Combination of bio- and metal catalysts in chemoenzymatic cascade reactions

Chemoenzymatic cascade reactions are an emerging field in organic synthesis, as they combine the selectivity of enzymes with the reactivity of chemical catalysts. Due to their broad reaction scope, metal catalysts are often used in chemoenzymatic cascade reactions. However, combinations of metal- and biocatalysts often suffer from mutual inactivation. While metal catalysts can coordinate to amino acids of the enzyme, cellular components can inactivate the metal catalyst.In this thesis, two strategies for the combination of transition metal catalysts and enzymes were designed. The first cascade reaction focused on the combination of a Cu scorpionate catalyst active in Sonogashira cross-coupling, and a variant of the monooxygenase P450 BM3 (A74G F87V L188Q, P450 BM3 trio). So far, chemoenzymatic cascade reactions involving cross-coupling reactions were limited to the use of palladium catalysts for Suzuki cross-coupling. The Cu scorpionate catalyst was active in DMSO and fully converted 2-iodophenol and 3-dimethylamino-1-propyne to N,N-dimethyl-2-benzofuranmethanamine. P450 BM3 trio was probed towards conversion of the benzofuran derivative. Reactions with purified N,N-dimethyl-2-benzofuranmethanamine and P450 BM3 trio yielded up to 88% of a novel methylene bridged bis(2-substituted) benzofuran, N,N’-bis(benzofuran-2-ylmethyl)-N,N’-dimethylmethandiamine. The product was solely accessible via enzymatic functionalization by P450 BM3 trio, as side chain hydroxylation of N,N-dimethyl-2-benzofuranmethanamine and further formaldehyde elimination was required for the formation of N,N’-bis(benzofuran-2-ylmethyl)-N,N’-dimethyl-methandiamine. The selectivity towards benzofurans in Sonogashira cross-coupling was lost when alkynes substituted with secondary or primary amines were involved. In the next step, the cascade reaction was investigated in a sequential fashion after completion of the Sonogashira cross-coupling, as reaction conditions for the Cu scorpionate catalyst were not tolerated by the enzyme. P450 BM3 trio was ...