Pyrrolidines chiral lithium amides

The diamine precursor 108 to the chiral lithium amide 4 introduced by Asami is accessible by different routes starting from (, >)-proline. In Asami s own synthesis, (S)-CBZ-proline was activated by DCC and then coupled by an amine such as pyrrolidine (Scheme 80). The reduction of the formed amide could then be carried out with LiAlHj or BH3, with the latter giving a cleaner reaction. After deprotection, the diamine was obtained by distillation in 44-48% yield from (.S j-CBZ-prolinc. 

Asymmetric rearrangement of cyclohexene oxide Cyclohexene oxide is rearranged to (S)-2-cyclohexene-l-ol in 92% ee by the chiral lithium amide (2) prepared from n-butyllithium and 1. Several related (S)-2-(disubstituted aminomethyl)pyrrolidines prepared from (S)-proline are almost as stereoselective.3... 

During the last decades, a number of chiral lithium amides have been developed for stereoselective deprotonation of, e.g., epoxides. For example, the lithium amide lithium (5 )-2-(pyrrolidin-l-yl-methyl)pyrroli-dide (4) was for a long time the most stereoselective base used in epoxide deprotonations. It gives 90% of the (5 )-enantiomer and 10% of the (/ )-enantiomer upon deprotonation of cyclohexene oxide 2 in THF solution (Scheme 2) [4-6]. 

Camphor- 10-sulfonic acid, 62 (S)-2-(l-Hydroxy-1-methylethyl)-pyrrolidine, 146 a-Methylbenzylamine, 185 Quina alkaloids, 264 Cycloaddition reactions 2-Oxazolidones, chiral, 225 Cyclopropanation Diiodomethane-Diethylzinc, 276 Simmons-Smith reagent, 275 Deprotonation Lithium amides, chiral, 159... 

The lithium derivative of the chiral chelating diamine (3 )-2-(l-pyrrolidinylmethyl)-pyrrolidine (6) has been used extensively in stereoselective synthesis, i.e. in the deprotonation of ketones and rearrangement of epoxides to homoallylic alcohols. The lithium amide has been crystallized from toluene solution, and X-ray analysis revealed that it forms a ladder-type tetramer with the two pyrrolidine nitrogens solvating the two lithiums at the end of the ladder38, (Li-6)4. 

In the presence of the corresponding pyrrolidine diamine, the chiral lithium pyrrolidide amide yields dimeric chelates composed of a lithium pyrrolidide amide dimer solvated by a pyrrolidine diamine, (Li-6)2 6, as shown by NMR spectroscopy39. The lithium amide gives two 6Li NMR signals in a 1 1 ratio. The addition of TMEDA to Li-6 results in a similar complex where TMEDA coordinates to the lithium pyrrolidide amide dimer, (Li-6)2 TMEDA. 

Miscellaneous. Lithium amides of chiral pyrrolidines, tetrahydrofurans, and tetrahydrothiophenes are evaluated as chiral ligands in the condensation of BuLi to o-tolualdehyde (eq 74). ... 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Chiral a-amino acids The lithium anion of the N-protected glycine amides 3, prepared by reaction of the pyrrolidine with [bis(methylthio)methylene]glycyl pivalic anhydride (DMAP), is alkylated with high diastereoselectivity. The (S)-amino acid (5) is obtained on acid hydrolysis. 

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