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. 2012 Mar 1;3(3):2346-2350.
doi: 10.1039/C2SC20331F.

A Computational Study of the Origin of Stereoinduction in NHC-Catalyzed Annulation Reactions of α,β-Unsaturated Acyl Azoliums

Eirik Lyngvi  1 , Jeffrey W Bode, Franziska Schoenebeck
Affiliations

A Computational Study of the Origin of Stereoinduction in NHC-Catalyzed Annulation Reactions of α,β-Unsaturated Acyl Azoliums

Eirik Lyngvi et al. Chem Sci. .

Abstract

The origin of stereoselectivity of NHC-catalyzed annulation reactions of ynals and stable enols was studied with Density Functional Theory. The data suggest that the C-C bond formation is the stereo-determining step. Only the deprotonated pathway (containing an oxy anion and overall neutral species) was found to give rise to discrimination of the competing stereoisomers. This is due predominantly to electrostatic repulsion of the β-stabilizing enolate functionality with the π-cloud of the aryl group in the NHC-catalyst.

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Figures

Figure 1
Figure 1
Proposed mechanism of annulations reaction involving a Claisen rearrangement as key C-C bond forming event.
Figure 2
Figure 2
Minimum energy conformations of the hemiacetal intermediates (9) derived from keto ester 3 calculated at ωB97XD/6-31G(d) (toluene). The R and S stereochemical descriptors refer to the carbon highlighted in green.
Figure 3
Figure 3
Claisen chair TSs, calculated at M06-2X/6-31++G(d,p) (toluene)//B3LYP/6-31G(d) (toluene). The R and S stereo descriptors refer to the carbon highlighted in green. ΔΔH‡ given in Table 2.
Figure 4
Figure 4
Transition states for the deprotonated, zwitterionic pathway for keto ester system 3. The R- and S-stereochemical descriptors refer to the carbon highlighted in green. ΔΔH‡ = 1.8 kcal/mol [at M06-2X/6-31++G(d,p) (toluene)//ωB97XD/6-31G(d)(toluene)].
Figure 5
Figure 5
S- and R-TSs for the protonated (=TS, top) and deprotonated (=TS*, bottom) pathways for kojic acid system 4. The R- and S-stereochemical descriptors refer to the carbon in green. ΔΔH‡ = 2.4 kcal/mol [at M06-2X/6-31++G(d,p) (toluene)//ωB97XD/6-31G(d) (toluene)] for deprotonated pathway. Energies in kcal/mol at 313.15 K; CPCM (toluene) B3LYP/6-31G(d) enthalpy given in parenthesis.
Figure 6
Figure 6
Electrostatic potential surfaces of R- (top) and S-chair (bottom) Claisen TSs* for the deprotonated pathway for kojic acid system 4, calculated at B3LYP/6-31G* [range: −4.885e-2 to 7.885e-2] with red corresponding to negative and blue to positive charge density.
Scheme 1
Scheme 1
Annulation reactions by Bode et al.
See this image and copyright information in PMC

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