Enantioselective hydrogenation of pyrrolidine-2,3,5-triones over the Pt- cinchonidine system

Article abstract of DOI:10.1016/S0957-4166(98)00499-6

1- and 4-Substituted pyrrolidine-2,3,5-triones 5, 6 and 9 have been synthesized and hydrogenated to 3-hydroxy derivatives 10-12 with 17-91% ee using a 5 wt% Pt/Al₂O₃ catalyst in the presence of small amounts of cinchonidine. The infl

Full text of DOI:10.1016/S0957-4166(98)00499-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 61–76
Enantioselective hydrogenation of pyrrolidine-2,3,5-triones over
the Pt–cinchonidine system
A. Szabo, N. Künzle, T. Mallat and A. Baiker ∗
Laboratory of Technical Chemistry, Swiss Federal Institute of Technology, ETH-Zentrum, CH-8092 Zürich, Switzerland
Received 15 October 1998; accepted 9 December 1998
Abstract
1- and 4-Substituted pyrrolidine-2,3,5-triones 5, 6 and 9 have been synthesized and hydrogenated to 3-hydroxy
derivatives 10–12 with 17–91% ee using a 5 wt% Pt/Al2O3 catalyst in the presence of small amounts of
cinchonidine. The influence of substituents on the enantioselectivity is discussed. © 1999 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Enantioselective hydrogenation of carbonyl compounds is one of the most intensively studied areas of
asymmetric catalysis.1 An efficient strategy to achieve reasonable enantioselectivity over solid catalysts is
the modification of an active metal by a preadsorbed homochiral compound.2 Since the first application
of cinchona-modified Pt,3 considerable effort has been made to broaden the application range of this
catalyst system. Good to high ees were obtained in the hydrogenation of α-ketoesters (97.5%),4 α-
ketoacids (85%)5 and ketopantolactone (91.6%).6 The hydrogenation of other types of activated carbonyl
compounds such as α-diketones, trifluoroacetophenone and pyruvamides was less successful, affording
only 60% ee or less.7
We have reported recently8 that a cyclic imidoketone could be hydrogenated to the corresponding
alcohol with 91% ee, using the Pt–cinchonidine system. The aim of the present work is to reveal
the influence of the structure of cyclic ketoimides on the enantiodifferentiation. A series of 1- and
4-substituted pyrrolidine-2,3,5-triones was prepared and hydrogenated with a cinchonidine-modified
Pt/Al2O3 catalyst. The simple and economical procedure, starting from easily available racemic com-
pounds, seems to be a promising method for the preparation of chiral alcohols. It has been reported
that enantiomerically pure alcohols such as (S)-N-methyl-2-hydroxysuccinimide are excellent chiral
auxiliaries for Lewis acid catalyzed enantioselective Diels–Alder reactions of enolates.9
∗
Corresponding author. E-mail: baiker@tech.chem.ethz.ch
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00499-6

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2. Results and discussion
2.1. Synthesis of substrates 5, 6 and 9
Most of the cyclic ketoimides were prepared from the racemic lactones 1 and 2, according to Scheme 1.
The lactone ring was cleaved by an amine and the amides 3 and 4 were oxidized with pyridinium
dichromate (PDC)10 in DMF solution affording the cyclic ketoimides 5 and 6.
Scheme 1. (i) R2NH2/MeOH, reflux, 2 h; (ii) PDC/DMF, RT, 24 h
Compounds 9a–c were synthesized by an alternative route starting from the corresponding diphenyl
acetamides 7a–c, as shown in Scheme 2. The oxazolinediones 8 formed in the reaction of amides with
oxalyl chloride were rearranged to 9a–c by refluxing in ethanolic solutions in the presence of catalytic
amounts of pyridine.11
Scheme 2. (i) Oxalylchloride/benzene, 60°C, 12 h; (ii) pyridine/EtOH, reflux, 12 h
2.2. Product conformation
The enantioselective hydrogenation of 1-ethyl-4,4-dimethylpyrrolidine-2,3,5-trione (5a in Scheme 3)
over cinchona-modified Pt/Al2O3 afforded 10a in over 90% ee.8 Taking the hydrogenation of other α-
functionalized carbonyl compounds with the same catalyst as analogies, it is likely that the (R)-isomer of
10a was formed in excess.
For the determination of the absolute configuration of the hydroxyimide 10a, the pure (R)-isomer (R)-
10a has been synthesized from (R)-pantolactone [(R)-1 according to Scheme 4]. The hydroxyl function
of (R)-1 was protected by a tetrahydropyranyl group. After treatment with ethylamine the resulting
hydroxyamide was oxidized with PDC in DMF. Deprotection in the presence of TsOH gave (R)-10
in enantiomerically pure form. Gas chromatographic analysis using a chiral column corroborated that
(R)-10 is identical with the main product obtained in the hydrogenation of 5a.

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63
Scheme 3. (i) H2/Pt/Al2O3, cinchonidine, toluene, 10°C
Scheme 4. (i) 3,4-Dihydro-2H-pyran, HCl/dioxane, RT, 2 h; (ii) EtNH2/MeOH, RT, 2 h; (iii) PDC, DMF, RT, 24 h; (iv) TsOH,
MeOH, RT, 2 h
2.3. Enantioselective hydrogenation
Preliminary experiments revealed that good ee could be achieved only if the catalyst was pretreated in
hydrogen at elevated temperatures (Table 1, entries 1 and 2). This behaviour and similar observations6,12
in the hydrogenation of other carbonyl compounds with cinchona-modified Pt may be explained by some
surface restructuring of the metal particles during the reductive heat treatment. Entry 3 in Table 1 shows
that an oxidative treatment subsequent to the reductive treatment at the same temperature, causes a drop
in selectivity to the initial value of the untreated catalyst. (Note that the ‘untreated’ Pt/Al2O3 was stored
in air and the surface was in an oxidized state.) Apparently, the transformation of the metal particles at
400°C from ‘unselective’ to ‘selective’ structures and vice versa is reversible.
It was found8 to be important to apply rather low modifier concentrations, in the range of 50–200 µmol
l−1. The modifier is simply added to the reaction mixture and during the initial period of the reaction a
steady state seems to be reached on the metal surface. It is assumed that the modifier competes for the
metallic active sites (Pt0) with hydrogen, substrate and product. Both too high and too low cinchonidine
concentrations diminish the final ee. For example, in the hydrogenation of 5a the ee decreased by 10%
when the cinchonidine concentration was higher than 1 mmol l−1 or lower than 1 µmol l−1. The optimum
corresponds to a substrate/modifier molar ratio of almost 70 000.
As shown in Fig. 1, the solvent plays a crucial role in the enantioselective hydrogenation of pyrrolidine-
2,3,5-triones. The ee increased with decreasing solvent polarity, except for strongly apolar solvents such
as cyclohexane or n-hexane, in which media the reactant and modifier are only sparsely soluble. Acidic
solvents (acetic acid, formic acid) afforded significantly higher ees than expected on the basis of their

