Pyrrolidine 2- -: chiral ligand

One of the most intensively studied protic chiral ligands, which moreover allows enantioselectivities of up to 95% ee, is the proline-derived (25 )-l- [(25,)-l-methyl-2-pyrrolidinyl]methyl -2-pyrrolidine methanol (6)19-21. 

Optically active alkynyl alcohols can, however, be conveniently prepared by the addition of dialkylzinc reagents of alkynyl aldehydes catalyzed by the chiral ligand (S)-l-methyl-a,a-diphenyl-2-pyrrolidine methanol33-34. 

Having demonstrated a practical and reliable method to access 2-arylpyrrolidines in high enantioselectivity, we felt that a noteworthy extension of this methodology would lie in its application to bis-arylated products 27, providing a rapid and efficient approach to enantiopure C2-symmetric 2,5-diarylpyrrolidines, which have been identified as valuable chiral auxiliaries and chiral ligand manifolds [29]. Towards this end, substrate 26a was subjected to the standard arylation conditions, which produced 2,5-diphenyl-N-Boc-pyrrolidine 27 in a 96 4 diastereomeric ratio, and 57% isolated yield (s-BuIi/TMEDA produced 27 in lower d.r. (66 34) and yield (42%)), as depicted in Scheme 8.13. 

Of greater synthetic interest is asymmetric induction by the use of chiral catalysis. Grigg was the first to report chiral catalysis of 1,3-dipolar cycloadditions in 1991 (101). A study of metal salts and chiral ligands revealed that 358 underwent cycloaddition with methyl acrylate to furnish adduct 359 in the presence of C0CI2 and (IR, 25)-A-methylephedrine as the chiral ligand. The pyrrolidine product was isolated in 55% yield with an ee of 84%. The use of methyl acrylate as solvent led to an improved yield of 84% with an excellent ee of 96% (Scheme 3.121). 

The above azomethine ylide cycloadditions have been extended to an enantioselective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine yhdes derived from achiral methyl 2-(arylmethyleneamino)acetates, cobalt(II) chloride [or manganese(II) bromide], and chiral amino alcohols, 1 and 2 equiv each, with methyl acrylate as solvent have been performed to provide the enantiomer-enriched pyrrolidine-2,4-dicarboxylates with the enantioselectivities of up to 96% enantiomeric excess (ee) (128,129). However, a large excess of the metal ions and the chiral source (ligand and base) have to be employed. 

Asymmetric reduction of ketonesLithium aluminium hydride in conjunction with this chiral ligand reduces prochiral aromatic ketones to (S)-secondary alcohols in 90-95% optical yields. Optical yields are lower (10-40% ee) in the case of alkyl aryl ketones. It is superior to (S)-2-(anilinomethyl)pyrrolidine for this reduction. Evidently the two methyl groups enhance the enantioselectivity. 

The binding of functionalized chiral ligands to water-soluble polymers has also been shown a (diphenylphosphino)pyrrolidine derivative reacts with poly(acrylic acid) to form a macroligand that is useful in biphasic reduction (35). 

Some of the highest enantiomeric excesses in hydroformylation reactions of styrene (-70-80% ee) have been obtained with a platinum catalyst containing the chiral ligand (2S,4S)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]pyrrolidine (17 (-)-BPPM).39... 

Chiral Ligands. Bidentate chelation of dirhodium(II) compounds by chiral oxazolidinones creates asymmetric sites on the metal, leading to induction in cyclopropanations and carbon-hydrogen insertion reactions. The oxazolidinones are less effective in this capacity than are the pyrrolidines. ... 

Cycloaddition of nitrones and pyrazolinones with a copper catalyst and a chiral ligand leads to pyrrolidine derivatives with good enantioselectivity. 

Relatively high optical yields were achieved in the asymmetric reduction of acetophenone by these chiral hydride reagents however, the optimum enantiomeric excess (e.e.) achievable was 83% at that time. Two effective methods have been reported since then Thus, we initiated a study on the exploration of a new and efficient chiral ligand suitable for the asymmetric reduction of prochiral ketones, and found that a chiral hydride reagent formed in situ from LiAlHj and the chiral diamine (S)-2-(anilinomethyI)pyrrolidine la) is efficient for the reduction of acetophenone, affording (S)-l-phenylethanol in 92% e.e. . Examination of the effect of the N-substituent in the diamine la-m) on the enantioselectivity in the asymmetric reduction of acetophenone, revealed that when a phenyl or 2,6-xylyl substituent was employed, 1-phenylethanol was obtained in 95% e.e. (Table 1)... 

The ligands 2b-g were also employed for the reaction of butyllilhium with benzaldehyde, and it was observed that formation of alcohol with R configuration is preferred when ligands with larger substituents, R and R, were employed (see Table 7). In addition, it is noteworthy that (R)-l-phenyl-l-pentanol is obtained in 68% e.e. by employing the chiral ligand 5 which has three pyrrolidine moieties (entry 15)... 

The asymmetric reduction of prochiral a- and P-hydroxy ketones has been realized with a regent generated from SnCL. a chiral diamine, and DIBAH [51]. Use of MEM ethers as a substrate and (5)-l-ethyl-2-(piperidinomethyl)pyrrolidine as a chiral ligand is the most effective to achieve hieh cnantiosclcction. 

Finding effective chiral ligands is the key to formation of semistabilized chiral lithio-alkanes. Success has been demonstrated from a combination of BuLi and 1C for benzyl trifluoromethyl sulfones and that of t-BuLi and the sparteine surrogate 14 for A-Boc pyrrolidine. ... 

The products are versatile auxiliaries not only for enantioselective deprotonation and elimination (Section C.), but are also valuable chiral ligands for complex hydrides in the enantioselective reduction of ketones (Section D.1.4.5.)- They are also applied in enolate reactions (Section D.l.5.2.1., D.1.5.2.4.). transition-metal-catalyzed Michael additions (Section D.l.5.8.), 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), and additions ofGrignard reagents (Section D.l.3.1.4.2.5.). (5 )-2-(Phenylaminomethyl)pyrrolidine has found most application and is also commercially available. Several methods exist for the preparation of such compounds. Two typical procedures for the synthesis of (.S)-2-(l-pyrrolidinylmcthyl)pyrrolidine are presented here. The methodology can be readily extended to other amides and alkylamino derivatives of proline. 

Asymmetric hydrogenation. L-Proline has been convened into a series of (S)-2-(aminomethyl)pyrrolidines, such as (S)-2-(anilinomethyl)pyrrolidine (1), d + 19.7°, obtained as shown in equation (I). The product is an efficient chiral ligand for asymmetric reduction of various ketones by lithium aluminum hydride. 

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

---