Aldehydes alcohol synthesis, lithium aluminum hydride

Numerous methods for the reduction of ketones and aldehydes to the corresponding secondary and primary alcohols, such as the use of several complex metal hydrides, have found wide application in organic synthesis. Lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4) are the most popular of these achiral reagents. However, since a natural product synthesis has to fulfill demands in terms of both efficiency and stereoselectivity, these methods can seldom be used with prochiral substrates. 

Jorgensen et al. found that reduction of an allylic alcohol by lithium aluminum hydride can be carried beyond the stage of the saturated alcohol to give a cyclopropane. Thus a cinnamyl acid, ester, aldehyde, or ketone on reduction with 100% excess LiAlHj in refluxing tetrahydrofurane or dimethoxyethane affords a phenyl-cyclopropane in yield of 45-80%. The reaction complements the Simmons-Smith synthesis. 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

The best way to prepare peptide aldehydes from the corresponding N -protected amino acids is by using a handle based on the Weinreb amide.f This commercial handle allows classical solid-phase elongation of peptides using protected Boc or Fmoc amino adds and, at the end of the synthesis, the peptide aldehyde is formed by reduction and concomitant cleavage from the resin with lithium aluminum hydride. Although the 4-hydro-xybenzoic acid handle also allows the preparation of peptide aldehydes by reduction of the resin-bound phenyl ester with lithium tri-tert-butoxyaluminum hydride, a noixture of the aldehyde and the alcohol is always formed. 

Treatment of alkyl-substituted l-acetoxy-2,2-difluorocyclopropanes 1 with lithium aluminum hydride allowed the stereoselective synthesis of P-Auovo allyl alcohols 2 as a result of reduction of the aldehyde intermediate. ... 

Apart from syntheses aimed at producing substances for biological evaluation, which will be discussed later, most work in this area has employed aldehydes rather than ketones. Acidic conditions must be avoided during the isolation of the alcohols, since ethers are readily formed.47,76 In the great majority of cases the alcohol has been successfully reduced by the lithium aluminum hydride-aluminum chloride method to which we have already referred. Halogen substituents on the thiophene ring (even iodine) survive this procedure. The methods of synthesis discussed in the preceding sections are not suitable for the preparation of unsymmetric dithienylmeth-anes with free thiophene a-positions, and it is for these substances that the... 

Cyclohexylideneacetaldehydes. Brink has reported a two-step synthesis of these aldehydes (3) from esters of cyclohexylideneacetic acids (1). These are reduced in absolute ether with lithium aluminum hydride at room temperature. The alcohols are oxidized with Attenburrow manganese dioxide... 

Several years ago, we reported the synthesis and synthetic utility of lithium aminoborohydrides (LABs) a new class of powerful, safe, and highly selective reducing agents (2, 3). These reagents performed many of the transformations for which lithium aluminum hydride is usually used. Thus, the following reduction reactions were carried out with LABs aldehydes and ketones to alcohols, esters to alcohols, oc,P>unsaturated ketones to allylic alcohols, a,P-unsaturated esters to allylic alcohols, alkyl halides to hydro-carbons, azides to amines, and epoxides to alcohols. These reduction reactions are summarized in Figure 3. 

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