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Table 1
Influence of catalyst pretreatment at 400°C on the enantiomeric excess at full conversion of 5a. Con-
ditions: 3.2 mmol N-ethyl-4,4-dimethylpyrrolidine-2,3,5-trione, 60 mg 5 wt% Pt/Al2O3, 2 mmol l−1
cinchonidine, 5 ml toluene, 30 bar, 15°C, reaction time: 60 min
N
Figure 1. Influence of the empirical solvent parameter ET on the ee in the hydrogenation of 5a. Conditions: 3.2 mmol
N-ethyl-4,4-dimethylpyrrolidine-2,3,5-trione, 70 bar, 15 C, 60 mg catalyst, 2 mmol l−1 cinchonidine, 5 ml solvent (1: cyclohex-
ane, 2: n-hexane, 3: toluene, 4: THF, 5: ethanol, 6: N-methylformamide, 7: water, 8: acetic acid, 9: formic acid, 10: ethanol+1.3
wt% acetic acid, 11: water+1 wt% acetic acid)
N 13
polarity, characterized by the empirical solvent parameter ET
.
Similarly, addition of small amounts
of acetic acid to protic polar solvents enhanced the ee remarkably. We have found very recently14 that
the conformation of cinchonidine changes with solvent polarity. Apolar solvents or protonation of the
quinuclidine N of cinchonidine enhances the proportion of the ‘open 3’ conformation.15 Molecular
modelling indicated2d,6a that this conformation affords the highest ee via interaction with the activated
carbonyl compound reactant on the Pt surface.
Another crucial parameter was the surface hydrogen concentration. Good ees could be achieved only
above 30 bar hydrogen pressure.8 The positive effect of high hydrogen concentration may be attributed
to the rapid removal of some surface contamination at the beginning of the reaction (as has been shown
for the enantioselective hydrogenation of ethyl pyruvate),16 but other effects can also play a role.
The enantioselectivity decreased gradually with increasing reaction temperature. This small but

A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
65
Figure 2. Influence of temperature on the ee in the hydrogenation of 5a. Conditions: 3.2 mmol N-ethyl-4,4-dimethyl-
pyrrolidine-2,3,5-trione, 70 bar, 60 mg catalyst, 10 mmol l−1 cinchonidine, 5 ml toluene
significant effect is illustrated in Fig. 2 by the example of the hydrogenation of 5a. A similar correlation
was observed in the hydrogenation of α-ketoesters17,18 and α-ketopantolactone.6
For the study of the influence of substituents in the 1 and 4 positions, 10 different pyrrolidine-2,3,5-
triones 5, 6 and 9 have been hydrogenated under identical conditions. The results are collected in Table 2.
The highest ee (85%) was obtained in the reduction of 6d. It is hoped that by optimizing the reaction
conditions, the ees can be significantly improved. For example, variation of some important parameters
afforded 91.2ꢀ0.5% ee in the hydrogenation of 5a. [Conditions: 80 bar, 10°C, in 5 ml toluene and 12
mmol l−1 acetic acid, 7.2 µmol l−1 cinchonidine and 60 mg catalyst (5 wt% Pt/Al2O3).8]
It seems from Table 2 that methyl and phenyl groups in the R1 position lead to higher ees, compared
to ethyl groups, except when R2 is cyclohexyl. For the R2 groups the selectivity order is Bn≥Et>n-
Bu>c-Hex. Apparently, bulky alkyl and cycloalkyl substituents disfavour the enantiodifferentiation,
but the electron-rich aromatic and alkyl-aromatic substituents are exceptions. This conclusion requires
further confirmation due to the presence of small amounts of impurities in substrates 5, 6 and 9. For
comparison, in the most selective reaction the chiral modifier cinchonidine was present in 15 ppm relative
to the substrate 5a. If traces of cinchonidine can result in dramatic changes in stereoselectivity, we
cannot exclude the possible influence of (unknown) impurities present in the substrates in much higher
concentrations (up to 0.1–0.5 wt%).
On the basis of the high ee achieved in the hydrogenation of 6d (Table 2) we suggest that the N-
benzyl group contributes to favourable adsorption of the substrate on the platinum surface and seems
to enhance enantiodifferentiation. Based on our previous theoretical studies on the structure of the
enantiodifferentiating complex6a,2d in α-ketoester hydrogenations we propose the complex shown in
Fig. 3 to be relevant. The top-side view of the half-hydrogenated state of 6d, stabilized by an H-
bond interaction with the quinuclidine N-atom of cinchonidine is presented. The minimum energy
conformations of 6d and cinchonidine (‘open 3’)15 have been determined independently using the
‘Hyperchem’ program. Note that the structure shown is not optimized, some deviations may be possible.
Optimization, including the metal surface interaction is targeted in future work.
Bulky substituents in the 1 and 4 positions are assumed to hinder the appropriate adsorption of the
substrate and diminish the ee. The best example of this case is the hydrogenation of 9c. A comparison of
substrates 6d and 9c can explain the 68% difference in ee in their hydrogenation. In 6d the electron-rich

