Straightforward preparation of enantiopure 3-amino-4,4-dimethylpyrrolidin- 2-one and its derivatives

Article abstract of DOI:10.1016/j.tetasy.2010.06.028

An easy access to both enantiomers of 3-amino- and 3-(dimethylamino)-4,4- dimethylpyrrolidin-2-one from rac-pantolactam using (R)-α- methylbenzylamine as a chiral auxiliary is described.

Full text of DOI:10.1016/j.tetasy.2010.06.028

Tetrahedron: Asymmetry 21 (2010) 2124–2135
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Straightforward preparation of enantiopure
3-amino-4,4-dimethylpyrrolidin-2-one and its derivatives
a
a
b
c
Pelayo Camps a, , Diego Muñoz-Torrero , Jordi Rull , José Antonio Mayoral , Teresa Calvet ,
*
Mercè Font-Bardia c
a Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona,
Av. Diagonal 643, E-08028 Barcelona, Spain
b Departamento de Química Orgánica, ICMA and IUCH, Facultad de Ciencias, Universidad de Zaragoza—CSIC, Pedro Cerbuna 12, 50009 Zaragoza, Spain
c Serveis Científico-Tècnics, Universitat de Barcelona, Av. Martí Franquès, s/n, E-08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2010
Accepted 22 June 2010
An easy access to both enantiomers of 3-amino- and 3-(dimethylamino)-4,4-dimethylpyrrolidin-2-one
from rac-pantolactam using (R)-
a
-methylbenzylamine as a chiral auxiliary is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Carmen Nájera on
the occasion of her 60th anniversary
1. Introduction
Me
Me
Me
OH
Me
Me
Me Me
OH
Me
(R)-Pantolactone, (R)-1 (Fig. 1), is a widely used chiral auxiliary.1
Several years ago, we prepared an improved, easily available,
closely related chiral auxiliary, 3-hydroxy-4,4-dimethyl-1-phenyl-
pyrrolidin-2-one (N-phenylpantolactam), 2 (Fig. 1), in both enan-
tiomeric forms.2 The main advantages of the enantiomers of 2 as
H
N
O
N
O
N
O
(R)-1
N
O
O
(S,S)-3
chiral auxiliaries over those of
1 are: (i) non-hygroscopic
(R)-2
crystalline compounds, which facilitate their recovery; (ii) easily
UV-detectable; and (iii) both enantiomers are equally available.
Compounds (R)- and (S)-2 were used as chiral auxiliaries in
different diastereoselective reactions, such as the deracemization
Me
Me
N
NRR'
O
Me
Me
Me
Me
NH
HN
Me
Me
NH2
N
O
O
of
a
-arylpropionic acids, Diels–Alder cycloadditions, and dynamic
N
N
kinetic resolutions of
a
-haloesters, and as resolution agents.1,3 Later
O
N
H
(R)-6
on, we synthesized derivatives 3–5 as potential chiral auxiliaries or
ligands for chiral catalysts, with limited success.4 Although (S)-4
(R = R0 = H) as a chiral auxiliary gave diastereoselectivities around
80% in a Michael reaction, none of the amines 3–5 showed any
enantioselectivity as chiral ligands of Cu(OTf)2, Sc(OTf)3, and
(S)-4
(S,S)-5
Figure 1. Structures of pantolactone and several pantolactam derivatives.
Yb(OTf)3 in catalyzed Diels–Alder reactions or of RuCl2[
g
6-(mesity-
lene)2]2 in catalyzed transfer hydrogenation reactions.4
give stronger metal complexes than lactams 4, if the lactam N–H
group was deprotonated.
With the aim of increasing the stability of the complexes
derived from these ligands and different transition metal cations,
as a first stage for the preparation of more efficient chiral catalysts,
we planned the preparation of both enantiomers of 3-aminopanto-
lactam 6 and other amino-substituted derivatives, which might
Since we had previously developed a one-step preparation of
different N-substituted pantolactams5 from pantolactone and the
known preparation of the 1-unsusbtituted pantolactam requires
a three-step sequence,6 we planned the preparation of (R)- and
(S)-6 from the new rac-N-(p-methoxybenzyl)pantolactam, rac-8
(Scheme 1). The protecting p-methoxybenzyl group might be re-
moved in the last step of the sequence using ammonium ceriu-
m(IV) nitrate [Ce(NH4)2(NO3)6, CAN].7
* Corresponding author. Tel.: +34 93 4024536; fax: +34 93 4035941.
E-mail address: camps@ub.edu (P. Camps).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.028

P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
2125
Me
Me
Me
Me
Me
Me
NH2
Me
Me
O
OH
O
Me
Me
NH2
Et3N
Me2S-Cl Cl
SMe2
H
O
O
O
O
O
N
N
N
R
O
N
R
H
N
H
Et3N
10
(R)-6
Me
Me
Me
Me
Me
Me
O
O
O
Swern
oxidation
OMe
OMe
H2O
(R)-7
rac-8
O
O
HO
O
N
R
N
R
rac-12
N
Scheme 1. Planned preparation of (R)-6.
R
11
R = p-methoxybenzyl
2. Results and discussion
Scheme 3. Proposed mechanism for the formation of 11 and rac-12 during the
Swern oxidation of rac-8 to 10.
The reaction of rac-1 with excess p-methoxybenzylamine, 9,
under p-TsOH catalysis and microwave irradiation gave solid rac-
N-(p-methoxybenzyl)pantolactam, rac-8, in 50% yield of chromato-
graphed product. Swern oxidation of rac-8 gave ketolactam 10 in
85% yield after column chromatography (Scheme 2).8
Toluene,
Me
Me
N
H
Me
reflux, 20 h
Dean-Stark
73%
+
10
NH2
H
NH2
DMSO, ClCOCOCl
O
p-TsOH (10% mol)
N
Me
CH2Cl2, Et3N, −78 ºC
Microwave irradiation
250 ºC, 44 W,
rac-1
+
(R)-13
rac-8
20.4 atm, 15 min
50%
OMe
OMe
9 (excess)
(R)-14
Me
Me
Me
Me
Me
O
O
O
Me
NaBH3CN,
MeOH, AcOH
−78 ºC, 5 h
99%
H
Me
Me
H
Me
Me
N
H
HN
+
H
Me
+
O
N
O
O
HO
+
O
N
Me
O
H
N
N
O
N
OMe
rac-12
(8%)
OMe
OMe
10
(85%)
11
(3%)
OMe
OMe
(3S,1'R)-15
Isolated as a salt of
(3R,1'R)-16
ratio 15/16 = 86:14
Scheme 2. Preparation of ketolactam 10.
(2R,3R)-(+)-tartaric acid
61% yield from (R)-14
From this reaction, over-oxidation products 11 (3% yield) and
rac-12 (8% yield) were also isolated and fully characterized. The
formation of 11 and rac-12 can be envisaged as shown in Scheme 3
by reaction of ketolactam 10 with excess Swern reagent (dim-
ethylchlorosulfonium chloride) to give a new sulfonium cation,
which on reaction with triethylamine would give an imonium
ion. Reaction of this imonium ion with adventitious water would
give rac-12, which on Swern oxidation would lead to 11. Alterna-
tively, oxidation of rac-8 using RuO4 generated from a catalytic
amount of RuCl3ꢀ3H2O and trichloroisocyanuric acid as the stoichi-
ometric oxidant under phase-transfer conditions in a biphasic sys-
tem acetonitrile/water9 gave ketolactam 10 in only 40% yield.
Similarly, chromic acid oxidation10 of rac-8 gave 10 in 34% yield,
some p-anisaldehyde (15%) and starting alcohol (8%) also being
isolated, thus showing partial oxidation of the protecting group.
The diastereoselective amination of ketolactam 10 was carried
H
2 (1 atm), 5% Pd/C,
MeOH, concd HCl,
H
N
H
67 h
94%
Me
Me
O
N
H
Me
Me
H
NH2
O
Ce(NH4)2(NO3)6
Acetonitrile, H2O,
r.t., 2.5 h
OMe
(S)-17
N
H2 (1 atm), 5% Pd/C
MeOH, r.t. 20 h
+
H
Me
Me
NH2
OMe
(S)-7
O
N
H
(S)-6
87% yieldf rom (S)-7
out using (R)-a-methylbenzylamine, (R)-13, as a chiral auxiliary
(Scheme 4).4 The reaction of 10 with (R)-13 in refluxing toluene
in the absence of any catalyst with continuous removal of water
with a Dean–Stark equipment gave imine (R)-14 in 73% yield of
chromatographed product. The sodium cyanoborohydride reduc-
tion of this imine in methanol at ꢁ78 °C gave a mixture of amines
(3S,10R)-15/(3R,10R)-16 in a 86:14 diastereomeric ratio, established
by 1H NMR on the basis of the integral of the singlet signal of the 3-
H proton [d = 2.97 ppm for (3S,10R)-15 and 2.83 ppm for (3R,10R)-
16]. The main diastereomer of the mixture was isolated as a white
solid by crystallization of its salt with (2R,3R)-(+)-tartaric acid in
61% overall yield from imine (R)-14. The corresponding amine
Scheme 4. Diastereoselective reductive amination of ketolactam 10 and prepara-
tion of amine (S)-6.
was liberated from the above-mentioned salt and both the prod-
ucts were fully characterized. The absolute configuration of C3
was established as follows; hydrogenation of (3S,10R)-15 at atmo-
spheric pressure using 5% Pd on charcoal as a catalyst in the pres-
ence of trace amounts of concentrated HCl gave the debenzylated

2126
P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
Me
Me
amine (S)-7 which was transformed into the salt derived from
(2R,3R)-di-O,O0-(p-toluoyl)tartaric acid. Single crystal X-ray diffrac-
tion analysis of this salt (Fig. 2)11 allowed us to establish the abso-
lute configuration of (S)-7 and, consequently, of its precursors,
amine (3S,10R)-15 and diastereomer (3R,10R)-16.
