Strategy for Engineering High Photolysis Efficiency of Photocleavable Protecting Groups through Cation Stabilization

Abstract

Photolabile protecting groups (PPGs) enable the precise activation of molecular function with light in many research areas, such as photopharmacology, where remote spatiotemporal control over the release of a molecule is needed. The design and application of PPGs in recent years have particularly focused on the development of molecules with high molar absorptivity at long irradiation wavelengths. However, a crucial parameter, which is pivotal to the efficiency of uncaging and which has until now proven highly challenging to improve, is the photolysis quantum yield (QY). Here, we describe a novel and general approach to greatly increase the photolysis QY of heterolytic PPGs through stabilization of an intermediate chromophore cation. When applied to coumarin PPGs, our strategy resulted in systems possessing an up to a 35-fold increase in QY and a convenient fluorescent readout during their uncaging, all while requiring the same number of synthetic steps for their preparation as the usual coumarin systems. We demonstrate that the same QY engineering strategy applies to different photolysis payloads and even different classes of PPGs. Furthermore, analysis of the DFT-calculated energy barriers in the first singlet excited state reveals valuable insights into the important factors that determine photolysis efficiency. The strategy reported herein will enable the development of efficient PPGs tailored for many applications.

Efficiency of Functional Group Caging with Second-Generation Green- and Red-Light-Labile BODIPY Photoremovable Protecting Groups

“…Others include the rate constants for ion-pair recombination, solvent separation, internal conversion, intersystem crossing, etc. For example, for coumarin photocages, the ion-pair recombination rate is important . If changing the leaving group alters any of these other rate constants in addition to the release rate constant, then a trend may not be clearly visible.…”

Synthesis and Characterization of a Cannabinoid Type 2 Receptor Photoactivated Prodrug

“…While formation of intermediate 15 and product 17 may be unique to this prodrug connectivity, this does demonstrate the importance of considering the effect that carbocation stabilization has on product formation, in particular branching from the coumarin α‐carbon. By example, coumarins containing an allylic system branched from the coumarin α‐carbon have been reported to undergo double bond rearrangement to a more stable carbocation before ‘water trapping’ occurred [22] . In the same report, [22] the analogous phenomenon was also observed for allylic‐BODIPY photocages.…”

“…By example, coumarins containing an allylic system branched from the coumarin α‐carbon have been reported to undergo double bond rearrangement to a more stable carbocation before ‘water trapping’ occurred [22] . In the same report, [22] the analogous phenomenon was also observed for allylic‐BODIPY photocages.…”

Selection methods for proximity-dependent enrichment of ligands from DNA-encoded libraries using enzymatic fusion proteins

“…Likewise, a photoprotecting group with increased spectral overlap with Nluc emission and better photolysis efficiency would yield improved selections. 26…”