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Table 2
Enantiomeric excess in the hydrogenation of 1- and 4-substituted pyrrolidine-2,3,5-triones according
to Scheme 3. Conditions: 60 bar, 10°C, 60 mg catalyst, 10 µmol l−1 cinchonidine, 5 ml toluene,
reaction time: 60 min. Conversion was always 100%
Figure 3. Top-side view of the half-hydrogenated state of 6d, stabilized by cinchonidine via an H-bond interaction. The benzyl
group may strengthen the adsorption of 6d on the metal surface
N-benzyl group can strongly interact with the Pt surface (soft acid). Besides, the benzyl and the two ethyl
groups possess enough flexibility to adopt the appropriate adsorption geometry on the surface of the Pt
particle. On the contrary, the bulky phenyl and cyclohexyl groups are assumed to hinder the adsorption
of the reducible carbonyl group parallel to the metal surface (Fig. 4). An η2 di-σ adsorption mode was
found to be the preferred adsorption geometry for carbonyl compounds on Pt by molecular modelling.19
Also, this adsorption mode was suggested by a theoretical study of cinchonidine–ethyl pyruvate and
cinchonidine–ketopantolactone activated complexes.6a

A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
67
Figure 4. Space-filled model of 9c (bottom-side view). Bulky substituents in the 1 and 4 positions represent steric barriers for
appropriate adsorption of the carbonyl group to be hydrogenated
3. Conclusions
Hydrogenations of pyrrolidine-2,3,5-triones represent an extension of the application range of
cinchona-modified Pt to a new class of reactants. Similarly to the former successful applications of this
catalyst system,3–7 the carbonyl groups in 5, 6 and 9 are activated by an electron-withdrawing group
in the α-position. The present work provides the first detailed investigation on the influence of reactant

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structure on the enantiomeric excess over chirally modified Pt. It is hoped that this study will contribute
to a better understanding of the mechanism of enantiodifferentiation.
4. Experimental
4.1. General
1
Melting points are uncorrected. H- and 13C-NMR spectra were recorded on a Bruker DPX300
instrument at 300.13 and 75.48 MHz in CDCl3 (internal standard: TMS). IR data were obtained
on a Perkin–Elmer 2000 FT-IR spectrometer in CCl4 solution. The optical purity of the compounds
prepared and enantiomeric excess of hydroxyimides formed in the hydrogenation were determined by
gas chromatography (10a–c, 11a–c, WCOT cyclodextrin-β-2,3,6-M-19 Chrompack column) or NMR
1
spectroscopy using (1R)-10-camphorsulphonic acid (10d, H-NMR) or (R)-MTPA (12a–c, 19F-NMR)
derivatives. Acylation was performed with the acid chloride (1.5 equiv.) in dichloromethane solution in
the presence of DMAP and triethylamine.20
4.2. 4,4-Diethyl-4,5-dihydro-3-hydroxy-2(3H)-furanone 2
4,4-Diethyl-4,5-dihydrofuran-2,3-dione21 (15.6 g, 0.10 mol) was hydrogenated in toluene (20 cm3) in
the presence of a 5 wt% Pt/C catalyst (200 mg) at room temperature under 60 bar pressure for 48 h.
The catalyst was filtered off and the solvent was evaporated under reduced pressure. Recrystallization of
the crude crystalline product from tert-butyl methyl ether and hexane (1:1) gave white platelets (14.6 g,
1
92%). Mp 76–78°C; IR (cm−1) 3700–2800, 1780; H-NMR 4.24 (s, 1H), 4.14 (d, J=9.3 Hz, 1H), 3.91
(d, J=9.3 Hz, 1H), 3.07 (br s, 1H), 1.65–1.52 (m, 4H), 0.98 (t, J=7.5 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H);
13C-NMR 178.6, 74.6, 73.2, 46.5, 28.1, 21.5, 8.4, 8.1. Anal. calcd for C8H14O3 (158.2) C 60.74, H 8.92;
found C 60.66, H 8.97.
4.3. Preparation of N-alkyl-2,4-dihydroxy-3,3-dialkylbutyramides 3, 4: general procedure
A solution of 4,4-dialkyl-4,5-dihydro-3-hydroxy-2(3H)-furanone (0.05 mol) in 20 cm3 methanol was
cooled with ice water and the corresponding alkylamine (0.06 mol) was added. After stirring at room
temperature for 3 h, the solvent was evaporated under reduced pressure. White crystalline materials
3a–d were obtained after recrystallization of the crude products from tert-butyl methyl ether and hexane.
Column chromatography (silica gel, tert-butyl methyl ether) of 4a–c resulted in colourless oils.
4.4. N-Ethyl-2,4-dihydroxy-3,3-dimethylbutyramide 3a
Yield 95%; mp 62–63°C; IR (cm−1) 3700–3200, 3419, 3100–2800 and 1657; 1H-NMR 7.03 (br s, 1H),
4.81 (br s, 1H), 4.30 (br s, 1H), 3.99 (d, J=4.6 Hz, 1H), 3.48 (qa, J=7.2 Hz, 2H), 3.41–3.20 (m, 2H), 1.16
(t, J=7.2 Hz, 3H), 0.98 (s, 3H), 0.91 (s, 3H); 13C-NMR 173.5, 77.3, 77.2, 49.3, 33.9, 21.2, 20.2, 14.8.
Anal. calcd for C8H17NO3 (175.2) C 54.84, H 9.78, N 7.99; found C 54.85, H 9.81, N 7.89.

