Pyrrolidine from /.-glutamic acid

The diamine (99) was prepared from (S)-proline90b) or (S)-glutamic acid I15) maintaining the asymmetric center. Racemic 2-(anilinomethyl)pyrrolidine, prepared from (RS)-5-oxopyrrolidine-2-carboxylic acid, was effectively resolved into a pair of enantiomers by fractional crystallization of its mandelic acid salt U6). Moreover, the preferential crystallization of its 4-hydrobenzoic acid salt was found to produce both enantiomers in high optical purities by alternate seeding116). 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

For pyrrolidines with more substituents on the five-membered ring, proline is not a convenient starting material. For pyrrolidines containing different substituents in positions 2 and 5, the enantiomers of glutamic acid are inexpensive starting materials. Thus, the esters of D- and L-pyroglutamic acid [(7 )- and (,S )-5-oxo-2-pyrrolidinecarboxylic acid] are readily obtained in a one-pot procedure from (R)- or (S)-glutamic acid ... 

Intramolecular ene reactions take place readily, even with compounds containing a normally unreactive enophile. The cyclization is parhcularly effective for the formation of hve-membered rings, although six-memhered rings can also be formed from appropriate unsaturated compounds. The geometrical constraints imposed on the transition state often result in highly selective reactions. For example, the homoallylic alcohol 242 with an axial alcohol substituent was the exclusive product from the cyclization of the unsaturated aldehyde 241 (3.157). In a synthesis of the neuroexcitatory amino acid (—)-a-kainic acid 245, the diene 243, itself prepared from (5)-glutamic acid, was cyclized to the pyrrolidine derivative 244 with almost complete stereoselectivity (3.158). ... 

In an overwhelming majority of cases the diamine 1 is (S)-2-(anilino-methyl)pyrrolidine (Ar = Ph), easily obtained from L-glutamic acid and nowadays commercially available. 

---