NHCbz
Benzyl chloroformate (CbzCl),
Et3N, CH2Cl2
,
reflux, 16 h
H
O
(S)-7
59%
N
Hydrogenation (24 atm, 24 h) of (S)-7 using palladium hydrox-
ide12 as the catalyst left the starting compound unchanged. The
treatment of (S)-7 with an excess of trifluoroacetic acid13 in CHCl3
solution led to a quantitative recovery of the starting compound.
Oxidation of (S)-7 with CAN7 in acetonitrile/water gave a neutral
fraction containing a mixture of imine (S)-17 and p-anisaldehyde,
and a basic fraction containing (S)-6. Catalytic hydrogenation of
the mixture of imine (S)-17 and p-anisaldehyde using 5% Pd/C as
the catalyst gave (S)-6. Altogether, (S)-6 was obtained in 87% total
yield.
Alternatively, CAN removal of the p-methoxybenzyl group was
performed on (S)-18, the N-Cbz-protected derivative of (S)-7
(Scheme 5). The reaction of (S)-7 with benzyl chloroformate gave
the Cbz-protected derivative (S)-18, which on reaction with CAN,
followed by treatment with aqueous 5 N NaOH gave a mixture of
the oxidation product (S)-19 and the expected product (S)-20,
which were isolated by silica gel column chromatography in 24%
and 42% yield, respectively. Hydrogenation of (S)-20 gave (S)-6 in
91% yield.
We also carried out the reductive methylation of (S)-7 with
formaldehyde and formic acid. From this reaction, the desired
dimethylamino derivative (S)-21 and the hydroxymethylated
derivative (S)-22 were isolated in 74% and 20% yield, respectively,
by column chromatography of the crude product (Scheme 5).
Although we had succeeded in obtaining (S)-6 from pactolac-
tam rac-8, in view of the problems associated with the use of the
p-methoxybenzyl-protecting group in these synthetic sequences:
(i) multi-step low yielding synthetic sequences, (ii) formation of
imine (S)-17 during CAN deprotection of amine (S)-7, (iii) oxidation
of the lactam ring during CAN deprotection of (S)-18, and (iv)
hydroxymethylation of the protecting group during reductive
methylation of amine (S)-7, we studied the possible preparation
of amine 6 from the known N-unsubstituted pantolactam rac-23.6
OMe
(S)-18
Me
Me
NHCbz
Me
Me
a) Ce(NH4)2(NO3)6
Acetonitrile, H2O, r.t., 3 h
b) 5 N NaOH
NHCbz
H
O
H
+
O
N
O
N
H
(S)-20
42%
OMe
(S)-19
24%
2 (1 atm), 5% Pd/C,
CH2O (37% in H2O)
HCOOH
H
MeOH, concd HCl, r.t., 17 h
91%
80 ºC, 20 h
Me
Me
Me
Me
NMe2
NMe2
H
O
H
O
Me
Me
NH2
H
+
N
N
CH2OH
O
N
H
OMe
(S)-6
OMe
(S)-21
(S)-22
20%
74%
Scheme 5. Preparation of (S)-6 and reductive methylation of (S)-7.
First, we synthesized rac-6 as shown in Scheme 6. Chromic acid
oxidation of rac-23 gave the new ketolactam 24 in 75% isolated
yield. The reaction of 24 with benzylamine in toluene at reflux,
and removing the water formed with a Dean–Stark equipment
gave the corresponding imine 25 in quantitative yield, which was
hydrogenated using 5% Pd/C as a catalyst to give rac-6 in high yield.
Figure 2. ORTEP representation of (S)-7ꢀ(2R,3R)-di-O,O0-(p-toluoyl)tartrate.

P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
2127
Me
Me
Me
Me
O
OH
Na2Cr2O7·2H2O,
H2SO4/AcOH
Benzylamine
Toluene, reflux, 20 h
NaBH3CN,
O
O
Me
Me
N
r.t., 30 min
75%
Dean-Stark
quantitative yield
N
N
H
H
(R)-13
MeOH, AcOH
Me
24
H
Toluene, reflux
Dean-Stark
−78 ºC, 5 h
93%
O
rac-23
24
N
H
quantitative yield
(R)-29
Me
Me
Me
Me
N
CH2C6H5
HN CH2C6H5
O
NaBH3CN
MeOH, AcOH
−78 ºC, 5 h
84%
O
N
H
N
Me
Me
H
Me
Me
H
N
HN
H
H
H
H
Me
25
rac-26
+
Me
H2 (1 atm),
O
O
N
N
H
5% Pd/C, EtOH, r.t., 24 h
97%
H
2 (1 atm),
H
(3S,1'R)-30
64%
ratio 30/31 = 80:20
(3R,1'R)-31
10%
5% Pd/C, EtOH ,r.t., 48 h
91%
Me
Me
NMe2
O
Me
Me
H
2 (1 atm),
H2 (1 atm),
NH2
excess CH2O (37% in H2O)
5% Pd/C, MeOH, HCl
18 h, 96%
5% Pd/C, MeOH, HCl
24 h, 94%
HCOOH, 80 ºC, 19 h
64%
O
N
N
H
NH2
H
Me
Me
Me
Me
CH2OH
rac-27
H
rac-6
NH2
O
MeNH2 (40% in H2O)
HCOOH, 80 ºC, 19 h
80%
O
N
N
H
H
(i) excess CH2O (37% in H2O)
HCOOH, 80 ºC, 15 h
(S)-6
(R)-6
Me
NMe2
O
Me
(i) CH2O (37% in H2O)
HCOOH, 80 ºC, 20 h
(ii) MeNH2 (40% in H2O)
HCOOH, 80 ºC, 15 h
78%
(i) CH2O (37% in H2O)
(ii) MeNH2 (40% in H2O)
HCOOH, 80 ºC, 20 h
HCOOH, 80 ºC, 23 h
(ii) MeNH2 (40% in H2O)
HCOOH, 80 ºC, 20 h
75%
N
H
74%
rac-28
NMe2
H
Me
Me
H
Me
Me
Scheme 6. Preparation of aminolactams rac-6 and rac-28 from pantolactam rac-23.
NMe2
O
O
N
N
Alternatively, sodium cyanoborohydride reduction of the imine 25
gave the benzylamino derivative rac-26, which was hydrogenated
as before to rac-6.
H
(S)-28
H
(R)-28
Methylation of rac-6 with an excess of formaldehyde and formic
acid gave amine rac-27 in good yield, derived from the complete
methylation of the primary amine and the hydroxymethylation
of the lactam N–H functionality. Heating rac-27 in water under for-
mic acid catalysis gave a mixture of the starting compound and
rac-28, thus showing that the hydroxymethylation of rac-28 might
be reverted. Reaction of rac-27 with 40% aqueous methylamine and
formic acid gave the desired amine rac-28 in good yield, the
methylamine acting as a formaldehyde trap through its reductive
methylation.
Then, we prepared the enantiopure amines (S)- and (R)-6 and
the corresponding dimethylated derivatives (S)- and (R)-28 as
shown in Scheme 7. The reaction of 24 with (R)-13 in toluene at re-
flux with azeotropic removal of water gave imine (R)-29, which on
reduction with sodium cyanoborohydride gave a diastereomeric
mixture of amines (3S,10R)-30/(3R,10R)-31 in 93% yield and an
approximate 80:20 diastereomeric ratio, established by 1H NMR
on the basis of the integral of the quartet signal of the CH3CH pro-
tons [d = 3.93 ppm for (3S,10R)-30 and 4.30 ppm for (3R,10R)-31].
Crystallization of the diastereomeric mixture of (3S,10R)-30 and
(3R,10R)-31 from a mixture of Et2O/hexane gave the less abundant
higher melting point amine (3R,10R)-31 (10% yield) and a mixture
of both amines (7% yield). Crystallization of the residue from an
Et2O/pentane mixture gave the more abundant lower melting
point diastereomeric amine (3S,10R)-30 in 64% yield. Alternatively,
the diastereomeric mixture of (3S,10R)-30 and (3R,10R)-31 was sep-
arated by silica gel column chromatography. The absolute configu-
Scheme 7. Preparation of aminolactams (R)-6, (S)-6, (R)-28 and (S)-28 from
ketolactam 24.
ration of (3R,10R)-31 was established by X-ray diffraction analysis
(Fig. 3).11 Consequently, the configuration of the main diastereo-
meric amine must be (3S,10R)-30.
