Chiral auxiliaries Pyrrolidines, 2,5-disubstituted

As well as the disubstituted C2-symmelrie pyrrolidines E and F, the monosubstituted (f> )-2-(mcthoxymethyl)pyrrolidine G can be used as chiral auxiliary for the diastereoselecti ve addition of organomctallic reagents to a-oxo amides16. As with the phenylglyoxylic acid derivatives derived from amines E and F. methyllithium or methylmagnesium bromide in diethyl ether preferentially attack the (,S)-mms-conformer 11 (R = ( 6H5), leading to predominant formation of the (2 S)-diastercomer by Re-side attack. 

Both the (2S,5S)- and the (27 ,5/ )-enantiomers of the trans-pyrrolidine auxiliary 1 are available in high diastereomeric purity and high enantiomeric excess via resolution of traw-l-benzyl-2,5-pyrrolidinedicarboxylic acid and subsequent functional group transformation (see Appendix)7,13, 14. The chiral auxiliaries so obtained are then acylated with the appropriate acylation agent, which yields the desired /rart.v-2,5-disubstituted 1-acylpyrrolidines 2. 

Perhydrobenzoxazine 73 was reported as being a chiral auxiliary used to control the stereoselectivity of a thermally induced Alder-Ene reaction. In this instance, both endo- or exo-transition states seemed plausible to provide the observed products. Both TS minimize non-bonding steric interactions and were used to explain the selectivity observed. Ultimately, 74 was used to prepare cw-3,4-disubstituted pyrrolidines. For the conversion of 73 into 74, it should be noted that the enophile was the a,P-unsaturated amide and that the new C-C bond formed was alpha to the carbonyl. This appeared counter-intuitive for a LUMO enophile controlled reaction. 

Kawanami Y, Ito Y, Kitagawa T, Taniguchi Y, Katsuki T, Yamaguchi M. Asymmetric alkylation of carboxyamides by using trans-2, 5-disubstituted pyrrolidines as chiral auxiliaries. Tetrahedron Lett. 1984 25 857-860. 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

The configurational stability of several a-amino tertiary benzylic organolithiums has been demonstrated at low temperatures on two different heterocycles in the absence of any chiral ligand or auxiliary." A variety of 2,2-disubstituted piperidines and pyrrolidines have been synthesized bearing a-amino quaternary stereocentres. The racemiza-tion has been found to be faster in THF than in Et20 and mostly entropy controlled. 

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