Mimicking Natural Catalytic Systems: Design Inspired Beyond the Traditional Paradigm.

Abstract

Organocatalysis has undergone remarkable conceptual expansion over the past two decades, evolving from isolated early 20th century observations into a broad platform for designing structurally diverse and functionally sophisticated catalysts. While early developments were strongly influenced by straightforward analogies to natural enzymes, recent advances demonstrate that inspiration from biological catalysis can extend far beyond direct mimicry. This review covers representative examples in which chemists reinterpret, broaden, or strategically depart from enzymatic logic to achieve new reactivity and improved catalytic performance. We first examine organocatalysts derived from enzymatic cofactors, including thiamine-inspired carbene catalysts and pyridoxal-based systems, whose functions have been adapted for transformations not observed in nature. We then discuss catalysts engineered for efficient operation in aqueous media, followed by chemoenzymatic cascade processes. Further sections illustrate how organocatalysis can emulate biosynthetic logic in the construction of complex natural products. Finally, we highlight the reverse flow of inspiration, where organocatalytic concepts inform the design of engineered biocatalysts.