Integrated Calendar

Today, enzymes can be reprogrammed beyond biology's natural reactions. This is achieved through noncovalent interactions decorating and templating enzyme active sites to stabilize a single transition state amid competing alternatives. We engineered a flavin-dependent oxidoreductase to generate tertiary radicals within its active site and channel them into stereoselective C–N coupling with unsubstituted anilines, delivering chiral α-tertiary amines with good yields and high chemo- and enantioselectivity, under visible light irradiation—without metal cofactors.Six rounds of directed evolution install a π-stacking/hydrogen-bond network that templates lone pair–radical hyperconjugation, overriding arene addition to enforce C(sp³)–N formation. DFT and multivariate statistical modeling reveal how this microenvironment flips innate radical reactivity toward N-alkylation. This establishes biocatalytic spatial programming as a general platform for non-natural radical transformations beyond both evolution and small-molecule catalysis.

Small-ring molecules occupy a sweet spot between stability and instability: compact, information-rich frameworks whose reactivity is often governed by the energetic penalty of ring strain. This lecture will survey practical strategies for building structurally diverse small-ring systems, then show how their intrinsic strain can be exploited as a programmable driving force for selective bond cleavage.Through case studies spanning strain-enabled ring openings, rearrangements, and catalytic transformations, we will illustrate how “stored” strain energy can be translated into otherwise difficult-to-access acyclic architectures, especially motifs featuring adjacent stereocenters.We will focus on selective C–C bond cleavage, highlighting a predictable and robust small-ring–derived platform that controls stereochemical outcomes in SN1-type processes initiated by strain-release ring-opening chemistry.