New applications of fluorinated building blocks

Abouabdellah, Ahmed; Boros, L. G.; Gyenes, Ferenc; Welch, John T.

doi:10.1016/0022-1139(94)00416-d

“…Finally, the optically active fluorinated retroamide isostere 20 was synthesized. Compound 20 is an HIV‐1 protease inhibitor that was prepared by Welch and co‐workers from enantiomerically pure 3‐fluoro‐2‐azetidinones by a ring‐opening reaction 5a,b. 20 However, the synthesis requires multiple‐step transformations including diastereoselective fluorination of 2‐azetidinones.…”

Section: Methodsmentioning

confidence: 99%

Desymmetrization‐like Catalytic Enantioselective Fluorination of Malonates and Its Application to Pharmaceutically Attractive Molecules

Reddy

¹

,

Shibata

²

,

Nagai

³

et al. 2007

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Optically active organofluorine compounds are attractive in both modern pharmaceutical chemistry and materials science, [1] especially the simple chiral vicinal fluorohydrins that are employed as important building blocks in the synthesis of polyfunctional bioactive molecules.[2] Fluorinated malonates with a fluorine atom at a quaternary carbon center are a class of versatile and important monofluorinated chiral synthons [2] utilized in the synthesis of liquid crystals, [3] antitumor agents, [4] enzyme inhibitors, [5] antiviral agents, [6a] antibiotics, [6b] and anti-Alzheimer agents.[6c] A variety of enantioselective syntheses of fluorinated compounds have been developed for the elaboration of optically active fluorinated malonates, as well as their synthetic equivalents such as vicinal fluorohydrins and fluorinated half hydroxy esters.[2] These approaches include the enzymatic desymmetrization of substituted 2-fluoromalonic diesters, 2-fluoropropane-1,3-diols, and 2-fluoro-1,3-diacetoxypropane derivatives, which lead in each case to similar 2-fluorinated synthons (Scheme 1). [2,7] These microbial transformations are more practical than the chemical approaches [8] for obtaining the target compounds; unfortunately, the resulting enantioselectivity is highly dependent on the substrate and thus significantly limits the applicability of this process.We have recently reported a highly enantioselective fluorination [9] of b-keto esters and oxindoles catalyzed by BoxÀPh/Cu(OTf) 2 or DBFOXÀPh/Ni(ClO 4 ) 2 (Box = bisoxazoline, Tf = triflate, DBFOX = 4,6-dibenzofurandiyl-2,2'-bisoxazoline. [9a, b] In response to the limitations associated with the use of microbial desymmetrization for the preparation of chiral fluorinated malonates and hydroxy esters, we have now extended our protocol to the desymmetrization-like enantioselective fluorination of malonates 1 and herein show that a DBFOXÀPh/Zn(OAc) 2 complex is an effective catalyst to give the optically active 2-fluorinated malonates 2 with very high enantioselectivity (up to 99 % ee). The 2-fluoromalonates 2 can be selectively converted into 2-fluorinated hydroxy esters 3. The synthetic utility of the method was demonstrated by the syntheses of pharmaceutically attractive compounds, namely, chiral fluorinated a-benzyl-b-alanine 4, fluorinated b-lactam 5, and fluoro-alacepril (6); Scheme 2. The synthesis of an HIV-1 protease inhibitor was also achieved through the chemoselective ester-amide exchange reaction of chiral malonates 2.Diastereoselective fluorination of malonates has been reported by Fukumoto and co-workers.[8b-d] l-Menthylphenyl esters of malonates were fluorinated with fluoropyridinium triflate in high yield with moderate diastereoselectivities by Scheme 1. Enzymatic desymmetrization approach for the synthesis of simple fluorinated synthons.Scheme 2. Desymmetrization-like approach for the synthesis of 2 and its application to pharmaceutically attractive molecules.

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“…The utility of 2‐fluorinated malonates was next demonstrated by synthesizing a 3‐fluorinated β‐lactam5a,b, 14 (Scheme ). Chemoselective reduction of the malonate ( S )‐ 2 b with the LiAl(O t Bu) 3 H procedure mentioned above gave 3 b (80 % yield).…”

Section: Methodsmentioning

confidence: 99%

Desymmetrization‐like Catalytic Enantioselective Fluorination of Malonates and Its Application to Pharmaceutically Attractive Molecules

