Boosting the Enantioselectivity of Conjugate Borylation of α,β-Disubstituted Cyclobutenones with Monooxides of Chiral C2 -Symmetric Bis(phosphine) Ligands

Abstract

Chiral bis(phosphine) monooxides (BPMOs) derived from C₂ -symmetric bis(phosphines) have been found to induce superior levels of enantioselection in copper-catalyzed conjugate borylation of α,β-disubstituted cyclobutenones. More precisely, enantiomeric excesses as well as chemical yields are exceedingly high with (R,R)-Bozphos as the chiral ligand while these values are low with parent (R,R)-Me-Duphos. A similar yet less pronounced effect was seen in the corresponding 1,6-addition to para-quinone methides.

Keywords: asymmetric catalysis; conjugate borylation; copper catalysis; cyclobutenones; hemilabile ligands.

Scheme 1

Enantioselective conjugate borylation of α,β‐disubstituted cyclobutenones under copper catalysis with chiral bis(phosphines) and mixed phosphine‐phosphine oxides as ligands, respectively. pin=pinacolato.

Scheme 2

Ligand identification. All reactions were performed on a 0.10 mmol scale. Yields were determined by ¹H NMR spectroscopic analysis of the crude reaction mixture by the addition of CH₂Br₂ as an internal standard. Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase after isolation of the major diastereomer. Diastereomeric ratios were estimated by ¹H NMR spectroscopy. X=lone pair or O.

Figure 1

Overview of the comparison between the bis(phosphines) and the corresponding BPMOs. ▪ for bis(phosphine); ▴ for bis(phosphine) monooxide; • for bis(phosphine) dioxide.

Scheme 3

Scope of the enantioselective, conjugate borylation of cyclobutenones. All reactions were performed on a 0.20 mmol scale. Yields are isolated after flash chromatography on silica gel; yields in parentheses were determined by ¹H NMR spectroscopic analysis of the crude reaction mixture by the addition of CH₂Br₂ as an internal standard. Enantiomeric excesses were determined by HPLC analysis on chiral stationary phases. Diastereomeric rations were estimated by ¹H NMR spectroscopy. [a] 73 %, 98 % ee, d.r.=94 : 6 on a 2.0 mmol scale. [b] Run for 1 h. [c] No baseline separation in the HPLC trace.

Scheme 4

1,6‐Borylation of a para‐quinone methide. Both reactions were performed on a 0.10 mmol scale. Yields are isolated after flash chromatography on silica gel. Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase.