Secondary alcohols from hydride reduction

The Meerwein-Ponndorf-Verley reduction of carbonyl compounds and the Oppenauer oxidation of alcohols, together denoted as MPVO reactions, are considered to be highly selective reactions. For instance, C=C double bonds are not attacked. In MPV reductions a secondary alcohol is the reductant whereas in Oppenauer oxidations a ketone is the oxidant. It is generally accepted that MPVO reactions proceed via a complex in which both the carbonyl and the alcohol are coordinated to a Lewis acid metal ion after which a hydride transfer from the alcohol to the carbonyl group occurs (Fig. 1) [1]. Usually, metal ec-alkoxides are used as homogeneous catalysts in reductions and metal t-butoxides in oxidations [1]. 

Recent refinements in hydride transfer reductions have enhanced the utility of oxazaborolidine- and BINAP-Ru (II) complex-catalyzed reductions. A review by Wills describes the development of catalysts for the syntheses of chiral nonracemic secondary alcohols from aryl ketones [5]. Among the more interesting catalysts discussed were f/ -arene ruthenium complexes, which utilize diamine and monotosylated diamine ligands. 

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

Similarly, the hydride reduction of the fluorenone and anthraquinone complexes gives the corresponding secondary alcohols with endo-OH groups resulting from stereospecific attack [134], This strategy is also known in the Cr(CO)3(arene)... 

Figure 2.23 Enantioselective reduction of unsymmetricaUy substituted ketones by dehydrogenases yields secondary alcohols. The reaction may either follow Prelog s rule (addition of hydride from re-side) or they may not (anti-Prelog).

Borane and aluminum hydrides modified by chiral diols or amino alcohols are well-known, effective reagents for the stoichiometric enan-tioselective reduction of prochiral ketones and related compounds (34). Reduction of prochiral aromatic ketones with the Itsuno reagent, which is prepared from a chiral, sterically congested /3-amino alcohol and borane, yields the corresponding secondary alcohols in 94-100% ee... 

The product is the racemic [(R)/(S)] alcohol since the free energies of the two diastereoisomeric transition states, resulting from hydride attack on the si-face of the ketone as shown (order of priorities O > R1 > R2, p. 16) or the re-face, are identical. The use of an aluminium alkoxide, derived from an optically pure secondary alcohol, to effect a stereoselective reaction (albeit in low ee%) was one of the first instances of an asymmetric reduction.48 Here (S)-( + )-butan-2-ol, in the form of the aluminium alkoxide, with 6-methylheptan-2-one was shown to give rise to two diastereoisomeric transition states [(5), (R,S) and (6), (S,S)] which lead to an excess of (S)-6-methylheptan-2-ol [derived from transition state (6)], as expected from a consideration of the relative steric interactions. Transition state (5) has a less favourable Me—Me and Et—Hex interaction and hence a higher free energy of activation it therefore represents the less favourable reaction pathway (see p. 15). 

Secondary alcohols may be oxidised to the corresponding ketones by the use of an aluminium alkoxide, frequently the t-butoxide, in the presence of a large excess of acetone (the Oppenauer oxidation). The reaction involves an initial alkoxy-exchange process followed by a hydride ion transfer from the so-formed aluminium alkoxide of the secondary alcohol by a mechanism analogous to that of the Meerwein-Ponndorf-Verley reduction (see Section 5.4.1, p. 520). 

Deoxygenation of primary and secondary alcohols.1 This deoxygenation has been effected by reduction of the thiocarbonyl esters with tributyltin hydride and AIBN as the radial initiator (11, 550). A newer, milder method uses diphenylsilane in a radical chain reaction initiated by triethylborane and air. Even secondary thiono-carbonates, particularly those derived from 4-fluorophenol, are deoxygenated at 25°. 

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were first (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-0-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlHzt, the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantios-electivity in the reduction of acetophenone to 70% ee with an ethanol-modified lithium aluminum hydride-sugar complex.10... 

The asymmetric reduction of carbonyl groups to form enantiopure secondary alcohols is a reaction of fundamental importance in modern synthetic chemistry. The carbonyl group is prochiral centre (if different groups are attached to carbonyl carbon) and can be attacked by hydride from re or si face to generate a racemic product if there are no additional chiral centres in the molecule. 

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