Experimental and Theoretical Exploration of the Kinetics and Thermodynamics of the Nucleophile-Induced Fragmentation of Ylidenenorbornadiene Carboxylates

Abstract

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with thiol nucleophiles to yield mixtures of four to eight diastereomers depending on the symmetry of the YND substrate. The mixtures of diastereomers fragment via a retro-[4 + 2] cycloaddition with a large variation in rate, with half-lives ranging from 16 to 11,000 min at 80 °C. The diastereomer-enriched samples of propane thiol adducts [YND-propanethiol (PTs)] were isolated and identified by nuclear Overhauser effect spectroscopy (NOESY) correlations. Simulated kinetics were used to extrapolate the rate constants of individual diastereomers from the observed rate data, and it correlated well with rate constants measured directly and from isolated diastereomer-enriched samples. The individual diastereomers of a model system fragment at differing rates with half-lives ranging from 5 to 44 min in CDCl3. Density functional theory calculations were performed to investigate the mechanism of fragmentation and support an asynchronous retro-[4 + 2] cycloaddition transition state. The computations generally correlated well with the observed free energies of activation for four diastereomers of the model system as a whole, within 2.6 kcal/mol. However, the observed order of the fragmentation rates across the set of diastereomers deviated from the computational results. YNDs display wide variability in the rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A Hammett study showed that the electron-rich aromatic rings attached to the ylidene bridge increase the fragmentation rate, while electron-deficient systems slow fragmentation rates.

Experimental and Theoretical Analysis of the Thiol-Promoted Fragmentation of 2-Halo-3-tosyl-oxanorbornadienes

“…In this sense, Finn, Houk, and co-workers have recently explored the thiol-promoted fragmentation of electrophilic oxanorbornadienes (ONDs) in the search for thiol-responsive cleavable linkers for drug delivery systems (Scheme , previous ONDs). − As a result, an exhaustive (theoretical and experimental) study of the influence of the substitution pattern of ONDs in the rate of fragmentation via retro-Diels–Alder (rDA) reaction was reported. , Some of these ONDs were successfully applied in drug delivery systems . Bercovici and co-workers recently extended this chemistry of ONDs to ylidenenorbornadiene carboxylate analogues . From our side, we have recently reported that azanorbornadienes containing the bromovinyl sulfone functionality are useful reagents for the selective modification of proteins .…”

“… 7 Bercovici and co-workers recently extended this chemistry of ONDs to ylidenenorbornadiene carboxylate analogues. 8 From our side, we have recently reported that azanorbornadienes containing the bromovinyl sulfone functionality are useful reagents for the selective modification of proteins. 9 This functionality is crucial for the bioconjugation process as it allows the reaction with the thiol function of cysteine residues of proteins through nucleophilic vinylic substitution (S N V σ ).…”