Dynamical Trajectory Study of the Transannular [6+4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamides

Abstract

We report the dynamical trajectory study of the transannular [6+4] and ambimodal cycloaddition proposed in the biosynthesis of heronamide natural products. The originally proposed bifurcation of the potential energy surface is found to strongly favor the formation of the [6+4] product, both in the gas phase and in an explicit water environment, as evidenced by our trajectory simulations. The detailed information on how the bonds are formed and how water influences the bonding dynamics was analyzed at the femtosecond time scale.

Evolution of the Diels–Alder Reaction Mechanism since the 1930s: Woodward, Houk with Woodward, and the Influence of Computational Chemistry on Understanding Cycloadditions

“…Figure 23 shows the natural products and the Houk group computations on a model system that show an ambimodal transition state that can give [6+4] and [4+2] adducts, the former more stable in this case. MD simulations of reaction trajectories show that the [6+4] adduct is favored as expected [82b] . The Cope rearrangement of the [4+2] adduct to give the [6+4] adduct proceeds readily, resulting in the more stable [6+4] adduct, exclusively.…”

Polyene Macrolactams from Marine and Terrestrial Sources: Structure, Production Strategies, Biosynthesis and Bioactivities

“…The process was similar, but the mechanism may be different. For example, the [6π + 4π] [124,125] and [4π + 2π] cycloaddition reaction [122] pathways may be caused by the changes in the energy levels of the bonding and antibonding orbitals in the pericyclic reactions. Heronamides were produced via two spontaneous pathways involving alternative thermal [6π + 4π] [29] and photochemical [6π + 6π] intramolecular cycloadditions.…”

Die Evolution des Diels‐Alder‐Reaktionsmechanismus seit den 1930er Jahren: Woodward, Houk zusammen mit Woodward und der Einfluss der Computerchemie auf das Verständnis von Cycloadditionen

“…Abbildung 23 zeigt die Naturstoffe und die Rechnungen der Houk‐Gruppe an einem Modellsystem, die einen ambimodalen Übergangszustand zeigen, der [6+4]‐ und [4+2]‐Addukte ergeben kann, wobei erstere in diesem Fall stabiler sind. Moleküldynamik‐Simulationen von Reaktionstrajektorien zeigen, dass das [6+4]‐Addukt erwartungsgemäß begünstigt wird [82b] . Die Cope‐Umlagerung vom [4+2]‐ zum [6+4]‐Addukt geht problemlos voran und führt ausschließlich zu dem stabileren [6+4]‐Addukt.…”