Stereochemical Studies. XLIV. Exploitation of the New Synthetic Scheme for Chiral Additives Usable in Asymmetric Syntheses. Novel Syntheses of optically Active y-Amino Acids and Pyrrolidines from L-a-Amino Acids

Abstract

Aiming to prepare optically active pyrrolidines (2) which are usable as chiral additives for asymmetric syntheses via enamines, and whose absolute configurations can correspond to that of D-proline (d-3c), an exploitation of the novel synthetic scheme for 2 from L-oc-amino acids (1-3) via optically active y-amino acids (4) was studied. Reaction of (S) ( —)-ditosylate ((S)( — )-10a) easily derivable from L-phenylalanine(L-3a), with diethyl potassiomalonate (3.0 eq.) in tetrahydrofuran, could directly give a mixture of (R)-pyrrolidine-2-one {(R)- 12a) and (R){—)-malonate ((R)(—)- 13a) in 70—80% yield. Some mechanistic studies revealed that the malonate reaction proceeded through the regiospecific ring opening of (S) ( + )-aziridine ((5) (+)-lla). Acidic hydrolysis of a crude mixture of (R)-12a and (R) ( — )-13a afforded (R) (—)-4a without racemization in 49% yield based on (S) ( —)-10a. The same synthetic route was applicable to L-valine (L-3b), giving (R) ( + )-4b. However, (S)-4c could be obtained from L-proline(L-3c), by the treatment of (S) ( — )-iodide ((5) ( — )-16c) prepared from (5) (—)-ditosylate ((5) ( —)-10c), with malonate anion, followed by acidic hydrolysis. (R) ( — )-4a and (R) (+)-4b thus obtained were readily converted into (R) (—)-2a and (R) ( + )-2b by dehydration and reduction. When the asymmetric synthesis of 4-methyl-4-phenyl-2-cyclohexenone(18) was examined by using (R) ( —)-2a and (R) ( + )-2b, (5) ( — )-18, being antipodal to that provided by using L-proline-derived pyrrolidines (1) as chiral additives, was successfullv obtained. © 1977, The Pharmaceutical Society of Japan. All rights reserved.