Organocatalytic, Enantioselective Intramolecular [6 + 2] Cycloaddition Reaction for the Formation of Tricyclopentanoids and Insight on Its Mechanism from a Computational Study

Abstract

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations, and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond adopt the gauche-syn conformation during the C-C bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 + 2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.

Catalytic Enantioselective [10+4] Cycloadditions

“…

The first peri-and stereoselective [10+ +4] cycloaddition between catalytically generated amino isobenzofulvenes and electron-deficient dienes is described. [5] Shortly thereafter,organocatalyzed [6+ +2] and [8+ +2] cycloadditions were reported to provide cyclic scaffolds in high enantioselectivities. Experimental and computational investigations support ak inetic distribution of intermediate rotamers dictating the enantioselectivity,w hichr elies heavily on additive effects.

For concise and controlled construction of chiral cyclic structures,c ycloadditions are recognized as highly valuable synthetic strategies.Diels-Alder reactions and dipolar cycloadditions,i nvolving 6p electrons,h ave been particularly useful and am ultitude of enantioselective catalytic versions have been developed.

…”

“…[3] Intermolecular higher-order cycloadditions remained elusive in asymmetric catalysis until the first metal-catalyzed [8+ +2] cycloaddition was reported in 2013. [5] Shortly thereafter,organocatalyzed [6+ +2] and [8+ +2] cycloadditions were reported to provide cyclic scaffolds in high enantioselectivities. [5] Shortly thereafter,organocatalyzed [6+ +2] and [8+ +2] cycloadditions were reported to provide cyclic scaffolds in high enantioselectivities.…”

Diarylprolinol Silyl Ethers: Development and Application As Organocatalysts

“…The reaction proceeds well with several substrates, and cis isomers were obtained in every example (Scheme . The proposed reaction mechanism was supported by computational analysis (Scheme 13-13), which showed that the model intermolecular [6þ2] cycloaddition reaction proceeds in a stepwise mechanism via a zwitterionic intermediate [45]. In contrast, the intramolecular [6þ2] cycloaddition leading to the cis-fused linear triquinane skeleton 57 proceeds in a concerted mechanism via a highly asynchronous transition state.…”

“…Although a racemic version of this intramolecular [6þ2] cycloaddition reaction (and its reaction mechanism) has been demonstrated by the Houk group [44], an asymmetric catalytic version of this chemistry had not been previously reported. When a linear substrate 53 was exposed to a catalytic amount of 9, a [6þ2] cycloaddition reaction proceeded to afford the tricyclic compound 54 [45]. Two new CÀC bonds are formed in this reaction, via domino enamine/iminium ion intermediates.…”

Benzofulvenes in Trienamine Catalysis: Stereoselective Spiroindene Synthesis

“…[6] Catalytic asymmetric strategies aimed at the analogous spiroindenes are more scarce. [7] We envisioned that organocatalysis [8] could be applied to the stereoselective formation of spiroindenes from benzoful-venes.Astrategy based on trienamine catalysis was chosen, which would grant access to indenes spiro-fused to cyclohexenes by af ormal [4+ +2] cycloaddition (Scheme 1a). [9] The spiroindene products targeted by the envisioned strategy offer an umber of molecular handles for further modifications.Most notably,aMichael acceptor present in the indene ring was demonstrated to facilitate intramolecular cyclizations to yield complex polycyclic products containing as piroindane core.…”