Simple Acyclic Ketones

The dihydroxyacetone reductase of Mucor javanicus is NADPH-dependent, and accepts a wide variety of simple acyclic ketones. For 2-alkanones, hydride attack occurs largely from the Si face with high selectivity to give the (/ )-product. However, butan-2-one was reduced to racemic butan-2-ol, indicating that methyl and ethyl are not differentiated by the enzyme. 

Simple ketones absorb at 1710-1715 cm" simple aldehydes absorb at 1720-1725 cm. Aldehydes also have a characteristic absorption near 2710 cm for the aldehyde C—H bond. Cyclohexanones have carbonyl absorptions at the same position as simple acyclic ketones. However, decreased ring size results in shifts to higher wavenumber. Cyclopentanone, cyclobutanone, and cyclopropanone absorb at 1745, 1780, and 1850 cm , respectively. 

There are several isolated examples of conformationally constrained a-diazo ketones that, under catalysis by copper salts, smoothly undergo intramolecular C-H insertion37. Although investigated in some detail, this cyclization in the simple acyclic series was not found to be a preparatively useful synthetic method38. 

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiently reduces all simple four- to nine-membered cyclic ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aliphatic acyclic ketones (C-4-C-10) (103,104) can be efficiently achieved by alcohol dehydrogenase isolated from Thermoanaerobium brockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse liver and T. brockii... 

Using isolated enzymes instead of whole cells, similar problems are to be considered only in a few cases. ADH from Thermoanaerobium brockii shows varying enantiomeric excess of the product depending on the structure of the ketone to be reduced. Conversions with this enzyme yield in products with low (20% for the reduction of acetophenone) or high ee value (100% for the reduction of p-Cl-acetophenone). Predictions about the stereospecificity of HLADH catalyzed reductions can be made for simple acyclic substrates applying Prelog s rule [37] and for more complex compounds using the cubic-space model developed by Jones and Jakovac [38],... 

Borane reduction of a variety of aromatic ketones using 5-10 mol% of 5-methyl catalyst 11 proceeded in >95% yield and in 80-97% ee. a-Haloketones were generally more reactive (90-97% ee) than simple ketones, which required higher temperatures (0°C compared to -20°C) to react to completion and led to lower enantioselectivities (80-90% ee).118 A complementary study by Umani-Ronchi and co-workers37 described the borane reduction of cyclic and acyclic ketones using catalyst 10. All products were obtained in >89% yield and >85% ee. Cyclic and hindered ketones led to the highest enantioselectivities (up to 96% ee) at room temperature. 

The carbenoid reaction between a-diazo ketones and simple alkenes or styrenes leads to acylcyclopropanes. (For the enantioselective cyclopropanation of styrene with 2-diazo-5,5-dimethylcyclohexane-l,3-dione, see Section 1.2.1.2.4.2.6.3.2.). With ketene acetals, 2,3-dihyd-rofurans are obtained. In contrast, l-acyl-2-oxycyclopropanes or 2-oxy-2,3-dihydrofurans can be formed in reactions with enol ethers and enol acetates the result depends strongly on the substitution pattern of both reaction partners.Whereas simple diazo ketones usually lead to cyclopropanes (Table 15), 3-diazo-2-oxopropanoates and 2-diazo-l,3-dicarbonyl compounds, such as 2-diazoacetoacetates, 3-diazopentane-2,4-dione, and 2-diazo-5,5-dimethylcy-clohexane-1,3-dione, yield 2,3-dihydrofurans and occasionally acyclic structural isomers thereof when reacted with these electron-rich oxy-substituted alkenes. 

In a very useful modification, simple ketones with CH2 adjacent to the carbonyl (cyclic ketones work much better than acyclic ketones) and ortfto-iodo-arylamines react under palladium catalysis to give indoles directly. The use of dimethylformamide as solvent and DABCO as the base are crucial to the success of the route. Mechanistically, the sequence certainly proceeds through the enamine. As well as being conceptually and practically simple, this method tolerates functional groups that would be sensitive to the acid of the traditional Fischer sequence. This method can also be applied to aldehydes, thus providing a direct route to 2-unsubstituted indoles, including side-chain-protected tryptophans. ... 

Lautens and Roy reported a synthesis of iV-(2,4-diaIkyloxazol-5-yl)oxazolidi-nones 288 from substituted A -acetoacetyl oxazolidinones 287 (Scheme 1.77). This reaction was initiated by acid-catalyzed addition of azide to the ketone in 287. It seems that this method is limited in scope to the chiral oxazoUdinone from IR,2S)-(—)-norephedrine. Simple acyclic dialkylamide analogs of 287 were unreactive or decomposed. Simple oxazolidinone analogs of 287 produced isoxazoles or afforded complex mixtures that contained both isoxazoles and 288. For aroylacetyl analogs of 287 (R = aryl), the authors recovered starting material but also encountered epimerization. In general, the yields were acceptable. 

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