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Asymmetric synthesis of [alpha]-amino acids and [alpha]-amino aldehydes via electrophilic substitution of chiral lithiocarbanions
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The asymmetric syntheses of N-protected-(alpha)-amino acid derivatives are reported. Deprotonation of N-benzoylglycine (-)-menthol ester (1) with lithium diisopropylamide (LDA) affords the stable dilithio derivative (9). Subsequent alkylations of 9 proceed in ca. 90% yield and in 5-55% diastereomeric excesses (d.e.) to give N-benzoyl-(alpha)-amino acid (-)-menthol esters (2-7). Similarly, N-benzoylglycine (S)-prolinol methyl ether amide (27), when deprotonated and alkylated as previously described, proceeds in ca. 90% yield and 21-46% d.e. to give N-benzoyl-(alpha)-amino acid (S)-prolinol methyl ether amides (29-31). The (S) isomer was observed to predominate for the esters and amides. Quaternary N-benzoyl-(alpha)-amino acid (-)-menthol esters (20-25) were synthesized in ca. 85% isolated yield and 16-48% d.e. Treatment of chiral nucleophiles derived from the deprotonation of N-protected-(alpha)-amino acid (-)-menthol esters and (S)-prolinol methyl ether amides with O,O-diacyl-tartaric acids resulted in disastereomeric excesses that approached 90%. The stereoselectivity of the deprotonation step of the electrophilic substitution reactions has been studied. Deprotonation of propionaldehyde dimethylhydrazone (34) with LDA, under kinetic conditions, produced the azaallyllithium reagent (35) in 95% (E(,C-C)) stereoselectivity, whereas deprotonation of 34 in the presence of ca. 2.5 molar equiv of hexamethylphosphoramide (HMPA) per lithium species produced (E(,C-C))-35 and (Z(,C-C))-35 in a 1:4 ratio as determined by ('1)H NMR spectroscopy. Similar studies of the dilithio derivatives of N-acyl-(alpha)-amino acid esters and N-acylaminoacetaldehyde dimethylhydrazones (DMH's) (44-46) showed that the stereoselectivity of the deprotonation produced only the cis (with respect to the negatively charged heteroatoms) intermediates. Deprotonation of N-pivaloylaminoacetaldehyde SAMP hydrazone followed by alkylation produced N-pivalolyl-(alpha)-amino aldehyde SAMP hydrazones (51-55) in ca. 95% yield and 6-20% d.e. The chiral SAMP hydrazone did not alter the stereoselectivity in the deprotonation step favoring the formation of a cis intermediate. A number of aldol condensation reactions involving lithio derivatives of N-pivaloylaminoacetaldehyde DMH (44) and N,N-diethylaminoacetaldehyde DMH (67) are reported. Diastereoselectivity approaching 90% has been reported for the condensation of aldehydes with the azaallyllithium reagent (77) of N,N-diethylaminoacetaldehyde DMH.
Davenport, Kenneth Geral (1982). Asymmetric synthesis of [alpha]-amino acids and [alpha]-amino aldehydes via electrophilic substitution of chiral lithiocarbanions. Texas A&M University. Texas A&M University. Libraries. Available electronically from
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