Synthesis of Sulfur-Substituted Bicyclo[1.1.1]pentanes by Iodo-Sulfenylation of [1.1.1]Propellane.

Thiols easily react with [1.1.1]propellane to give sulfur-substituted bicyclo[1.1.1]pentanes in radical reactions, but this reactivity is not replicated in the case of heterocyclic thiols. Herein, we address this issue by electrophilically activating [1.1.1]propellane to promote its iodo-sulfenylation with 10 classes of heterocyclic thiols in two protocols that can be conducted on a multigram scale without exclusion of air or moisture

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs

Horner–Wadsworth–Emmons olefination of proteins and glycoproteins

Acknowledgements: We acknowledge funding by the Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (BBSRC) and AstraZeneca plc under the Prosperity Partnership grant no. EP/S005226/1. We are grateful to M. Cliff, R. Spiess, M. Papworth and T. Murray for their support with 19F-NMR, MS analyses and antibody glycoengineering discussions.Funder: EPSRCAbstractChemo-selective modifications of proteins are fundamental to the advancement of biological and pharmaceutical sciences. The search for biocompatible chemical reactions has prompted us to investigate Horner–Wadsworth–Emmons (HWE) olefinations, iconic reactions in organic synthesis that would give rise to new selective protein olefinations. Our choice of HWE olefinations was inspired by the growing number of methods for generating aldehydes as transient reactive groups in proteins and the potential for mild and simple reaction conditions. Here we show that HWE olefination reactions on aldehydes, produced by both chemical and enzymatic methods, are compatible with physiological conditions and highly selective in small and large proteins, including therapeutic antibodies and stable recombinant proteins exemplified by green fluorescent protein. Reaction kinetics can be fine-tuned over orders of magnitude both by judicious use of substituents and pH regulation. The electrophilic nature of the HWE olefination products can be tuned to allow for subsequent nucleophilic additions, including thiol- and phospha-Michael additions. Our results demonstrate that HWE olefination of aldehydes in proteins provides efficient and selective bioconjugation chemistries that are orthogonal to existing methods.</jats:p