Convenient General Asymmetric Synthesis of Roche Ester Derivatives through Catalytic Asymmetric Hydrogenation: Steric and Electronic Effects of Ligands

Abstract

An efficient and concise asymmetric hydrogenation of acrylate esters promoted by the cat-+ BF 4 À is reported. A full investigation of the effects of catalyst precursors, solvents, temperature, hydrogen pressure, substrates as well as steric and electronic properties of ligands was carried out. The corresponding valuable Roche ester derivatives were obtained in good to excellent isolated yields and high enantioselectivities under mild conditions. The robustness and practicability of this highly enantioselective hydrogenation was demonstrated by the synthesis of the 3-hydroxy-2-methylpropanoic acid tert-butyl ester on a multigram scale, resulting in excellent yield and ee up to 94%.

Asymmetric bioreduction of activated alkenes to industrially relevant optically active compounds

“…Prominent routes for its preparation include enzymatic oxidation of prochiral diols (Molinari et al, 2003) or the transition metal-catalyzed asymmetric hydrogenation of acrylate esters using Rh- (Holz et al, 2008; Qiu et al, 2009; Wassenaar et al, 2008) or Ru-catalysts (Pautigny et al, 2008). A biocatalytic equivalent was shown using ene-reductases.…”

Asymmetric Synthesis of (R)‐3‐Hydroxy‐2‐methylpropanoate (‘Roche Ester’) and Derivatives via Biocatalytic CC‐Bond Reduction

“…The latter is a popular chiral building block for the synthesis of vitamins (e.g., a-tocopherol [6] ), fragrance components (e.g., muscone [7] ), and antibiotics (e.g., calcimycin, [8] palinurin, [9] rapamycin, [10] 13-deoxytedanolide, [11] dictyostatin [12] ) and natural products (e.g., spiculoic acid A [13] ). Classical methods for its preparation include the diastereoselective addition of non-racemic alcohols as chiral auxiliaries, [14] the transformation of a chiral homoallylic acetate [15] or involve aldol condensation [16] and -most prominent -the transition metal-catalysed asymmetric hydrogenation of acrylate esters using Rh [17] (ee up to 99%) or Ru [18] (ee up to 94%). For the biocatalytic synthesis of the Roche ester only few examples are reported: the stereoselective oxidation of 2-methyl-1,3-propanediol by Gluconobacter and Acetobacter spp.…”

An Expedient and Practical Approach to Functionalized 3-Aza-, 3-Oxa-, and 3-Thiabicyclo[3.3.1]nonane Systems

“…The MBH reaction was chosen because it has already demonstrated high yields and scalability in similar syntheses. 13,14 Benzyl is a protecting group for CO 2 H, which is easily cleaved without epimerization at position 7 during the final transformations.…”

“…Column chromatography was performed using silica gel (230-400 mesh) as the stationary phase. 1 H, 13 C NMR, and all 2D NMR spectra were recorded at 499.9 or 400.4 MHz for 1 H and 124.9 or 100.4 MHz for 13 C. Chemical shifts are reported in ppm downfield from TMS ( 1 H, 13 C) as an internal standard. Mass spectra were recorded either on an Agilent 1100 LC/MSD SL instrument by chemical ionization (CI) or on a GCMS instrument with electron impact ionization (EI).…”