Chloro ketones, reduction

Bromo ketones are commonly employed and are much easier to dehydro-halogenate than chloro ketones, although the latter are not so susceptible to reduction and rearrangement. lodo ketones are generally less accessible and very prone to reduction. 

An example of a whole-cell process is the two-step synthesis of an enantiopure epoxide by asymmetric reduction of an a-chloro ketone (Scheme 6.4), catalyzed by recombinant whole cells of an Escherichia coli sp. overexpressing an (R)-KRED from Lactobacillus kefir and GDH from Thermoplasma acidophilum, to the corresponding chlorohydrin, followed by non-enzymatic base-catalyzed ring closure to the epoxide [17]. 

There is a net reduction of a-chlorosulfenyl-oc-chloro ketones under hydrolytic conditions [267]. The sulfur atom undergoes a series of contrapolarizing changes (a-d-a). The carbonyl group also plays a crucial accentuation role in the various steps of the reaction. 

Since cyclobutanones are often produced by dichloroketene addition to an alkene (see Section 1.3.5.1.), a,a-dichlorocyclobutanones are very common intermediates. These can be reduced to the monochlorocyclobutanones (see Section 5.2.1.1.). It was reported249 that the C —Cl dipole has a pronounced effect on the sodium borohydride reduction of these compounds. For example, in the reduction of e ra-7-chloro-7-methylbicyclo[3.2.0]hept-2-en-6-one, the normal preference for an exo-face attack was reversed and the exo-alcohol was the major product exo-7-chlorobicyclo[3.2.0]hept-2-en-exo-6-ol exo-2d and exo-7-chlorobicy-clo[3.2.0]hept-2-en-en /o-6-ol endo-2A were obtained in a 78 22 ratio. On the other hand, when the corresponding endo-chloro ketones were reduced, the C —Cl dipole resulted in exclusive formation of the endo-alcohols endo-2b, c. 

Reduction of a-halo ketones. a-Bromo and a-chloro ketones are reduced to the purent ketone hy this reagent in CM iC N at room temperature in 3 12 hours. Yields tre in I he range 75 )5" . 

This methodology has been used for an iterative synthesis of the tricyclopenta-noid hirsulene (6), as outlined in equation (II).2 Two steps in the synthesis involve conversion of an -chloro ketone to an alkcne. This reaction was accomplished by reduction to a chlorohydrin followed by treatment with chromium(ll) perchlorate.1... 

Reductive dehalogenation of fi-halo ketones.1 a-Bromo or a-chloro ketones undergo reductive dehalogenation on reaction with freshly prepared A1I3 in refluxing CH3CN (80-95% yield). The reaction probably involves an aluminum enolate since addition of benzaldehyde results in an aldol condensation. 

Various transformations of the optically active a-chloro ketones were also presented [28] optically active 2-chloro cyclohexanone was oxidized by a Baeyer-Villiger oxidation to the corresponding lactone in 81% yield without reduction in enantiomeric excess, and the ketone functionality was selectively reduced to the corresponding syn-a-chloro alcohol with a high diastereomeric ratio. 

OL-Alkenylcarbinols Reduction of alkynyl chlorohydrins, readily available from reaction of a-chloro ketones with lithium acetylides, with lithium aluminum hydride and sodium methoxidc results in partial reduction of the triple bond as well as a facile rearrangement to provide a-alkenylcarbinols. One useful feature is that only (E)-disubstitutcd alkenes are formed. The addition and reductive rearrangement can be conducted in a single operation. 

Under radical conditions tributyltin hydride reduced a-chlorocarbonyl compounds to the corresponding saturated carbonyl derivatives but in the presence of phosphine oxides (HMPA or BU3PO) chemose-lective reduction of the carbonyl group was observed. a-Chloro ketones and aldehydes were reduced with this reagent combination to give good yields of the chlorohydrins. The choice of ligand was important as neither phosphines nor amines were effective substitutes for the phosphine oxides. 

The alkene reduction reactions most frequently observed are of a,3-unsaturated aldehydes, ketones, acids and esters. Examples of stereospecific reductions of acyclic substrates are given in Scheme 50.148.157-159 (j, (, e formation of (123), the double bond of (122) is reduced prior to the aldehyde function. The conversion of (124) to (125) involves oxidation of the intermediate alcohol to the carboxylic acid by bubbling air into the fermentation medium. Stereospecific reductions of a, 3-unsaturated ketones may be similarly effected (Scheme 61). The reduction of the chloro ketone (126) gives (127) initially. This epimerizes under the reaction conditions, and each enantiomer is then reduced further to (128) and (129), with the predominance of the (128) stereoisomer increasing with the size of the R-group. Reduction of ( )-(130) leads to (131) and (132). ... 

The chloromethyl imines lOa-lOi were employed as representatives of derivatives with a potentially reactive group in the side chain. Their reduction afforded the corresponding amines in >90% ee (Table 4.6, entries 1 9). The resulting amino chlorides were then cyclized to the corresponding aziridines on treatment with t BuO K with retention of the stereochemical integrity [ 12d]. It is pertinent to note that the preparation ofthe sensitive chloro imines lOa-lOi from the a chloro ketones was not entirely free of problems while the electron neutral and electron poor imines lOa-lOc were synthesized and isolated as individual substances, their electron rich counterparts lOg and lOh could not be obtained as pure compounds, since the reaction did not proceed to completion. Therefore, in the latter instances, the imines were generated in situ [12d]. 

CBS reduction of a-chloro ketone commercial production PPG-Sipsy (Callery) [18]... 

Hydrophobic interactions may also serve to purify products of combinatorial syntheses. As an example, penta-O-lauroyl-l-thio-p-galactose was subjected to a Michael addition to a,p-unsaturated ketones or to alkylation by a-chloro ketones followed by reduction of the keto groups or by reductive alkylation with amino acid esters. The reaction mixtures were passed through Cl8 silica gel, whereby the desired products were adsorbed while unwanted products were washed away. Desorption was carried out with pentane, and the hydrophobic labels were removed with methanolic sodium methoxide.The methyl laurates were finally separated from the desired products by chromatography on silica... 

Owing to the sensitivity of 5,6-dimethoxytryptophyl bromide, it could not be used in condensation with (111) hence the chloro-ketone (114) was used instead, and the carbonyl group in the product was removed by reduction with a large excess of sodium borohydride in acetic acid. Otherwise the synthesis follows the pattern of that reported earlier (Scheme 17). 

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