Enantioselective reduction processes

The control of reactivity to achieve specific syntheses is one of the overarching goals of organic chemistry. In the decade since the publication of the third edition, major advances have been made in the development of efficient new methods, particularly catalytic processes, and in means for control of reaction stereochemistry. For example, the scope and efficiency of palladium- catalyzed cross coupling have been greatly improved by optimization of catalysts by ligand modification. Among the developments in stereocontrol are catalysts for enantioselective reduction of ketones, improved methods for control of the... 

Several synthesis patents are reported in the literature for brinzolamide [7-10]. The process reported in references 8-10 represents an improvement over earlier processes and a schematic of this synthesis process is shown in Scheme 1. In this scheme, brinzolamide is produced in 8 steps starting fiom dichloroacetyl-thiophene(I). Chirality is introduced by enantioselective reduction of a bromoketone (VI) using a chiral reagent (+)-(i-chlorodi-... 

The enantioselective reduction of ketones using oxazaborolidine-borane complexes is a useful synthetic route to chiral alcohols (equation 63). Additives such as simple alcohols have been found to enhance the enantioselectivity of the process, and the reaction has been used in the large-scale synthesis of an important drug with anti arrhythmic properties249. 

In order to preserve enzyme activity during the reaction process, special attention must be paid on the substrates that cause direct or indirect enzyme inactivation. Since peroxide is a strong peroxidase inhibitor, a low peroxide/enzyme ratio must be selected. When treating phenolic compounds, the polymeric products obtained from the action of peroxidases also cause enzyme inactivation [9]. If the enzyme is inactivated, not only is the reaction hindered but, sometimes, there is a direct oxidation of the substrate by the peroxide, which causes an enantioselective reduction in some synthetic reactions [10, 11]. In these cases, an appropriate enzyme concentration and usually an adequate enzyme addition strategy are considered [8],... 

Potentially useful asymmetric reduction using boron-based reducing agents involves stoichiometric and catalytic processes.1060,1061 Of the stoichiometric reagents reported, those that are the most promising for the highly enantioselective reduction of various functionalized ketones are 532,1062 533,1062 48a,1063-1065 534,1063,1066-1071 anc 535 (Scheme 41).1061... 

In an alternate process, enantioselective microbial reduction of 6-oxobus-pirone (19, Fig. 18.6) to either (R)- and (.S )-6-hydroxybuspirone was described. About 150 microorganisms were screened for the enantioselective reduction of 19. Rhizopus stolonifer SC 13898, Rhizopus stolonifer SC 16199, Neuros-pora crassa SC 13816, Mucor racemosus SC 16198, and Pseudomonas putida SC 13817 gave >50% reaction yields and >95% ee s of (,S )-6-hydroxybuspi-rone. The yeast strains Hansenula polymorpha SC 13845 and Candida maltosa SC 16112 gave (R)-6-hydroxybuspirone in >60% reaction yield and >97% ee (Patel et aL, 2005). 

As before, the enzymatic reduction is the method of choice for the enantioselective reduction of purely aliphatic ketones and only in the case of fert-butyl methyl ketone could the bench mark of 90 % ee be crossed by the transfer hydrogenation and both other catalytic hydrogenation methods. However, substantial success in the hydrogenation of aromatic ketones by transition metal complexes with respect to the enantioselectivity and the activity (TON) strengthens the confidence that further progress is possible, enabling us to use some advantages of these nonenzymatic processes for extended application in the near future, for example in the facilitation of product isolation. 

Itsuno s amino alcohol (70), prepared from L-valine, is an extremely efficient auxiliary for enantioselective reduction of aryl alkyl ketones using BH3. The corresponding alcohols are obtained in up to 100% ee using BH3 and 0.5 equiv. of (70) in THF at 30 °C. Reduction of dialkyl ketones affords (R)-carbinols in 55-73% ee. Halomethyl t-butyl ketones are also converted to the corresponding (5)-carbinols in high optical purity (Scheme 15). Immobilized amino alcohol (70) permits reduction in a continuous flow system. 1-Phenylpentanol of 90% ee was prepared by this catalytic process in almost 1000% chemical yield based on the quantity of chiral auxiliary used. ... 

The synthetic application of redox enzymes (oxidoreductases), especially in the field of enantioselective reductions and chemo-, regio-, and stereoselective oxidations, is very important [7,8] and covers a wide range of processes, as listed ... 

Yonehara et al. [16] recently extended the scope of surfactant-promoted enantioselective hydrogenation on simple enamides. With respect to other reductive processes conducted in the presence of surfactants, it is noteworthy that the efficiency of an artifical nitrogenase model was selectively very enhanced by the addition of phospholipids [17]. 

A related rhodium catalyzed enantioselective reductive coupling of acetylene to N arylsulfonyl imines leads to the formation of (Z) dienyl allylic amines (Scheme 1.28) [105]. The scope of the reaction is comparable to that demonstrated for the analogous iridium catalyzed process. The reaction between the acetylene and rhodium leads to the oxidative dimerization of acetylene to form a cationic rhoda cyclopentadiene that then reacts with the imine to generate the product after the protolytic cleavage and reductive elimination. 

The first reported example of enantioselective reductive amination was that of Blaser et al. at Solvias (Scheme 7.7) [2]. At the time, 1999, they were still tweaking the industrial process for metolachlor, the active ingredient of the herbicide Dual , and examined its synthesis via the reductive amination of methoxyacetone with 2 methyl 5 ethyl aniline (MEA, limiting reagent). Working at the 100 mmol scale, they showed that a very low loading of an Ir xyhphos complex, under 80 bar (1160 psi) H2, neat, 50 °C, and 14 h, were optimal. By doing so, a 76% ee with full conversion was achieved. 

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