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Progress in Chemistry 2014, Vol. 26 Issue (06): 976-986 DOI: 10.7536/PC131139 Previous Articles   Next Articles

• Review •

Bioactivities and Synthesis of Trifluoromethyl Alkyl Ketones

Yang Dongmei, Zhou Yuhan*, Chang Qing, Zhao Yilong, Qu Jingping   

  1. State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, China
  • Received: Revised: Online: Published:
  • Supported by:

    The work was supported by the National Natural Science Foundation of China (No.21376040), the Scientific Research Starting Foundation for Returned Overseas Chinese Scholars, Ministry of Education, China (No.20121707) and the Fundamental Research Funds for the Central Universities (No.DUT13LAB03)

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With high lipophicity and metabolic stability, trifluoromethyl alkyl ketones (TFMKs) act as important bioactive molecules, especially enzyme inhibitors. Besides, they are superior intermediates for pharmaceuticals and materials. Due to severe electrophilicity of trifluoromethyl, TFMKs form covalent hemiketal adducts targeting at many hydrolytic enzymes such as phospholipase A2 (PLA2) both in mammal and plant, human leukocyte elastase, oleamide hydrolase, human plasma kallikrein, pig liver esterase. TFMKs are inhibitors of human renin in the regulation of blood pressure and electrolyte homeostasis. Structure of chymotrypsin-trifluoromethyl ketone inhibitor complexes have been presented by XRD and NMR spectroscopy, this inhibition is depended on pH. TFMKs are also served as outstanding inhibitors of SARS-CoV 3CL protease. Diversity methods have been used in synthesis of TFMKs, involving the reactions of organometallic reagent like Grignard reagent or alkyl lithium with trifluoromethyl acid, acetate, or their salts, ester or amide react with TMSCF3 or Et3GeNa/PhSCF3 to generate nucleophilic trifluoromethylation, treatment of carboxylic acid chlorides with pyridine and trifluoroacetic anhydride, sulfone-mediated synthesis of TFMKs from alkyl and alkenyl bromides, oxidation of trifluoromethyl carbinols, catalytic aerobic oxidative decarboxylation of trifluoromethylhydroxy acids, conversion of trifluoroethyl amines by the treatment of NBS/DBU, conversion of enolizable carboxylic acids to TFMKs via enediolate trifluoroacetylation/decarboxylation, and ring opening of alkyl 2-siloxycyclopropanecarboxylates by triethylamine trihydrofluoride. Bioactive TFMKs on enzyme inhibition are summarized and synthesis methods are discussed in this paper, trend on both application and preparation are described.

Contents
1 Introduction
2 Possible mechanism and bioactivities of TFMKs
2.1 Inhibition on phospholipase A2(PLA2)
2.2 Inhibition on FAAH hydrolases
2.3 Inhibition on AChE
2.4 Inhibition on chymotrypsin
2.5 Inhibition on SARS-CoV 3CL
2.6 Inhibition on juvenile hormone esterase
2.7 Inhibition on other hydrolases
3 Synthesis of TFMKs
3.1 Organometallic reagent with trifluoromethyl acid, acetate, or their salts
3.2 Nucleophilic trifluoromethylation with TMSCF3 or Et3GeNa/PhSCF3
3.3 Carboxylic acid chlorides with pyridine and trifluoroacetic anhydride
3.4 Ethanolysis after condensation
3.5 Oxidation of trifluoromethylcarbinols
3.6 Trifluoroacetic ester/ketone exchange
3.7 Other methods
4 Conclusion and outlook

Key words: trifluoromethyl alkyl ketones, bioactivities, enzyme inhibitor, synthesis

CLC Number: 

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