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Title: Synthetic and enzymatic studies related to the biosynthesis of penicillic acid and acetoin
Author: Gaudet, Veroniuque Suzanne
ISNI:       0000 0001 3492 4533
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1989
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The stereochemistry of the loss of one enantiotopic C-2 hydrogen atom of malonyl-coenzyme A units during the transformations leading to pencillic acid was undertaken. Aspartic acid stereospecifically deuterated at C-3 via the formation of N-benzyl aspartic acid was attempted. The addition of benzylamine in 2H20 or dioxan across the double bond of maleic or fumaric acids was revealed to be non stereospecific and these results have been tentatively explained. (2S,3R)-[32H1]- and (2S,3S)-(2,3-2H2)-aspartic acids were derivatized to the corresponding deuterated diethyl N-p-toluenesulfonyl aspartates for vibrational infra red circular dichroism measurements. This technique enabled the determination of the absolute configuration at C-2 of [22H2)-aspartic acids. These stereospecifically deuterated aspartic acids were used for biological tracer experiments but no significant deuteration of penicillic acid was achieved. Malate was the next possible precursor to be used. The preparation of stereospecifically deuterated L-malic acid was undertaken via the reduction of cis- and trans-2,3-epoxysuccinate derivatives which had to be prepared enantiomerically pure. New chemical routes were devised for the preparation of diethyl trans- and cis-2,3-epoxysuccinate in high yield. The key intermediates were diethyl 2-tosyl tartrate for the synthesis of cis- and trans- isomers and its tert-butyldimethylsilyl ether for the preparation of diethyl cis-epoxysuccinate. The enzymatic kinetic resolution of diethyl cis- and trans-2,3-epoxysuccinates were attempted by ester hydrolysis but proved to be difficult due to their decomposition in aqueous medium. The transesterification of diethyl trans-2,3-epoxysuccinate with 1 - heptanol was catalyzed by lipases. Diheptyl (2S,3S)- and diethyl (2R,3R)-epoxysuccinates were obtained with an ee ≥ 97%. Diethyl cis-2,3-epoxysuccinate did not undergo transesterification with any of the enzymes tested. Nevertheless, ethyl isobutyl cis-(2,3)-epoxysuccinate was prepared indirectly in enantiomerically pure form. An enzymatic method involved a regioselective and/or stereoselective hydrolysis of racemic or enantiomerically pure diethyl 2-tosyl-tartrate by α-chymotrypsin. The resulting epoxide had an ee of ≥ 97%. Also, a chemical regioselective transesterification of enantiomerically pure diethyl 2-tosyl tartrate with isobutyl alcohol was achieved, leading to epoxides with ee values ranging from 71% to 94%. Thus, it was undoubtedly possible to obtain from these enantiomerically pure epoxides L-malic acid stereospecifically deuterated at C-3. In an attempt to understand the mode of action of pyruvate decarboxylase, an analytical method for estimating the enantiomeric composition of enzymatically produced samples of acetoin was required. Formation of the (S)-(-)-α-methoxy-α-(trifluoromethyl) phenyl acetate of acetoin was achieved using different coupling agents. The diastereomeric ratio could then be determined by HPLC, 1H and 19F NMR, but racemization was found to accompany ester formation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry