Selective Biocatalytic Synthesis of Glycerol Ethers

• Applicant: Dr. Felix Kaspar
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation ; Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492196858

Ethers are a fundamental functional group in organic chemistry. However, despite widespread progress in the field, methods for their regioselective preparation are currently lacking, which typically requires protecting groups and/or retrosynthetic considerations to obtain the desired ether product. Recent expansions of the biocatalytic toolbox have introduced several highly selective alkylation systems, but these are largely limited to methyl ethers, with some examples of ethyl or propyl ethers. Enzymatic methods for the synthesis of sterically more demanding ethers are missing. Consequently, a biocatalytic approach enabling the regioselective preparation of sterically demanding ethers under mild conditions would be highly desirable. Therefore, I envision a biocatalytic strategy for the synthesis of glycerol ethers based on geranylgeranylglyceryl phosphate synthases. These enzymes perform a nucleophilic substitution between glycerol-1-phosphate and alkyl pyrophosphates to obtain amphiphilic glycerol ethers. Although these enzymes have been subject to considerable biochemical research, including several crystal structures, biocatalytic applications have not been explored. Within this project, geranylgeranylglyceryl phosphate synthases will be expressed in E. coli and characterized with high-throughput analytical tools. These enzymes will then be applied in preparative chemoenzymatic transformations, employing a spectrum of alkyl pyrophosphates. Building on the existing structural information on these enzymes, the product scope of this chemoenzymatic approach will be extended through semi-rational protein engineering, enabling access to a variety of ether products. Lastly, I aim to implement these enzymes in a fully biocatalytic phosphorylation cascade for the synthesis of glycerol ethers through formal condensation of two alcohols, which is a long-standing synthetic challenge. Collectively, this project represents an important step in the development of novel biocatalytic transformations and will establish methods for regioselective ether synthesis.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Philipp Klahn; Professorin Dr. Anett Schallmey