Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from α,β-unsaturated aldehydes for enantioselective Diels–Alder reactions

Abstract

The catalytic generation of chiral ester enolate equivalents from α,β-unsaturated aldehydes with chiral N-hetereocyclic carbene catalysts makes possible highly enantioselective hetero-DielsAlder reactions. The reactions proceed under simple, mild conditions with both aliphatic and aromatic substituted enals as substrates. Previous attempts to employ these starting materials as enolate precursors gave structurally different products via catalytically generated homoenolate equivalents. Critical to the success of the enolate generation was the strength of the catalytic base used to generate the active N-heterocyclic carbene catalyst. To complement these studies, we have investigated the enolate structure using computational methods and find that it prefers conformations perpendicular to the triazolium core.asymmetric synthesis | catalysis | reaction mechanism

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

“…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.…”

“…[27] Note that the above g-protonation of the diamino dienol 3 g to the azolium enol 5, in an intermolecular fashion by an external proton source (here TFA), corresponds to the decisive step in the mechanism of redox esterification of a,b-enals formulated by Bode et al [17,25] and by Scheidt et al [28] However, at room temperature and throughout the 12 h of our measurement, the azolium enol 5 did not show any tendency to tautomerize to the corresponding acyl azolium cation, the subsequent step typically formulated for redox esterification. [17,25,28] In our crystallization experiments, the azolium enolate 4 a was identified as the product resulting from the interaction of the carbene SIPr (1) with a-methyl E-cinnamic aldehyde 2 h (X-ray structure of 4 a: Note that the diamino dienol 3 g, derived from the same carbene SIPr (1) and E-cinnamic aldehyde (2 g), that is, just lacking the a-methyl group, did not undergo tautomerization to an azolium enolate in solution under the same conditions. When 2 equiv of methanol was added to the 3 h/4 a mixture present after 10.5 h reaction time, the concentration of the diamino dienol 3 h dropped sharply, with concomitant regeneration of a-methyl E-cinnamic aldehyde (2 h) and formation of the methanol adduct of SIPr (6, Figure 4 b).…”

“…such that one pathway is favored over the other. [16][17][18] In sharp contrast to their pivotal character in conjugate umpolung, no homoenolate II appears to have ever been characterized. Azolium enolates III have been accessed by addition of carbenes to ketenes.…”

Organocatalysis

“…Kaeobamrung et al (9) developed conditions by which they are able to access chiral ester enolate intermediates, in preference to homoenolates, through the condensation of chiral N-heterocyclic carbene catalysts onto α,β-unsaturated aldehydes. This selectivity, governed by the identity of the catalytic base used, promotes highly enantioselective hetero-Diels-Alder reaction over homoenolate-mediated cyclopentene formation (9). Alternatively, Filloux et al (10) used an achiral N-heterocyclic carbene catalyst in combination with a chiral prolinol derivative to affect an asymmetric cascade involving a Michael addition and subsequent Stetter reaction sequence, promoted by their respective catalysts.…”

“…This section highlights examples from the fields of iminium, enamine, dienamine, and singly occupied molecular orbital (SOMO) catalysis, in which mechanistic insight, reaction partner scope, or product accessibility has been expanded in significant ways. The next classification of articles is somewhat broader and includes those modes of activation that are catalyzed by nonamine-centered Lewis bases (7)(8)(9)(10). Although there are fewer established modes of generic activation that fall into this category, the potential for reaction discovery in this arena is evident from the highlighted examples, which represent quite disparate modes of activation arising from phosphorus, chalcogen, and N-heterocyclic carbene catalysts.…”