Use of 1,3-Dioxin-4-ones and Their Related Compounds in Synthesis. Part 35. Synthesis of Optically Pure Fluoromalonamic Acids by Means of Asymmetric Fluorination of Chiral 1,3-Oxazine-4,6-diones

Sato, Masayuki; Kaneko, Chikara; Kitazawa, Noritaka

doi:10.3987/com-91-s33

Cited by 44 publications

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“…L ‐Menthylphenyl esters of malonates were fluorinated with fluoropyridinium triflate in high yield with moderate diastereoselectivities by using lithium hexamethyldisilazane (LiHMDS). Kaneko and co‐workers also reported that fluorination of chiral 5‐substituted 1,3‐oxazine‐4,6‐dione derivatives proceeded diastereoselectively to give the 5‐fluorooxazinediones, which were readily transformed to optically pure fluoromalonic acids 8e. Sodeoka and co‐workers reported the enantioselctive fluorination of lactones and lactams, which were catalyzed by chiral palladium(II)–bisphosphine complexes 10.…”

Section: Methodsmentioning

confidence: 99%

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

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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Section: Methodsmentioning

confidence: 99%

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

et al. 2007

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“…Several examples of radical cyclization to the enamide double bond have been reported over the past few years. , Aryl radical cyclizations onto cyclic enamides generally produce heterocycles in which the nitrogen atom is present in the newly formed ring . Rigby 38 and Schultz have conducted selective 6- endo and 7- endo cyclizations of aryl radicals onto hydroindole and hydroquinoline enamide systems and have used this reaction as the key step for several alkaloid syntheses.…”

Section: Resultsmentioning

confidence: 99%

Generation and Trapping of N-Acyliminium Ions Derived from Isomünchnone Cycloadducts. A Versatile Route to Functionalized Heterocycles

Brodney

Padwa

1999

J. Org. Chem.

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A series of 2-diazo-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids underwent facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomu ¨nchnone-type intermediates. Subsequent 1,3-dipolar cycloaddition across the pendant olefin afforded intramolecular cycloadducts in high yield. The cascade sequence is simple, direct, and extremely tolerant of structural diversity. Exposure of these cycloadducts to Lewis acids resulted in oxabicyclic ring opening. N-Acyliminium ions of wide structural variety can be easily generated by this sequence of reactions. Different cyclization pathways become available depending on the nature of the substituent group attached to the amide nitrogen. When the tethered group is electrophilic in nature, proton loss from the initially formed N-acyliminium ion occurs rapidly to give an acyl enamide which undergoes a subsequent cyclization at the electrophilic center.N-Acyliminium ions can be considered to be one of the more versatile carbon electrophiles for use in carboncarbon bond forming reactions. [1][2][3] They have been extensively utilized as intermediates to produce a large variety of structurally diverse nitrogen heterocycles. [4][5][6][7][8][9][10][11][12][13][14]

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“…These compounds have been tested as inhibitors of the tumor cell growth and have exhibited the activity comparable with that for some natural pyrimidines (Scheme 8) [29,30].…”

Section: 3-oxazinesmentioning

confidence: 96%

Fluorinated azines and benzazines containing oxygen or sulfur atoms

Носова

Lipunova

Charushin

et al. 2010

Journal of Fluorine Chemistry

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Use of 1,3-Dioxin-4-ones and Their Related Compounds in Synthesis. Part 35. Synthesis of Optically Pure Fluoromalonamic Acids by Means of Asymmetric Fluorination of Chiral 1,3-Oxazine-4,6-diones

Cited by 44 publications

References 0 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

Generation and Trapping of N-Acyliminium Ions Derived from Isomünchnone Cycloadducts. A Versatile Route to Functionalized Heterocycles

Fluorinated azines and benzazines containing oxygen or sulfur atoms

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