Coupled Electrocyclization/Prototropic Shift in the Biosynthesis of Crotinsulidane Diterpenoids

Area of Science:

• Organic Chemistry
• Computational Chemistry
• Biochemistry

Background:

• Crotinsulidane diterpenes are complex natural products with potential biological activities.
• Understanding their biosynthetic pathways is crucial for chemical synthesis and drug discovery.
• The formation of the characteristic five-membered ring is a key step requiring mechanistic elucidation.

Purpose of the Study:

• To computationally assess the energetic feasibility of proposed mechanisms for the five-membered ring formation in crotinsulidane diterpenes.
• To identify the most likely pathway for this critical cyclization step.

Main Methods:

• Density functional theory (DFT) calculations were employed to model reaction pathways.
• Transition states and activation energies for proposed mechanisms were computed.

Main Results:

• One proposed mechanism, a protonation-assisted coupled four-electron electrocyclization followed by a prototropic shift, demonstrated a low energetic barrier.
• This pathway is predicted to be energetically viable under biologically relevant conditions.

Conclusions:

• The protonation-assisted electrocyclization/prototropic shift mechanism is a energetically favorable route for the formation of the five-membered ring in crotinsulidane diterpenes.
• This finding provides valuable insights into the biosynthesis of these diterpenes and can guide synthetic efforts.