| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1348115 | Tetrahedron: Asymmetry | 2012 | 11 Pages |
A new bifunctional thiourea II catalyzed methodology was developed for the synthesis of chiral trisubstituted pyrrolidines using 4-aminocrotonate 1a/1b and nitroolefins 2a–g as starting materials. Two different N-protected 4-aminocrotonates 1a and 1b were tested for the reaction with 1a giving the desired product 3a with a high diastereomeric ratio (>20:1) but with low enantioselectivity (ee up to 7%). N-Tosyl-4-aminocrotonate 1b, however, yielded the product with moderate dr (up to 68:32) but with high ee in the case of the major trans–trans-isomers 4a–g (ee from 92% to 98%) and modest enantiomeric excess for the minor trans–cis-isomers 4a′–g′ (ee up to 57%). This methodology was also successfully applied when (E)-β-methyl-trans-β-nitrostyrene 2h was used as the starting nitroalkene to provide the product with dr 70/30 and with ee of 63% and 67%, respectively. The absolute configuration of both isomers was established using chiral derivatization with Mosher’s and mandelic acids, with the relative stereochemistry being determined via NMR analysis.
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Ethyl 2-((3S,4R,5S)-4-amino-5-cyclohexyl-1-tosylpyrrolidin-3-yl)acetateC21H30N2O6ee = 92%[α]D25=-62 (c 0.10, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,5S)
Ethyl 2-((3S,4R,5S)-4-amino-5-cyclohexyl-1-tosylpyrrolidin-3-yl)acetateC21H30N2O6See = 36%[α]D25=-40 (c 0.07, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R,5S)
Ethyl 2-((3S,4R,5S)-4-amino-5-cyclohexyl-1-tosylpyrrolidin-3-yl)acetateC21H32N2O4See = 92%[α]D25=-34 (c 0.51, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R,5S)
Ethyl-2-((3S,4R,5S)-5-cyclohexyl-1-tosyl-4-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)pyrrolidin-3-yl)acetateC31H39F3N2O6See = 92%[α]D25=-51.5 (c 0.20, CHCl3)Source of chirality: asymmetric synthesis and (R)-Mosher’s acidAbsolute configuration: (3S,4R,5S), (4R)
Ethyl-2-((3S,4R,5S)-5-cyclohexyl-1-tosyl-4-((S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)pyrrolidin-3-yl)acetateC31H39F3N2O6See = 92%[α]D25=-57.9 (c 0.20, CHCl3)Source of chirality: asymmetric synthesis and (S)-Mosher’s acidAbsolute configuration: (3S,4R,5S), (4S)
Ethyl 2-((3S,4R,5S)-4-amino-5-cyclohexyl-1-tosylpyrrolidin-3-yl)acetateC29H38N2O6See = 92%[α]D25=-101.3 (c 0.23, CHCl3)Source of chirality: asymmetric synthesis and (R)-Mandelic acidAbsolute configuration: (3S,4R,5S), (4R)
Ethyl 2-((3S,4R,5S)-4-amino-5-cyclohexyl-1-tosylpyrrolidin-3-yl)acetateC29H38N2O6See = 92%[α]D25=-28.5 (c 0.22, CHCl3)Source of chirality: asymmetric synthesis and (S)-Mandelic acidAbsolute configuration: (3S,4R,5S), (4S)
