New Synthetic Approach to Cyclopenta-Fused Heterocycles Based upon a Mild Nazarov Reaction. 2. Further Studies on the Torquoselectivity

Abstract

Conjugated alkoxytrienes in which one of the double bonds is embedded in a heterocyclic moiety are obtained by the Pd-catalyzed coupling reaction of lactam- and lactone-derived vinyl triflates with alpha-alkoxydienylboronates. These compounds undergo a 4pi electrocyclization process (Nazarov reaction) under acidic conditions and afford cyclopenta-fused heterocycles in good yields. As a continuation of a previous study, the torquoselectivity of this Nazarov reaction has been investigated using 2-alkyl-substituted pyrrolidinone and 2- and 4-substituted delta-valerolactone derivatives. High or complete stereoselectivity has only been observed with the 2-alkyl-substituted heterocycles. Both steric and stereoelectronic effects could contribute to determining the stereoselection of the ring closure.

Density Functional Studies on the Nazarov Reaction Involving Cyclic Systems

“…Cyclopenta[b]pyranones 2 are obtained in good yields when the reaction is carried out under mild acidic conditions (Amberlyst-15 resin in dichloromethane at room temperature). [29] The isolated divinyl ketones 3, which are formed as minor products (less than 10 %) in the hydrolysis of 1, do not cy-clize under the same conditions, but require stronger mineral acids to cyclopentannulate. [40] Interestingly, the analogous carbocyclic derivative 4 (Scheme 2) simply hydrolyzes to the open-chain ketone 5 upon treatment with Amberlyst-15 and the latter cyclizes only upon treatment with stronger acids.…”

“…However, it was also possible that in all cases the differences in the activation free energies could be due to stereoelectronic reasons, in particular, to a slightly different superimposition of the orbitals of the atoms involved in the cyclization reaction, as previously suggested. [29] As an example, the molecular orbital describing the newly forming bond in Equation (7) is shown in Figure 3. At the same isocontour level, such a molecular orbital seems to show a higher degree of completeness in the distorted twist-boat TS ( Figure 3A) than in the chair-like one ( Figure 3B).…”

“…(2) and (4)], [25,[28][29][30] which generate in situ an intermediate suitable to undergo electrocyclization, have very recently been used for this purpose. Moreover, strained polycyclic dienones have also been employed as substrates.…”

“…(3) and (4)]. [28,29] A surprisingly high remote stereocontrol was in fact observed in the formation of the new C5 stereocenter on the cyclopentenone moiety with 2-alkyl-substituted O-heterocycles [Eq. (3), R 1 = R 3 = H, and Eq.…”

“…[28,29,33] Intriguingly, the exclusive formation of 2,5-cis-disubstituted N-heterocyclic derivatives was observed and plausibly imputed to steric interactions, [28] whereas the reasons behind the prevailing formation of the 2,5-trans-disubstituted products in the hydrolysis of the corresponding dihydropyran derivatives was less clear. [29] A survey of the literature concerning theoretical studies of the Nazarov reaction revealed some works aimed at the theoretical prediction of torquoselectivity in the electrocyclization process. However, these computational studies focused only on acyclic systems [34][35][36][37] and on the retro-Nazarov reaction.…”