Abstract
Mechanistic theoretical studies about the feasibility of the traditional proposed mechanism of formation for icetexane diterpene dimer grandione were assessed using density functional method at the M06-2X/6-31G(d,p) level of theory. Bulk water solvent effects were taken into account implicitly using the polarizable continuum model (SCI-PCM). The results were compared with the selectivity found in the biomimetic synthesis performed by experimental research groups. The relative free energy calculation shows that the one-step H-DA formation mechanism nominated in the literature is not a viable mechanism. We found that an alternative competing Tandem pathway is consistent with the experimental trends. Thus, our results suggested that the compound grandione is formed via a H-DA/retro-Claisen rearrangement and not by the traditional H-DA mechanism proposed early in the experimental studies. The H-DA initial step produce a biecyclic adduct followed by a domino retro-Claisen rearrangement that releases the energy strain of the bicyclic intermediary. Steric issues and hyperconjugation interactions are the mainly factors driving the reaction nature and the selectivity in the formation reaction. Finally, the enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.
Highlights
The Diels-Alder (DA) and the Hetero Diels-Alder (H-DA) reactions are important ring-forming reactions in organic synthesis that have been postulated as a key steps in more than 400 biosynthetic conversions [1]. enzymes that catalyze biotransformations that could involve a Diels-Alder reaction have been identified [2,3,4,5,6,7,8,9], until now it has been difficult to verify the existence of a naturalDiels-Alderase enzyme [10,11,12,13]
We have analyzed the feasibility of the Hetero Diels-Alder cycloaddition in the biosynthetic mechanism of the icetexane dimer grandione using the DFT method at the M06-2X/
We establish that the one-step H-DA transformation mechanism proposed in the literature cannot account for the experimental results
Summary
The Diels-Alder (DA) and the Hetero Diels-Alder (H-DA) reactions are important ring-forming reactions in organic synthesis that have been postulated as a key steps in more than 400 biosynthetic conversions [1]. enzymes that catalyze biotransformations that could involve a Diels-Alder reaction have been identified [2,3,4,5,6,7,8,9], until now it has been difficult to verify the existence of a naturalDiels-Alderase enzyme [10,11,12,13]. Results from synthesis of natural products via biomimetic. From the computational point of view, several theoretical efforts have been realized to give support or discard the H-DA hypothesis in different natural products [17,18,19,20]. In this sense, the computational tools are valuable since they provide additional information on the biogenesis of natural compounds, such as the geometry and energy of the involved intermediary and Molecules 2018, 23, 2505; doi:10.3390/molecules23102505 www.mdpi.com/journal/molecules
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