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. 2022 Apr 28;27(9):2810.
doi: 10.3390/molecules27092810.

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products

Mabel M Montenegro-Sustaita  1 , Hugo A Jiménez-Vázquez  1 , Elena Vargas-Díaz  1 , J Enrique Herbert-Pucheta  1 , L Gerardo Zepeda-Vallejo  1
Affiliations

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products

Mabel M Montenegro-Sustaita et al. Molecules. .

Abstract

A representative number of decalin and hydrindane derivatives 2a-l were prepared in 11-91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael-Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the 1H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the 1H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.

Keywords: cycloalkanone enolates; decalin/hydrindane derivatives; double Michael addition; methyl acrylate; stereochemical outcome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General approach for the synthesis of decalin derivatives via Michael’s double addition of cycloalkanone enolates over conjugated vinylic systems.
Figure 2
Figure 2
ORTEP projections of (from left to right): (a) trans-decalin derivative 2c; (b) cis-decalin derivative 2d, and (c) perhydrophenanthrene derivative 2j. Displacement ellipsoids for the non-hydrogen atoms are drawn at 30% probability.
Figure 3
Figure 3
Decalin diastereomers obtained by MIMIRC reaction between cycloalkanone lithium enolate and methyl/ethyl acrylate described for different research groups [17,20].
Figure 4
Figure 4
Plain and optimized 3D structures of the eight possible diastereomers (I–VIII) obtained by MIMIRC reaction between cyclohexanone lithium enolate and methyl acrylate. These projections show the most stable conformer for each diastereomer and its relative energies in brackets. Diastereomers 2n (R = Et), 2a and 2m correspond to the protonated version of compounds I, IV and VIII, respectively. The energy shown for 2n is for the dimethyl ester (R = Me).
Figure 5
Figure 5
Transition states (TSs) proposed for the MIMIRC reaction between methyl acrylate and lithium enolate of substituted cycloalkanones. Substituent patterns will determine the stereochemistry of the obtained products.
Figure 6
Figure 6
Experimental (A,C) and simulated (B,D) 1H NMR spectra of 2h and 2i, respectively. Full 1H NMR simulated parameters were considered only for shown protons.
Figure 7
Figure 7
Experimental (A,C) and simulated (B,D) 1H NMR spectra of hydrindanes cis-2k and cis-2l, respectively. Full 1H NMR simulated parameters were considered only for the shown protons. (E–H) show the relative energies of conformers for cis-hydrindanes 2k and 2l, respectively, which illustrate the conformational influence of CO2Me and Me groups attached at C-3 and C-7, respectively. Structures inside rectangles belong to the most stable conformers.
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