The β-Fluorine Effect. Electronic Versus Steric Effects in Radical Deoxygenations of Fluorine-Containing Pentofuranose Nucleosides

Wnuk, Stanislaw F.; Companioni, Dania R.; Neschadimenko, Vladimir; Robins, Morris J.

doi:10.1021/jo020428b

Cited by 5 publications

(9 citation statements)

References 22 publications

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“…50 Barton-McCombie deoxygenation was accomplished in two steps through conversion to the corresponding thionocarbonate 44 followed by treatment with Bu 3 SnH in refluxing toluene to yield 45 . 50 Deprotection of the TBS group with TFA provided alcohol 46 , which was transformed to azide 47 using methodology reported by Liu and Austin. 51 The sulfamide moiety at C-5' in 48 was then installed using our new protocol described in the previous section through azide reduction of 47 and in situ sulfamoylation of the crude aminonucleoside.…”

Section: Resultsmentioning

confidence: 99%

“…5′-O-tert-Butyldimethylsilyl-2′-deoxy-2′-fluoroadenosine (43). 50 To a stirring solution of 42 (0.750 g, 2.8 mmol, 1.0 equiv) in DMF (25 mL) at 0 °C was added sequentially TBSCl (0.462 g, 4.5 mmol, 1.6 equiv) and imidazole (0.322 g, 4.7 mmol, 1.7 equiv). The reaction mixture was stirred for 7 h at 23 °C, then quenched with MeOH (20 mL) and concentrated.…”

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

“…The analytical data ( 1 H NMR, 19 F NMR, MS) agreed with previously reported values. 50 13 C NMR data and R f have not been disclosed and are provided herein: R f = 0.22 (EtOAc). 13 5′-O-tert-Butyldimethylsilyl-2′-deoxy-2′-fluoro-3′-O-(phenoxythiocarbonyl)adenosine (44).…”

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

“…13 5′-O-tert-Butyldimethylsilyl-2′-deoxy-2′-fluoro-3′-O-(phenoxythiocarbonyl)adenosine (44). 50 To a stirring solution of 43 (0.800 g, 2.1 mmol, 1.0 equiv) in MeCN (25 mL) was added sequentially O-phenyl chlorothionoformate (0.540 g, 3.1 mmol, 1.5 equiv) and DMAP (0.765 g, 6.3 mmol, 3.0 equiv). The reaction mixture was stirred for 1 h at 23 °C then quenched with H 2 O (10 mL).…”

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

“…The analytical data ( 1 H NMR, 19 F NMR, MS) agreed with previously reported values. 50 13 C NMR data and R f have not been disclosed and are provided herein: R f = 0.38 (3:1 EtOAc−hexane). 13 C NMR (100 MHz, CDCl 3 ) δ −5.5, −5.4, 18.4, 25.9, 61.8, 77.6 (d, 2 J C−F = 14.0 Hz), 81.6, 86.3 (d, 2 J C−F = 32.1 Hz), 90.7 (d, 1 J C−F = 196.8 Hz), 119.9, 121.…”

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

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Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

et al. 2015

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MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in Mycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5′-O-[N-(salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from sub-optimal drug disposition properties resulting in a short half-life (t1/2), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pKa of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in t1/2 and AUC. Increasing the pKa of the acyl-sulfonyl linker yielded incremental enhancements while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters.

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Section: Resultsmentioning

confidence: 99%

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

Section: ′-N-[n-(2-hydroxybenzoylmentioning

confidence: 99%

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Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

et al. 2015

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The Barton‐McCombie Reaction

2012

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Deoxygenations of alcohols, i.e., processes that replace a hydroxyl group with hydrogen at a saturated carbon, find applications in both total synthesis and the systematic modifications of natural products. They may also be employed to introduce deuterium or tritium in a site‐specific manner. Reductive methods that involve ionic or highly polarized reagents or intermediates can be limited in their applicability: for example, competing reaction pathways including cationic rearrangements and anionic eliminations may be encountered in sterically hindered systems with substrates bearing heteroatoms close to the center undergoing reduction. As evidenced by developments over the last few decades, methods that involve the generation and direct quenching via hydrogen atom abstraction of the derived, carbon‐centered radical typically show the greatest tolerance for the presence of other functional groups and for variations in both the steric acid and the electronic environment in the vicinity of the center undergoing deoxygenation. Derivatization of the hydroxyl is a prerequisite, the determinant factors for efficient formation of the deoxygenated product lies in the ability of the combination of the substrate and reagents to induce homolysis of the C‐O bond coupled with the induction of homolysis to rapidly reduce a free radical by hydrogen donation, thereby propagating an efficient chain process. A high‐yielding way to realize this sequence was first described by Barton McCombie using the free‐radical chain reaction of O ‐thioacyl derivatives of secondary alcohols with tri‐ n ‐butylstannane. This chapter provides a detailed description and comparison of the combinations of substrates and reagents that will bring about these processes and provides a summary and evaluation of alternative deoxygenation methods. Mechanistic and stereochemical issues set out the scope and limitations of these processes with respect to both the thioacylation and reduction steps and exemplify some applications to both total synthesis and the modification of natural products.

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Carbonyl Ylides Derived from Palladium Carbenes: The Impressive Fluorine Effect

Zhu

Chen

et al. 2017

Adv Synth Catal

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The first example for the generation of carbonyl ylides from palladium carbenes is reported. Systematic investigation of the substituents attached to the carbonyl group indicates that the employment of trifluoromethyl group as the substituent is very critical for the success of this transformation. The remarkable fluorine effect on the reactivity is very impressive, which allows the construction of various trifluoromethylated oxiranes in high yields and diastereoselectivities.magnified image

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The β-Fluorine Effect. Electronic Versus Steric Effects in Radical Deoxygenations of Fluorine-Containing Pentofuranose Nucleosides

Cited by 5 publications

References 22 publications

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

The Barton‐McCombie Reaction

Carbonyl Ylides Derived from Palladium Carbenes: The Impressive Fluorine Effect

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