Premium
General, Divergent Platform for Diastereoselective Synthesis of trans ‐Cyclooctenes with High Reactivity and Favorable Physiochemical Properties **
Author(s) -
Pigga Jessica E.,
Rosenberger Julia E.,
Jemas Andrew,
Boyd Samantha J.,
Dmitrenko Olga,
Xie Yixin,
Fox Joseph M.
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202101483
Subject(s) - bioorthogonal chemistry , chemistry , nucleophile , reactivity (psychology) , yield (engineering) , combinatorial chemistry , nanotechnology , organic chemistry , click chemistry , catalysis , materials science , alternative medicine , pathology , metallurgy , medicine
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.