Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

Abstract

The unimolecular nucleophilic substitution (S_N1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via S_N1 pathways. Here we report asymmetric catalysis of an S_N1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres.

Figure 1. Approaches to the enantiocontrolled construction of quaternary stereocenters

a, Traditional methods for synthesis of quaternary stereocenter-containing molecules employ stereochemically defined prochiral substrates. b, S_N1 approach to the construction of quaternary stereocenters. c, Enantioselective allylation of propargyl acetates using chiral squaramide catalysts and TMSOTf promoter. TMS, trimethylsilyl; Np, naphthyl.

Figure 2. Asymmetric allylation of propargyl acetates

a, Substrate scope. Reactions were run on 0.6 mmol scale with 0.1 equiv. 1a, 1.0 equiv. TMSOTf, and 6.0 equiv. allyltrimethylsilane in 0.1M Et₂O at −78 °C for 24 h. ^a Reaction time was 4 h. ^b Reaction time was 14 d. ^c NMR yield. b, Hammett plot of σ⁺ values of substituents in 2a–d versus enantiomer ratios obtained in the formation of 3a–d. c, Hammett plot of σ⁺ values on substituents in 2a–d versus relative reaction rates determined for each substrate. d, Linear free energy plot of the calculated polarizability of the aromatic rings in 2a, 2e–g versus enantiomer ratios obtained in the formation of 3a, 3e–g. e, The absolute configuration of (–)-3b was determined by X-ray crystallography (structure shown), following derivatization to triazole 5b; the configuration of all other products was assigned by analogy. Conditions: (a) TBAF (2.0 equiv.), THF, r.t.; (b) 4-nitrobenzylbromide (1.1 equiv.), NaN₃ (1.1 equiv.), CuSO₄ (0.1 equiv.), sodium ascorbate (0.2 equiv.), tBuOH/H₂O (1:2), 50 °C; (c) HCl (3M in Et₂O).

Figure 3. Kinetic data and catalytic cycle

a, Reaction progress kinetic analysis of the reaction of 2b with allyltrimethylsilane. 0.047M; [allyltrimethylsilane]₀ = 0.195M; different excess: [2b]₀= 0.08M; [allyltrimethylsilane]₀ = 0.315M. b, Proposed catalytic mechanism for the enantioselective allylation of propargyl acetates.

Figure 4. Mechanistic studies probing the post-rate-limiting steps of the allylation reaction

a, Crossover experiment establishing irreversible formation of alkene byproduct. b, Partial reaction with scalemic 2g demonstrating that allylation proceeds via a stereoablative mechanism rather than by a dynamic kinetic resolution process. c, Predicted and measured ¹²C/¹³C kinetic isotope effects (KIEs).