Fluorinated lactones, synthesis

The synthesis of AFP-07 is shown in Scheme 9 [107], The enone 59 prepared from the Corey lactone was reduced with aluminum reagent and protected with f-butyidimethylsilyl chloride. Fluorination of the lactone 60 under the standard conditions gave the difluorolactone 61. The carbonyl group of the difluorolactone... 

The production of quaternary centers was also utihzed by Kosugi to develop a synthesis of mesembrine [132]. Lactones bearing fluorinated side-chains are also available by this methodology [133]. The lactonization of a 50 50 mixture of cyclohexylsulfinyl butenolides has been examined. It was expected that a mixture of bis-lactones would be produced in 50 50 ratio. Instead, an 80 20 mixture of dichloro bis-lactones was obtained and, dehalogenation with Ra - Ni gave the lactone shown as the major isomer of a 95 5 mixture [133] (Scheme 19). 

Synthetic approaches to fluorinated p-lactones (oxetane-2-ones) are very similar to oxetane synthesis. Usually p-lactones are prepared either by cycloaddition of ketenes to aldehydes or ketones or by cyclodehydration of p-hydroxycarboxylic acids. 

The first p-lactone with fluorinated substituents reported in 1960 by Cheburkov and Knunyants was prepared by cycloaddition of the ketene with hexa-fluoroacetone. The reaction takes place at —78°C in the absence of catalyst to give p-lactone 59 in quantitative yield (Scheme 2.27). Other methods of synthesis of lactones 59 include dehydration of the appropriate hydroxybutyric acid with phosphorus pentoxide or dehydrobromination of the corresponding butyryl bromide. 

Pyrolysis of 59 typically results in fluorinated p-lactones extrusion of CO2 and high-yield formation of (Cp3)2C=CH2. The reaction is used for the synthesis of this olefin on commercial scale. 

The difluoroiodotoluene is an elfective reagent for the fluorination of a-phenelsul-fanyl lactones 95. The reaction involves fluoro-Pummerer rearrangment. A sequence involving conversion of a-fluorosulfide 95 into sulfoxide and elimination step was used for the synthesis of 3-fluoro-2(5H) furanones 96. ... 

Watanabe, S. Sakai, Y. Takeda, M. Kitazume, T. Yamazaki, T. Synthesis of optically active y-lactones and dopants for ferroelectric liquid crystals possessing a trifluoromethyl group. J. Fluorine Chem. 1994, 67, 149-152. 

Haufe, G. Bruns, S. Runge, M. Enantioselective ring-opening of epoxides by HF-reagents. Asymmetric synthesis of fluoro lactones. J. Fluorine Chem. 2001, 772(1), 55-61. 

Construction of furan ring of 131 by acid-catalyzed cyclization of 134 cannot be achieved due to low reactivity of the a,a-difluorinated double bond toward protonation. Therefore, the following sequence was employed for the total synthesis of 131 (Scheme 12.20) fluorination of lactone 133, introduction of a double bond to 136 by Wittig olefination, and modification of R part of O ." " The use of manganese enolate of lactone 133 is useful for one-pot difluorination. The reaction of the lithium enolate of 133 with the conventional electrophilic fluorinating reagent such as N-fluorobenzenesulfonimide provides only monofluoride 135. 

Ort/io-selectivity is generally observed in the reactions of 2,4-dichloro- and 2,4-difluoro-nitrobenzene with alkoxide and thiophenoxide ions [199]. Also in less activated systems, nucleophiles generated from phenols and thiophenols with potassium fluoride-alumina and 18-crown-6-polyether will react in DMSO with cyano- or nitro-substituted fluoro- or chloro-benzenes [200]. Interestingly, the reaction of difluorobenzenes with two diffoent alcohols can occur sequentially. Introduction of the first etho" function deactivates the ring, and use of more forcing conditions allows substitution of the second fluorine [201]. Consecutive displacements of fluorine and nitro groups have been observed in the reaction of ort/io-fluoronitrobenzene with chiral acyl bicyclic lactones in a highly enantioselective synthesis of spirooxindoles [202]. 

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