Theoretical Analysis of the Retro-Diels–Alder Reactivity of Oxanorbornadiene Thiol and Amine Adducts

Abstract

Additions of amines or thiols to 7-oxanorbornadienes promote retro-[4 + 2] reactions to yield furans. Substitution at the bridgehead position also greatly influences the stability of the oxanorbornene adducts. Activation and reaction energies were computed with the M06-2X density functional, the origins of amine and thiol promoted fragmentation, and how substituent effects control fragmentation rates and reaction energetics are reported.

Azabicyclic vinyl sulfones for residue-specific dual protein labelling

“…S12 in the ESI†) reproduced the experimentally observed slight slowing down of the reaction when replacing the Boc by the Ac group, and when using a more polar solvent (DMSO vs. CHCl 3 ), reflecting the high nonpolar character of the rDA transition structures. However, and unlike in the case of Finn's oxanorbornadiene thiol and amine adducts, which have different substitution patterns and exhibit much more asynchronous transition structures as studied by Houk,35 the difference in reactivity of the bridgehead-methylated and non-methylated analogues was not so apparent computationally, and only using nearly complete models could reproduce the experimental trend. While the rDA can take place under physiologically relevant conditions, our data shows that this reaction is very slow (>59 h) for conjugates formed through modification of cysteine with [2.2.1]azabicyclic vinyl sulfone reagents, which is promising for their potential utility to build conjugates for in vivo studies.…”

The Influence of Substitution on Thiol-Induced Oxanorbornadiene Fragmentation

“…Bridgehead aromatic substitution produced a strong acceleration of the rDA process, with half-lives of 2–14 h for aromatic analogues 2f – 2i . While steric effects can contribute, electronics plays a significant role as indicated by the apparent linear correlation of relative rate with the Hammett σ + constant shown in the inset in Figure , with electron donation stabilizing the Diels–Alder transition state.…”

“…Following clean Michael addition, each adduct underwent a first-order rDA process, chronicled by the integration of characteristic 1 Bridgehead aromatic substitution produced a strong acceleration of the rDA process, with half-lives of 2−14 h for aromatic analogues 2f−2i. While steric effects can contribute, 16 electronics plays a significant role as indicated by the apparent linear correlation of relative rate with the Hammett σ + constant shown in the inset in Figure 2, with electron donation stabilizing the Diels−Alder transition state. Electronic effects at the bridgehead position were further explored with fluorinated OND derivatives 1j−1o.…”

Microgels as drug carriers for sonopharmacology

“…This eventually spurs the release of either fluorogenic furylated dansyl 1 or the furylated antibiotic trimethoprim (TMP) 2 (Scheme 1). 50,51 …”

“…This eventually spurs the release of either fluorogenic furylated dansyl 1 or the furylated antibiotic trimethoprim (TMP) 2 (Scheme 1). 50,51 Furylated dansyl is chosen to track the release process since it shows turn-on fluorescence upon release. 52,53 TMP is investigated as drug since it is active against a broad spectrum of Gram-positive and Gram-negative bacteria.…”