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

Styrene oxide synthons

Chiral amino alcohol moieties (ArCH(O)CH2N) account for a large proportion of secondary alcohol synthons found in clinical drug candidates. For example, this category accommodates the adrenoreceptor modulators used for treating asthma and related respiratory disorders, and these drug compounds are typically made by coupling a chlorohydrin (ArCH(OH)CH2Cl) or styrene oxide with an amine component. In one example, the authors needed to develop a synthesis of (R)-3-chlorostyrene oxide on a multikilogram scale. (R)-3-Chlorostyrene oxide is a potential synthon for several clinical candidates, including Solabegron (3'-[2-[2(R)-(3-chlorophenyl)-2-hydroxyethylamino]ethyl amino]biphenyl-3-carboxylic acid hydrochloride) and SR-58611 (N-[7-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydronaphth-2(S)-yl]-2(R)-(3-chlorophenyl)-2-hydroxyethanamine hydrochloride).


Figure 2: Different approaches to the preparation of (R)-styrene oxides. (FIGURE IS COURTESY OF THE AUTHOR)
There are four main methods for preparing chiral styrene oxides: asymmetric expoxidation, two approaches based on kinetic resolution, and asymmetric reduction (see Figure 2). The kinetic resolution approaches (see Figures 2b and 2c) are likely to be the least favored because of the 50% theoretical yield of the resolution step and the extra step that is required beyond the corresponding asymmetric approach. Asymmetric epoxidation of a styrene (see Figure 2a) is the most direct, but biological approaches to this reaction suffer from both low yields and volumetric productivity, and the chemocatalytic approaches that may be applied are not presently feasible on commerical scale. The most attractive option is asymmetric reduction of a phenacyl halide followed by ring closure (see Figure 2d). Several chemocatalysts and biocatalysts are available for the reduction, and the final step appears facile. For (R)-3-chlorostyrene oxide, the authors decided to focus on the biocatalytic approach due to a simpler patent landscape as well as past work suggesting that catalytic asymmetric hydrogenation of the chloroketones is difficult to accomplish with both high selectivity and catalyst productivity.

Screening of 3-chlorophenacyl chloride against CPS–Chirotech's collection of ADH enzymes revealed several hits, the best of which were investigated further. One enzyme that was available at scale gave a highly enantioselective bioreduction of 3-chlorophenacyl chloride with a conversion of > 90%. This reaction was optimized to proceed at 100 g/L substrate concentration to give 2-chloro-1-(3-chlorophenyl)ethanol of > 99.5% enantiomeric excess (ee) and > 90% yield. Cofactor recycling was achieved using glucose dehydrogenase, thereby allowing for the use of a concentration of 0.25 mM NADP+ in the reaction. The halohydrin product was used directly in the next step and cyclized using a base to give (R)-3-chlorostyrene oxide of > 99% ee. This material was purified by distillation to give a final product of > 99% purity. This procedure is highly amenable to large-scale manufacture and was readily scaled up using standard equipment to several 100-kg scale.

Asymmetric hydrogenation of ketones

Catalytic asymmetric hydrogenation of prochiral ketones is another efficient method to prepare secondary alcohols. Two efficient technologies have been developed in recent years. The first is pressure hydrogenation by which diphosphine ruthenium diamine complexes catalyze the hydrogenation of simple ketones with gaseous hydrogen (2). The precatalysts require base activation, with the resulting catalysts being among the most highly active systems developed. The second approach is catalytic transfer hydrogenation, by which monosulfonated diamino ruthenium arene complexes use hydrogen donors such as propan-2-ol and formic acid as hydrogen sources (3). Reaction conditions are mildly acidic, thus allowing the hydrogenation of base-sensitive ketones. Transfer hydrogenation does not require pressure, but catalyst loadings are higher. In both cases, either isomer of the alcohol can be prepared depending on the isomer of the catalyst used. CPS–Chirotech has access to both technologies via a license from the Japan Science and Technology Corporation (Tokyo). This relationship allows CPS–ChiroTech to develop processes for complementary substrates.


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