The asymmetric Meerwein-Pondorf-Verley (MPV) reduction of prochiral ketones with 2-propanol catalyzed by chiral aluminum alkoxides

Tetra- through hexacoordinate alkylaluminum(III) Schiff base complexes were synthesized in high yield (70–90%) and investigated as catalysts for the Meerwein-Pondorf-Verley (MPV) reduction. In the reduction of cyclohexanone (1 equiv cyclohexanone and 4 equiv 2-propanol) the pentacoordinate aluminum complexes (10 mol%) were found to be inactive for the reaction. Although the tetra- and hexacoordinate complexes (10 mol%) exhibited little reactivity within the initial 24 h, over an extended period of time (72 h) high yield (75–80%) of cyclohexanol was obtained.; In the presence of excess 2-propanol (20 equiv), the pentacoordinate complexes were shown to be stable for over two days. However, when the tetracoordinate aluminum complex is treated with 2-propanol (10 equiv), the metal center was alcoholized from the ligand after 24 h to yield a mixture of free ligand and aluminum tris(isopropoxide) ((AlOiPr) ₃). The Al(OiPr)₃ generated from this alcoholysis reaction was soluble in organic solvents in contrast to commercial, oligomeric Al(OiPr)₃. Thus it is believed that the in situ-generated Al(OiPr) ₃ was soluble due to a lower aggregation state (low amount of bridging isopropoxy ligands) than commercial Al(OiPr) ₃. Rathke et al. have previously postulated that the bridging alkoxy ligands of the aluminum alkoxide reagents used in the MPV reduction were catalytically ineffective. Hence, the efficiency of in situ-generated Al(O iPr)₃ in the MPV reduction was tested.; It was found that simple alkylalumiunm reagents (AlMe₃ or AlMe₂Cl) dealkylated in the presence of excess 2-propanol (40 equiv) and formed low-aggregated aluminum alkoxides that were soluble in organic solvents. Treatment of this reaction mixture with carbonyl substrates (10 equiv) produced the corresponding primary and secondary alcohols in high yield (50–99%) under mild conditions.; This aluminum-catalyzed MPV reaction was also modified for the asymmetric synthesis of chiral alcohols. Treatment of prochiral, aromatic ketones (10 equiv) with a solution of enatiopure BINOL (1 equiv), AlMe₃ (1 equiv), and 2-propanol (40 equiv) yields chiral alcohols in high yield (50–99%) and good ee (50–80%) after 16 h. Although the asymmetric aluminum-catalyzed MPV reduction has been sought after for over four decades to date, this thesis reports the first example that is initiated by a chiral aluminum catalyst and an achiral hydride source (2-propanol).