Dynamic Kinetic Resolution Enabled by Intramolecular Benzoin Reaction: Synthetic Applications and Mechanistic Insights

Abstract

The highly enantio-, diastereo-, and regioselective dynamic kinetic resolution of β-ketoesters and 1,3-diketones was achieved via a chiral N-heterocyclic carbene catalyzed intramolecular cross-benzoin reaction. A variety of tetralone derivatives bearing two contiguous stereocenters and multiple functionalities were liberated in moderate to excellent yields and with high levels of stereoselectivity (>95% ee and >20:1 dr in most cases). In addition, the excellent regioselectivity control for aryl/alkyl 1,3-diketones, and the superior electronic differentiation of 1,3-diarylketones were highlighted. Moreover, a set of new mechanistic rationale that differs with the currently widely accepted understanding of intramolecular benzoin reactions was established to demonstrate the superior preference of benzoin over aldol transformation: (1) A coexistence of competitive aldol and benzoin reactions was detected, but a retro-aldol-irreversible benzoin process performs a vital role in the generation of predominant benzoin products. (2) The most essential role of an N-electron-withdrawing substituent in triazolium catalysts was revealed to be accelerating the rate of the benzoin transformation, rather than suppressing the aldol process through reducing the inherent basicity of the catalyst.

Asymmetric Synthesis of Dihydronaphthalene‐1,4‐Diones via Carbene‐Catalyzed Stereodivergent Reaction

“…In the whole process, the benzoin reaction happens much faster than the racemization and aldol process, and both aldol and benzoin reactions are irreversible. This mechanism is sharply different to the previous reports …”

Asymmetric 1,6‐Conjugate Addition of para‐Quinone Methides for the Synthesis of Chiral β,β‐Diaryl‐α‐Hydroxy Ketones

“…Zhang's group presents the α ‐allylation of α ‐hydroxy ketones to afford chiral α ‐hydroxyl‐ γ,δ ‐unsaturated ketones containing vicinal stereocenters . More recently, Liu's group demonstrates the dynamic kinetic resolution of α ‐electron‐withdrawing groups substituted ketones to get α ‐hydroxy ketones bearing two contiguous stereocenters . However, the chiral α ‐hydroxy ketones with continuous stereogenic centers containing a diarylmethine has not been reported yet.…”

Asymmetric total synthesis of rotenoids via organocatalyzed dynamic kinetic resolution

“…In recent years, the kinetic resolutions of a series of racemates have been achieved via NHC organocatalysis [44][45][46][47][48] . Particularly, the elegance of NHC-catalyzed DKR processes have been demonstrated by the Scheidt, Johnson, Wang, Chi, Fang, and Biju groups, respectively [49][50][51][52][53][54][55][56][57][58] . Therefore, to test our hypothesis, we selected racemic 2a as model substrate for further studies (Fig.…”