Organocatalytic asymmetric synthesis of Si-stereogenic silacycles

Abstract

A strong and confined Brønsted acid catalyzed enantioselective cyclization of bis(methallyl)silanes provides enantioenriched Si-stereogenic silacycles. High enantioselectivities of up to 96.5:3.5 er were obtained for a range of bis(methallyl)silanes. NMR and ESI-MS studies reveal that the formation of a covalent adduct irreversibly inhibits turnover. Remarkably, we found that acetic acid as an additive promotes the collapse of this adduct, enabling full turnover. Experimental investigation and density functional theory (DFT) calculations were conducted to elucidate the origin of this phenomenon and the observed enantioselectivity.

Fig. 1. Biologically active Si-stereogenic silanes and organocatalytic synthesis of Si-stereogenic silanes.

a Biological activity of Si-stereogenic silacycles. b Our previous work; Organocatalytic synthesis of Si-stereogenic silyl ethers. c This work; organocatalytic synthesis of Si-stereogenic silacycles. d Yu’s work; organocatalytic synthesis of Si-stereogenic silacycles.

Fig. 2. Substrate scope of the reaction ^a.

^aReactions were carried out with 0.1‒0.2 mmol of substrate 1, catalyst 6d (5 mol %), acetic acid (1 equiv.) in toluene at the specified temperature for the specified time. Yields are for the isolated compounds. The enantiomeric ratios (er) were determined by HPLC analysis. ^bPivalic acid was used instead of acetic acid.

Fig. 3. Control experiments.

a Effect of catalyst acidity on the stability of silacycle. b Effect of temperature on the stability of silacycle. c Effect of allyl substituent on the reactivity.

Fig. 4. Mechanistic studies.

a ³¹P NMR experiments. b ESI-MS experiments.

Fig. 5. Proposed catalytic cycle and computational studies.

a Proposed catalytic cycle. b Free energy profile of the catalytic cycle calculated at CPCM(Toluene)-ωB97M-V/(ma)-def2-TZVPP//r²SCAN-3c level of theory. The thermal corrections were calculated at 173.15 K. The energy profile leading to the major enantiomer is depicted in black, and the one to the minor enantiomer is in red. The calculated yield and enantiomeric ratio are given by the ratio between 2, 2’, and 8 + 8’ based on the Boltzmann distribution (see the Supplementary Information for details). c Visualized structure of TS4 leading to the covalent adduct 8. Substrate is depicted in magenta.