Aliphatic 3-keto ester reduction

R) -specific ADH from L. kefir was used for the reduction of various ketones to the corresponding secondary alcohols. Aliphatic, aromatic, and cyclic ketones as well as keto esters were accepted as substrates. The activities achieved with several substrates were compared with the activity obtained with the standard substrate of ADH, acetophenone (Fig. 2.2.4.4). As the figure shows, recombinant LK-ADH has a very broad substrate spectrum, including many types of ketones. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

The following tables are intended to include all the reductions with aluminum alkoxides which were reported prior to February, 1943, although some examples doubtless have been overlooked. Table I lists the reduction of aldehydes, which have been subdivided into (a) aliphatic aldehydes and (b) alicyclic and aromatic aldehydes. Table II lists the reduction of ketones, which have been classified as (a)-satu-rated and unsaturated aliphatic ketones, (b) aromatic ketones, (c) alicyclic ketones, (d) unsaturated alicyclic and aromatic ketones, (e) a- — halogen substituted ketones, (f) diketones, (g) protected diketones, (h) alcoholic and phenolic ketones (and ethers or esters of these), and (i) keto esters. 

The keto group of a keto ester may be preferentially reduced by catalytic hydrogenation. Excellent yields of hydroxy esters are obtained. Copper-chromium oxide catalyst has been employed in the preparation of methyl p-(a-hydroxyethyl)-benzoate and several aliphatic -hydroxy esters. The last compounds have also been made by hydrogenation over nickel catalysts.Substituted mandelic esters are prepared by catalytic reduction of aromatic a-keto esters over a palladium catalyst. Similarly, platinum oxide and copper-chromium oxide have been used in the aliphatic series for the preparation of the a-hydroxy diester, diethyl... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

The versatility of the APG4 reduction system is further exemplified by the use of P-keto esters as substrates. 3-Oxobutyrates involving methyl, ethyl, t-butyl, or neopentyl esters are reduced to the (S)-hydroxyesters with > 99% ee and in quantitative yield. Moreover, simple aliphatic ketones from 2-octanone to 2-undecanone, as well... 

Yang and Listhave developed Cu(OTf)2/Bn-BOX (32)-catalyzed asymmetric transfer hydrogenation ofa-keto esters (407) with Hantzsch ester (408) (Scheme 17.92) [129]. Under optimized conditions the desired a-hydroxy esters (409) are isolated in good to excellent yields with good enantioselectivity. It is interesting to note that although the Cu(OTf)2/Bn-BOX (32) catalyzes the reduction efficiently, Cu(OTf)2 complexes of other common bisoxazolines result in poor reactivity. The protocol is effective for both aromatic and aliphatic a-keto esters, but reduced enantioselectivities are observed with aliphatic a-keto esters. 

The intermolecular asymmetric reduction of various keto esters with (-)-DIP-Cl has also been investigated. Interestingly, the opposite stereochemistry is observed for the products from the reduction of aromatic and aliphatic a-keto esters (Scheme 23.55). Due to facile enolization, reductions of P-keto esters are unsuccessful. 

The reductions of y-keto esters and 5-keto esters are also facile using (-)-DIP-Cl. The reductions provide high % ee for the reduction of aryl ketones, while low % ee are observed in the case of aliphatic ketones (Scheme 23.56). The products obtained, y-hydroxy esters and 8-hydroxy esters, are valuable intermediates they can be readily converted to the corresponding lactones by treatment with a catalytic amount of trifluoroacetic acid. 

SCHEME 23.55 Reduction of aromatic and aliphatic a-keto esters using (-)-DIP-Cl. 

The reductions of aliphatic p-keto esters by yeasts are well documented [13,21, 67,68,292,293]. The general feature for these reductions is that the absolute configuration... 

Isotopic atoms have been introduced into amino acids or molecules employed in the synthesis of amino acids, by (a) catal]rtic addition of D to carbon-carbon double bonds (161, 459, 758, 852), (b) methylation with trideuteromethyliodide (831, 833), (c) syntheses of deuteromalonio ester derivatives from u-phenyl deuteroalkyl bromides and malonic ester (626), (d) preparation of deutero amino acids by reaction of amino acids with deuterosulfuric acid (576, 667, 692, 758, 805, 852), (e) catalytic reduction with DgO and amination of a-keto acids (668), (f) preparation of deuteroaliphatic acids by reaction of aliphatic acids with DjO (690), (g) catalytic reduction and amination with of a-keto acids (690,... 

---