Abstract:Computational studies at the HF/3-21G and B3LYP/6-31G(d) levels suggest that 5,6,8-tri(tert-butyl)-1,2,3,4-tetraphenylnaphthalene (2) is perhaps the most crowded naphthalene derivative that will show normal stability; more highly congested naphthalenes will prefer to exist as the corresponding Dewar isomers. Initial attempts to prepare 2 by reacting 3,4,5,6-tetraphenylbenzyne with 2,3,5-tri(tert-butyl)cyclopentadienone at 83 degrees C gave instead a stable norbornadienone, 1,2,4-tri(tert-butyl)-5,6,7,8-tetraph… Show more
“…Other octasubstituted naphthalenes are compounds 13 (Figure ), a bulked-up octaalkylnaphthalene with a 34° twist, and 14 , where silver complexation of the already large cyclohexylthio substituents gives maximal crowding and the greatest twist (52°) of the “simple” crowded naphthalenes . Compounds 15 and 16 , as well as all of the octaphenylnaphthalenes, were prepared by the reaction of crowded cyclopentadienones with tetraphenylbenzyne generated by the diazotization of tetraphenylanthranilic acid. − ,, 4 …”
“…Other octasubstituted naphthalenes are compounds 13 (Figure ), a bulked-up octaalkylnaphthalene with a 34° twist, and 14 , where silver complexation of the already large cyclohexylthio substituents gives maximal crowding and the greatest twist (52°) of the “simple” crowded naphthalenes . Compounds 15 and 16 , as well as all of the octaphenylnaphthalenes, were prepared by the reaction of crowded cyclopentadienones with tetraphenylbenzyne generated by the diazotization of tetraphenylanthranilic acid. − ,, 4 …”
“…For prodrugs that would release CO under physiological conditions, we thought about using pericyclic reactions, which are well-known for the ability to easily break and form C–C bond under mild conditions . Specifically, our design strategy relies on the ability of norbornadien-7-ones to undergo facile cheletropic reaction to extrude CO under mild conditions . Therefore, precursors of norbornadien-7-ones could serve as stable CO prodrugs.…”
Section: Introductionmentioning
confidence: 98%
“…25 Specifically, our design strategy relies on the ability of norbornadien-7-ones to undergo facile cheletropic reaction to extrude CO under mild conditions. 26 Therefore, precursors of norbornadien-7-ones could serve as stable CO prodrugs. Two major strategies were employed in our design to make precursors of norbornadien-7ones, namely, an inter-and intramolecular "click and release" strategy and a β-elimination-based strategy.…”
Carbon monoxide is widely acknowledged as an important gasotransmitter in the mammalian system with importance on par with that of nitric oxide. It has also been firmly established as a potential therapeutic agent with a wide range of indications including organ transplantation, cancer, bacterial infection, and inflammation-related conditions such as colitis and sepsis. One major issue in developing CO based therapeutics is its delivery in a pharmaceutically acceptable form. Currently, there are generally five forms of deliveries: inhaled CO, photosensitive CO-releasing molecules, encapsulated CO, CO dissolved in drinks, and molecules that would release CO under physiological conditions without the need for light. For over a decade, the last category only included metal-based CO releasing molecules. What had been missing were organic CO prodrugs, which release CO under physiological conditions with tunable rates and in response to various exogenous and endogenous triggers such as water, chemical reagents, esterase, ROS, and changes in pH. This Account describes our work in this area as well as the demonstration for these organic prodrugs to recapitulate CO's pharmacological effects both in vitro and in vivo. Generally, two categories of CO prodrugs have been developed in our lab. Both can be considered as precursors of norbornadien-7-ones, which readily undergo cheletropic reaction under very mild conditions to extrude CO. The first category of CO prodrugs capitalizes on the inter- and intramolecular inverse electron demand Diels-Alder (DA) reaction to trigger CO release under physiological conditions. As for the bimolecular CO prodrugs, we proposed a new concept of "enrichment triggered CO release" by conjugating both components with a mitochondria-targeting moiety to achieve targeted CO delivery with improved biological outcomes in vitro and in vivo. As for the unimolecular CO prodrugs, the release half-lives can be readily tuned from minutes to days by varying the substituents on the dienone ring, the tethering linker, and the alkyne. Some significant structure-release rates relationships (SRRs) have been unveiled. An esterase-activated CO prodrug and a cascade prodrug system for co-delivery of CO and another payload have also been devised using such an intramolecular click and release strategy. The second category of CO prodrugs leverage on an elimination reaction to generate norbornadien-7-ones for CO release from norborn-2-en-7-ones. In the case of pH-sensitive ones, the CO release is triggered by β-elimination, and the release rate can be quantitatively predicted using the Hammett constant of the substituents on the leaving group. The ROS-activated ones take advantage of ROS-induced selenoxide elimination to achieve targeted CO delivery to disease sites with elevated ROS level. We strongly believe that these CO prodrugs could serve as powerful tools for CO-associated biological studies and are promising candidates for ultimate clinical applications.
“…Furthermore, the formation of an easily characterized organic by-product after CO release would allow determination of the CO-release kinetics whilst potentially reducing residual compound toxicity. Our approach is based upon the bridged carbonyl compound norbornadien-7-one ( 8 ) 37 which undergoes cheletropic loss of carbon monoxide (CO) giving benzene as a by-product ( Fig. 2A ).…”
Section: Introductionmentioning
confidence: 99%
“…It is well known that compound 8 is remarkably prone to fragmentation with loss of CO and several computation studies 37 , 39 have been carried out on this reaction where the activation energy for this process was calculated to be between 11 to 12 kcal mol –1 with the corresponding rate constant at 300 K (27 °C) of 4.2 × 10 5 s –1 ( t 1/2 = 1.6 × 10 –5 s).…”
A prodrug strategy for the release of the gasotransmitter carbon monoxide (CO) at physiological pH, based upon 3a-bromo-norborn-2-en-7-one Diels–Alder cycloadducts has been developed.
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