Reddy

¹

,

Shibata

²

,

Nagai

³

et al. 2007

View full text Add to dashboard Cite

Optically active organofluorine compounds are attractive in both modern pharmaceutical chemistry and materials science, [1] especially the simple chiral vicinal fluorohydrins that are employed as important building blocks in the synthesis of polyfunctional bioactive molecules.[2] Fluorinated malonates with a fluorine atom at a quaternary carbon center are a class of versatile and important monofluorinated chiral synthons [2] utilized in the synthesis of liquid crystals, [3] antitumor agents, [4] enzyme inhibitors, [5] antiviral agents, [6a] antibiotics, [6b] and anti-Alzheimer agents.[6c] A variety of enantioselective syntheses of fluorinated compounds have been developed for the elaboration of optically active fluorinated malonates, as well as their synthetic equivalents such as vicinal fluorohydrins and fluorinated half hydroxy esters.[2] These approaches include the enzymatic desymmetrization of substituted 2-fluoromalonic diesters, 2-fluoropropane-1,3-diols, and 2-fluoro-1,3-diacetoxypropane derivatives, which lead in each case to similar 2-fluorinated synthons (Scheme 1). [2,7] These microbial transformations are more practical than the chemical approaches [8] for obtaining the target compounds; unfortunately, the resulting enantioselectivity is highly dependent on the substrate and thus significantly limits the applicability of this process.We have recently reported a highly enantioselective fluorination [9] of b-keto esters and oxindoles catalyzed by BoxÀPh/Cu(OTf) 2 or DBFOXÀPh/Ni(ClO 4 ) 2 (Box = bisoxazoline, Tf = triflate, DBFOX = 4,6-dibenzofurandiyl-2,2'-bisoxazoline. [9a, b] In response to the limitations associated with the use of microbial desymmetrization for the preparation of chiral fluorinated malonates and hydroxy esters, we have now extended our protocol to the desymmetrization-like enantioselective fluorination of malonates 1 and herein show that a DBFOXÀPh/Zn(OAc) 2 complex is an effective catalyst to give the optically active 2-fluorinated malonates 2 with very high enantioselectivity (up to 99 % ee). The 2-fluoromalonates 2 can be selectively converted into 2-fluorinated hydroxy esters 3. The synthetic utility of the method was demonstrated by the syntheses of pharmaceutically attractive compounds, namely, chiral fluorinated a-benzyl-b-alanine 4, fluorinated b-lactam 5, and fluoro-alacepril (6); Scheme 2. The synthesis of an HIV-1 protease inhibitor was also achieved through the chemoselective ester-amide exchange reaction of chiral malonates 2.Diastereoselective fluorination of malonates has been reported by Fukumoto and co-workers.[8b-d] l-Menthylphenyl esters of malonates were fluorinated with fluoropyridinium triflate in high yield with moderate diastereoselectivities by Scheme 1. Enzymatic desymmetrization approach for the synthesis of simple fluorinated synthons.Scheme 2. Desymmetrization-like approach for the synthesis of 2 and its application to pharmaceutically attractive molecules.

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“…[2h] In this context, fluorinated pharmaceuticals show notable and very diverse biological activities . They include HIV‐protease inhibitors ( A , Figure ), anticancer and antiviral drugs ( B ), antibacterials ( C ), and drugs for the treatment of neurodegenerative disorders ( D ) . Lastly, fluorine‐18 ( 18 F; t 1/2 = 109.7 min) is the most commonly used radioisotope for radiopharmaceuticals used in molecular imaging by positron‐emission tomography (PET) .…”

Section: Introductionmentioning

confidence: 99%

The Organocatalytic α‐Fluorination of Chiral γ‐Nitroaldehydes: the Challenge of Facing the Construction of a Quaternary Fluorinated Stereocenter

Emma

¹

,

Lombardo

²

,

Trombini

³

et al. 2016

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Chiral γ‐nitroaldehydes 1 are easily accessible by the organocatalytic Michael addition of aldehydes to nitroalkenes. In this paper, we report the organocatalytic fluorination of 1 with N‐fluorobenzenesulfonimide (NFSI) leading to the highly stereoselective construction of a challenging quaternary fluorinated stereocenter at the α position of α,α‐dialkyl aldehydes. The reaction takes place via a chiral trisubstituted enamine, so far rather unexplored in the field of organocatalysis. Fluorinated products 3 are direct precursors of chiral monofluorinated 3,4‐polysubstituted pyrrolidines. Mechanistic details are discussed with the aid of computational results.

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New applications of fluorinated building blocks

Cited by 15 publications

References 38 publications

Desymmetrization‐like Catalytic Enantioselective Fluorination of Malonates and Its Application to Pharmaceutically Attractive Molecules

Desymmetrization‐like Catalytic Enantioselective Fluorination of Malonates and Its Application to Pharmaceutically Attractive Molecules

Desymmetrization‐like Catalytic Enantioselective Fluorination of Malonates and Its Application to Pharmaceutically Attractive Molecules

The Organocatalytic α‐Fluorination of Chiral γ‐Nitroaldehydes: the Challenge of Facing the Construction of a Quaternary Fluorinated Stereocenter

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