DFT Analysis of Diels-Alder Reactions for the preparation of forskolin derivatives


                 Erik Kalla, Hugo Semrád, Miriama Mateášová and Markéta Munzarová

                            Department of Chemistry, Masaryk University


Diels-Alder reactions represent one of the most significant steps in the synthesis of forskolin
derivatives. The cycloaddition in question takes place between a structurally invariable diene
(tert-butyldimethylsilyloxybuta-1,3-diene) and a dienophile (methyl-p-benzoquinone)
characteristically substituted in meta-position with respect to the methyl group. Depending on the
nature of the substituent, individual stereoisomers of products are formed in various ratios. The
presented theoretical study focuses on the calculation of reaction energy profiles for a set of
substituted dienophiles. Trends in activation barriers are in good agreement with experimental
stereochemical outcomes. Relative energies of transition states are interpreted in terms of orbital
interactions between diene HOMO and dienophile LUMO. Both energy differences and frontier orbital
compositions within the Mulliken population analysis are considered, with a straightforward
correlation to the heights of activation barriers in the cycloaddition reactions.

Calculations of activation barriers were carried out at the  B3LYP/6-31G* or B3LYP/6-31+G* levels
of theory using the SMD implicit solvatation model within the Gaussian09 or Gaussian16
implementation. Comparative energy profile calculations and all orbital analyses have been done at
the B3LYP/STO-DZ level using the ADF package.

Figure 1. General scheme of Diels-Alder reaction for the preparation of forskolin derivatives.