3-Aminopyrrolidine

Quinolones possessing a 7-(3-aminopyrrolidin-l-yl) substituent are particularly potent antibacterial agents. However, they often have very low solubility. Based on the observations that the hydroxymethylpyrrolidine (38) is significantly more potent against bacteria than its enantiomer (39) (the hydroxymethyl substituent in (39) apparently has a deleterious effect on activity while the same substituent in (38) has little effect on potency based on comparisons with the unsubstituted pyrrolidine analogue (40)) [84] and the enantiomer (41) is at least as potent as,... 

Among other enantioselective alkylations, a series of 3-aminopyrrolidine lithium amides (67 derived from 4-hydroxy-L-proline) have been used to induce high ee% in the addition of alkyllithiums to various aldehydes. Structure-activity relationships are identified, and the role of a second chiral centre (in the R group) in determining the stereochemistry of the product is discussed. 

Enantiomeric excesses of up to 76% have been obtained for alkyllithium-aldehyde condensations using 3-aminopyrrolidine lithium amides as chiral auxiliaries. Addition of organolithiums to imines has been achieved with up to 89% ee, in the presence of C2-symmetric bis(aziridine) ligands. ... 

Resolution of 3-aminopyrrolidine is reported in the hterature using diben-zoyltartaric acid via a 2 1 salt. We found that the (R)-enantiomer of the IN-Boc protected racemate could be crystallized in 32% yield and 99.5% ee from ethanol in a single crystallization with 0.25 mol equivalents of (R,R)-dibenzoyltartaric acid (Scheme 13.9). Other solvents tested gave poorer results. 

Polyaniline-supported Co(II) catalyst 41 was used to catalyze the epoxidation of various alkenes under oxygen atmosphere at ambient temperature.61 63 One report61 described a synthesis of a-hydroxy- 3-aminopyrrolidine amides as potential HIV protease inhibitors (Scheme 1). In this synthesis, catalyst 41 also mediated epoxide ring opening of the epoxide intermediate by an aniline to afford the desired product. 

The intramolecular amino- and amido-mercuration of <5-unsaturated-/J-amino-amines and carbamates 293 have been found to afford the corresponding 3-aminopyrrolidines... 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

Enantiopure 3-aminopyrrolidines have been prepared by boron trifluoride-mediated rearrangement of 2-aminomethylazetidines (Scheme 41).67... 

Ethyl 7-(3-aminopyrrolidin-1 -yl)-4-oxo-1 -(thiazol-2-yl)-1,4-dihydro-1,8-naphthyri-dine-3-carboxylate (2, R = Et) gave the corresponding 3-carboxylic acid (2, R = H) (10% HC1, reflux 89%).166... 

Ar= 1-naphthyl, 2-naphthyl R2NH = piperazine, 2-methylpyperazine, N-methylpiperazine, (2R,6S)-2,6-dimethylpiperazine, (3S)-3-aminopyrrolidine. 

For an example of cyclization used to reduce hERG binding in a series of farnesyltransferase inhibitors, see Bell, I.M., et al., 3-aminopyrrolidine farnesyltransferase inhibitors Design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. J. Med. Chem. 2002, 45, 2388-2409. 

Duhamel s group employed 3-aminopyrrolidine derivatives and obtained with 10 enantioselectivities of up to 73 % in n-BuLi additions to o-tolualdehyde [ratio 1.5 2.5 1.0,in THF at -78°C,(i )-configured product] [44]. Structural variations of the ligands were performed to elucidate the basis for the observed enantioselectivities [45]. 

Note added in proof. Complexes between MeLi and Chiral 3-aminopyrrolidine lithium amides bearing a second asymmetric center on their lateral amino group have been studied using multinuclear low-temperatme NMR spectroscopy, and a relationship between the topology of these complexes and the sense of induction in the enantioselective alkylation of aaromatic aldehydes by alkyllithiums has been proposed [115], 1,2-Amino sulfides have been used as chiral ligands in the enantioselective addition of BuLi and MeLi to various aldehydes (PhCHO, EtCHO) at low temperatures in up to 98.5% ee [16],... 

Aminomethylazetidines have been shown to undergo ring expansion to 3-aminopyrrolidines upon exposure to Bp3-Et20 in good yields, and in high diastereoselectivity, other Lewis acids or pro tic acids did not promote the rearrangement (eq 59). ... 

For 2-substituted pyrrolidinyl derivatives, major antibacterial activity differences exist between both enantiomers, in contrast to 3-aminopyrrolidines were differences between R and 5 isomers are less. In this case the substituent in the... 

The chiral derivatization reagents bearing an amino group include l-(4-dimethylamino-l-naph-thyl)ethylamine (DANE), 4-(3-aminopyrrolidin-l-yl)-7-nitro-2,l,3-benzoxadiazole (NBD-APy), and 4-(3-aminopyrroHdin-l-yl)-7-(N,N-dimethylaminosul-fonyl)-2,l,3-benzoxadiazole (DBD-APy). The derivatization of amino acids with these reagents yielded the corresponding amide derivatives, and the diastereo-meric amide derivatives produced were separated by normal or reversed-phase chromatography. 

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