Experimental and Computational Investigations of the Reactions between α,β-Unsaturated Lactones and 1,3-Dienes by Cooperative Lewis Acid/Brønsted Acid Catalysis

Abstract

The reactions of α,β-unsaturated δ-lactones with activated dienes such as 1,3-dimethoxy-1-[(trimethylsilyl)oxy]-1,3-butadiene (Brassard's diene) are barely known in literature and show high potential for the synthesis of isocoumarin moieties. An in-depth investigation of this reaction proved a stepwise mechanism via the vinylogous Michael-products. Subsequent cyclisation and oxidation by LHMDS and DDQ, respectively, provided six mellein derivatives (30-84 %) and four angelicoin derivatives (40-78 %) over three steps. DFT-calculations provide insights into the reaction mechanism and support the theory of a stepwise reaction.

Keywords: Michael additions; catalysis; computational chemistry; density functional calculations; natural products.

Figure 1

Selected structures of natural products containing an isocoumarin moiety (blue).

Scheme 1

A) Diels–Alder product of α,β‐unsaturated δ‐lactone 7 and cyclopentadiene (9) as positive control. B) Initial approach towards Diels–Alder product after desilylation and subsequent oxidation. C) Reaction conditions for Diels–Alder reaction between α,β‐unsaturated δ‐lactone 7 and cyclopentadiene (9). D) Reaction conditions for reaction between α,β‐unsaturated δ‐lactone 7 and Brassard's diene (8).

Scheme 2

Diels–Alder type reaction of Brassard's diene (8) and 5,6‐dihydro‐2H‐pyran‐2‐one (7).

Scheme 3

Proton proximity as detected by the nOe coupling between 3‐H_a and 2′‐H for (Z)‐13 (left). Dieckmann reaction vinylogous (E)‐Michael‐product (E)‐13 (right).

Scheme 4

Synthesis of isocoumarins from δ‐substituted α,β‐unsaturated δ‐lactone.

Scheme 5

Synthesis of alternariol derivatives from coumarins.

Scheme 6

Calculated Gibbs free energies (in kcal mol⁻¹) for the uncatalyzed cycloaddition between 7 and 8 (above) and structure as well as selected bond lengths (in Å) for the transition states TS1 (below).

Scheme 7

Calculated Gibbs free energies (in kcal mol⁻¹) for the Brønsted acid catalyzed cycloaddition between 7 and 8 (above) and structure as well as selected bond lengths (in Å) for the transition states TS2 (below).

Scheme 8

Calculated Gibbs free energies (in kcal mol⁻¹) for the AlMe₃‐catalyzed cycloaddition between 7 and 8 (above) and structure as well as selected bond lengths (in Å) for the transition states TS3 (below).

Scheme 9

Formation of the catalytically active species between Tf₂CH₂ and AlMe₃ (free energies in kcal mol⁻¹) (above) and structures of the transition state TS4 and the potential catalyst I3 and selected bond lengths (in Å, below).

Scheme 10

Calculated free energies for the isodesmic proton‐transfer reactions between I2 and I3 and the Tf₂CH anion (in kcal mol⁻¹).

Scheme 11

Calculated Gibbs free energies (in kcal mol⁻¹) for the cycloaddition between 7 and 8 catalyzed by the Lewis acid I2 or I3 (above). Structure and selected bond lengths (in Å) for the complexes between 7 and I2 or I3, respectively (below).