Syntheses of ω-Hydroxy-α,α-difluoromethylphosphonates by Oxacycle Ring-Opening Reactions

Ozouf, Paul; Binot, Gregory; Pommelet, J. C.; Lequeux, Thierry

doi:10.1021/ol048549g

Cited by 33 publications

(21 citation statements)

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“…We assumed that the nucleophilicity of PhSO(NTBS)CF 2 − towards the epoxide was not high enough and that activation of 4 a would be needed to achieve the ring‐opening difluoromethylation reaction. Previously, BF 3 ⋅ Et 2 O has often been used as a Lewis acid to activate epoxides in their reactions with carbanions 6b. 8, 14 Two traditional procedures have been applied: 1) adding the epoxide to mixtures of BF 3 ⋅ Et 2 O and carbanions;14 2) adding BF 3 ⋅ Et 2 O immediately after the addition of the epoxide to a solution of the carbanion 6b.…”

Section: Resultsmentioning

confidence: 99%

“…8, 14 Two traditional procedures have been applied: 1) adding the epoxide to mixtures of BF 3 ⋅ Et 2 O and carbanions;14 2) adding BF 3 ⋅ Et 2 O immediately after the addition of the epoxide to a solution of the carbanion 6b. 8 As discussed by Ganem et al.,14 these successful reactions would indicate that combinations of such carbanions and BF 3 ⋅ Et 2 O are reasonably stable under certain reaction conditions, allowing them to react independently as potent nucleophile and strong Lewis acid, respectively 6b. 8, 14 However, in the case of sulfoximine 2 , compound 5 was not obtained by using either of these two procedures (Scheme b, c).…”

Section: Resultsmentioning

confidence: 99%

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Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF₂H by a Preorganization Strategy

Shen¹,

Liu²,

Luo³

et al. 2014

Chemistry A European J

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Unlike the facile synthesis of β-monofluoromethyl alcohols by nucleophilic monofluoromethylation of epoxides, the synthesis of β-difluoromethyl alcohols by nucleophilic difluoromethylation of epoxides still remains a challenge. Herein, studies on tackling this problem with PhSO(NTBS)CF2H (2; TBS=tert-butyldimethylsilyl) are reported. The preorganization of 2 and epoxides with BF3⋅Et2O was found to be crucial for the reaction. The reaction shows excellent regioselectivity and has a broad substrate scope. The facile transformation of the ring-opened products to β-difluoromethyl, γ-difluoromethyl, and β-difluoromethylenyl alcohols demonstrates the synthetic utility of the reaction.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF₂H by a Preorganization Strategy

Shen¹,

Liu²,

Luo³

et al. 2014

Chemistry A European J

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“…Synthesis of an enantiomerically pure amino alcohol moiety could be achieved by selective ring opening of chiral aziridines with various nucleophiles (Hu, 2004). Oxirane ring opening by α,α-difluoromethylene-phosphonate anion to furnish γ-hydroxy-α,α-difluoromethylenephosphonates has been reported (Ozouf et al, 2004; Pajkert et al, 2008); however, aziridine ring opening with the same anion has not been reported to date. Thus, we speculated that the reaction of chiral aziridine with α,α-difluoromethylene diethylphosphonate anion might provide facile access to the desired non-hydrolyzable phosphoserine core structure.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity

Arrendale

Kim

Choi

et al. 2012

Chemistry & Biology

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SUMMARY Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs containing phosphorylated serine and threonine residues. To create small molecules that inhibit such interactions, we developed methodology for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small molecule inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylene-phosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concentrations when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concentration-dependent manner that correlates well with its ability to inhibit cell growth. This methodology can be applied to target a variety of proteins containing phosphoserine and other phosphoamino acid binding domains.

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“…Lequeux and co‐workers [163] and later Koroniak, Röschenthaler, and co‐workers [164,165] reported regiocontrolled ring‐opening of epoxides with LiCF 2 P(O)(OEt) 2 in the presence of Lewis acids as a route toward α,α‐difluoro‐γ‐hydroxyphosphonates 102 (Scheme 43). Alternatively, cyclic sulfates of 1,2‐diols could be used as substrates providing products 102 in even better yields and excellent regioselectivity [166,167] .…”

Section: Synthetic Methodsmentioning

confidence: 99%

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

et al. 2021

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For almost 40 years, difluoromethylene phosphonates have proven to be versatile molecular tools in biochemical studies owing to their close resemblance to naturally occurring phosphates and phosphonates. As bioisosteric, non‐hydrolyzable analogs of these essential molecules, difluoromethylene phosphonates can target the critical parts of the cellular machinery and therefore exhibit a diverse spectrum of biological activity. In the past ten years, there have appeared many new methods for the synthesis of difluoromethylene phosphonates. Most notably, photoredox catalysis has firmly entered the field, while cross‐coupling and nucleophilic strategies have met considerable elaboration and refinement, entirely in accord with the current trends in synthetic organic chemistry. Herein, we introduce difluoromethylene phosphonates as a distinct, high‐tech subclass of synthetic phosphonates resulting from the research efforts on the cross‐section of organophosphorus, organofluorine, and bioorganic chemistry. We then proceed to the discussion of general methods for the preparation of difluoromethylene phosphonates, comprehensively reviewing reactions developed in the past 15 years while providing the context of earlier works where appropriate. Finally, we present selected examples of molecules with high biological activity, their biological targets, and the synthetic steps employed for their preparation.

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Syntheses of ω-Hydroxy-α,α-difluoromethylphosphonates by Oxacycle Ring-Opening Reactions

Cited by 33 publications

References 33 publications

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF₂H by a Preorganization Strategy

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF₂H by a Preorganization Strategy

Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

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Syntheses of ω-Hydroxy-α,α-difluoromethylphosphonates by Oxacycle Ring-Opening Reactions

Cited by 33 publications

References 33 publications

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF2H by a Preorganization Strategy

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF2H by a Preorganization Strategy

Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

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Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF₂H by a Preorganization Strategy

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF₂H by a Preorganization Strategy