstituted β-Monofluoroalkenes3 Trisubstituted Monofluoroalkenes4 Tetrasubstituted Monofluoroalkenes5 Conclusions

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Section: Wittig Olefinationmentioning

confidence: 95%

Synthesis of Monofluoroalkenes: A Leap Forward

2018

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“…In fact, the Wittig reaction is a versatile and reliable method for the production of substituted alkenes due to easy application and good yields of the desired products. The stereoselectivity of the Wittig reaction depends on the substrates (Depré et al, 2017), and all the synthesis of climacostol using the ( Z) -selective Wittig reaction revealed the presence of the ( E) -diastereomer (Abe and Mori, 2001). The importance of protection and deprotection of hydroxyl groups in the synthesis of biologically active small molecules (Cappa et al, 1999) helped us to solve the problem of the low quantity of unwanted ( E) -isomer.…”

Section: Introductionmentioning

confidence: 99%

The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

et al. 2019

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We synthesized and characterized MOMO as a new small molecule analog of the cytotoxic natural product climacostol efficiently activated in mild extracellular acidosis. The synthesis of MOMO had a key step in the Wittig olefination for the construction of the carbon-carbon double bond in the alkenyl moiety of climacostol. The possibility of obtaining the target ( Z )-alkenyl MOMO derivative in very good yield and without presence of the less active ( E )-diastereomer was favored from the methoxymethyl ether (MOM)-protecting group of hydroxyl functions in aromatic ring of climacostol aldehyde intermediate. Of interest, the easy removal of MOM-protecting group in a weakly acidic environment allowed us to obtain a great quantity of climacostol in biologically active (Z)-configuration. Results obtained in free-living ciliates that share the same micro-environment of the climacostol natural producer Climacostomum virens demonstrated that MOMO is well-tolerated in a physiological environment, while its cytotoxicity is rapidly and efficiently triggered at pH 6.3. In addition, the cytostatic vs. cytotoxic effects of acidified-MOMO can be modulated in a dose-dependent manner. In mouse melanoma cells, MOMO displayed a marked pH-sensitivity since its cytotoxic and apoptotic effects become evident only in mild extracellular acidosis. Data also suggested MOMO being preferentially activated in the unique extra-acidic microenvironment that characterizes tumoural cells. Finally, the use of the model organism Drosophila melanogaster fed with an acidic diet supported the efficient activity and oral delivery of MOMO molecule in vivo . MOMO affected oviposition of mating adults and larvae eclosion. Reduced survival of flies was due to lethality during the larval stages while emerging larvae retained their ability to develop into adults. Interestingly, the gut of eclosed larvae exhibited an extended damage (cell death by apoptosis) and the brain tissue was also affected (reduced mitosis), demonstrating that orally activated MOMO efficiently targets different tissues of the developing fly. These results provided a proof-of-concept study on the pH-dependence of MOMO effects. In this respect, MOM-protection emerges as a potential prodrug strategy which deserves to be further investigated for the generation of efficient pH-sensitive small organic molecules as pharmacologically active cytotoxic compounds.

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“…While this array of applications has attracted attention to their synthesis, , there are several features of current strategies that limit their general utility (Figure B). For example, the fluoro-olefination of carbonyls contends with stereoselectivity issues and requires anion-stabilizing groups next to the C–F bond. − The control of regioselectivity in direct alkyne hydrofluorination can be challenging unless a large electronic disparity exists on the alkyne. − Finally, the defluorofunctionalization of gem -difluoroalkenes can occur via radical, carbanion, or migratory insertion pathways but are generally constrained to styrenyl substrates, and the stereoselectivity is variable without a directing group. − …”

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confidence: 99%

Silver-Catalyzed (Z)-β-Fluoro-vinyl Iodonium Salts from Alkynes: Efficient and Selective Syntheses of Z-Monofluoroalkenes

Sedikides,

Lennox

2024

J. Am. Chem. Soc.

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Monofluoroalkenes are stable and lipophilic amide bioisosteres used in medicinal chemistry. However, efficient and stereoselective methods for synthesizing Z-monofluoroalkenes are underdeveloped. We envisage (Z)-β-fluoro-vinyl iodonium salts (Z-FVIs) as coupling partners for the diverse and stereoselective synthesis of Z-monofluoroalkenes. Disclosed herein is the development and application of a silver(I)-catalyzed process for accessing a broad scope of (Z)-FVIs with exclusive Z-stereoselectivity and regioselectivity from alkynes in a single step. Experimental and computational studies provide insight into the mechanism of the catalytic cycle and the role of the silver(I) catalyst, and the reactivity of (Z)-FVIs is explored through several stereospecific derivatizations.

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Origin of the E/Z Selectivity in the Synthesis of Tetrasubstituted Olefins by Wittig Reaction of α-Fluorophosphonium Ylides: An Explanation for the Low Stereoselectivity Observed in Reactions of α-Alkoxy Aldehydes

Cited by 10 publications

References 14 publications

Synthesis of Monofluoroalkenes: A Leap Forward

Synthesis of Monofluoroalkenes: A Leap Forward

The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

Silver-Catalyzed (Z)-β-Fluoro-vinyl Iodonium Salts from Alkynes: Efficient and Selective Syntheses of Z-Monofluoroalkenes

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