Asymmetric Routes to Chiral Secondary Alcohols - Pharmaceutical Technology

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Asymmetric Routes to Chiral Secondary Alcohols
The authors describe several examples of using asymmetric hydrogenation and biocatalysis for synthesizing several secondary alcohol compounds.

Pharmaceutical Technology
pp. s6-s13

1-Aryl alcohols

1-Aryl alcohol synthons are often used as intermediates in the production of active pharmaceutical ingredients. Access to the prochiral ketone starting material is straightforward, and many are commercially available at low cost, thereby making asymmetric reduction of the ketone an attractive method to synthesize these intermediates. Asymmetric hydrogenation using catalysts derived from PhanePhos (i.e., (R) or (S)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane) is particularly efficient for these substrates in terms of enantioselectivity, conversion, and the amount of catalyst required (low to modest hydrogen pressure is required, and a ratio of molar substrate to catalyst (S/C ratio) as high as 2.4 million has been demonstrated). CPS–Chirotech has ready access to these catalysts at commerical scale, and therefore was the authors' method of choice when preparing 1-aryl alcohols.

Figure 3: Asymmetric reduction approach to (S)-1-(4-fluorophenyl)ethanol. S/C is the molar substrate to catalyst ratio. iPrOH is propan-2-ol, and t-BuOK is potassium tert-butoxide. GC is gas chromatography, and ee is enantiomeric excess. (FIGURE IS COURTESY OF THE AUTHOR)
(S)-1-(4-Fluorophenyl)ethanol was required at multikilogram scale (4). [((S)-xylyl-PhanePhos)Ru((R,R)-DPEN)Cl2] (where DPEN is 1,2-diphenylethane-1,2-diamine) precatalyst was shown to proceed at a S/C ratio of 100,000 giving alcohol of 99% ee (see Figure 3). Wiped-film distillation of the ketone prior to reaction is required to achieve these low catalyst loadings. The chiral alcohol is obtained as a colorless oil of 99% purity and 99% ee in 93% yield with no metal contamination from the catalyst.

1-Aryl-2-imidazol-1-yl ethanols

Figure 4: Asymmetric transfer hydrogenation of imidazolyl acetophenones. SC is the molar substrate to catalyst ratio, and ee is enantiomeric excess. (FIGURE IS COURTESY OF THE AUTHOR)
Two imidazolyl acetophenone substrates were examined for reduction via catalytic asymmetric hydrogenation (see Figure 4) (5). Pressure hydrogenation was initially examined using diphosphine ruthenium diamine complexes; however, no significant conversion was observed under various conditions. When standard conditions for catalytic asymmetric transfer hydrogenation using [(R,R)TsDPENRu (cymene)Cl] as the catalyst precursor were applied, both ketones were reduced in high conversions and ee. Reaction conditions were optimized so that (S)-1-phenyl-2-imidazol-1-yl ethanol could be produced in 97% ee in quantitative yield and (S)-1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethanol in 91% ee in 98% yield.


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