Sustainable Natural Product Glycosylation: A Critical Evaluation of Biocatalytic and Chemical Approaches

The glycosylation of natural products can significantly enhance their physicochemical properties, with numerous synthetic and biocatalytic methodologies continuously being developed, each presenting unique advantages and challenges. Biocatalytic methods are often presumed to be more sustainable alternatives to chemical approaches; however, their environmental and economic viabilities require critical evaluation. This review summarizes the recent advancements in natural product glycosylation and provides a comprehensive techno-economic and environmental assessment based on yield, titer, rate, environmental factor, and impact on endpoint categories using a life cycle impact assessment approach. Although biocatalytic methods are highlighted for their superior yields, they are frequently hindered by lower titers and reaction rates compared to their chemical counterparts. Surprisingly, chemical glycosylation exhibited lower environmental factors (E-factors), whereas biocatalytic approaches displayed lower impacts on endpoint categories, highlighting that E-factors fail to capture the environmental implications of a process. This review demonstrates the challenges associated with quantifying the environmental impacts of a process, especially given the lack of experimental detail reporting in the biocatalytic field. It exposes the misguided assumption that biocatalytic processes always exert lower environmental burdens and identifies key opportunities to enhance process efficiency and sustainability, providing guidance for selecting and developing a given natural product glycosylation reaction.