The observed diastereoselectivity was similar to that previously
observed in the reduction of the N-(p-methoxybenzyl) imine (R)-
14 or the corresponding N-phenyl derivatives.4 Hydrogenation of
amines (3S,10R)-30 and (3R,10R)-31 using 5% Pd on charcoal as a
catalyst in the presence of trace amounts of concentrated HCl gave
the corresponding primary amines (S)- and (R)-6 in high yields.
Reductive methylation of these amines with formaldehyde and
formic acid followed by treatment with methylamine and formic
acid to dehydroxymethylate the lactam N–H group, as described
before for the preparation of rac-28, gave (S)- and (R)-28 in good
yields.
3. Conclusion
A straightforward preparation of 3-amino-4,4-dimethylpyrroli-
din-2-ones unsubstituted at the lactam nitrogen and derivatives
thereof, which does not require the protection of the lactam func-
tion, has been developed. Work is currently in progress to apply
the new aminolactams 6 and 28 as chiral ligands or catalysts for
enantioselective transformations.

2128
P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
HCl (2 ꢂ 30 mL) and the aqueous phase was extracted with EtOAc
(3 ꢂ 30 mL). The combined organic extracts were washed with
water (10 mL), dried (anhydrous MgSO4), and concentrated under
reduced pressure and the residue (600 mg) was subjected to col-
umn chromatography (silica gel, 60 g, hexane/EtOAc 5:1) isolating
the lactam rac-8 (250 mg, 50% yield) as a yellow solid. The analyt-
ical sample of rac-8 was obtained as a white solid by crystallization
from hexane/EtOAc 1:3 (3 mL), mp 120–121 °C (hexane/EtOAc
1:3); Rf 0.46 (silica gel, 7.2 cm, hexane/EtOAc 1:3); IR 3310 (OH),
2955, 2930, 1671 (CO), 1512, 1460, 1301, 1240, 1172, 1128,
1026, 809 cmꢁ1 1H NMR 0.93 (s, 3H) and 1.16 (s, 3H) [4-(CH3)2],
;
2.82 (d, J = 9.6 Hz, 1H) and 2.93 (d, J = 9.6 Hz, 1H) (5-H2), 3.69 (br
s, 1H, OH), 3.79 (s, 3H, OCH3), 4.00 (d, J = 3.6 Hz, 1H, 3-H), 4.29
(d, J = 14.4 Hz, 1H) and 4.46 (d, J = 14.4 Hz, 1H) (N–CH2), 6.85
[dm, J = 8.8 Hz, 2H, Ar-3(5)-H], 7.15 [dm, J = 8.8 Hz, 2H, Ar-2(6)-
H]; 13C NMR 20.0 (CH3) and 24.8 (CH3) [4-(CH3)2], 38.6 (C, C4),
46.2 (CH2, N–CH2), 55.2 (CH3, OCH3), 56.1 (CH2, C5), 77.9 (CH,
C3), 114.1 [CH, Ar-C3(5)], 127.8 (C, Ar-C1), 129.6 [CH, Ar-C2(6)],
159.2 (C, Ar-C4), 174.3 (C, C2). Anal. Calcd for C14H19NO3: C,
67.45; H, 7.68; N, 5.62. Found: C, 67.33; H, 7.76; N, 5.59. HRMS
(ESI) calcd for ([M+H]+): 250.1438; found 250.1438.
4.3. Swern oxidation of rac-8: obtention of 1-(p-methoxyben-
zyl)-4,4-dimethylpyrrolidine-2,3-dione 10 and isolation of
1-(p-methoxybenzyl)-4,4-dimethylpyrrolidine-2,3,5-trione 11
and rac-5-hydroxy-1-(p-methoxybenzyl)-4,4-
Figure 3. ORTEP representation of (3R,10R)-31.
4. Experimental
dimethylpyrrolidine-2,3-dione rac-12
4.1. General experimental details
To a cooled (ꢁ78 °C) solution of oxalyl chloride (1.65 mL, 2.48 g,
19.5 mmol) in anhydrous CH2C12 (20 mL) was added anhydrous
DMSO (2.75 mL, 3.02 g, 38.7 mmol). After 1 h at ꢁ78 °C, a solution
of rac-8 (2.41 g, 9.67 mmol) in anhydrous CH2Cl2 (15 mL) was
added dropwise, keeping the temperature under ꢁ50 °C. After
10 min at ꢁ78 °C, freshly distilled Et3N (8.0 mL, 5.81 g, 57.4 mmol)
was added dropwise, keeping the temperature at ꢁ78 °C. After
30 min at this temperature, the mixture was allowed to warm to
room temperature for 1 h. Then, water (22 mL) was added and
the mixture was extracted with Et2O (3 ꢂ 50 mL) and the com-
bined organic phases were washed with saturated aqueous solu-
tions of NH4Cl (15 mL) and NaHCO3 (20 mL) and with brine
(15 mL). The solution was dried (anhydrous MgSO4) and concen-
trated under reduced pressure to give a residue (2.39 g) that was
subjected to column chromatography (silica gel, 123 g, CH2Cl2/
MeOH mixtures). In the order of elution, product 11 (70 mg, 3%
yield), ketolactam 10 (2.02 g, 85% yield) (CH2Cl2/MeOH 100:1),
and rac-12 (200 mg, 8% yield) (CH2Cl2/MeOH 50:1) were isolated.
Compound 10: The analytical sample was obtained as a white
solid by crystallization from EtOAc/Et2O 3:5 (10 mL), mp
105ꢁ106 °C (EtOAc/Et2O 3:5); Rf 0.36 (silica gel, 5.5 cm, CH2Cl2/
MeOH 100:1); IR 2968, 2925, 1765 and 1712 (CO), 1610, 1513,
Melting points were determined in open capillary tubes. Unless
otherwise stated, NMR spectra were recorded at 25 °C in CDCl3: 1H
NMR (400 MHz), 13C NMR (100.6 MHz). All chemical shifts (dH and
dC) are reported in parts per million (ppm) related to internal stan-
dard (CHCl3 at dH = 7.26 ppm, dC = 77.0 ppm). Assignments given
for the NMR spectra are based on DEPT sequence, 1H/1H COSY,
1H/13C HETCOR (HSQC sequence), and 1H/1H NOESY experiments
for selected compounds. Coupling constants J are given in hertz
(Hz). Mass spectra were recorded on a LC/MSD-TOF (2006, Agilent
technologies), using electrospray (ESI-MS, positive mode, capillary:
3.5 kV, fragmentor: 215 V). The samples were introduced into the
source with an HPLC system (Agilent 1100), using a mixture of
H2O/acetonitrile 1:1 as an eluent (200 lL/min) and depending on
the nature of the samples 1% formic acid was added to the eluent.
Unless otherwise stated, IR spectra were performed with the atten-
uated total reflection (ATR) technique and the absorption values
are given as wavenumbers (cmꢁ1). Elemental analyses were done
at the Microanalysis Service of the IIQAB (CSIC, Barcelona, Spain).
Optical rotations were determined on a polarimeter using a 1-dm
cell. Column chromatography was performed on Silica Gel 60 A
C.C. (35–70 mesh) or basic aluminum oxide. For the thin layer
chromatography (TLC), aluminum-backed sheets with Silica Gel
60 F254 or aluminum oxide ALOX N/UV254 were used and the spots
were visualized with UV light and/or 1% aqueous KMnO4.
1469, 1443, 1304, 1235, 1180, 1066, 1033, 839, 817 cmꢁ1 1H
;
