Asymmetric synthesis of beta-hydroxy phoshponates via benzaldehyde lyase catalyzed cross acyloin reactions

Date

2014

Author

Kazancı, Ceren

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Synthetically useful asymmetric cross acyloin reactions with functionalized aliphatic aldehyde have a broad range of application. The products of acyloin reactions are α-hydroxy ketone which are the subunits in several compounds and can be found in many biologically important compounds. Phosphonates can be used as an intermediate in the synthesis of potentially significant peptide analogues, catalytic antibodies, and phosphonic acid-based antibiotics which are also acknowledged as biologically important compounds. On the other hand, lyases are an important class of enzymes that achieve several important reactions including C-C bond formations. In this study asymmetric synthesis of novel β-hydroxy phosphonates with cross acyloin reactions was achieved via benzaldehyde lyase (BAL) catalyst. By making a contribution to β-hydroxy phosphonate synthesis methods, this application can also be a preference to chemoenzymatic methods for the synthesis of β-hydroxy phosphonates. In this study, first of all diethyl 2,2-diethoxyethylphosphate was synthesized by Michaelis-Arbuzov reaction of triethylphosphite and bromoacetaldehyde diethylacetal. Then by hydrolyzing phoshorylated diethylacetal, phosphonoacetaldehyde which was used as aliphatic substrate in chemoenzymatic reaction was synthesized. Secondly, benzaldehyde lyase was produced by using recombinant E.coli. Finally, by using ThDP dependent benzaldehyde lyase in DMSO solvent, C-C bond formation was achieved between benzaldehyde derivatives and aliphatic phosphonoacetaldehyde and asymmetric novel β-hydroxy phosphonates was synthesized. As a result, high enantiomeric excesses up to 98% ee were obtained. These results made a significant contribution to both the hydroxy phosphonates synthesis methods and the aliphatic substrate range of benzaldehyde lyase catalyzed reactions.

Subject Keywords

Ketones., Phosphonates., Benzaldehyde., Lyases., Acyloin reaction., Asymmetric synthesis.

URI

http://etd.lib.metu.edu.tr/upload/12616829/index.pdf
https://hdl.handle.net/11511/23305

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Graduate School of Natural and Applied Sciences, Thesis