(2S,4S)-2-(Anilinomethyl)-1-ethyl-4-hydroxypyrrolidine1

[77973-75-8]  · C13H20N2O  · (2S,4S)-2-(Anilinomethyl)-1-ethyl-4-hydroxypyrrolidine  · (MW 220.31)

(chiral catalyst for the enantioselective conjugate addition of thiols to a,b-unsaturated ketones2 and esters)

Physical Data: bp 150-170 °C/2 mmHg; [a]23D -58.1° (c 1.03, EtOH).

Solubility: sol toluene, benzene, CH2Cl2, CCl4, ethanol.

Preparative Methods: (2S,4S)-1-benzyloxycarbonyl-4-hy-droxyproline (Z-allohydroxyproline)3 is acetylated with Acetic Anhydride and Pyridine to give the acetate (1). The acetate (1) is treated with aniline-1,3-Dicyclohexylcarbodiimide and the subsequent removal of the benzyloxycarbonyl group affords (2). Acetylation of (2) followed by reduction with Lithium Aluminum Hydride affords (2S,4S)-2-(anilinomethyl)-1-ethyl-4-hydroxypyrrolidine (3) in 60% overall yield from (1) (eq 1).2

Enantioselective Addition of Thiols to a,b-Unsaturated Ketones and Diisopropyl Maleate.

(2S,4S)-2-(Anilinomethyl)-1-ethyl-4-hydroxypyrrolidine (3) is a chiral amino alcohol which acts as a chiral base catalyst for the enantioselective conjugate addition of aromatic thiols to a,b-unsaturated ketones.2 When an aromatic thiol is treated with a 2-cycloalkenone in the presence of 1 mol % of amino alcohol (3) in toluene at -5 °C, 3-arylthio-1-cycloalkanones with 42-88% ee are obtained in 74-85% yields (eq 2).

The results are shown in Table 1. The reaction between various aromatic thiols and 2-cyclohexen-1-one in the presence of (3) affords the adduct in good ee. The best selectivity is observed in the addition of 4-t-butylbenzenethiol to 2-cyclohexen-1-one using 1 mol % of (3). (R)-3-(4-t-Butylphenylthio)cyclohexan-1-one is obtained in 88% ee. When cinchonine is employed as a chiral catalyst in the same reaction, the corresponding adduct with (S) configuration is obtained in 67% ee.4

In the addition of benzenethiol to 2-cyclohexen-1-one, the enantioselectivities using (3)2b and cinchonidine4b are 77 and 54% ee, respectively. Thus (3) is more enantioselective than cinchonine and cinchonidine in the addition of RSH to 2-cyclohexen-1-one. However, in the addition of 4-t-butylbenzenethiol to a substituted enone (5,5-dimethyl-2-cyclohexen-1-one), the cinchonidine catalyst showed higher enantioselectivity (62% ee)4 than catalyst (2) (42% ee).

Cinchonidine is more enantioselective than (3) in the addition to acyclic a,b-unsaturated esters. When benzenethiol is allowed to react with diisopropyl maleate using chiral catalyst (3), (R)-diisopropyl phenylthiosuccinate with 6% ee is obtained. The same reaction employing cinchonine afforded the (S) adduct with 81% ee (eq 3).5


1. Mukaiyama, T. T 1981, 37, 4111.
2. (a) Mukaiyama, T.; Ikegawa, A.; Suzuki, K. CL 1981, 165. (b) Suzuki, K.; Ikegawa, A.; Mukaiyama, T. BCJ 1982, 55, 3277.
3. Patchett, A. A.; Witkop, B. JACS 1957, 79, 185.
4. (a) Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. TL 1977, 2181. (b) Hiemstra, H.; Wynberg, H. JACS 1981, 103, 417.
5. Yamashita, H.; Mukaiyama, T. CL 1985, 363.

Kenso Soai

Science University of Tokyo, Japan



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.