Search for: All records

The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a significant challenge in drug optimization campaigns. The late-stage introduction of alkyl fragments is especially desirable due to the high sp³-character and structural versatility of these motifs. Given their prevalence in molecular frameworks, C(sp²)−H bonds serve as attractive targets for diversification, though this process often requires difficult pre-functionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by employing Friedel–Crafts reaction conditions using strong Brønsted or Lewis acids. However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Herein, we report the application of a novel strategy for the selective coupling of differently hybridized radical species, which we term dynamic orbital selection. This mechanistic paradigm overcomes common limitations of Friedel-Crafts alkylations via the in situ formation of two distinct radical species, which are subsequently differentiated by a copper-based catalyst based on their respective binding properties. As a result, we demonstrate herein a general and highly modular reaction for the direct alkylation of native arene C−H bonds using abundant and benign alcohols and carboxylic acids as the alkylating agents. Ultimately, this solution overcomes the synthetic challenges associated with the introduction of complex alkyl scaffolds into highly sophisticated drug scaffolds in a late-stage fashion, thereby granting access to vast new chemical space. Based on the generality of the underlying coupling mechanism, dynamic orbital selection is expected to be a broadly applicable coupling platform for further challenging transformations involving two distinct radical species. 

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritizes reducing time to target and maximizing exploration of chemical space, harnessing these building blocks for carbon-carbon bond-forming reactions is a key goal in organic chemistry. In particular, leveraging a single activation mode to form a new C(sp³)–C(sp³) bond from two alcohol subunits would enable access to an extraordinary level of structural diversity. In this work, we report a nickel radical sorting–mediated cross-alcohol coupling wherein two alcohol fragments are deoxygenated and coupled in one reaction vessel, open to air. 

Abstract We extend the Lebesgue decomposition of positive measures with respect to Lebesgue measure on the complex unit circle to the non-commutative (NC) multi-variable setting of (positive) NC measures. These are positive linear functionals on a certain self-adjoint subspace of the Cuntz–Toeplitz $$C^{\ast }-$$algebra, the $$C^{\ast }-$$algebra of the left creation operators on the full Fock space. This theory is fundamentally connected to the representation theory of the Cuntz and Cuntz–Toeplitz $$C^{\ast }-$$algebras; any *−representation of the Cuntz–Toeplitz $$C^{\ast }-$$algebra is obtained (up to unitary equivalence), by applying a Gelfand–Naimark–Segal construction to a positive NC measure. Our approach combines the theory of Lebesgue decomposition of sesquilinear forms in Hilbert space, Lebesgue decomposition of row isometries, free semigroup algebra theory, NC reproducing kernel Hilbert space theory, and NC Hardy space theory.