New syntheses of haloketo acid methyl esters and their transformation to halolactones by reductive cyclization
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Russian Chemical Bulletin, International Edition, Vol. 69, No. 9, pp. 1804—1810, September, 2020
New syntheses of haloketo acid methyl esters and their transformation to halolactones by reductive cyclization* H. China,a H. Yatabe,a N. Kageyama,a M. Fujitake,b K. Kikushima,a and T. Dohia aCollege
of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan. Tel.: +81 77 561 4908. E-mail:[email protected]; [email protected] bOsaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan A new method for haloketo acid methyl ester synthesis on the basis of the ring-opening of cyclic ,-unsaturated ketones followed by halogenation under mild conditions is reported. Di- and tri-haloketo acid methyl esters are conveniently synthesized via the hydrolytic ringopening reaction through this method. Halolactones were readily obtained from these haloketo acid methyl esters by reductive cyclization employing NaBH4 and trifluoroacetic acid. Derivatizations of the obtained halolactone utilizing the exo-halomethylene moiety were also demonstrated. Key words: haloketo acid methyl ester, halolactone, hydrolytic ring-opening reaction, reductive cyclization, cyclic -diketone.
Halolactones are useful synthetic intermediates1 for derivatization to various compounds including natural products with interesting biological activities. Recently, several biologically active halolactones have also been reported.2—4 Halolactones are typically synthesized by halocyclizations of olefinic acids, such as iodo-, bromo-, and chlorolactonizations (Scheme 1, A).5—15. However, the halolactonization reaction offers limited control of the regioselectivity of endo- and exo-cyclizations in the case of internal alkenes. The classical intramolecular cyclization strategies based on the condensation of hydroxy acids are advantageous since a mixture of these exo- and endolactones are not formed in principle. This halolactonization requires an excess amount of an organic base and diluted hydroxy acids in order to avoid dimer formation,16—20 whereas the cyclization of hydroxy acid methyl esters under acidic or basic conditions readily provides lactones without a dimer byproduct.21—24 Moreover, the strategy of halolactone synthesis using carboxylic acid methyl esters with a halohydrin moiety derived by the reduction of haloketo acid methyl esters as a synthetic intermediate does not produce the corresponding dimer and regioisomeric byproducts (Scheme 1, B). The previously reported method for the synthesis of monohaloketo acid methyl esters (Scheme 1, C) typically * Based on the materials of the International Conference "Catalysis and Organic Synthesis" (ICCOS-2019) (September 15—20, 2019, Moscow, Russian Federation).
involved the use of diazomethane as the C(1)-carbon source.25,26 On the next step, diazomethyl ketone, generated from acyl chloride, is converted to monohaloketo acid methyl ester by the reaction with dry hydrogen halide. Alternatively, monobromoketo acid alky
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