Study On The Synthesis Of Chiral Amino Alcohols

Chiral amino alcohols are a class of optically active amino alcohols obtained by the reduction of α-amino acids as starting materials. At present, the application of chiral amino alcohols has been attracted due to their importance in asymmetric synthesis, pharmaceutical, fine chemicals, materials, etc. In the field of pharmacy, chiral amino alcohols have been applied in peptides and quinolone pharmaceuticals. In the filed of asymmetric catalysis, much attention has been attracted to chiral amino alcohols due to its extensive sources and diversified structures. Accordingly, study on the high efficiency, low cost and larger scale preparation of chiral amino alcohols has important practical value . The comprehensive review about the application and preparation of chiral amino alcohols was reported. Bases on dissolvability of amino acids, the preparation method of amino alcohols of lipophilicity and hydrophilicity was systemically studied using NaBH₄ system and catalytic hydrogenation. The process was optimized and the cost of each amino alcohol was estimated according to each NaBH₄ system. The new synthetic route of chiral amino alcohols, such as Fmoc-threoninol and Fmoc-leucinol, utilizing NaBH₄-NMM-iBuOCOCl using Fmoc protecting amino acid as starting materials was developed. Firstly, chiral amino alcohols was prepared by the reduction of four reductive methods, such as NaBH₄-LiCl, NaBH₄-CH₃OH, NaBH₄-H₂SO₄, NaBH₄-I₂ from lipophilic amino acids as starting matericals,. Six amino alcohols, such as L-phenylalaninol, L-phenylglycinol, L-leucinol, L-isoleucinol, L-valinol, L-prolinol were synthesized. Using single factor analysis, the chief conditions, such as reaction time and temperature were optimized. Six amino alcohols L-phenylalaninol (yield 81.5%), L-phenylglycinol (yield 90.2%), L-leucinol (yield 84.9%), L-isoleuciol (yield 85.6%), L-valinol (yield 81.1%) and L-prolinol (yield 41.5%) were prepared using NaBH₄-LiCl reduction system. The yields of six amino alcohols using other reduction system were obtained. The cost of six amino alcohols was estimated according to each system. In the matter of cost, the best reduction method of L-phenylglycinol was NaBH4-LiCl system, the best reduction method of L-prolinol was NaBH4-I2 system and other amino alcohols were obtained by NaBH4-H2SO4 system. Secondly, reduction process of hydrophilicity amino acids was studied. The aqueous-phase hydrogenation of L-alanine to L-alaninol was studied in the presence of 5% Ru/C catalyst. This facile hydrogenation constituted a new "green"route for producing chiral amino alcohols. Direct aqueous-phase catalytic hydrogenation of free amino acids offered an alternative that is atom-economical and amenable to continuous processing, obviates the need for intermediate esterification and use of organic solvents, and avoids byproduct waste streams. The L43 optium conditions were obtained .Under the conditions of the molar ratio of phosphorus acid and alanine 0.5:1, 120℃,8MPa for 12h with the 97.5% converting yield of L-alanine and 98.1% e.e. Under the same conditions, the converting yield of L-threoninol was 90% and the optical yield was 97%. All hydrophilic amino alcohols could be prepared utilizing this method. Finally, N-protected amino alcohols Fmoc-Threoninol (yield 86.3%), Fmoc-Leucinol (yield 96.1%), Fmoc-Alaninol (yield 90.6%), Fmoc-Valinol (yield 95.4%), Boc-Alaninol (yield 75.3%), Fmoc-Serinol(tBu) (yield 94.3%) and Boc-Phenylalaninol (yield 96.4%) were prepared using NaBH4-NMM-iBuOCOCl reduction system and Boc-hydroxyprolinol (yield 90.1%) was synthesized using NaBH4-LiCl reduction system.