A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
69
4.5. N-Butyl-2,4-dihydroxy-3,3-dimethylbutyramide 3b
1
Yield 89%; mp 40–42°C; IR (cm−1) 3500–3200, 3000–2820, 1653; H-NMR 7.02 (t, J=5.7 Hz, 1H),
4.80 (br s, 1H), 4.32 (br s, 1H), 4.00 (s, 1H), 3.47 (s, 2H), 3.25 (m, 2H), 1.51 (qa, J=8.6 Hz, 2H), 1.35
(sex, J=8.6 Hz, 2H), 1.19 (s, 3H), 0.93 (t, J=8.6 Hz, 3H), 0.91 (s, 3H); 13C-NMR 173.6, 76.6, 71.2, 49.4,
39.3, 31.5, 21.3, 20.1, 20.0, 13.7. Anal. calcd for C10H21NO3 (203.3) C 59.09, H 10.41, N 6.89; found C
59.33, H 10.44, N 6.62.
4.6. N-Cyclohexyl-2,4-dihydroxy-3,3-dimethylbutyramide 3c
1
Yield 90%; mp 100–103°C; IR (cm−1) 3700–3200, 3100–2800, 1655; H-NMR 6.88 (d, J=8.4 Hz,
1H), 4.42 (br s, 2H), 3.97 (s, 1H), 3.75 (m, 1H), 3.47 (s, 2H), 1.90–1.10 (m, 10H), 0.98 (s, 3H), 0.90
(s, 3H); 13C-NMR 172.6, 76.4, 71.2, 47.9, 39.3, 25.5, 24.8, 24.7, 24.6, 21.3, 18.9, 14.1. Anal. calcd for
C12H23NO3 (229.3) C 62.85, H 10.11, N 6.11; found C 62.70, H 10.03, N 6.11.
4.7. N-Benzyl-2,4-dihydroxy-3,3-dimethylbutyramide 3d
1
Yield 93%; mp 101–104°C; IR (cm−1) 3700–3200, 3000–2850, 1653; H-NMR 7.34–7.22 (m, 5H),
4.42 (dqa, J=6.1 and 12.3 Hz, 2H), 4.05 (s, 1H), 3.46 (s, 2H), 0.97 (s, 3H), 0.91 (s, 3H); 13C-NMR 173.4,
137.8, 128.7, 127.7, 127.6, 77.6, 71.3, 43.1, 39.4, 21.2, 20.3. Anal. calcd for C13H20NO3 (237.3) C 65.80,
H 8.07, N 5.90; found C 65.75, H 7.85, N 5.99.
4.8. N-3,3-Triethyl-2,4-dihydroxybutyramide 4a
1
Yield 85%; IR (cm−1) 3600–3050, 3020–2800, 1653; H-NMR 7.03 (br s, 1H), 4.14 (s, 1H), 3.61 (s,
2H), 3.32 (qi, J=3.5 Hz, 2H), 1.48 (qa, J=7.5 Hz, 4H), 1.17 (t, J=7.3 Hz, 3H), 0.88 and 0.86 (overlapping
ts, J=7.5 Hz, 6H); 13C-NMR 174.2, 76.2, 66.8, 43.8, 34.1, 24.4, 23.2, 14.7, 7.9, 7.6. Anal. calcd for
C10H21NO3 (203.3) C 59.08, H 10.41, N 6.89; found C 58.87, H 10.38, N 6.93.
4.9. N-Butyl-2,4-dihydroxy-3,3-diethylbutyramide 4b
1
Yield 92%; IR (cm−1) 3600–3200, 3000–2830, 1653; H-NMR 6.91 (br s, 1H), 4.16 (s, 1H), 3.62 (s,
2H), 3.30 (m, 2H), 1.60–1.30 (m, 8H), 0.93, 0.89 and 0.87 (overlapping ts, J=7.4 Hz, 9H); 13C-NMR
173.9, 76.3, 67.0, 43.9, 39.0, 31.5, 24.5, 23.3, 20.1, 13.7, 7.9, 7.6. Anal. calcd for C12H25NO3 (231.3) C
62.31, H 10.89, N 6.06; found C 62.44, H 10.67, N 6.02.
4.10. N-Cyclohexyl-2,4-dihydroxy-3,3-diethylbutyramide 4c
1
Yield 90%; IR (cm−1) 3700–3200, 3050–2850, 1654; H-NMR 6.70 (d, J=8.1 Hz, 1H), 4.13 (s, 1H),
3.80 (m, 1H), 3.62 (s, 2H), 1.94–1.10 (m, 14H), 0.90 and 0.86 (overlapping ts, J=7.3 Hz, 6H); 13C-NMR
173.1, 76.1, 66.9, 48.1, 43.9, 33.0, 32.8, 25.5, 24.8, 24.7, 24.6, 23.3, 7.9, 7.6. Anal. calcd for C14H27NO3
(257.4) C 65.33, H 10.57, N 5.44; found C 65.25, H 10.50, N 5.61.