NMR 1.18 [s, 6H, 4-(CH3)2], 3.24 (s, 2H, 5-H2), 3.81 (s, 3H, OCH3),
4.63 (s, 2H, N–CH2), 6.89 [dm, J = 8.8 Hz, 2H, Ar-3(5)-H], 7.21
[dm, J = 8.8 Hz, 2H, Ar-2(6)-H]; 13C NMR 23.6 [CH3, 4-(CH3)2],
39.9 (C, C4), 47.8 (CH2, N–CH2), 55.1 (CH2, C5), 55.3 (CH3, OCH3),
114.4 [CH, Ar-C3(5)], 126.5 (C, Ar-C1), 129.9 [CH, Ar-C2(6)], 159.0
(C) and 159.6 (C) (C2 and Ar-C4), 203.9 (C, C3). Anal. Calcd for
4.2. rac-3-Hydroxy-1-(p-methoxybenzyl)-4,4-dimethylpyrroli-
din-2-one rac-8
C
14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.94; H, 7.00; N,
A solution of rac-pantolactone, ( )-1 (260 mg, 2.00 mmol),
p-TsOHꢀH2O (34 mg, 0.20 mmol), and p-methoxybenzylamine
5.60. HRMS (ESI): calcd for ([M+H]+): 248.1281; found 248.1286.
Compound 11: The analytical sample was obtained as a white
solid by crystallization from Et2O (5 mL), mp 79–80 °C (Et2O); Rf
0.74 (silica gel, 5.4 cm, CH2Cl2/MeOH 100:1); IR 2946, 1800 (CO),
1778 and 1702 (CO), 1610, 1512, 1463, 1429, 1392, 1333, 1293,
(520 lL, 550 mg, 4.01 mmol) was placed in a sealed cylindrical
pyrex vessel. The mixture was introduced into a monomode reac-
tor, Synthwave 402 Prolabo focused MW 2.45 GHz, at a power of
44 W, and heated at 250 °C and 20.4 atm for 15 min. The mixture
was allowed to cool to room temperature, after which EtOAc
(20 mL) was added. The solution was washed with aqueous 2 M
1244, 1133, 1062, 1035, 812 cmꢁ1
;
1H NMR 1.33 [s, 6H, 4-
(CH3)2], 3.78 (s, 3H, OCH3), 4.80 (s, 2H, N–CH2), 6.85 [d,
J = 9.0 Hz, 2H, Ar-3(5)-H], 7.35 [d, J = 9.0 Hz, 2H, Ar-2(6)-H]; 13C

P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
2129
NMR 19.9 [CH3, 4-(CH3)2], 42.2 (CH2, N–CH2), 45.9 (C, C4), 55.2
(CH3, OCH3), 114.2 [CH, Ar-C3(5)], 126.8 (C, Ar-C1), 130.4 [CH,
Ar-C2(6)], 159.6 (C) and 159.8 (C) (C2 and Ar-C4), 176.4 (C, C5),
197.1 (C, C3). Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N,
5.36. Found: C, 64.34; H, 5.70; N, 5.31. HRMS (ESI) calcd for
([M+NH4]+): 279.1339; found 279.1348.
tracted with CH2Cl2 (3 ꢂ 50 mL). The combined organic extracts
were dried (anhydrous MgSO4) and concentrated under reduced
pressure to give a diastereomeric mixture of (3S,10R)-15 and
(3R,10R)-16 (359 mg, 99% yield) in a ratio of 86:14 (1H NMR). This
mixture (359 mg, 1.02 mmol) was taken in MeOH (2 mL) and trea-
ted with a solution of (2R,3R)-(+)-tartaric acid (160 mg, 1.06 mmol)
in MeOH (3 mL), and the mixture was concentrated to dryness in
vacuo. The obtained solid was taken in a mixture of Et2O/EtOAc/
acetonitrile 3:2:1 (13 mL) and the mixture was cooled to ꢁ20 °C
for 24 h. The precipitated solid was collected by filtration and
washed with a mixture of Et2O/EtOAc 5:1 (2 mL) to give, after dry-
ing, (3S,10R)-15ꢀ(2R,3R)-tartrate (315 mg, 61% yield) as a white so-
Compound rac-12: The analytical sample was obtained as a white
solid by crystallization from CH2Cl2 (5 mL), mp 179–180 °C (CH2Cl2);
Rf 0.23 (silica gel, 7.8 cm, CH2Cl2/MeOH 40:1); IR 3298 (OH), 2976,
2941, 1769 and 1703 (CO), 1612, 1512, 1469, 1455, 1304, 1235,
1088, 1053, 1034, 866, 839, 815, 678, 662 cmꢁ1 1H NMR (DMSO-
;
d6) 0.98 (s, 3H) and 1.01 (s, 3H) [4-CH3)2], 3.73 (s, 3H, OCH3), 4.25
(d, J = 14.6 Hz, 1H) and 4.77 (d, J = 14.6 Hz, 1H) (N–CH2), 4.73 (dm,
J = 6.6 Hz, 1H, 5-H), 6.55 (d, J = 6.6 Hz, 1H, OH), 6.91 [dm, J = 8.4 Hz,
2H, Ar-3(5)-H], 7.26 [d, J = 8.4 Hz, 2H, Ar-2(6)-H]; 13C NMR (DMSO-
d6) 17.9 (CH3) and 22.5 (CH3) [4-(CH3)2], 43.4 (CH2, N–CH2), 45.6 (C,
C4), 55.2 (CH3, OCH3), 84.2 (CH, C5), 114.1 [CH, Ar-C3(5)], 127.8 (C,
Ar-C1), 129.8 [CH, Ar-C2(6)], 158.7 (C) and 158.9 (C) (Ar-C4 and C2),
203.9 (C, C3). Anal. Calcd for C14H17NO4ꢀ0.15CH2Cl2: C, 61.57; H,
6.32; N, 5.07. Found: C, 61.26; H, 6.21; N, 5.10. HRMS (ESI) calcd for
([M+H]+): 264.1230; found 264.1219.
lid, mp 112–113 °C (Et2O/EtOAc/acetonitrile 3:2:1). ½a D23
¼ þ9 (c
ꢃ
1.10, MeOH); IR 3600–2400 (max at 3420, 2967, 2940, 2842,
2713, OH, +NH and CH), 1700 (CO), 1610, 1586, 1513, 1441,
1242, 1207, 1176, 1125, 1071, 1029, 896, 834, 814, 763, 699,
670 cmꢁ1 1H NMR (CD3OD) 0.95 (s, 3H) and 1.16 (s, 3H) [4-
;
(CH3)2], 1.48 (d, J = 6.8 Hz, 3H, CH3-CH), 2.83 (d, J = 9.6 Hz, 1H)
and 2.97 (d, J = 9.6 Hz, 1H) (5-H2), 3.40 (s, 1H, 3-H), 3.77 (s, 3H,
OCH3), 4.20 (d, J = 14.4 Hz, 1H) and 4.49 (d, J =14.4 Hz, 1H) (N–
CH2), 4.29 (q, J = 6.8 Hz, 1H, CH3-CH), 4.48 (s, 2H, CH tartrate),
4.88 (br s, 5H, COOH, 2OH and +NH2), 6.87 [dm, J = 8.8 Hz, 2H,
Ar-3(5)-H p-methoxybenzyl], 7.16 [dm, J = 8.8 Hz, 2H, Ar-2(6)-H
p-methoxybenzyl], 7.31 (tt, J = 7.4, 1.7 Hz, 1H, Ar-Hpara phenyl),
7.39 (tm, J = 7.4 Hz, 2H, Ar-Hmeta phenyl), 7.45 (dm, J = 7.4 Hz, 2H,
Ar-Hortho phenyl); 13C NMR (CD3OD) 21.4 (CH3), 22.4 (CH3) and
25.6 (CH3) [4-(CH3)2 and CH3-CH], 39.5 (C, C4), 47.0 (CH2, N–
CH2), 55.7 (CH3, OCH3), 57.9 (CH2, C5), 58.7 (CH, CH3-CH), 66.2
(CH, C3), 73.7 [CH, C2(3) tartrate], 115.1 [CH, Ar-C3(5) p-methoxy-
benzyl], 128.3 (CH, Ar-Cortho phenyl), 129.0 (CH, Ar-Cpara phenyl),
129.1 (C, Ar-C1 p-methoxybenzyl), 129.9 (CH, Ar-Cmeta phenyl),
130.7 [CH, Ar-C2(6) p-methoxybenzyl], 143.3 (C, Ar-Cipso phenyl),
160.9 (C, Ar-C4 p-methoxybenzyl), 173.8 (C, C2), 175.5 [C, C1(4)
tartrate]. Anal. Calcd for C22H28N2O2ꢀC4H6O6ꢀ0.75H2O: C, 60.51; H,
6.93; N, 5.43. Found: C, 60.17; H, 6.61; N, 5.32.
