Mechanistic Studies of Carbon Monoxide Release from Norborn‐2‐en‐7‐one CORMs

• Published in: Asian journal of organic chemistry 2022-10, Vol.11 (10), p.n/a
• Main Authors: Bell, Nathan T., Payne, China M., Sammut, Ivan A, Larsen, David S.
• Format: Article
• Language: English
• Subjects: Carbon monoxide; Drug design; Organic chemistry; Phthalimides; Prodrugs; Reaction mechanism; Substitutes; Synthesis
• ISSN: 2193-5807; 2193-5815
• DOI: 10.1002/ajoc.202200350

A study has been performed to determine the factors that control carbon monoxide (CO) release from 3a‐bromo‐norborn‐2‐en‐7‐one‐based organic CO‐releasing molecules (oCOms). Such molecules have recently become of interest for the therapeutic potential of targeted delivery of the gasotransmitter CO, however the mechanism controlling the release of CO has not been comprehensively studied. Elucidation of this mechanism would enable tuning of the rate of CO release to specific therapeutic needs, such as acute vs chronic administration. By the synthesis and evaluation of substituted oCOms, CO release has been shown to be controlled by a rate‐determining E1cB(irr)‐type elimination of HBr followed by rapid chelotropic decomposition to give CO and a substituted phthalimide byproduct. Based on this result we report the successful rational design and synthesis of water‐soluble oCOms with targeted half‐lives intermediate to those reported previously. The exploration of the CO release mechanism from pH‐triggered 3a‐halonorbornenone organic carbon monoxide prodrugs is described. A rate‐limiting E1cB(irr) HX elimination was found to control the rate of CO release, allowing rate control using EWG but not by changing the leaving group. Application of the mechanistic understanding obtained has been used to design and synthesise prodrugs with targeted half‐lives.