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4.11. Preparation of pyrrolidine-2,3,5-triones 5, 6: general procedure
The corresponding N-alkyl-2,4-dihydroxy-3,3-dialkylbutyramide (0.03 mol) and pyridinium dichro-
mate (PDC, 67.7 g, 0.18 mol) were dissolved in 120 cm3 dry DMF and the mixture was stirred for 24 h at
room temperature. The solution was poured into 10 volumes of water and then extracted with tert-butyl
methyl ether. After drying of the combined organic layers over MgSO4 the solvent was removed under
reduced pressure. The crude product was purified by Kugelrohr distillation 5a–b, 6a–c or recrystallization
5c–d from tert-butyl methyl ether.
4.12. 1-Ethyl-4,4-dimethylpyrrolidine-2,3,5-trione 5a
Pale yellow oil; yield 55%; IR (cm−1) 3050–2800, 1775, 1717; 1H-NMR 3.78 (qa, J=7.2 Hz, 2H), 1.37
(s, 6H), 1.28 (t, J=7.2 Hz, 3H); 13C-NMR 197.3, 176.6, 160.0, 45.6, 34.2, 19.8, 12.8. Anal. calcd for
C8H11NO3 (169.2) C 56.80, H 6.55, N 8.28; found C 56.67, H 6.71, N 8.28.
4.13. 1-Butyl-4,4-dimethylpyrrolidine-2,3,5-trione 5b
Pale yellow oil; yield 80%; IR (cm−1) 3000–2850, 1777, 1724, 1701; 1H-NMR 3.70 (t, J=7.3 Hz, 2H),
1.62 (qi, J=7.5 Hz, 2H), 1.33 (s, 6H), 1.32 (sex, J=7.4 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); 13C-NMR 197.3,
176.8, 160.2, 45.7, 39.0, 29.6, 20.0, 13.5. Anal. calcd for C10H15NO3 (197.2) C 60.90, H 7.67, N 7.10;
found C 60.63, H 7.73, N 7.13.
4.14. 1-Cyclohexyl-4,4-dimethylpyrrolidine-2,3,5-trione 5c
1
Pale yellow crystals; yield 78%; mp 91–93°C; IR (cm−1) 3020–2830, 1775, 1718; H-NMR 4.20 (tt,
J=3.8 and 12.3 Hz, 1H), 2.30–1.15 (m, 16H); 13C-NMR 197.3, 176.9, 160.0, 52.3, 45.2, 28.8, 25.6, 24.8,
20.0. Anal. calcd for C12H17NO3 (223.3) C 64.55, H 7.67, N 6.27; found C 64.38, H 7.60, N 6.44.
4.15. 1-Benzyl-4,4-dimethylpyrrolidine-2,3,5-trione 5d
1
White crystals; yield 75%; mp 108–110°C; IR (cm−1) 3250–2800, 1778, 1723, 1700; H-NMR
7.47–7.23 (m, 5H), 4.87 (s, 2H), 1.34 (s, 6H); 13C-NMR 197.0, 176.4, 159.8, 134.6, 128.9, 128.8, 128.4,
45.9, 42.7, 19.9. Anal. calcd for C13H13NO3 (231.3) C 67.52, H 5.67, N 6.06; found C 67.62, H 5.79, N
6.12.
4.16. 1,4,4-Triethylpyrrolidine-2,3,5-trione 6a
1
Pale yellow oil; yield 70%; IR (cm−1) 3020–2820, 1774, 1719, 1701; H-NMR 3.83 (qa, J=7.3 Hz,
2H), 1.89 (qa, J=7.5 Hz, 4H), 1.29 (t, J=7.3 Hz, 3H), 0.83 (t, J=7.5 Hz, 6H); 13C-NMR 199.4, 176.0,
160.6, 55.8, 34.2, 27.9, 13.2, 9.0. Anal. calcd for C10H15NO3 (197.2) C 60.91, H 7.67, N 7.10; found C
61.04, H 7.76, N 7.05.
4.17. 1-Butyl-4,4-diethylpyrrolidine-2,3,5-trione 6b
Pale yellow oil; yield 80%; IR (cm−1) 3000–2800, 1774, 1719; 1H-NMR 3.78 (t, J=7.3 Hz, 2H), 1.88
(qa, J=7.5 Hz, 4H), 1.67 (qi, J=7.5 Hz, 2H), 1.37 (sex, J=7.4 Hz, 2H), 0.96 (t, J=7.2 Hz, 3H), 0.83 (t,

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J=7.5 Hz, 6H); 13C-NMR 199.3, 176.1, 160.7, 55.7, 38.9, 29.8, 27.8, 20.0, 13.4, 8.9. Anal. calcd for
C12H19NO3 (225.3) C 63.97, H 8.50, N 6.22; found C 63.76, H 8.59, N 6.14.
4.18. 1-Cyclohexyl-4,4-diethylpyrrolidine-2,3,5-trione 6c
Pale yellow oil; yield 81%; IR (cm−1) 3000–2820, 1773, 1714; 1H-NMR 4.26 (tt, J=3.8 and 12.3 Hz,
1H), 2.23 (m, 2H), 1.85 (qa, J=7.5 Hz, 4H), 1.70 (m, 4H), 1.34 (m, 4H), 0.92 (m, 2H), 0.81 (t, J=7.5
Hz, 6H); 13C-NMR 199.6, 176.3, 160.7, 55.3, 52.6, 29.1, 28.1, 27.0, 25.7, 24.9, 8.9. Anal. calcd for
C14H21NO3 (251.3) C 66.91, H 8.42, N 5.57; found C 66.82, H 8.32, N 5.70.
4.19. Preparation of pyrrolidine-2,3,5-triones 9a–c: general procedure
(i) A solution of N-alkyl-2,2-diphenyl acetamide (0.025 mol) in dry benzene (30 cm3) was heated to
60°C and oxalylchloride (2.7 cm3, 0.031 mol) was added dropwise. The resulting yellow solution
was stirred at the same temperature overnight. After cooling to room temperature, water (50 cm3)
was added, the mixture was stirred for 15 min then 100 cm3 tert-butyl methyl ether was added. The
organic layer was separated, washed with water (2×50 cm3) and dried over MgSO4. After evapo-
ration of the solvent under reduced pressure, the yellow solid residue was crystallized from tert-
butyl methyl ether and hexane (1:1) resulting in the corresponding diphenylmethyleneoxazoline-
4,5-dione 8a–c.
(ii) Diphenylmethyleneoxazoline-4,5-dione derivative 8a–c (0.015 mol) was dissolved in abs. ethanol
(50 cm3) and 2 drops of pyridine were added. The mixture was refluxed gently overnight (the yellow
colour of the solution turned to pale yellow). Ethanol was evaporated after cooling and the product
was crystallized from the appropriate solvent 9a,c or chromatographed (9b, silica gel, tert-butyl
methyl ether/hexane).
4.20. 3-Ethyl-2-diphenylmethyleneoxazoline-4,5-dione 8a
1
Yellow crystals; yield 83%; mp 163–165°C; IR (cm−1) 1828, 1751, 1653; H-NMR 7.45–7.21 (m,
10H), 3.36 (qa, J=7.1 Hz, 2H), 0.94 (t, J=7.1 Hz, 3H); 13C-NMR 154.7, 151.7, 137.3, 136.8, 135.4,
130.8, 130.0, 129.0, 128.8, 128.2, 127.8, 108.3, 78.7, 38.7, 13.0. Anal. calcd for C18H15NO3 (293.3) C
73.71, H 5.16, N 4.78; found C 73.51, H 5.26, N 4.90.
4.21. 3-Butyl-2-diphenylmethyleneoxazoline-4,5-dione 8b
1
Yellow crystals; yield 80%; mp 122–123°C; IR (cm−1) 1828, 1750, 1653; H-NMR 7.45–7.20 (m,
10H), 3.29 (t, J=8.0 Hz, 2H), 1.33 (qa, J=8.0 Hz, 2H), 0.86 (sex, J=7.6 Hz, 2H), 0.69 (t, J=7.2 Hz, 3H);
13C-NMR 154.7, 151.8, 137.6, 136.9, 135.5, 131.0, 130.0, 128.9, 128.7, 128.3, 127.9, 108.3, 78.7, 43.4,
29.7, 19.5, 13.3. Anal. calcd for C20H19NO3 (321.4) C 74.74, H 5.96, N 4.36; found C 74.58, H 6.08, N
4.31.
4.22. 3-Cyclohexyl-2-diphenylmethyleneoxazoline-4,5-dione 8c
1
Yellow crystals; yield 85%; mp 204–205°C; IR (cm−1) 3000–2830, 1822, 1750, 1653; H-NMR
7.45–7.20 (m, 10H), 2.97 (tt, J=3.6 and 12.0 Hz, 1H), 2.19 (m, 2H), 1.58 (m, 4H), 1.40 (m, 1H), 1.04
(m, 1H), 0.50 (m, 2H); 13C-NMR 155.0, 151.7, 137.8, 137.1, 136.4, 130.0, 130.0, 128.9, 128.8, 128.2,

