A computational study was performed to explore the possible mechanisms of β-isocinchonine-catalyzed asymmetric C(sp2)-H allylation of trisubstituted allenoates using Morita-Baylis-Hillman (MBH) carbonates for synthesis of axially chiral tetrasubstituted allenoates. The calculated results indicate that the most energetically favorable pathway includes (1) nucleophilic attack on MBH carbonate by β-isocinchonine, (2) BocO- dissociation, (3) stereoselective formation of the C-C bond, and (4) regeneration of the catalyst. By tracking the orbital overlap/interaction changes, the half shoulder-to-head orbital overlap mode can be smoothly switched to a head-to-head orbital overlap mode for the key C-C σ bond formation, which is also identified as the stereoselectivity-determining process. Further distortion/interaction, noncovalent interaction (NCI), and atom-in-molecule (AIM) analyses demonstrate that C-H···O and C-H···π interactions should be key for controlling the axial and central chirality. This work would be useful for rational design of organocatalytic allylic alkylation reactions for synthesis of axially chiral compounds in the future.

Insights into Organoamine-Catalyzed Asymmetric Synthesis of Axially Chiral Allenoates Using Morita-Baylis-Hillman Carbonates and Trisubstituted Allenoates: Mechanism and Origin of Stereoselectivity.

Aldol addition of α-triisopropylsilyl-α-diazoacetone (TIPS-diazoacetone), promoted by excess lithium diisopropylamide (LDA), was developed and applied to the synthesis of original C-TIPS diazoaldols, C-TIPS diazoketols, and a related Mannich-type product. An unprecedented mechanistic pathway has been proposed, involving a lithiated triazene intermediate resulting from the nucleophilic addition of LDA on the diazo moiety, supported by experimental results and DFT calculations.

Sylvain Henrion

Papers

TIPS-Diazoacetone Aldol Addition: Mechanistic Aspects and Contribution to the Synthesis