4.4. (R)-1-(p-Methoxybenzyl)-4,4-dimethyl-3-[(1-phenylethyl)-
imino]pyrrolidin-2-one (R)-14
A solution of 10 (410 mg, 1.66 mmol) and (R)-1-phenylethyl-
amine, (R)-13 (215 lL, 202 mg, 1.67 mmol), in toluene (50 mL)
was heated at reflux for 20 h in Dean–Stark equipment. Evapora-
tion of the solvent under reduced pressure gave an oily residue
(608 mg) that was subjected to column chromatography (alumi-
num oxide, 60 g, hexane/EtOAc 10:1) isolating (R)-14 (425 mg,
73% yield) as a colorless oil. ½a D23
¼ þ39 (c 0.76, CH2Cl2); Rf 0.38
ꢃ
(aluminum oxide, 7.1 cm, hexane/EtOAc 9:1); IR 2964, 2925,
1681 (CO), 1611, 1512, 1439, 1302, 1246, 1175, 1032, 761,
699 cmꢁ1 1H NMR (300 MHz) 1.15 (s, 3H) and 1.19 (s, 3H) [4-
;
(CH3)2], 1.46 (d, J = 6.6 Hz, 3H, CH3-CH), 3.08 (s, 2H, 5-H2), 3.80
(s, 3H, OCH3), 4.43 (d, J = 14.4 Hz, 1H) and 4.50 (d, J = 14.4 Hz,
1H) (N–CH2), 6.57 (q, J = 6.6 Hz, 1H, CH3-CH), 6.87 [dm, J = 8.5 Hz,
2H, Ar-3(5)-H p-methoxybenzyl], 7.18 [dm, J = 8.5 Hz, 2H, Ar-
2(6)-H p-methoxybenzyl], 7.21 (overlapped tm, J = 7.5 Hz, 1H, Ar-
Hpara phenyl), 7.32 (tm, J = 7.5 Hz, 2H, Ar-Hmeta phenyl), 7.49 (dm,
J = 7.5 Hz, 2H, Ar-Hortho phenyl); 13C NMR (75.4 MHz) 25.4 (CH3),
25.9 (CH3) and 26.7 (CH3) [4-(CH3)2 and CH3-CH], 37.8 (C, C4),
46.7 (CH2, CH2-N), 55.3 (CH3, OCH3), 56.1 (CH, CH3-CH), 56.5
(CH2, C5), 114.2 [CH, Ar-C3(5) p-methoxybenzyl], 126.3 (CH, Ar-
Cpara phenyl), 126.6 (CH, Ar-Cortho phenyl), 127.5 (C, Ar-C1 p-
methoxybenzyl), 128.2 (CH, Ar-Cmeta phenyl), 129.7 [CH, Ar-C2(6)
p-methoxybenzyl], 146.5 (C, Ar-Cipso phenyl), 159.3 (C) and 160.3
(C) (Ar-C4 p-methoxybenzyl and C2), 164.6 (C, C3). Anal. Calcd
for C22H26N2O2ꢀ0.1H2O: C, 75.01; H, 7.50; N, 7.95. Found: C,
74.92; H, 7.48; N, 7.78. HRMS (ESI): calcd. for ([M+H]+):
351.2067; found 351.2067.
A sample of (3S,10R)-15 as the free base was obtained as follows:
(3S,10R)-15ꢀ(2R,3R)-tartrate (136 mg, 0.27 mmol) was taken in
EtOAc (30 mL); the solution was washed with aqueous 2 M NaOH
(3 ꢂ 5 mL), dried (anhydrous MgSO4), and concentrated in vacuo
to give (3S,10R)-15 (85 mg, 90% yield) as a colorless oil. ½a 2D3
¼ þ14
ꢃ
(c 0.54, CH2Cl2); Rf 0.43 (aluminum oxide, 7.7 cm, CH2Cl2); IR
2959, 2925 (NH and CH), 1686 (CO), 1612, 1512, 1438, 1244, 1174,
1151, 1032, 816, 762, 700 cmꢁ1 1H NMR 0.93 (s, 3H) and 1.09 (s,
;
3H) [C4ꢁ(CH3)2], 1.37 (d, J = 6.6 Hz, 3H, CH3CH), 1.7–2.1 (br s, 1H,
N-H), 2.68 (d, J = 9.6 Hz, 1H) and 2.78 (d, J = 9.6 Hz, 1H) (5-H2),
2.97 (s, 1H, 3-H), 3.78 (s, 3H, OCH3), 3.92 (q, J = 6.6 Hz, 1H, CH3CH),
4.18 (d, J = 14.4 Hz, 1H) and 4.46 (d, J = 14.4 Hz, 1H) (N–CH2), 6.82
[dm, J = 8.4 Hz, 2H, Ar-3(5)-H p-methoxybenzyl], 7.11 [dm,
J = 8.4 Hz, 2H, Ar-2(6)-H p-methoxybenzyl], 7.22–7.25 (m, 2H) and
7.32–7.34 (complex signal, 3H) (Ar-H phenyl); 13C NMR 21.4
(CH3), 24.9 (CH3) and 26.1 (CH3) [4-(CH3)2 and CH3-CH], 38.9 (C,
C4), 46.2 (CH2, N–CH2), 55.2 (CH3, OCH3), 56.6 (CH2, C5), 56.9 (CH,
CH3-CH), 65.1 (CH, C3), 114.0 [CH, Ar-C3(5) p-methoxybenzyl],
126.7 (CH, Ar-Cortho phenyl), 126.9 (CH, Ar-Cpara phenyl), 128.3 (C,
Ar-C1 p-methoxybenzyl), 128.5 (CH, Ar-Cmeta phenyl), 129.6 [CH,
Ar-C2(6) p-methoxybenzyl], 145.1 (C, Ar-Cipso phenyl), 159.0 (C,
Ar-C4 p-methoxybenzyl), 174.2 (C, C2). Anal. Calcd for
4.5. (3S,10R)-1-(p-Methoxybenzyl)-4,4-dimethyl-3[(1-
phenylethyl)amino]pyrrolidin-2-oneꢀ(2R,3R)-tartrate, (3S,10R)-
15ꢀ(2R,3R)-tartrate
To a cold (ꢁ78 °C) solution of (R)-14 (360 mg, 1.03 mmol) in
C
22H28N2O2ꢀ0.25H2O: C, 74.02; H, 8.05; N, 7.85. Found: C, 74.09; H,
anhydrous MeOH (20 mL), a solution of NaBH3CN (95% purity,
8.02; N, 7.82. HRMS (ESI) calcd for ([M+H]+): 353.2224; found
353.2209.
137 mg, 2.18 mmol) and AcOH (100 lL, 100 mg, 1.67 mmol) in
anhydrous MeOH (5 mL) was added dropwise and the reaction
mixture was stirred at this temperature for 4 h. Then more
NaBH3CN (80 mg, 1.27 mmol) was added and the mixture was stir-
red for 1 h. Water (50 mL) was then added and the organic solvent
was evaporated under reduced pressure. The remaining aqueous
phase was treated with aqueous 2 M NaOH until pH 12–13 and ex-
4.6. (S)-3-Amino-1-(p-methoxybenzyl)-4,4-dimethylpyrrolidin-
2-one (S)-7
A mixture of (3S,10R)-15 (620 mg, 1.76 mmol), concentrated HCl
(56 lL), and 5% Pd/C (1.61 g) in MeOH (50 mL) was hydrogenated

2130
P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
at 1 atm and room temperature for 67 h. The mixture was filtered
through a pad of CeliteÒ washing the filter with MeOH (10 mL). The
filtrate was basified with aqueous 2 M NaOH (15 mL) and extracted
with EtOAc (3 ꢂ 40 mL). The combined organic extracts were dried
(anhydrous MgSO4) and concentrated under reduced pressure to
1 atm and room temperature for 20 h, using 5% Pd/C (500 mg) as
the catalyst. The mixture was filtered through a pad of CeliteÒ
washing the residue with MeOH (10 mL). The combined filtrate
and washing were concentrated under reduced pressure to give
(S)-6 (30 mg, total yield of (S)-6 as a white solid from (S)-7,
67 mg, 87%). The analytical sample was obtained by crystallization
from EtOAc/MeOH 11:1, mp 95–96 °C (EtOAc/MeOH 11:1);
give (S)-7 (410 mg, 94% yield) as a colorless oil. ½a D23
¼ ꢁ43 (c
ꢃ
0.90, CH2Cl2); IR 2955, 2930, 1689 (CO), 1611, 1512, 1442, 1243,
1175, 1109, 1031, 811, 621 cmꢁ1
;
1H NMR 0.87 (s, 3H) and 1.13
½
a 2D3
ꢃ
¼ ꢁ17 (c 0.53, CH2Cl2). The IR, 1H and 13C NMR are coinciden-
(s, 3H) [C4-(CH3)2], 1.60 (br s, 3H, NH2 and water), 2.80 (d,
J = 9.6 Hz, 1H) and 2.94 (d, J = 9.6 Hz, 1H) (5-H2), 3.17 (s, 1H, 3-
H), 3.80 (s, 3H, OCH3), 4.31 (d, J = 14.4 Hz, 1H) and 4.45 (d,
J = 14.4 Hz, 1H) (N–CH2), 6.85 [dm, J = 8.6 Hz, 2H, Ar-3(5)-H], 7.15
[dm, J = 8.6 Hz, 2H, Ar-2(6)-H]; 13C NMR 20.2 (CH3) and 25.0
(CH3) [4-(CH3)2], 38.0 (C, C4), 46.3 (CH2, N–CH2), 55.3 (CH3,
OCH3), 56.7 (CH2, C5), 62.5 (CH, C3), 114.0 [CH, Ar-C3(5)], 128.3
(C, Ar-C1), 129.6 [CH, Ar-C2(6)], 159.1 (C, Ar-C4), 175.2 (C, C2).
Anal. Calcd for C14H20N2O2ꢀ0.5H2O: C, 65.34; H, 8.23; N, 10.89.
Found: C, 65.35; H, 8.11; N, 10.61. HRMS (ESI): calcd for
([M+H]+): 249.1598; found 249.1594.
tal with those of (R)-6, which are described later on. Anal. Calcd for
C6H12N2Oꢀ0.15H2O: C, 55.06; H, 9.47; N, 21.40. Found: C, 54.95; H,
9.63; N, 21.37. HRMS (ESI) calcd for ([M+H]+): 129.1022; found
129.1021.