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A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
127.7, 107.8, 78.7, 57.3, 27.7, 25.5, 24.4. Anal. calcd for C22H21NO3 (347.4) C 76.06, H 6.09, N 4.03;
found C 75.81, H 6.34, N 4.14.
4.23. 1-Ethyl-4,4-diphenylpyrrolidine-2,3,5-trione 9a
Pale yellow crystals; yield 84%; mp 84–86°C (tert-butyl methyl ether/hexane); IR (cm−1) 3000–2820,
1773, 1719; 1H-NMR 7.4–7.2 (m, 10H), 3.91 (qa, J=7.3 Hz, 2H), 1.34 (t, J=7.3 Hz, 3H); 13C-NMR 192.9,
172.8, 159.8, 135.1, 129.2, 128.9, 128.8, 128.7, 128.3, 63.3, 35.0, 13.0. Anal. calcd for C18H15NO3
(293.3) C 73.71, H 5.16, N 4.78; found C 73.96, H 5.29, N 4.99.
4.24. 1-Butyl-4,4-diphenylpyrrolidine-2,3,5-trione 9b
1
Yellow oil; yield 61%; IR (cm−1) 3050–2850, 1773, 1718, 1703; H-NMR 7.40–7.30 (m, 10H), 3.85
(t, J=7.4 Hz, 2H), 1.70 (qi, J=7.4 Hz, 2H), 1.40 (sex, J=7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); 13C-NMR
192.9, 173.1, 157.9, 135.2, 129.1, 129.0, 128.9, 128.8, 128.4, 63.1, 39.7, 29.6, 20.0, 13.5. Anal. calcd for
C20H19NO3 (321.4) C 74.74, H 5.96, N 4.36; found C 74.47, H 6.17, N 4.18.
4.25. 1-Cyclohexyl-4,4-diphenylpyrrolidine-2,3,5-trione 9c
Pale yellow crystals; yield 86%; mp 108–109°C (EtOH); IR (cm−1) 3000–2830, 1773, 1717, 1700;
1H-NMR 7.45–7.15 (m, 10H), 4.34 (tt, J=3.8 and 12.3 Hz, 1H), 2.34–1.20 (m, 10H); 13C-NMR 192.9,
173.1, 160.0, 135.3, 129.1, 128.7, 128.4, 62.9, 53.2, 28.9, 25.7, 24.9. Anal. calcd for C22H21NO3 (347.4)
C 76.06, H 6.09, N 4.03; found C 75.80, H 6.17, N 4.02.
4.26. 1-Ethyl-3-hydroxy-4,4-dimethylpyrrolidine-2,5-dione 10a
1
Colourless oil; 82% ee; IR (cm−1) 3600–3100, 3050–2800, 1705; H-NMR 4.29 (s, 1H), 3.54 (qa,
J=7.2 Hz, 2H), 1.37 (s, 3H), 1.22 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); 13C-NMR 180.7, 177.7, 75.4, 45.2,
33.6, 22.3, 19.8, 12.8. Anal. calcd for C8H13NO3 (171.2) C 56.12, H 7.65, N 8.18; found C 56.00, H
7.47, N 7.97.
4.27. 1-Butyl-3-hydroxy-4,4-dimethylpyrrolidine-2,5-dione 10b
1
Colourless oil; 58% ee; IR (cm−1) 3700–2800, 1784, 1702; H-NMR 4.30 (s, 1H), 3.49 (t, J=7.5 Hz,
2H), 1.55 (qi, J=7.5 Hz, 2H), 1.37 (s, 3H), 1.30 (sex, J=7.5 Hz, 2H), 1.22 (s, 3H), 0.92 (t, J=7.4 Hz, 3H);
13C-NMR 180.8, 177.9, 75.4, 45.2, 38.5, 29.6, 22.4, 20.0, 19.9, 13.6. Anal. calcd for C10H17NO3 (199.3)
C 60.27, H 8.60, N 7.03; found C 60.03, H 8.60, N 7.10.
4.28. 1-Cyclohexyl-3-hydroxy-4,4-dimethylpyrrolidine-2,5-dione 10c
1
White crystals; 61% ee; mp 101–102°C; IR (cm−1) 3700–2800, 1773, 1709; H-NMR 4.21 (s, 1H),
3.92 (tt, J=3.9 and 12.3 Hz, 1H), 2.17–1.15 (m, 10H), 1.37 (s in m), 1.18 (s in m); 13C-NMR 180.6, 177.9,
75.4, 51.6, 45.2, 29.2, 28.5, 25.8, 25.0, 25.7, 22.2, 20.0. Anal. calcd for C12H19NO3 (225.3) C 63.98, H
8.50, N 6.22; found C 64.02, H 8.43, N 6.27.

