Biosynthesis of Grandione: An Example of Tandem Hetero Diels-Alder/Retro-Claisen Rearrangement Reaction?

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.

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions

“…Another approach to ring-opening reactions of strained organic compounds is the retro-Claisen reaction, which has a long history in chemical , and enzymatic transformations. Despite their broad applications, however, this transformation has rarely been used for strain-induced ring-opening reactions . Catalysts are required for ring-opening, and although access to achiral substrates is becoming convenient, chiral cyclobutane derivatives that may be appropriate for ring-opening reactions are rare .…”

Recent Developments with Icetexane Natural Products

“…[100] Further, (À )-demethylsalvicanol ( 29) was oxidized under the action of silver(I) oxide to construct demethylsalvicanol quinone (54) which was dimerized upon heating at 100 °C to furnish (+)-grandione (193) (accompanied by (À )-brussonol (56) as a minor product, Scheme 27). [101,102] Additionally, exposure of demethylsalvicanol quinone (54) to silica gel can generate (À )-przewalskin E (55) but accompanied by 56 as a minor product and 193 as the major product.…”