Traceless chiral coupling reagent. A new concept for synthesis of optically active products from racemic carboxylic acids.
|Beata Kolesińska 1, Katarzyna Kasperowicz-Frankowska , Justyna Frączyk 1, Zbigniew J. Kamiński 1|
1. Technical University of Łódź, Institute of Organic Chemistry (PŁ), Żeromskiego 116, Łódź 90-924, Poland
The advances in stereoselective bioanalysis led to a new awareness of the importance of stereoselective pharmacodynamics and pharmacokinetics, enabling the differentiation of the relative contributions of enantiomers to overall drug action. This results in formal obligation to recognize the occurrence of chirality in new drugs, attempt to separate the stereoisomers, assess the contribution of the various stereoisomers to the activity of interest and make a rational selection of the stereoisomeric form that is proposed for marketing. In order to facilitate this studies in case of syntheses involving condensation of chiral carboxylic acid we developed the concept of a traceless chiral coupling reagent useful for enantioselective synthesis of optically active products (also peptides) from racemic carboxylic acids (amino acids). According to the concept coupling reagents consists of two fragments with chiral auxiliary responsible for enantioselectivity expelled just during activation of carboxylic group. The reagent were prepared by the treatment of chiral ammonium tetrafluoroborate (1) with 2-chloro-4,6-dimethoxy-1,3,5-triazine (2) in the presence of sodium bicarbonate yielding stable N-(4,6-dimethoxy-1,3,5-triazin-2-yl)ammonium tetrafluoroborate (3) in high yield [1a]. Chiral coupling reagents 3 were found stable at room temperature and in a broad range of solvents yielded in high yield acylated products (amides, esters and peptides) [1b] with fully predictable configuration and ee (dr) ranging from 95/5 to 60/40 under reaction conditions identical as optimized for its achiral equivalent.
Acknowledgement: This work was supported by MSHE Grants 6/PMPP/U/30-09.08/E-370/2009 and N N204 326737.
 (a) B. Kolesińska, Z.J. Kamiński, Org. Lett., 11 (3), 765-768 (2009). (b) B. Kolesińska, K. Kasperowicz, M. Sochacki, A. Mazur, S. Jankowski, Z.J. Kamiński. Tetrahedron Lett. 51, 20–22 (2010).
Presentation: Oral at VII Multidyscyplinarna Konferencja Nauki o Leku, by Beata Kolesińska
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku
Submitted: 2010-03-19 18:23 Revised: 2010-03-20 08:49
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