Lithium aluminum hydride alcohol synthesis from esters

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. 

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. 

Amino acids are fundamental biological chemicals and most are commercially available. Exceptions and the preparation of derivatives are discussed in Section 2.4. The compounds themselves, as well as their esters, may be reduced with complex hydrides (e.g., lithium aluminum hydride or sodium borohydride) to the corresponding a-amino alcohols (mostly named after the amino acid, e.g., alaninol from alanine). As a typical example of the in situ preparation of an amino acid ester and reduction to the amino alcohol, the synthesis of (- )-(S )-phenylalaninol is given1. 

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... 

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