12 α,α-二置換α-アミノ酸の不斉合成(口頭発表の部)

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α,α-Disubstituted α-amino acids, often found in nature, have attracted substantial synthetic interest because of its importance as enzyme inhibitors, neurotropic factors, and conformational modifier of bioactive peptides. We describe here a new method for the synthesis of optically active α,α-disubstituted α-amino acids by the use of an intramolecular version of asymmetric Strecker reaction. Our synthetic plan is the use of α-amino acid as the amino and chirality transferring group. Strecker reaction of the ketimine intermediate gives CN adducts which would readily be converted to the desired chiral amino acids via an oxidative removal of the chirality transferring group followed by a hydrolysis of the nitrile group (eq 1). After removal of the Boc group of the amino acid ester 6 (R=iPr), the treatment of the obtained ketimine intermediate with NaCN in iPrOH gave, stereoselectively, desired amino nitrile 7a and 7b (72%, 7a:7b=25:1). The reaction involved an imine-enamine equilibrium (between 8 and 9) which was ascertained by the following experiments: (1) the use of 2-PrOD as the solvent gave 7 where significant amounts of D atom were incorporated into its C5 methyl and C6 methylene groups; (2) the treatment of 7a with Na^<13>CN in the presence of lequiv TFA gave a mixture of 7a and ^<13>CN enriched 7a. The amino acid residue was removed by (1) t-BuOCl and (2) conc HCl to give (R)-α-methylserine 1a in 84% yield. The use of D-valine afforded (S)-1b. This method was applyed to the syntheses of α-(hydroxymethyl)phenylalanine (2a, b) and α-(hydroxymethyl)aspartic acid (3a, b). The syntheses of four enantio- and diastereomers of α-methylthreonine (4a, 5a) and its allo-isomer (4b, 5b) were also accomplished based on the above mentioned method starting from dl-acetoin.
1995-09-01

12 α,α-二置換α-アミノ酸の不斉合成(口頭発表の部)

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