A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
73
4.29. 1-Benzyl-3-hydroxy-4,4-dimethylpyrrolidine-2,5-dione 10d
White crystals; 85% ee; mp 61–65°C; IR (cm−1) 3700–2800, 1772, 1716; 1H-NMR 7.31 (m, 5H), 4.63
(s, 2H), 4.26 (s, 1H), 1.36 (s, 3H), 1.17 (s, 3H); 13C-NMR 180.4, 177.4, 135.4, 128.7, 128.6, 128.5, 128.0,
75.6, 45.4, 42.3, 22.3, 19.8. Anal. calcd for C13H15NO3 (233.3) C 66.93, H 6.48, N 6.00; found C 66.86,
H 6.39, N 5.93.
4.30. 1,4,4-Triethyl-3-hydroxypyrrolidine-2,5-dione 11a
1
Colourless oil; 40% ee; IR (cm−1) 3700–3000, 3020–2800, 1773, 1700; H-NMR 4.39 (s, 1H), 3.57
(qa, J=7.2 Hz, 2H), 1.77 (m, 4H), 1.19 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H), 0.85 (t, J=7.5 Hz, 3H);
13C-NMR 179.2, 178.6, 72.2, 52.8, 33.6, 27.3, 25.8, 13.1, 9.3, 8.6. Anal. calcd for C10H17NO3 (199.3) C
60.27, H 8.60, N 7.03; found C 60.05, H 8.68, N 7.12.
4.31. 1-Butyl-3-hydroxy-4,4-diethylpyrrolidine-2,5-dione 11b
Colourless oil; 33% ee; IR (cm−1) 3700–3000, 3050–2800, 1773, 1701; 1H-NMR 4.38 (s, 1H), 3.48 (t,
J=7.5 Hz, 2H), 1.75 (m, 4H), 1.55 (qi, J=7.5 Hz, 2H), 1.30 (sex, J=7.5 Hz, 2H), 0.93 and 0.91 (overlapping
ts, J=7.3 Hz, 6H), 0.84 (t, J=7.5 Hz, 3H); 13C-NMR 179.4, 178.8, 72.2, 52.8, 38.4, 29.8, 27.2, 25.7, 20.1,
13.6, 9.3, 8.5. Anal. calcd for C12H21NO3 (227.3) C 63.41, H 9.31, N 6.16; found C 62.50, H 9.37, N
5.85.
4.32. 1-Cyclohexyl-3-hydroxy-4,4-diethylpyrrolidine-2,5-dione 11c
1
Colourless oil, 69% ee; IR (cm−1) 3700–3100, 3050–2800, 1773, 1700; H-NMR 4.30 (s, 1H), 4.00
(tt, J=3.8 and 12.4 Hz, 1H), 2.20–1.54 (m, 10H), 1.36–1.23 (m, 4H), 0.93 and 0.84 (overlapping ts, J=7.4
Hz, 6H); 13C-NMR 179.3, 178.8, 72.0, 52.5, 51.7, 29.4, 28.7, 27.4, 25.9, 25.8, 25.7, 25.0, 9.4, 8.5. Anal.
calcd for C14H23NO3 (253.3) C 66.39, H 9.16, N 5.53; found C 66.30, H 9.10, N 5.71.
4.33. 1-Ethyl-3-hydroxy-4,4-diphenylpyrrolidine-2,5-dione 12a
81% ee; mp 59–60°C; IR (cm−1) 3700–2800, 1750, 1716; 1H-NMR 7.66 (m, 2H), 7.43–7.22 (m, 6H),
7.01 (m, 2H), 5.15 (s, 1H), 3.71 (qa, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz); 13C-NMR 176.0, 175.3, 139.1,
137.5, 128.9, 128.8, 128.7, 128.3, 128.1, 128.0, 75.0, 61.8, 34.2, 12.8. Anal. calcd for C18H17NO3 (295.3)
C 73.21, H 5.80, N 4.74; found C 73.45, H 5.90, N 4.56.
4.34. 1-Butyl-3-hydroxy-4,4-diphenylpyrrolidine-2,5-dione 12b
1
White crystals; 58% ee; mp 100–104°C; IR (cm−1) 3700–2850, 1772, 1700; H-NMR 7.66 (d, J=7.2
Hz, 2H), 7.43–7.26 (m, 6H), 7.03 (d, J=7.9 Hz, 2H), 5.16 (s, 1H), 3.65 (t, J=7.2 Hz, 2H), 1.63 (qi, J=7.2
Hz, 2H), 1.32 (sex, J=7.3 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H); 13C-NMR 176.3, 175.5, 139.2, 137.5, 129.0,
128.9, 128.8, 128.7, 128.3, 128.1, 128.0, 75.1, 63.2, 39.1, 29.6, 20.1, 13.6. Anal. calcd for C20H21NO3
(323.4) C 74.28, H 6.55, N 4.33; found C 74.42, H 6.59, N 4.20.