NMR data of (S)-17 from the spectrum of the mixture with
p-anisaldehyde: 1H NMR
d 1.14 (s, 3H) and 1.15 (s, 3H)
[4-(CH3)2], 3.12 (d, J = 9.6 Hz, 1H) and 3.28 (dd, J = 9.6, 1.2 Hz,
1H) (5-H2), 3.50 (s, 1H, 3-H), 3.83 (s, 3H, OCH3), 6.84–6.90 (broad
s, 1H, 1-H), 6.90 [dm, J = 9.0 Hz, 2H, Ar-3(5)-H], 7.73 [dm,
J = 9.0 Hz, 2H, Ar-2(6)-H], 8.26 (s, 1H, CH@N); 13C NMR 22.0
(CH3) and 26.0 (CH3) [4-(CH3)2], 41.3 (C, C4), 53.5 (CH2, C5), 55.3
(CH, C3), 79.1 (CH3, OCH3), 113.8 [CH, Ar-C3(5)], 129.0 (C, Ar-C1),
130.1 [CH, Ar-C2(6)], 161.8 (C) and 163.1 (C) (C@N and Ar-C4),
176.3 (C2).
4.7. (S)-7ꢀMono-(2R,3R)-O,O0-di-(p-toluoyl)tartrate
Amine (S)-7 (183 mg, 0.74 mmol) was taken in MeOH (3 mL)
and a solution of (2R,3R)-(ꢁ)-O,O-di-(p-toluoyl)tartaric acid (97%
purity, 327 mg, 0.81 mmol) in MeOH (5 mL) was added. The result-
ing solution was concentrated to dryness in vacuo to give a white
solid, which was crystallized from a mixture of MeOH/Et2O/hexane
1:1:1 (25 mL) to give (S)-7ꢀmono-(2R,3R)-O,O0-di-(p-toluoyl)tar-
trate (389 mg, 81% yield), mp 186–187 °C (MeOH/Et2O/hexane
4.9. Benzyl (S)-N-[1-(p-methoxybenzyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl]carbamate (S)-18
A solution of (S)-7 (580 mg, 2.34 mmol) in dry CH2Cl2 (10 mL)
and freshly distilled Et3N (500
in an ice-bath. While the solution was stirred, a solution of benzyl
chloroformate (500 L, 598 mg, 3.56 mmol) in dry CH2Cl2 (5 mL)
lL, 363 mg, 3.56 mmol) were chilled
1:1:1). ½a 2D3
ꢃ
¼ ꢁ117 (c 0.95, MeOH); IR 3200–2500 (max at 3204,
l
2956, 2922, COOH, OH, +NH and CH), 1708 (CO), 1670, 1610,
1513, 1272, 1242, 1176, 1134, 1123, 1111, 1028, 834, 747, 690,
was added dropwise. After 15 min, the reaction mixture was al-
lowed to warm to room temperature and the solution was heated
at reflux for 16 h. The reaction mixture was cooled to room temper-
ature and poured into aqueous 2 M HCl (30 mL). The organic phase
was separated and the aqueous one was extracted with CH2Cl2
(3 ꢂ 40 mL). The combined organic phase and extracts were dried
(anhydrous MgSO4) and concentrated in vacuo to give a viscous res-
idue which was purified by column chromatography (silica gel, 90 g,
hexane/EtOAc 1:1) obtaining (S)-18 (528 mg, 59% yield) as a color-
;
679 cmꢁ1 1H NMR (CD3OD) 0.95 (s, 3H) and 1.20 (s, 3H)
[C4ꢁ(CH3)2], 2.41 (s, 6H, CH3 p-toluoyl), 2.95 (d, J = 10.0 Hz, 1H)
and 3.15 (d, J = 10.0 Hz, 1H) (5-H2), 3.78 (s, 3H, OCH3), 3.83 (s,
1H, 3-H), 4.25 (d, J = 14.4 Hz, 1H) and 4.53 (d, J = 14.4 Hz, 1H)
(N–CH2), 4.89 (s, mobile H), 5.88 [s, 2H, 2(3)-H tartrate], 6.89
[dm, J = 8.4 Hz, 2H, Ar-3(5)-H], 7.20 [dm, J = 8.4 Hz, 2H, Ar-2(6)-
H], 7.29 [d, J = 8.0 Hz 4H, 3(5)-H p-toluoyl], 8.01 [d, J = 8.0 Hz, 4H,
2(6)-H p-toluoyl]; 13C NMR (CD3OD) 21.0 (CH3) and 24.6 (CH3)
[4-(CH3)2], 21.7 (CH3, toluoyl CH3), 38.1 (C, C4), 47.0 (CH2, N–
CH2), 55.7 (CH3, OCH3), 58.0 (CH2, C5), 61.2 (CH, C3), 74.8 [CH,
C2(3) tartrate], 115.2 [CH, Ar-C3(5)], 128.4 (C, C1 p-toluoyl),
128.7 (C, Ar-C1), 130.1 [CH, C3(5) p-toluoyl], 130.8 [CH, Ar-
C2(6)], 131.1 [CH, C2(6) p-toluoyl], 145.4 (C, C4 p-toluoyl), 161.0
(C, Ar-C4), 167.4 (C, CO p-toluoyl), 170.0 (C, C2), 171.5 [C, C1(4) tar-
trate]. Anal. Calcd for C14H20N2O2ꢀC20H18O8: C, 64.34; H, 6.03; N,
4.41. Found: C, 64.44; H, 6.14; N, 4.28.
less oil. ½a 2D3
¼ þ25 (c 0.62, CH2Cl2); Rf 0.58 (silica gel, 7.4 cm,
ꢃ
EtOAc/hexane 1:1); IR (NaCl) 3290 (NH), 2960, 2931, 1713 and
1694 (CO), 1613, 1514, 1454, 1315, 1247, 1176, 1052, 817, 739,
698 cmꢁ1; 1H NMR 0.83 (s, 3H) and 1.21 (s, 3H) [4-(CH3)2], 2.80 (d,
J = 9.6 Hz, 1H) and 3.03 (d, J = 9.6 Hz, 1H) (5-H2), 3.79 (s, 3H,
OCH3), 4.25 (d, J = 6.6 Hz, 1H, 3-H), 4.33 (d, J = 14.4 Hz, 1H) and
4.43 (d, J = 14.4 Hz, 1H) (N–CH2), 5.13 (s, 2H, CH2-Ph), 5.19 (br d,
J = 6.6 Hz, 1H, NH), 6.85 [dm, J = 8.8 Hz, 2H, Ar-3(5)-H p-methoxy-
benzyl], 7.14 [dm, J = 8.8 Hz, 2H, Ar-2(6)-H p-methoxybenzyl],
7.29–7.37 (m, 5H, Ar-H phenyl); 13C NMR 21.0 (CH3) and 25.2
(CH3) [4-(CH3)2], 38.9 (C, C4), 46.5 (CH2, N–CH2), 55.2 (CH3, OCH3),
56.4 (CH2, C5), 62.0 (CH, C3), 67.1 (CH2, CH2-Ph), 114.1 [CH, Ar-
C3(5) p-methoxybenzyl], 127.8 (C, Ar-C1 p-methoxybenzyl),
128.09 (CH), 128.13 (CH) and 128.5 (CH) (Ar-Cortho, Ar-Cmeta and
Ar-Cpara phenyl), 129.6 [CH, Ar-C2(6) p-methoxybenzyl], 136.2 (C,
Ar-C1 phenyl), 157.0 (C, OCON), 159.2 (C, Ar-C4 p-methoxybenzyl),
171.4 (C, C2); Anal. Cald for C22H26N2O4ꢀ0.2H2O: C, 68.45; H, 6.89; N,
7.26. Found: C, 68.44; H, 6.89; N, 7.18. HRMS (ESI): calcd for ([M+H]+)
383.1965; found 383.1958.
4.8. (S)-3-Amino-4,4-dimethylpyrrolidin-2-one, (S)-6, from (S)-7
To a solution of (S)-7 (150 mg, 0.60 mmol) in acetonitrile
(2 mL), a solution of Ce(NH4)2(NO3)6 (CAN, 1.35 g, 2.46 mmol) in
water (2 mL) was added dropwise and the mixture was stirred
for 2.5 h at room temperature until no more starting compound
(TLC) was observed. The mixture was basified with aqueous 2 M
NaOH until pH 7–8 and extracted with CH2Cl2 (3 ꢂ 50 mL). The
combined organic extracts were washed with water, dried (anhy-
drous MgSO4), and concentrated under reduced pressure to give
a residue, mixture of p-anisaldehyde and imine (S)-17 (75 mg).
