D(+)-Phenylalaninol: Synthesis, Chiral Recognition, and Gastric Acid Secretion Inhibition

D(+)-Phenylalaninol is used as a chiral auxiliary for asymmetric Michael reactions. It is an enantiomer of L-Phenylalaninol, an inhibitor of intestinal Phenylalanine absorption. It acts as an inhibiting agent to the enzymes which are responsible for the breakdown of endorphins. Phenomena, including gelation and fluorescence, are used as easily detected sensors of chiral recognition. Qin et al. have developed a new type of isomerized diphenylalanine-based supramolecular gel (LFDF), which showed the visible enantiomeric discrimination of phenylalaninol enantiomers via fluorescence and gelation measurements. The addition of L- or D(+)-Phenylalaninol to the peptide gel led to complete collapse within one minute after adding the L-form, which was not observed in D(+)-Phenylalaninol. Meanwhile, by doping with the fluorescent dye thioflavin T (ThT), the prepared ThT-LFDF gel system can sensitively detect the L/D-phenylalanine enantiomer through fluorescence quenching, which has the advantages of visualization, easy manipulation, and high detection sensitivity.

High-effective approach from amino acid esters to chiral amino alcohols

Chiral amino alcohols, especially D(+)-Phenylalaninol, are very important one of chiral organic compounds, and have been widely applied as the building blocks in biologically active molecules, pharmaceutical synthesis, fine chemicals as well as resolution of racemic mixtures, etc. Traditionally, amino alcohols were synthesized by homogeneous hydrogenation of amino acids with metal hydrides or the catalytic aminolysis of epoxides with amines. But these methods above or processes suffer from production of a large amount of salts, using large excessive reagents, and high production cost, which make them less attractive for industrial and technical applications. Herein, a series of L-phenylalanine esters with different ester group substituents (or protection of amino group) were used as the reaction substrates, to study the adaptability or versatility of the CuZn0.3Mg0.1AlOx catalyst for their hydrogenation to chiral D(+)-Phenylalaninol. Based on the results above, the reactivities of various reaction substrates over this catalyst would be compared. Furthermore, density functional theory (DFT) calculation, served as a powerful tool for studying the catalysis and reaction mechanism, was used to investigate the adsorption configuration of the substrate molecules with different groups on the catalyst surface and explore the possible reaction pathways of synthesizing D(+)-Phenylalaninol by D-phenylalanine methyl ester hydrogenation, to further validate our experiment results. Combined with experimental and theoretical study, the catalytic reaction mechanism over the CuZn0.3Mg0.1AlOx catalyst for the title hydrogenation was clearly demonstrated.[1]

In summary, the effects of L-phenylalanine esters with different ester group substituents and protection of amino group as the substrates on the catalytic hydrogenation over the CuZn0.3Mg0.1AlOx catalyst were investigated, verifying that the CuZn0.3Mg0.1AlOx catalyst is an effective heterogeneous catalyst for the hydrogenation of amino acid esters to chiral amino alcohols. To identify the preferred active sites on the catalyst for adsorbing functional groups of substrates and explore the possible reaction pathways for hydrogenation of D-phenylalanine methyl ester to D(+)-Phenylalaninol, the DFT theoretical calculations for substrates adsorption on the Cu6/γ-Al2O3(100) model were also performed. The results show that the presence of amino group at the α-position of carboxy group in α-amino acid esters is essential for this catalytic hydrogenation.

Effects of D(+)-Phenylalaninol on Centrally Induced Gastric Acid Secretion

Ephedrine and amphetamine stimulate the central nervous system and have been found to inhibit stress ulcers in rats. We have reported that methamphetamine can inhibit gastric acid secretion, which is an important factor in the formation of gastrointestinal ulcers. N-Benzyl- phenylalaninol and N,N-dimethyl-phenylalaninol have been reported to inhibit inflammation. These suggest that phenylpropylamine derivatives have many pharmacological activities. The effects of phenylalaninol and its derivatives that we synthesized on gastric acid secretion, glucose level, fibrinolysis and coagulative activity in blood were measured to find novel pharmacological active compounds. D(+)-Phenylalaninol remarkably inhibited gastric acid secretion, but had no other effects. Because there have been few studies of the effect of this substance on the gastrointestinal tract, we will report and discuss the effect of D(+)-Phenylalaninol on gastric acid secretion and gastric ulcer in rats.

References

[1]Zhang S, Yu J, Li H, Mao D, Lu G. High-effective approach from amino acid esters to chiral amino alcohols over Cu/ZnO/Al2O3 catalyst and its catalytic reaction mechanism. Sci Rep. 2016 Sep 13;6:33196. doi: 10.1038/srep33196. PMID: 27619990; PMCID: PMC5020414.

[2] H Hashizume. (1992). Effects of phenylalaninol on centrally induced gastric acid secretion. Chemical & Pharmaceutical Bulletin, 40 11, 3113–3114.

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