Primary alcohols from hydride reduction

Reduction of carbonyl compounds with metal hydrides or boranes a. primary alcohols from aldehydes, acids, acid halides, and esters... 

Esters are more readily reduced than carboxylic acids because there are not the problems associated with carboxylate formation. Thus reduction with lithium aluminium hydride gives a primary alcohol from the carboxylic acid component (Scheme 3.70). 

Steps (1) and (2) are the aldol condensation between acetyl CoA and the 3-ketothioester. Step (3) is the hydrolysis of one of the thioester groups. Steps (4) and (5) involve the reduction of the thioester to a primary alcohol via hydride transfers from NADPH,... 

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). 

The homology between 22 and 21 is obviously very close. After lithium aluminum hydride reduction of the ethoxycarbonyl function in 22, oxidation of the resultant primary alcohol with PCC furnishes aldehyde 34. Subjection of 34 to sequential carbonyl addition, oxidation, and deprotection reactions then provides ketone 21 (31% overall yield from (—)-33). By virtue of its symmetry, the dextrorotatory monobenzyl ether, (/ )-(+)-33, can also be converted to compound 21, with the same absolute configuration as that derived from (S)-(-)-33, by using a synthetic route that differs only slightly from the one already described. 

There is a rather important difference between chemical reductions using complex metal hydrides and enzymic reductions involving NADH, and this relates to stereospecificity. Thus, chemical reductions of a simple aldehyde or ketone will involve hydride addition from either face of the planar carbonyl group, and if reduction creates a new chiral centre, this will normally lead to a racemic alcohol product. Naturally, the aldehyde primary alcohol conversion does not create a chiral centre. 

Probably the most widely used reagent for partial reduction of esters and lactones at the present time is diisobutylaluminum hydride.44 45 46 47 48 By use of a controlled amount of the reagent at low temperature, partial reduction can be reliably achieved. The selectivity results from the relative stability of the hemiacetal intermediate that is formed. The aldehyde is not liberated until the hydrolytic workup and is therefore not subject to overreduction. At higher temperatures, at which the intermediate undergoes elimination, diisobutylaluminum hydride reduces esters to primary alcohols. 

As illustrated in Figure 19.7, the reduction of an acid derivative, such as an ester, with lithium aluminum hydride produces an aldehyde as an intermediate. Reduction of the aldehyde gives a primary alcohol as the ultimate product. It would be useful to be able to stop such a reduction at the aldehyde stage so that an aldehyde could be prepared directly from a carboxylic acid derivative. 

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