A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost

Krupa, Małgorzata; Chodyński, Michał; Ostaszewska, Anna; Cmoch, Piotr; Dams, Iwona

doi:10.3390/molecules22020217

Cited by 12 publications

(4 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…α,α‐Difluoro‐γ‐lactone 38 is a fluorinated analogue of a sex pheromone of the male African sugarcane borer, Eldana saccharina , and 38 exhibited a slightly higher pheromone activity compared to the natural pheromone [46] . Matsumura and co‐workers developed the gem ‐difluorinated prostaglandin analogue 39 (Taflprost) [47] which is currently used as the most powerful medicine of glaucoma [47,48] . Gemcitabine ( 40 ) is a gem ‐difluorinated nucleoside analogue and a potent anti‐cancer activity was reported for this compound [49] .…”

Section: Introductionmentioning

confidence: 99%

“…[46] Matsumura and co-workers developed the gem-difluorinated prostaglandin analogue 39 (Taflprost) [47] which is currently used as the most powerful medicine of glaucoma. [47,48] Gemcitabine ( 40) is a gem-difluorinated nucleoside analogue and a potent anti-cancer activity was reported for this compound. [49] KAG-308 (41) was developed as medicine for treating ulcerative colitis with a lower risk of colorectal carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of Selectively gem‐Difluorinated Molecules; Chiral gem‐Difluorocyclopropanes via Chemo‐Enzymatic Reaction and gem‐Difluorinated Compounds via Radical Reaction

Itoh

Hayase

Nokami

2023

The Chemical Record

View full text Add to dashboard Cite

The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem‐difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active‐gem‐difluorocyclopropanes via the chemo‐enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem‐difluorocyclopropane derivatives. The second section describes the synthesis of selectively gem‐difluorinated compounds via a radical reaction; we synthesized fluorinated analogues of a sex pheromone of the male African sugarcane borer, Eldana saccharina, and used the compounds as proof for investigating the origin of pheromone molecule recognition on the receptor protein. The third involves the synthesis of 2,2‐difluorinated‐esters by visible light‐driven radical addition of 2,2‐difluoroacetate with alkenes or alkynes in the presence of an organic pigment. The last section describes the synthesis of gem‐difluorinated compounds via the ring‐opening of gem‐difluorocyclopropanes. We further developed a novel method of synthesizing gem‐difluorohomoallylic alcohols via the ring‐opening of gem‐difluorocyclopropane and aerobic oxidation by photo‐irradiation in the presence of an organic pigment. Since gem‐difluorinated compounds that were prepared by the present method have two olefinic moieties with a different reactivity at the terminal position, we accomplished the synthesis of four types of gem‐difluorinated cyclic alkenols via the ring‐closing‐metathesis (RCM) reaction.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of Selectively gem‐Difluorinated Molecules; Chiral gem‐Difluorocyclopropanes via Chemo‐Enzymatic Reaction and gem‐Difluorinated Compounds via Radical Reaction

Itoh

Hayase

Nokami

2023

The Chemical Record

View full text Add to dashboard Cite

show abstract

“…Meanwhile, the proportion of fluorine-containing pharmaceuticals in commercial pharmaceuticals has exceeded 20% . However, pharmaceuticals with gem -difluoroallylic moieties, such as Glecaprevir, Tafluprost, and so forth, − accounted for a very low proportion in known fluorine-containing pharmaceuticals, which was related to the lack of efficient synthetic approaches for such construction. , Several recent studies have focused on the synthesis of functionalized Z -allylic building blocks with gem -difluoromethylene motifs, which will undoubtedly speed up and facilitate the construction of pharmaceutically interesting molecules and advanced materials. − However, the methods to access these specific skeletons are mainly finite to the semihydrogenation and diverse cross-coupling of relatives with organometallics under certain conditions (Scheme a) . Inherently, all of these strategies rely on kinetic controls and the use of specific reagents. − On the other hand, photoredox catalysis with various photosensitizers has played an important role and been recognized as an efficient green process and stimulated numerous contributions of advances for the C–C bond coupling in organic synthesis in the past 2 decades. − Nevertheless, not many successful cases of the photo-induced electron transfer (PET) process for the construction of organofluorine molecules have been reported yet (Scheme b,c). , …”

Section: Introductionmentioning

confidence: 99%

Hantzsch Ester-Mediated Visible-Light-Induced Radical Ethoxycarbonyldifluoromethylation of Aryl Alkynes: Kinetic-Controlled Stereoselective Synthesis of Z-gem-Difluoroallyl Esters

et al. 2022

View full text Add to dashboard Cite

A kinetic-controlled photocatalyst-free visible-light-induced stereoselective synthesis of α,α-gem-difluoro-Z-allyl esters was succeeded at room temperature in moderate to excellent yields with up to Z-isomer-only stereoselectivities through a reductive radical ethoxycarbonyldifluoromethylation of terminal aryl alkynes with blue LED (465 nm)-excited Hantzsch ester. The geometry optimizations obtained by the DFT/B3LYP calculation with a standard 6-31G(d,p) basis set were also employed for the mechanism study on the formation of a key α,α-difluoroallyl ester radical intermediate, which was generated from the addition of the ethoxycarbonyldifluoromethyl radical to aryl alkyne substrates and the stabilization effect of the neighboring group. Subsequent steric hindrance-determined hydrogen generated from the Hantzsch ester radical cation led to the formation of final aryl-substituted Z-difluoroallyl esters. This methodology provided convenient access to the synthetically important Z-configured gem-difluoroallylic building blocks.

show abstract

“…Tafluprost, developed by Asahi Glass Co., Ltd., and Santen Pharmaceutical Co., is Santen’s and Merck Sharp & Dohme’s prostaglandin PGF 2 α analogue for the treatment of intraocular pressure in open-angle glaucoma and ocular hypertension . Previous syntheses of Tafluprost ( 1 ) have relied on the Corey lactone to access the densely functionalized cyclopentane core. , …”

mentioning

confidence: 99%

An Asymmetric Suzuki–Miyaura Approach to Prostaglandins: Synthesis of Tafluprost

2020

View full text Add to dashboard Cite

We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo-and enantioselective Rh-catalyzed Suzuki−Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio-and diastereoselective Pd-catalyzed Tsuji−Trost reaction with an enolate surrogate.

show abstract

A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost

Cited by 12 publications

References 36 publications

Synthesis of Selectively gem‐Difluorinated Molecules; Chiral gem‐Difluorocyclopropanes via Chemo‐Enzymatic Reaction and gem‐Difluorinated Compounds via Radical Reaction

Synthesis of Selectively gem‐Difluorinated Molecules; Chiral gem‐Difluorocyclopropanes via Chemo‐Enzymatic Reaction and gem‐Difluorinated Compounds via Radical Reaction

Hantzsch Ester-Mediated Visible-Light-Induced Radical Ethoxycarbonyldifluoromethylation of Aryl Alkynes: Kinetic-Controlled Stereoselective Synthesis of Z-gem-Difluoroallyl Esters

An Asymmetric Suzuki–Miyaura Approach to Prostaglandins: Synthesis of Tafluprost

Contact Info

Product

Resources

About