Ketones enantioselective ethylation

A ligand having C2-symmetry is not a necessity and a variety of catalysts are known that promote highly enantioselective Diels-Alder reactions. For example, the oxazaborolidine 148 is a good catalyst for the cycloaddition of cyclopentadi-ene and 2-bromoacrolein (3.104). The cycloaddition reaction is highly diastereo-and enantioselective in favour of the exo-aldehyde. However, the enantioselectiv-ity is poor with this catalyst when the dienophile lacks a substituent (for example bromine) in the 2-position. A solution to this problem is the use of the protonated oxazaborolidine 149, which promotes highly selective cycloaddition of cyclopen-tadiene with a range of dienophiles, such as ethyl vinyl ketone or ethyl acrylate (3.105). Asymmetric cycloaddition of a,p-unsaturated aldehydes or ketones with various dienes can alternatively be achieved in the presence of a chiral secondary amine as a catalyst. 

Evans DA, Ng HP, Clark JS, Rieger DL. Diastereoselective anti aldol reactions of chiral ethyl ketones enantioselective processes for the synthesis of polypropionate natural products. Tetrahedron 1992 48 2127-2142. 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Several other ehiral S/O ligands have been involved by Yang and Lee in this type of reaetions, sueh as [(lf ,25 ,3f )-3-mercaptocamphan-2-ol)], MerCO, whieh produeed, when applied to aryl methyl ketones, the corresponding 1-aryl ethyl alcohols in enantioselectivities of up to 92% ee (Scheme 10.63)." ... 

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

Enantioselective hydrogenation of prochiral ketones has rarely been studied in aqueous biphasic media. In addition to the chiral bisphosphonic acid derivatives of 1,2-cyclohexanediamine [130], the protonated 4,4 -, 5,5 -, and 6,6 -amino-methyl-substituted BINAP (diamBINAP 2HBr) ligands (Scheme 38.7) served as constituents of the Ru(II)-based catalysts in the biphasic hydrogenations of ethyl acetoacetate [131, 132]. These catalysts were recovered in the aqueous phase and used in at least four cycles, with only a marginal loss of activity and enantio-selectivity. 

The Baylis-Hillman reaction (Scheme 3) of ethyl vinyl ketone with electron-deficient aromatic aldehydes (e.g. where R = 0-NO2C6H4), in MeCN or EtCN solution, has been found to proceed enantioselectively in presence of catalytic base (32) derived from proline. The Michael adduct formed between the catalyst and the vinyl... 

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or a-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from... 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Williams group observed low enantioselectivities for the Michael addition of a prochiral nucleophile, ethyl 2-cyanopropionate 623, to methyl vinyl ketone 624 catalyzed by chiral platinum complexes (Scheme 8.196)." The NMR analysis indicated that these cationic Pt complexes act as Lewis acids toward nitriles. The X-ray crystal structure as well NMR analysis showed that the solvent ligand that is readily displaced by an organic substrate is situated cis to the nitrogen donor in the Pt complex and, therefore, is in a chiral pocket created by the oxazoline ring. 

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