Short communication Continuous-flow asymmetric biomimetic transamination Vadim A. Soloshonok a,b, *, Hector T. Catt a,b , Taizo Ono a,b a National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Aichi Prefecture 463-8560, Japan b Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States In recent decade the development of synthetic methodology mimicking biological processes has been at the forefront of organic chemistry [1]. The major advantage of the biomimetic approach over traditional, purely chemical methods is that it is based on transition metal-free organocatalytic reactions, offering a ‘‘greener’’ and operationally convenient [2] methodological option for preparation of various organic compounds. In particular, the biological cofactor pyridoxal 5 0 -phosphate-catalyzed transamina- tion [3] inspired many organic chemists to discover its mechanism [4] and develop its chemical models [5] for possible synthetic applications (Scheme 1). The major issue in using the principle of biological transamina- tion is the control of equilibrium between imines 3 and 4, which serves as an intramolecular reduction–oxidation step. Usually, this type of azomethine–azomethine isomerization occurs quite sluggishly and requires application of relatively strong base- catalyst [5b]. In general, the control of equilibrium between 3 and 4 could be provided in combination of highly electrophilic carbonyl compound 2 and nucleophilic amine 1 or, vice versa, electrophilic amine 1 and nucleophilic carbonyl compound 2. Since the latter option is virtually impossible, the realistic synthetic application of biological transamination should focus on the maximum possible differences between the electrophilicity of a carbonyl compound 2 and nucleophilicity of an amine 1. However, there is still a great degree of synthetic flexibility as one may target preparation of carbonyl compound 6 (oxidative deamination) or amine 1 (reductive amination). Both processes were successfully realized with the development of particularly electrophilic carbonyl compounds 2 [6] and amines 5, structurally mimicking the enzymatic pyridoxal [7,8]. Of particular importance is application of this biomimetic methodology for reductive amination of fluorinated carbonyl compounds (Scheme 2). Due to the strong electron-withdrawing nature of fluorine the equilibrium between the corresponding imines 3 and 4 is virtually completely shifted towards 4 rendering this reaction extraordinary general and truly practical for preparation of fluorine-containing amines and amino acids. Thus, as shown in Scheme 2, fluoroalkyl/fluoroaryl aldehydes and ketones 7 (R = H, alkyl, aryl) can be efficiently transaminated to the corresponding amines 8 using benzylamine, as a reducing Journal of Fluorine Chemistry 130 (2009) 512–515 ARTICLE INFO Article history: Received 31 January 2009 Received in revised form 17 February 2009 Accepted 18 February 2009 Available online 3 March 2009 Dedicated to Academician of National Academy of Sciences of Ukraine, Professor Valerii Pavlovich Kukhar (Institute of Bioorganic Chemistry and Petrochemistry of National Academy of Sciences of Ukraine) on the occasion of his 67th birthday. Keywords: Asymmetric synthesis 1,3-Proton shift reaction On-column reactions Continuous process Biomimetic transamination Reductive amination Fluorine-containing amino compounds ABSTRACT This study has demonstrated that conceptually new continuous-flow reaction procedure for biomimetic transamination of perfluoroalkyl-containing ketones is substantially more efficient as compared with conventional in-flask approach, allowing preparation of the target fluorinated amines with generally improved chemical yields and enantioselectivity. ß 2009 Elsevier B.V. All rights reserved. * Corresponding author. E-mail address: vadim@ou.edu (V.A. Soloshonok). Contents lists available at ScienceDirect Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor 0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2009.02.010