General, Divergent Platform for Diastereoselective Synthesis of trans‐Cyclooctenes with High Reactivity and Favorable Physiochemical Properties

• Published in: Angewandte Chemie International Edition Vol. 60; no. 27; pp. 14975 - 14980
• Main Authors: Pigga, Jessica E., Rosenberger, Julia E., Jemas, Andrew, Boyd, Samantha J., Dmitrenko, Olga, Xie, Yixin, Fox, Joseph M.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 25.06.2021; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: biorthogonal reactions; Chemistry; Chemistry, Multidisciplinary; Chemistry, Physical; Computer applications; Cycloaddition Reaction; Cyclooctanes - chemical synthesis; Cyclooctanes - chemistry; diastereoselectivity; Divergence; Fluorescence; HeLa Cells; Humans; Hydrophobicity; Molecular Structure; New class; Nucleophiles; Physical Sciences; Physicochemical processes; Physicochemical properties; Physiochemistry; Science & Technology; Stereoisomerism; Stereoselectivity; synthetic methods; tetrazines; trans-cyclooctenes; trans-cyclooctenes; biorthogonal reactions; MECHANISM; IMPROVED STABILITY; diastereoselectivity; BIOORTHOGONAL CHEMISTRY; CLICK; RELEASE; LIVE CELLS; SELECTIVITY; synthetic methods; tetrazines
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202101483

trans‐Cyclooctenes (TCOs) are essential partners in the fastest known bioorthogonal reactions, but current synthetic methods are limited by poor diastereoselectivity. Especially hard to access are hydrophilic TCOs with favorable physicochemical properties for live cell or in vivo experiments. Described is a new class of TCOs, “a‐TCOs”, prepared in high yield by stereocontrolled 1,2‐additions of nucleophiles to trans‐cyclooct‐4‐enone, which itself was prepared on a large scale in two steps from 1,5‐cyclooctadiene. Computational transition‐state models rationalize the diastereoselectivity of 1,2‐additions to deliver a‐TCO products, which were also shown to be more reactive than standard TCOs and less hydrophobic than even a trans‐oxocene analogue. Illustrating the favorable physicochemical properties of a‐TCOs, a fluorescent TAMRA derivative in live HeLa cells was shown to be cell‐permeable through intracellular Diels–Alder chemistry and to wash out more rapidly than other TCOs. Hydrophilic trans‐cyclooct‐4‐enones (TCOs) with favorable physicochemical properties for live cell or in vivo experiments are especially hard to access. Readily accessible TCOs are now shown to undergo diastereoselective additions with a broad range of nucleophiles to give access to functionalized axial‐5‐hydroxy‐trans‐cyclooctenes (a‐TCO), a family of trans‐cyclooctenes with high reactivity and improved physiochemical properties.