Esters alcohol synthesis, lithium aluminum hydride

On the basis of this mechanistic reasoning, it is apparent that acyl chlorides and anhydrides should also be reduced to primary alcohols by lithium aluminum hydride. Indeed, this is the case. However, because these compounds are less convenient to work with than esters and offer no advantages in synthesis, they are seldom used as substrates for such reductions. 

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. 

In 1983 we developed a synthesis of (R)-87 without recourse to the Wittig reaction.62 Figure 4.33 summarizes our synthesis. Asymmetric reduction of keto ester A with lithium aluminum hydride in the presence of Darvon alcohol B furnished hydroxy ester C of moderate enantiomeric purity (78.6% ee). Recrystallization of D was the successful way to enrich its enantiomeric purity. Accordingly, the hydroxy ester C was hydrolysed, and the resulting acid was treated with (R)-(+)-l-(l-naphthyl)ethylamine to give D, which was recrystallized from acetonitrile to furnish the pure salt D. Acidification of D was followed by the Lindlar hydrogenation to give enantiomerically pure (R)-87. This process was once used for the commercial production of (R)-87. 

The reaction of esters with Gngnard reagents and with lithium aluminum hydride both useful m the synthesis of alcohols were described earlier They are reviewed m Table 20 4 on page 848... 

The reaction of esters with Gr-ignard reagents and with lithium aluminum hydride, both useful in the synthesis of alcohols, were described earlier. They are reviewed in Table... 

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

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). 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

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. 

For the synthesis of 13-hydroxysparteine the starting material was a-picoline iV-oxide (CXVIII) which was nitrated and the nitro group then replaced by benzyloxy. The action of acetic anhydride induced the Boekelheide rearrangement to the acetoxymethyl derivative CXIX. The latter, via the alcohol, the chloride, the cyanide, and the ester, was condensed with ethyl hydroxymethylenepyridylacetate to the quinol-izone CXX, hydrogenation and reduction of which with lithium aluminum hydride gave a separable mixture of hydroxysparteines. The... 

Caprifoliaceae). Lithium aluminum hydride reduction of the ester produced a mixture of the alcohols 401, and Alazard et al. were able to find conditions under which these alcohols could be doubly formylated (see Scheme 35) a discussion of this interesting reaction has been given. Cyclization of the dialdehyde and dehydrogenation completed the synthesis of 400. ... 

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