Asymmetric Hydrogenation Of 2-Trifluoromethyl Allylic Alcohol And Its Application In Synthesis Of Trifluoromethyl-containing Amino Acids

In recent years, several studies report that selectively introducing the fluorine atom to the specific position of some bio-active molecules would significantly change the pharmacological properties. Thus, developing the new synthetic methods for efficiently and highly stereoselective introduction of fluorine atoms into useful intermediates or desired substrates has attracted great interests. It is well known that 2-trifluoromethyl allylic alcohol is a kind of widely-used medical intermediate. In this thesis, we studied the hydrogenation of these compounds and constructed the chirality of trifluoromethyl group. Furthermore, we tried to apply this methodology to the synthesis of (2S)-2-amino-4,4,4-trifluoro-3-methylbutanoic acid. The whole thesis consists of two parts:Part I: Ru(OAc)₂(BINAP) was used to catalyze the asymmetric hydrogenation of a series of 2-trifluoromethyl allylic alcohols, which were prepared from 2-bromo-3,3,3-trifluoroprop-1-ene and corresponding aldehyde. The syn-isomers were found as the predominant product and the value of diastereomer excess ran up to 98%. We discussed the effect of catalyst and the conformation of substrate on reaction speed and stereoselectivity. And we found that the conformation of hydroxyl group will affect the stereoselectivity of the reaction. That means when the conformation of substrate can match that of catalyst, the reaction is fast and vice versa.Part II: Corresponding allylic alcohol was prepared by the reaction of 2-bromo-3,3,3-trifluoroprop-1-ene and facile chiral source, (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, which was catalyzed with zinc powder or BuLi. Then the asymmetric hydrogenation described in part I was used to introduce the trifluoromethyl group stereoselectively. Finally, the synthesis of (2S)-2-amino-4,4,4-trifluoro-3-methylbutanoic acid was tried but failed. We did not get the target molecule owing to the rearrangement of isopropylidene ketal. Thus, we supposed that the synthesis of (2S)-2-amino-4,4,4-trifluoro-3-methylbutanoic acid could be realized by choosing different protective group. This part of work needs to be studied deeply.