Organocatalytic asymmetric synthesis of trisubstituted pyrrolidines via a cascade reaction

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.

Figure optionsDownload as PowerPoint slide

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)