Date of Award

Summer 2002

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)

Department

Chemical Engineering, Chemistry and Environmental Science

First Advisor

Sanjay V. Malhotra

Second Advisor

Teddy Greenstein

Third Advisor

Norman W. Loney

Fourth Advisor

Robert G. Luo

Fifth Advisor

R. P. T. Tomkins

Sixth Advisor

Marino Xanthos

Abstract

Chiral separation has attracted tremendous attention in pharmaceutical and chemical fields, especially in the area of chiral drug development. Chiral amino acids are among the most important intermediates in the asymmetric synthesis of modem drugs. This research has developed an effective method for obtaining optically pure amino acids by enzymatic resolution using a "green" solvent, named an ionic liquid.

Ionic liquids, a new type of "green" solvents, have been used in many organic reactions and other chemical processes (such as liquid-liquid extraction) with improved performance. This is mainly due to their favorable properties for chemical applications, such as low vapor pressure, low melting point, catalytic features, chemical and thermal stability, nonflammability, and high ionic conductivity, etc. In this study, three different ionic liquids were prepared, 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM]+[BF4]-), N-ethyl pyridinium tetrafluoroborate ([EtPy]+[BF4]-) and N-ethyl pyridinium trifluoroacetate ([EtPy]+ [CF3OO]-). They were used as "green" solvents in the enzymatic resolution and as catalysts for the esterification reactions.

Amino acid L-(-)-piperazine-2-carboxylic acid was prepared with 98.1% enantiomeric excess (ee) and 40.6% resolution yield ( max 50% possible) by several steps, including N-protection, esterification, and enzymatic resolution in an organic solvent by the enzyme Bacillus licheniforms alcalase (BL-alcalase). Another important unnatural amino acid N-acetyl homophenylalanine ethyl ester was synthesized by a three step-reaction strategy. Further, L-(+)-homophenylalanine hydrochloride with 92.4% ee was obtained by an enzymatic resolution in acetonitrile-water mixture using enzyme BL-alcalase.

The solvent effects on the kinetic resolution of N-acetyl homophenylalanine ethyl ester were systematically investigated using the enzyme BL-alcalase in several organic solvents and ionic liquids ([EMIM]+[BF4]-, [EtPy]+[BF4]-, and [EtPy]+[CF3OO]-). It has been shown that a high concentration of ionic liquids can decrease the performance of the enzyme, while low content of ionic liquids might increase the activity of the enzyme BL-alcalase. The enzymatic resolution reaction was also studied at different reaction temperatures and reaction times. High ee and yield achieved in ionic liquids indicate that ionic liquids can be ideal substitutes for organic solvents in the kinetic resolution of amino acid esters.

For the first time, it has been shown that the ionic liquid [EtPy]+[CF3COO]- can be used as a "green" catalyst in the synthesis of amino acid esters, including unnatural amino acid esters. Satisfactory conversion was achieved for the formation of amino acid esters under mild conditions. This straightforward process provided starting racemic amino acid esters for the kinetic resolution studies.

Furthermore, the ionic liquid [EtPy]+[CF3OO]- was applied as a "green" solvent for the kinetic resolution of several other N-acetyl amino acid esters using different enzymes: BL-alcalase and porcine pancreas lipase (PPL). High optical purity and yield were generally achievable under low concentration of ionic liquids. It also shows that this method could be a general process in the production of chiral amino acids for pharmaceutical and biotechnology applications.

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