Methyl tert-butyl ketone, reduction

A reinvestigation of ketone reduction with lithium aluminum hydride and d-camphor (Portoghese, 1962) refutes an earlier claim (Bothner-By, 1951) that this system produces asymmetric reduction. Addition of 0.2 mole of d-camphor to 0.2 mole of LiAlH and subsequent addition of either 2-butanone or methyl tert-butyl ketone yielded, after hydrolysis, inactive alcohol. Portoghese speculates that A1H4, rather than Al(OR)H3 , may be the primary reducing agent. 

In another type of application, water-immiscible ILs can form biphasic systems, where the enzyme and the cofactor dissolved in the aqueous phase is physically separated from the substrates and products mainly in the IL phase. The first report of enzymatic ketone reduction in an IL-buffer biphasic system described the IfoADH-catalyzed enantioselective reduction of 2-octanone in a biphasic system containing buffer and [BMIM][Tf2N], which showed higher reaction rates than that in buffer-methyl tert-butyl ether biphasic system [53]. 

The typical CBS reduction sees use of between 2-10 mol% of the oxaza-borolidine catalyst, with BHg THF, BH3 DMS or less commonly DEANB as reducing agent, the reactions being run in solvents such as THF, methyl tert-butyl ether (MTBE) or toluene at temperatures usually between 0-25 °C. The ketone is usually added in a slow, dropwise fashion to a preformed mixture of the oxazaborolidine catalyst and borane (addition usually complete within 1-1.5 h). However, it is also possible to simultaneously add the borane and ketone together this sometimes results in improvements to the enantios-electivily of the reaction. 

Steric bulkiness of substituents in ketones (25), for example, makes it possible to differentiate two pairs of lone-pair electrons (a or b in 25) on carbonyl oxygen for coordinating with the Lewis acidic center of boron in oxazaborolidine (28). The complex (29) formed from 28 with catecholborane binds ketone (32) stereospecifically by using the lone-pair electrons at the less hindered side so as to direct the smaller substituent Rs toward the bulky N-tert-butyl group. The intramolecular hydride transfers to the favorably coordinated carbonyl group as shown in 30, Scheme 1.82, results in asymmetric reduction of ketones. Reduction of trifluoromethyl and methyl ketones (25) (R = CF3 or CH3) by this system afforded the corresponding alcohols (26 or 27) with an opposite stereochemistry (Scheme 1.82). 

The reduction of tert-butyl 2-methoxy-3-oxo esters has also been investigated. These behave in a manner reminiscent of the a-alkoxy ketones 3-benzyloxy-4-methyl-4-hexen-2-one and 2-methoxy-l,2-diphenylethanone (see p 3994) in that, even with sodium borohydride in 2-propanol, they appear to react under chelation control, giving non-products54. Unfortunately, the analogous 2-/< rt-butoxy-3-oxo esters, which would be more versatile as intermediates, react with rather less selectivity. 

The starting material, methoxytetralin (293), was converted into the a,(3-unsaturated ketone (294) by Birch reduction. The allene adduct (295) was prepared from ketone 294 and was then rearranged to the hydroxyl ketone (298) via intermediates 296 and 297. Compound 298 was methylated with sodium hydride and methyliodide to give the methoxyketone (299) in quanitative yield. Compound 299 was rearranged to 300 by refluxing with tert-butyl perbenzoate and cuprous bromide in absolute... 

The Grignard reagent prepared from (-f-)-l-chloro-2-methyl-butane reduces a tert-butyl, phenyl, or cyclohexyl ketone to unequal amounts of the corresponding enantiomeric secondary alcohols (Fig. 13). The per cent asymmetric reduction obtained with several of the above types of ketones is shown in Table I. 

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