Active Site Design in a Chemzyme: Development of a Highly Asymmetric and Remarkably Temperature-Independent Catalyst for the Imino Aldol Reaction

Abstract

Unusually robust: A remarkably temperature‐independent catalyst has been developed for the imino aldol reaction of imines derived from ortho‐aminophenols (see scheme). This catalyst is prepared from two equivalents of the VAPOL ligand and a zirconium tetraalkoxide. From a consideration of likely intermediates in the catalytic cycle it was deduced that a methyl substituent ortho to the phenol (R1) should enhance induction. This resulted in asymmetric inductions in excess of 98 % ee at room temperature as well as at 100°C. TMS=trimethylsilyl.

2,2′-Diphenyl-[3,3′-biphenanthrene]-4,4′-diol (VAPOL) and 3,3′-Diphenyl-[2,2′-binaphthrene]-1,1′-diol (VANOL)

“…It was observed that, there was a profound change in asymmetric inductions (>98% ee), when the ortho-position was methylated. 12 The VAPOL-zirconium catalyst is remarkably temperature independent giving an induction of >98% ee at 25 • C and at 100 • C. Moreover, the inductions could be maintained when 2 mol % of the catalyst was employed at 100 • C (Table 3, entries 6-10) and this is true for a variety of imines. Chiral β-amino esters can be then obtained from the corresponding imino-aldol products by treatment with five equiv of cerric ammonium nitrate in 1 M nitric acid (eqs 11 and 12).…”

“…The use of VAPOL as a chiral ligand was investigated and was compared with 6,6 -dibromoBINOL and BINOL based catalysts on the imino-aldol reaction mediated by zirconium (eq 10). 12 The catalyst is prepared by reaction of the ligand with 0.5 equiv of zirconium tetralkoxide in the presence of 0.6 equiv of N-methyl imidazole at room temperature for 1 h. It was found that VAPOL and 6,6-diboromoBINOL catalysts are superior to BINOL at −45 • C. 15 When the reaction was performed at room temperature, the asymmetric induction for VAPOL remained unchanged, while that for dibromoBINOL and BINOL decreased. Additionally, a series of imines 19 were prepared where the position of the methyl group on the arene ring was changed.…”

Enantiomeric impurities in chiral catalysts, auxiliaries, and synthons used in enantioselective syntheses. Part 4

“…[30][31][32][33][34] (3) A biaryl derived catalyst, used in the synthesis of chiral b-amino esters. 35,36 ( …”

Zirconium Tetraisopropoxide

“…20 (2), the resulting Lewis acid (3) catalyzes the addition of silyl ketene acetals to imines in high yield and enantiomeric excess (eqs 7 and 8). 21 In these reactions, the role of N-methylimidazole cannot be overlooked. Isolation of the catalyst prepared from Zr(O-i-Pr) 4 , N-methylimidazole and (R)-6,6 -dibromo-1,1 -bi-2-naphthol revealed that 2 equiv of N-methylimidazole are included in the complex.…”

“…22 These results are supported by NMR data of catalyst 3 in solution. 21 In a similar fashion, enantioselective addition of Et 2 Zn to imines was accomplished using Zr(O-i-Pr) 4 and peptide-based ligand, 4. 23 This reaction was successfully converted into a three-component, one-pot procedure, allowing imine formation to occur in situ followed by asymmetric addition of Et 2 Zn (eq 9).…”