Origin of Stereoselectivity in a Chiral N-Heterocyclic Carbene-Catalyzed Desymmetrization of Substituted Cyclohexyl 1,3-Diketones

Abstract

The mechanism and stereoselectivity in a chiral N-heterocyclic carbene-catalyzed desymmetrization of a 1,3-diketone is established by using density functional theory computations. The Breslow intermediate formation is identified to involve Hunig's base-assisted proton transfer. The relative energies of stereoselectivity-determining intramolecular aldol cyclization transition states reveal that in the most preferred mode the re-face of enolate adds to the si-face of carbonyl leading to a tricyclic lactone with a configuration (2aS,4aS,8'S) in excellent agreement with previous experimental reports.

Characterization of the Key Intermediates of Carbene‐Catalyzed Umpolung by NMR Spectroscopy and X‐Ray Diffraction: Breslow Intermediates, Homoenolates, and Azolium Enolates

“…In line with results obtained by Sunoj et al, [15] intramolecular proton transfer appears feasible at room temperature. Note that the diene moiety in the computed optimized structure of the diamino dienol 3 h is only slightly distorted, as evidenced by the dihedral angle C2-C6-C21-C23 of 1648 (cf.…”

“…Again, crystallization from benzene was successful, and the X-ray crystal structure of the azolium enolate 4 b is shown in Figure 2 d. As in the case of the azolium enolate 4 a, the enolate partial structure is almost planar, with a dihedral angle O1-C6-C21-C22 of 3.4(9)8 and 1.0(10)8, respectively (two independent molecules per unit cell). We were delighted to see that the Z configuration of the enolate typically assumed (based on calculations) for reaction intermediates of this type [15,17,18] is indeed present in the crystal structures of both 4 a and 4 b, and thus proven experimentally for the first time. Close inspection of the crystal structure of 4 b furthermore indicates that the enolate C-H hydrogen atom is oriented towards the plane of the "left-hand" benzene ring.…”

“…In the latter, the g-position (b-position of the former enal) carries a partial negative charge, and the diamino dienols II consequently react as homoenolate equivalents. A subsequent OH-Cg proton shift [15] in the diamino dienol II leads to the azolium enolate III. In the latter, the b-position (aposition of the former enal) carries a partial negative charge, and the azolium enolates III are therefore considered as enolate equivalents.…”

Catalytic kinetic resolution of a dynamic racemate: highly stereoselective β-lactone formation by N-heterocyclic carbene catalysis

“…66,122–136 This study builds on these earlier reports and reveals not only an unusual method of stereocontrol, but also an unprecedented mechanism. The computed catalytic cycle and the reaction coordinate diagram are shown in Figure 1.…”

Charakterisierung der Schlüsselintermediate von carbenkatalysierten Umpolungen durch Kristallstrukturanalyse/NMR‐Spektroskopie: Breslow‐Intermediate, Homoenolate und Azoliumenolate

“…[13,14] Hierbei wird wiederum ein Breslow-artiges Intermediat als zentrales Schlüsselintermediat angenommen: In diesem Diaminodienol II trägt die g-Position (b-Position des vormaligen Enals) eine negative Partialladung, sodass die Diaminodienole II als Homoenolat-¾quivalente reagieren. Durch eine nachfolgende OH-Cg-Protonenwanderung [15] kann das Diaminodienol II zu dem Azoliumenolat III tautomerisieren. In letzterem ist die b-Position (a-Position des vormaligen Enals) partiell negativ geladen, sodass die Azoliumenolate III als Enolat-¾quivalente betrachtet werden.…”