The aqueous phase was alkalinized with 5 M NaOH (5 mL) and ex-
tracted with CH2Cl2 (3 ꢂ 50 mL). The combined organic extracts
were washed with water, dried (anhydrous MgSO4), and concen-
trated under reduced pressure to give (S)-6 (37 mg) as a white so-
lid. A solution of the above-mentioned mixture of (S)-17 and p-
anisaldehyde (75 mg) in MeOH (5 mL) was hydrogenated at
4.10. Oxidation of (S)-18 with ammonium cerium(IV) nitrate.
Isolation of benzyl (S)-N-[1-(p-methoxybenzyl)-4,4-dimethyl-
2,5-dioxopyrrolidin-3-yl]carbamate (S)-19 and benzyl (S)-N-
[4,4-dimethyl-2-oxopyrrolidin-3-yl]carbamate (S)-20
To a solution of (S)-18 (517 mg, 1.35 mmol) in acetonitrile
(7 mL), a solution of ammonium cerium(IV) nitrate (CAN, 2.00 g,

P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
2131
3.65 mmol) in water (7 mL) was added dropwise and the mixture
was stirred for 3 h at room temperature until no more starting
compound (TLC) was observed. The mixture was basified with
aqueous 5 M NaOH (5 mL) and extracted with EtOAc
(3 ꢂ 50 mL). The combined organic extracts were dried (anhy-
drous MgSO4) and concentrated under reduced pressure. The res-
idue (450 mg) was subjected to column chromatography (silica
gel, 54 g, CH2Cl2 and CH2Cl2/MeOH mixtures). On elution with
CH2Cl2, p-anisaldehyde (90 mg) was isolated and on elution with
CH2Cl2/MeOH 20:1, a mixture of (S)-19 and (S)-20 (331 mg) was
obtained. This mixture was subjected to a new column chroma-
tography (silica gel, 30 g, hexane/EtOAc mixtures). On elution
with hexane/EtOAc 1:1, (S)-19 (127 mg, 24% yield) was isolated
as a colorless oil, and on elution with hexane/EtOAc 1:10, (S)-20
(331 mg, 42% yield) was isolated as a white solid. The analytical
sample of (S)-20 was obtained as a white solid by crystallization
from EtOAc (5 mL).
4.12. Methylation of (S)-7. Obtention of (S)-3-(dimethylamino)-
1-(p-methoxybenzyl)-4,4-dimethylpyrrolidin-2-one (S)-21 and
(S)-3-(dimethylamino)-1-[3-(hydroxymethyl)-4-methoxybenzyl]-
4,4-dimethylpyrrolidin-2-one (S)-22
Formic acid (1.55 mL, 1.90 g, 41.2 mmol) was added to a cold
mixture (ice-water bath) of aqueous formaldehyde (37%, 1.55 mL,
20.8 mmol) and (S)-7 (218 mg, 0.88 mmol) and the reaction mix-
ture was heated at 80 °C for 20 h. The mixture was allowed to cool
to room temperature, basified with aqueous 2 M NaOH (30 mL),
and extracted with Et2O (3 ꢂ 30 mL). The combined organic ex-
tracts were dried (anhydrous MgSO4) and concentrated under re-
duced pressure to give
a crude product (227 mg) that was
subjected to column chromatography (aluminum oxide, 20 g, hex-
ane/EtOAc 1:2 and MeOH). In the order of elution, (S)-21 (180 mg,
74% yield) as a colorless oil and (S)-22 (54 mg, 20% yield) as a yel-
lowish oil were obtained.
Compound (S)-19: ½a D23
ꢃ
¼ ꢁ28 (c 0.46, CH2Cl2); Rf 0.89 (silica gel,
(S)-21: ½a 2D3
¼ ꢁ76 (c 0.58, CH2Cl2); Rf 0.68 (aluminum oxide,
ꢃ
5.5 cm, EtOAc); IR 3318 (NH), 2960, 1714 and 1667 (CO), 1604,
6.8 cm, hexane/EtOAc 1:2); IR 2956, 2928, 2865, 1677 (CO), 1611,
1537, 1511, 1303, 1251, 1174, 1052, 1027, 842, 762, 697 cmꢁ1
;
1512, 1440, 1367, 1304, 1244, 1173, 1031, 844, 819 cmꢁ1 1H
;
1H NMR (main rotamer) 1.03 (s, 3H) and 1.32 (s, 3H) [4-(CH3)2],
3.54 (d, J = 11.2 Hz, 1H) and 3.87 (d, J = 11.2 Hz, 1H) (N–CH2),
3.85 (s, 3H, OCH3), 4.49 (d, J = 7.6 Hz, 1H, 3-H), 5.05 (br d,
J = 7.6 Hz, 1H, NH), 5.13 (s, 2H, CH2-Ph), 6.90 [dm, J = 8.8 Hz, 2H,
Ar-3(5)-H p-methoxybenzyl], 7.32–7.39 [m, 5H, Ar-H phenyl],
7.61 [dm, J = 8.8 Hz, 2H, Ar-2(6)-H p-methoxybenzyl]; 13C NMR
20.5 (CH3) and 24.6 (CH3) [4-(CH3)2], 37.7 (C, C4), 55.0 (CH2, N–
CH2), 55.4 (CH3, OCH3), 63.3 (CH, C3), 67.4 (CH2, CH2-Ph), 113.2
[CH, Ar-C3(5) p-methoxybenzyl], 125.7 (C, Ar-C1 p-methoxyben-
zyl), 128.1 (CH), 128.3 (CH) and 128.6 (CH) (Ar-Cortho, Ar-Cmeta
and Ar-Cpara phenyl), 131.7 [CH, Ar-C2(6) p-methoxybenzyl],
135.9 (C, Ar-C1 phenyl), 156.8 (C, NHCOO), 159.6 (C, Ar-C4 p-
methoxybenzyl), 169.2 (C), 172.0 (C) (C2 and C5). Anal. Calcd for
NMR 1.04 (s, 3H) and 1.05 (s, 3H) [C4ꢁ(CH3)2], 2.46 [s, 6H,
N(CH3)2], 2.77 (d, J = 9.6 Hz, 1H) and 2.92 (d, J = 9.6 Hz, 1H) (5-
H2), 2.85 (s, 1H, 3-H), 3.80 (s, 3H, OCH3), 4.34 (d, J = 14.4 Hz, 1H)
and 4.43 (d, J = 14.4 Hz, 1H) (N–CH2), 6.84 [dm, J = 8.6 Hz, 2H, Ar-
3(5)-H], 7.20 [dm, J = 8.6 Hz, 2H, Ar-2(6)-H]; 13C NMR 21.5 (CH3)
and 29.4 (CH3) [4-(CH3)2], 36.2 (C, C4), 43.7 [CH3, N(CH3)2], 45.8
(CH2, N–CH2), 55.2 (CH3, OCH3), 58.5 (CH2, C5), 74.4 (CH, C3),
114.0 [CH, Ar-C3(5)], 128.5 (C, Ar-C1), 129.8 [CH, Ar-C2(6)], 159.1
(C, Ar-C4), 172.3 (C, C2). Anal. Calcd for C16H24N2O2: C, 69.53; H,
8.75; N, 10.14. Found: C, 69.20; H, 8.88; N, 9.80. HRMS (ESI) calcd
for ([M+H]+): 277.1911; found 277.1918.
Compound (S)-22: ½a D23
¼ ꢁ40 (c 0.59, CH2Cl2); Rf 0.19 (alumi-
ꢃ
num oxide, 6.8 cm, hexane/EtOAc 1:2); IR (NaCl) 3600–2400
(max at 3398, 3049, 2956, 2933, 2869, 2838, 2786, OH and CH),
1674 (CO), 1612, 1499, 1460, 1388, 1369, 1309, 1289, 1249,
C
22H24N2O5: C, 66.65; H, 6.10; N, 7.07. Found: C, 66.60; H, 6.15;
N, 7.04. HRMS (ESI) calcd for ([M+H]+) 397.1758; found 397.1755.
Compound (S)-20: Mp 173–174 °C (EtOAc); ½a D23
ꢃ
¼ ꢁ12 (c 0.30,
1220, 1178, 1152, 1126, 1045, 822, 734 cmꢁ1 1H NMR 1.03 (s,
;
CH2Cl2); Rf 0.35 (silica gel, 5.8 cm, EtOAc); IR (KBr) 3298 (NH),
3225, 3106, 3065, 3033, 2960, 2926, 2858, 1736 and 1691 (CO),
1543, 1449, 1390, 1378, 1367, 1327, 1244, 1050, 1024, 753,
3H) and 1.04 (s, 3H) [C4ꢁ(CH3)2], 2.44 [s, 6H, N(CH3)2], 2.77 (d,
J = 9.6 Hz, 1H) and 2.92 (d, J = 9.6 Hz, 1H) (5-H2), 2.84 (s, 1H, 3-
H), 3.84 (s, 3H, OCH3), 4.34 (d, J = 14.4 Hz, 1H) and 4.39 (d,
J = 14.4 Hz, 1H) (N–CH2), 4.64 (s, 2H, CH2OH), 6.81 [d, J = 8.4 Hz,
1H, Ar-5-H], 7.14 [overlapped d, J = 8.4 Hz, 1H, Ar-6-H], 7.16 (s,
1H, Ar-2-H); 13C NMR 21.4 (CH3) and 29.4 (CH3) [4-(CH3)2], 36.2
(C, C4), 43.7 [CH3, N(CH3)2], 45.8 (CH2, N–CH2), 55.3 (CH3, OCH3),
58.5 (CH2, C5), 61.7 (CH2, Ar-CH2OH), 74.4 (CH, C3), 110.3 (CH,
Ar-C5), 128.4 (C, Ar-C3), 128.8 (CH) and 128.9 (CH) (Ar-C2 and
Ar-C6), 129.3 (C, Ar-C1), 156.8 (C, Ar-C4), 172.3 (C, C2). Anal. Calcd
for C17H26N2O3: C, 66.64; H, 8.55; N, 9.14. Found: C, 66.32; H, 8.46;
N, 9.08. HRMS (ESI) calcd for ([M+H]+): 307.2016; found 307.2024.
