Although C-N bonds are ubiquitous in natural products, pharmaceuticals, and agrochemicals, biocatalysts that forge these bonds with high atom e ciency and enantioselectivity have primarily been limited to a few select enzymes. In particular, the use of ammonia lyases has emerged as a powerful strategy to access C-N bond formation through hydroamination reactions, which has no counterpart in traditional synthetic chemistry. However, the broad utility of ammonia lyases is rather restricted due to their narrow synthetic scope, and the conjugate addition of a matrix of nucleophilic donors to electrophilic acceptors remains a longstanding challenge. Herein, we report the computational redesign of aspartase, a highly speci c ammonia lyase, to yield C-N lyases with unprecedented cross-compatibility of nonnative nucleophiles and electrophiles. A wide range of noncanonical amino acids (ncAAs) are afforded with excellent conversion (up to 99%), regioselectivity > 99%, and product enantiomeric excess > 99%, and the process is scalable under industrially relevant protocols (demonstrated in kilogram-scale synthesis). Furthermore, the redesigned enzymes can be facilely integrated in cascade reactions, as we demonstrated the synthesis of β-lactams with different substitution patterns at the N-1 and C-4 positions in a one-pot reaction. This versatile and e cient C-N lyase platform supports the preparation of diverse libraries of ncAAs and their derivatives and will present opportunities in medicinal chemistry and synthetic biology.
The use of 2-ketoacids is very common
in feeds, food additives,
and pharmaceuticals, and 2-ketoacids are valuable precursors for a
plethora of chemically diverse compounds. Biocatalytic synthesis of
2-ketoacids starting from l-amino acids would be highly desirable
because the substrates are readily available from biomass feedstock.
Here, we report bioinformatic exploration of a series of aminotransferases
(ATs) to achieve the desired conversion. Thermodynamic control was
achieved by coupling an l-glutamate oxidation reaction in
the cascade for the recycling of the amine acceptor. These enzymes
were able to convert a majority of proteinogenic amino acids into
the corresponding 2-ketoacids with high conversion (up to 99%) and
atom-efficiency. Furthermore, this enzyme cascade was extendable,
and one-pot two-step processes were established for the synthesis
of d-amino acids and N-methylated amino
acids, achieving great overall conversion (up to 99%) and high ee
values (>99%). These developed enzymatic methodologies offer convenient
routes for utilizing amino acids as synthetic reagents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.