Intramolecular Diels–Alder Approaches to the Decalin Core of Verongidolide: The Origin of the exo-Selectivity, a DFT Analysis

Abstract

Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, Verongidolae. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a cis-decalin core and we hypothesize that the relative configuration of the cis-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels-Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels-Alder reactions was exo and an in-depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity.

Recent Developments in Transannular Reactions

“…Template for SYNTHESIS Thieme partially and tentatively assigned (Scheme 5). 8 In this case, although the transannular Diels-Alder reaction proceed very efficiently upon heating the macrocyclic lactone substrate under microwave irradiation, the observed exo selectivity was not the required one for the preparation of the target compound.…”

“…A related approach has been followed by Cossy and co-workers in an attempt to prepare the decaline core of the cytotoxic natural product verongidolide whose stereostructure has only been partially and tentatively assigned (Scheme 5 ). 8 In this case, although the transannular Diels–Alder reaction proceed very efficiently upon heating the macrocyclic lactone substrate under microwave irradiation, the observed exo -selectivity was not the required one for the preparation of the target compound. Calculations also supported the kinetic preference for the substrate to undergo cycloaddition through the exo -TS and also disregarded the possibility for a reversible-Diels–Alder process that could eventually provide the more stable endo -product.…”

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

“…Therefore the presence of a cyclohexane moiety in natural products with a defined stereochemistry is not unambiguous proof of Diels-Alderase activity since the cycloaddition can occur without catalysis or, as some studies propose, the transformation could proceed via polar/non-polar mechanisms or via stepwise reactions [ 12 , 15 , 16 ]. 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 transition estate structure and the feasibility of biological enzymatic assisted reactions.…”

Epoxy-Tethered Diels–Alder Reaction toward the Tricyclic Core of Kalihinols

“…The leftover pendent prenyl unit facilitates access to both pyran- and furan-containing kalihinols. Computational studies on template-tethered IMDA reactions have been well-explored . We have proposed some possible synthons with different tethering templates for the IMDA reaction, and corresponding density functional theory (DFT) calculations were carried out to gain insight into the impact on the stereocontrolled IMDA reaction.…”