Biocatalytic C-C bond formation employing the enzyme BBE

Carbon-carbon (C-C) forming reactions represent the most important transformations in organic synthesis to set up the carbon backbone of organic compounds. Surprisingly, only a very limited number of enzymatic C-C bond forming methods are applicable for organic synthesis until to date. The berberine bridge enzyme (BBE) catalyses an outstanding intra-molecular C-C bond forming reaction, for which no chemical equivalent exists. The only reagent required for this transformation is molecular oxygen. Since very recently this enzyme can be produced in significant quantities, which allows now to perform a thorough investigation of the scopes and limitations of the enzyme for organic synthesis. Additionally, the crystal structure of the enzyme has just become available allowing a detailed study of the binding of substrates in the active site. Very promising experiments have just demonstrated that BBE accepts also various non-natural substrates. For instance a phenol alcohol could be substituted by NH 2 or even omitted and still activity could be detected. This very exciting result went in hand with a loss of activity so that enzyme engineering to improve the activity is intended. Optimisation of the reaction conditions (O2 -pressure, catalase, light) will enable an upscaling of the remarkable C-C bond forming transformation to a preparative scale. Changing the substitution pattern from N-methyl to N- ethyl will clarify a possible chiral induction on a novel chiral carbon centre. The possibility to perform an inter- molecular C-C bond formations instead an intra-molecular C-C formation will be evaluated (e.g. iso-chinolin derivatives with gaiacol). The kinetic resolution catalysed by BBE will be tested to be coupled with racemisation to achieve in the ideal case dynamic kinetic resolution. Nevertheless, to avoid the preparation of racemic substrates a recently successful expressed enzyme, namely a `Pictet-Spenglerase` will be tested. This study will stimulate novel efforts to exploit biochemical C-C bond forming reactions for organic synthesis. Especially the cheap reagent required for this outstanding reaction, namely molecular oxygen shows the incredible possibilities Nature provides us for reactions, which mankind is not able to do with standard chemical means.

Carbon-carbon (C-C) forming reactions represent the most important transformations in organic synthesis to set up the carbon backbone of organic compounds. Surprisingly, only a very limited number of enzymatic C-C bond forming methods are applicable for organic synthesis until to date. The berberine bridge enzyme (BBE) catalyses an outstanding intra-molecular C-C bond forming reaction, for which no chemical equivalent exists. The only reagent required for this transformation is molecular oxygen. Since very recently this enzyme can be produced in significant quantities, which allows now to perform a thorough investigation of the scopes and limitations of the enzyme for organic synthesis. Additionally, the crystal structure of the enzyme has just become available allowing a detailed study of the binding of substrates in the active site. Very promising experiments have just demonstrated that BBE accepts also various non-natural substrates. For instance a phenol alcohol could be substituted by NH 2 or even omitted and still activity could be detected. This very exciting result went in hand with a loss of activity so that enzyme engineering to improve the activity is intended. Optimisation of the reaction conditions (O2 -pressure, catalase, light...) will enable an upscaling of the remarkable C-C bond forming transformation to a preparative scale. Changing the substitution pattern from N-methyl to N- ethyl will clarify a possible chiral induction on a novel chiral carbon centre. The possibility to perform an inter- molecular C-C bond formations instead an intra-molecular C-C formation will be evaluated (e.g. iso-chinolin derivatives with gaiacol). The kinetic resolution catalysed by BBE will be tested to be coupled with racemisation to achieve in the ideal case dynamic kinetic resolution. Nevertheless, to avoid the preparation of racemic substrates a recently successful expressed enzyme, namely a `Pictet-Spenglerase` will be tested. This study will stimulate novel efforts to exploit biochemical C-C bond forming reactions for organic synthesis. Especially the cheap reagent required for this outstanding reaction, namely molecular oxygen shows the incredible possibilities Nature provides us for reactions, which mankind is not able to do with standard chemical means.