Stereoselectivity keto esters

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

A fluorinated keto ester reacts as an electrophile with hydrides, giving a hydroxy ester in a highly stereoselective reduction [30] (equation 25). 

A representative set of a- and -keto esters was also tested as substrates (total 11) for each purified fusion protein (Figure 8.13b,c) [9bj. The stereoselectivities of -keto ester reductions depended both on the identity of the enzyme and the substrate stmcture, and some reductases yielded both l- and o-alcohols with high stereoselectivities. While a-keto esters were generally reduced with lower enantioselec-tivities, it was possible to identify pairs of yeast reductases that delivered both alcohol antipodes in optically pure form. These results demonstrate the power of genomic fusion protein libraries to identify appropriate biocatalysts rapidly and expedite process development. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Rodriguez, S., Kayser, M.M. and Stewart, J.D. (2001) Highly stereoselective reagents for/3-keto ester reductions by genetic engineering of baker s yeast. Journal of the American Chemical Society, 123 (8), 1547-1555. 

Kaluzna, I.A., Feske, B.D., Wittayanan, W. et al. (2005) Stereoselective, biocatalytic reductions of alpha-chloro-beta-keto esters. The Journal of Organic Chemistry, 70 (1), 342-345. 

Highly enantioselective hydrogenation of / -keto esters is achieved by using a Raney Ni catalyst modified by tartaric add and NaBr (Fig. 32.14) [9, 55]. The catalyst should be prepared under controlled conditions induding suitable pH (3-4), temperature (100°C), and concentration of the modifier (1%) to achieve an optimum stereoselectivity. The addition of NaBr, an achiral modifier, is important. Furthermore, ultrasonic irradiation of the catalyst tends to increase the activity and enantioselectivity [9f,g]. Ultrasonication may remove nonselective sites of the catalyst surface. 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Diastereoselective reduction of p-keto esters.1 Reduction of p-keto esters (3) of the chiral a-naphthylborneol (2)2 is stereoselective because one face of the carbonyl group is blocked by the naphthyl group. Chelation of the keto ester with... 

Table 9.1 Enzyme-catalysed stereoselective reduction of diketones/keto esters to keto alcohols/hydroxy esters...

Kalaitzakis, D., Rozzell, J.D., Kambourakis, and S. Smonou, L, Highly stereoselective reductions of a-alky 1-1,3-diketones and a-alkyl-/3-keto esters catalyzed by isolated NADPH-depen-dent ketoreductases. Org. Lett., 2005, 7, 4799-4801. 

The range of the asymmetric epoxidation reaction may be extended still further to include dienes (Entries 7,12,17) and even tetraenes (Entry 26). It is of interest to note that only double bonds adjacent to the carbonyl function are epoxidised and any remaining double bonds are left untouched (Entry 26). This selective reactivity allows for further elaboration of unreacted alkene units at a later stage, (see Sect. 5). Enediones (Entries 21-23) and unsatuxated keto esters (Entries 24 and 25) can also be oxidised in good yields and good to excellent stereoselectivity using polyamino acids. 

Dihydrofuran reacts with /3,7-unsaturated a-keto esters with copper or zinc complex catalysts to generate furo[2,3-/ ]pyran derivatives in good yields with high stereoselectivity. The synthesis proceeds via an inverse electron demand hetero-Diels-Alder reaction <2000CC459>. 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

The reaction of the enol diethylphosphate of a p-keto ester with a primary dialkyl cuprate provides a useful stereoselective synthesis of / -alkyl-a,j -unsaturated esters (equation II).3 This coupling was used in two steps in a recent synthesis of mokupalide, a novel C30-isoprenoid.A... 

Reduction of a-alkoxy-fl-keto esters.1 r-Butoxy esters of a-alkoxy-/3-keto acids are reduced by NaBH4 in 2-propanol selectively to erythro-a-alkoxy-fl-hydmxy curboxylates. The report suggests that the selectivity results from reduction of an intermediate five-membcred chelate involving Na+ and, in fact, no stereoselectivity is observed if a crown ether is present. 

Stereoselective reduction of fS-keto esters. A few years ago Canceill and Jacques1 noted that methyl 2-benzoylpropionatc (1) is reduced by LiAlH4 mainly to the... 

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