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A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
4.35. 1-Cyclohexyl-3-hydroxy-4,4-diphenylpyrrolidine-2,5-dione 12c
1
White crystals; 17% ee; mp 156–159°C; IR (cm−1) 3750–2830, 1777, 1700; H-NMR 7.66 (m, 2H),
7.44–7.26 (m, 6H), 7.02 (m, 2H), 5.13 (s, 1H), 4.12 (tt, J=12.3 and 3.8 Hz, 1H), 2.19 (m, 3H), 1.88–1.67
(m, 4H), 1.42–1.18 (m, 3H); 13C-NMR 176.2, 175.2, 139.2, 137.7, 128.9, 128.8, 128.7, 128.4, 128.0,
127.9, 74.6, 61.6, 52.4, 29.3, 28.5, 25.8, 25.7, 25.0. Anal. calcd for C22H23NO3 (349.4) C 75.62, H 6.64,
N 4.01; found C 75.42, H 6.69, N 4.00.
4.36. Determination of the absolute configuration of 10a
(3R)-4,5-Dihydro-4,4-dimethyl-3-(2-tetrahydropyranyloxy)-2(3H)-furanone 13 was prepared and
purified by the method of Ito and Kibayashi22 starting from (R)-pantolactone and 3,4-dihydro-2H-pyran.
4.37. (R)-N-Ethyl-4-hydroxy-3,3-dimethyl-2-(2-tetrahydropyranyloxy)butyramide 14
A solution of (3R)-dihydro-4,4-dimethyl-3-(2-tetrahydropyranyloxy)-2(3H)-furanone (4.28 g, 0.020
mol) in 20 cm3 methanol was cooled with ice water and ethylamine (1.13 g, 0.025 mol) was added.
After stirring for 3 h at room temperature the solvent was evaporated under reduced pressure. The crude
product was purified by Kugelrohr distillation. Colourless oil; yield 92%; IR (cm−1) 3750–2750, 1653;
1H-NMR 6.39 (br s, 1H), 4.40 (t, J=7.3 Hz, 1H), 4.13 (s, 1H), 3.50–3.25 (m, 4H), 1.90–1.50 (m, 6H),
1.19 (t, J=8.4 Hz, 3H), 1.02 (s, 3H), 0.90 (s, 3H); 13C-NMR 171.6, 99.8, 81.4, 70.1, 65.1, 39.4, 33.8,
31.4, 27.0, 24.9, 21.0, 20.9, 15.0. Anal. calcd for C13H25NO4 (259.3) C 60.22, H 9.72, N 5.40; found C
60.04, H 9.65, N 5.47.
4.38. (R)-1-Ethyl-4,4-dimethyl-3-(2-tetrahydropyranyloxy)pyrrolidine-2,5-dione 15
(2R)-N-Ethyl-4-hydroxy-3,3-dimethyl-2-(2-tetrahydropyranyloxy)butyramide (1.03 g, 0.004 mol) and
pyridinium dichromate (7.5 g, 0.02 mol) were dissolved in 20 cm3 dry DMF and the mixture was stirred
for 24 h at room temperature. The solution was poured into 10 volumes of water and then extracted
with tert-butyl methyl ether. After drying of the combined organic layers over MgSO4 the solvent was
removed under reduced pressure. The product was purified by Kugelrohr distillation. Colourless oil; yield
1
63%; IR (cm−1) 3010–2820, 1772, 1716; H-NMR 5.20 (m, 1H), 4.28 (s, 1H), 3.53 (m, 4H), 1.50–1.80
(m, 6H), 1.36 (s, 3H), 1.25 (s, 3H), 1.16 (t, J=7.3 Hz, 3H); 13C-NMR 180.7, 176.0, 98.6, 78.9, 62.4, 44.6,
33.4, 30.1, 25.3, 22.8, 20.2, 19.0, 12.9. Anal. calcd for C13H21NO4 (255.3) C 61.16, H 8.29, N 5.49;
found 61.09, H 8.13, N 5.40.
4.39. (R)-1-Ethyl-3-hydroxy-4,4-dimethylpyrrolidine-2,5-dione (R)-10a
(R)-1-Ethyl-4,4-dimethyl-3-(2-tetrahydropyranyloxy)pyrrolidine-2,5-dione (1.02 g, 0.004 mol) was
dissolved in methanol (10 cm3). To this solution TsOH·H2O (10 mg) was added and the mixture was
stirred at room temperature for 4 h. After evaporation of the solvent, the residue was dissolved in
dichloromethane, washed with 5% aqueous NaHCO3 solution and water, and dried over MgSO4. The
solvent was removed and the crude product was purified by Kugelrohr distillation. Colourless oil; yield
1
90%; IR (cm−1) 3600, 3050–2800, 1705; H-NMR 4.29 (s, 1H), 3.54 (qa, J=7.2 Hz, 2H), 1.37 (s, 3H),
1.22 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); 13C-NMR 180.7, 177.7, 75.4, 45.2, 33.6, 22.3, 19.8, 12.8. Anal.
calcd for C8H13NO3 (171.2) C 56.12, H 7.65, N 8.18; found C 55.98, H 7.61, N 8.15.

A. Szabo et al. / Tetrahedron: Asymmetry 10 (1999) 61–76
75
4.40. Hydrogenation of pyrrolidine-2,3,5-triones: general procedure
For all experiments a 5 wt% Pt/Al2O3 catalyst (Engelhard 4759) was used. The catalyst was pretreated
in a fixed bed reactor by flushing with 12.5 ml min−1 nitrogen (O2 <10 ppm) at 400°C for 30 min followed
by a reductive treatment in 30 ml min−1 hydrogen (O2 <2 ppm) for another 90 min. The catalyst was then
cooled to room temperature in hydrogen and transferred into the autoclave under exclusion of oxygen.
The catalyst was first contacted with the solvent containing the appropriate amount of modifier.
Hydrogenation of the pyrrolidine-2,3,5-triones was carried out in a 100 ml stainless steel autoclave
(Baskerville) with a 50 ml glass liner and PTFE cover, to provide clean conditions. Under standard
conditions 60 mg pretreated catalyst, 10 µmol l−1 cinchonidine, 3.2 mmol substrate and 5 ml toluene
were used at 60 bar and 10°C.
The enantiomeric excess was determined by gas chromatographic analysis using a chiral column in
1
the case of 10a–d and 11a–c (WCOT Cyclodextrin-β-2,3,6-M-19 Chrompack column), and H-NMR
spectroscopy via the corresponding MTPA esters for 12a–c. Concerning the chemoselectivity of the
hydrogenation reactions, no other products beside the alcohols 10a–d and 11a–c could be detected by
GC analysis.
4.41. Molecular modelling
As molecular modelling software, the program ‘Hyperchem’ was used. The minimum energy con-
formations of cinchonidine and substrate molecules were determined independently using molecular
mechanics (MM+) method.
Acknowledgements
Financial support by the Swiss National Science Foundation (Chiral 2) is kindly acknowledged.
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