694 cmꢁ1 1H NMR (main rotamer) 0.97 (s, 3H) and 1.26 (s, 3H)
;
[4-(CH3)2], 3.01 (d, J = 9.2 Hz, 1H) and 3.17 (d, J = 9.2 Hz, 1H) (5-
H2), 4.24 (d, J = 8.0 Hz, 1H, 3-H), 5.12 (s, 2H, CH2-Ph), 5.24 (br s,
1H, NHCOO), 6.29 (br s, 1H, 1-H), 7.31–7.37 [m, 5H, Ar-H]; 13C
NMR 20.9 (CH3) and 25.3 (CH3) [4-(CH3)2], 41.1 (C, C4), 52.3
(CH2, C5), 61.1 (CH, C3), 67.2 (CH2, CH2-Ph), 128.1 (CH), 128.2
(CH) and 128.5 (CH) (Ar-Cortho, Ar-Cmeta and Ar-Cpara), 136.2 (C,
Ar-C1), 157.0 (C, NHCOO), 174.9 (C, C2). Anal. Calcd for
C
14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C, 64.13; H, 6.93;
N, 10.42. HRMS (ESI) calcd for ([M+H]+): 263.1390; found
263.1391.
4.13. (S)-21ꢀMono-(2R,3R)-O,O0-di-(p-toluoyl)tartrate
An aliquot of (S)-21 (130 mg, 0.52 mmol) was taken in MeOH
(5 mL) and a solution of (2R,3R)-(ꢁ)-O,O0-di-(p-toluoyl)tartaric acid
(97% purity, 200 mg, 0.52 mmol) in MeOH (5 mL) was added. The
resulting solution was concentrated to dryness in vacuo and the
white residue was crystallized from a mixture of EtOAc/hexane
5:2 (7 mL) to give (S)-21ꢀmono-(2R,3R)-O,O0-di-(p-toluoyl)tartrate
as a white solid (248 g, 75% yield), mp 190–191 °C (EtOAc/hexane
4.11. Compound (S)-6 from (S)-20
A mixture of (S)-20 (92 mg, 0.35 mmol), concentrated HCl
(150 lL), and 5% Pd/C (400 mg) in MeOH (30 mL) was hydroge-
nated at 1 atm and room temperature for 17 h. The mixture was fil-
tered through a pad of CeliteÒ washing the filter with MeOH
(10 mL). The solvent from the combined filtrate and washing was
eliminated under reduced pressure and the residue was basified
with aqueous 2 M NaOH (5 mL) and extracted with CH2Cl2
(3 ꢂ 30 mL). The combined organic extracts were dried (anhydrous
MgSO4) and concentrated in vacuo to give (S)-6 (41 mg, 91% yield)
as a white solid, whose analytical and spectroscopic data are coin-
cidental with those of the sample previously prepared.
5:2); ½a 2D3
¼ ꢁ105 (c 0.79, MeOH); IR (KBr) 3600–2500 (max at
ꢃ
3429, 3035, 2953, 2879, 2842, OH, +NH and CH), 1709 and 1697
(CO), 1610, 1513, 1487, 1455, 1338, 1304, 1267, 1248, 1179,
1126, 1111, 1033, 839, 750, 694 cmꢁ1 1H NMR (CD3OD) 1.09 (s,
;
3H) and 1.18 (s, 3H) [C4-(CH3)2], 2.41 (s, 6H, CH3 p-toluoyl), 2.91
[s, 6H, N(CH3)2], 2.98 (d, J = 10.0 Hz, 1H) and 3.02 (d, J = 10.0 Hz,
1H) (5-H2), 3.67 (s, 1H, 3-H), 3.77 (s, 3H, OCH3), 4.33 (d,

2132
P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
J = 14.4 Hz, 1H) and 4.45 (d, J = 14.4 Hz, 1H) (N–CH2), 4.88 (s, mo-
bile H), 5.90 [s, 2H, 2(3)-H tartrate], 6.90 [dm, J = 8.4 Hz, 2H, Ar-
3(5)-H], 7.21 [dm, J = 8.4 Hz, 2H, Ar-2(6)-H], 7.30 [d, J = 8.0 Hz,
4H, 3(5)-H p-toluoyl], 8.01 [d, J = 8.0 Hz, 4H, 2(6)-H p-toluoyl];
13C NMR (CD3OD) 21.3 (CH3) and 27.4 (CH3) [4-(CH3)2], 21.7
(CH3, p-toluoyl CH3), 38.9 (C, C4), 44.1 [CH3, N(CH3)2], 47.0 (CH2,
N–CH2), 55.7 (CH3, OCH3), 58.6 (CH2, C5), 74.4 (CH, C3), 74.5 [CH,
C2(3) tartrate], 115.2 [CH, Ar-C3(5)], 128.2 (C, C1 p-toluoyl),
128.7 (C, Ar-C1), 130.2 [CH, C3(5) p-toluoyl], 131.0 [CH, Ar-
C2(6)], 131.1 [CH, C2(6) p-toluoyl], 145.6 (C, C4 p-toluoyl), 161.0
(C, Ar-C4), 167.3 (C, CO p-toluoyl), 169.2 (C, C2), 171.1 [C, C1(4) tar-
trate]. Anal. Calcd for C16H24N2O2ꢀC20H18O8: C, 65.24; H, 6.39; N,
4.23. Found: C, 65.26; H, 6.46; N, 4.00.
and 26.0 (CH3) [4-(CH3)2], 40.9 (C, C4), 52.4 (CH2, C5), 53.5 (CH2,
N–CH2), 66.6 (CH, C3), 127.0 (CH, Ar-Cpara), 128.2 (CH) and 128.3
(CH) (Ar-Cortho and Ar-Cmeta), 140.3 (C, Ar-Cipso), 177.9 (C, C2). Anal.
Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C, 71.53; H,
8.41; N, 12.83. HRMS (ESI) calcd for ([M+H]+): 219.1492; found
219.1494.
4.16. rac-3-Amino-4,4-dimethylpyrrolidin-2-one rac-6
4.16.1. By hydrogenation of rac-26
A mixture of rac-26 (820 mg, 3.76 mmol), concentrated HCl
(2.0 mL), and 5% Pd/C (2.50 g) in EtOH (20 mL) was hydrogenated
at 1 atm and room temperature for 48 h. The mixture was filtered
through a pad of CeliteÒ and the residue was washed with EtOH
(10 mL). The combined filtrate and washing were concentrated un-
der reduced pressure, and the residue was basified with aqueous
2 M NaOH (10 mL) and extracted with CH2Cl2 (3 ꢂ 50 mL). The
combined organic extracts were dried (anhydrous MgSO4) and
concentrated under reduced pressure to give rac-6 (440 mg, 91%
yield) as a white solid. The analytical sample was obtained by crys-
tallization from a mixture of EtOAc/MeOH 11:1 giving a white so-
lid, mp 96–97 °C (EtOAc/MeOH 11:1). IR 3204 (NH), 2948, 2894,
2868, 1701 and 1677 (CO), 1591, 1464, 1355, 1309, 1140, 948,
4.14. 4,4-Dimethylpyrrolidine-2,3-dione 24
To a cooled (0 °C) solution of rac-23 (1.43 g, 11.1 mmol) in AcOH
(70 mL), a solution of Na2Cr2O7ꢀ2H2O (1.87 g, 6.30 mmol) in H2SO4
(20% aqueous solution, 17 mL) was added dropwise. After 30 min
at room temperature, water (20 mL) was added, and the mixture
was extracted with CH2Cl2 (3 ꢂ 100 mL). The combined organic
phases were concentrated in vacuo. The residue was taken in
CH2Cl2 (200 mL) and washed with saturated aqueous NaHCO3
(2 ꢂ 50 mL) and brine (15 mL). The solution was dried (anhydrous
MgSO4) and concentrated under reduced pressure to give a residue
(1.53 g) that was subjected to column chromatography (silica gel,
31 g, CH2Cl2 and CH2Cl2/MeOH 20:1), isolating 24 (1.05 g, 75%
yield) as a white solid. The analytical sample was obtained by crys-
tallization from CH2Cl2 (17 mL), mp 198–200 °C (CH2Cl2); Rf 0.47
(silica gel, 6.6 cm, CH2Cl2/MeOH 10:1); IR 3259 (NH), 2962, 2930,
2904, 2863, 1755 (CO), 1742 and 1698 (CO), 1467, 1437, 1317,
841, 775, 659 cmꢁ1 1H NMR (300 MHz) 1.02 (s, 3H) and 1.21 (s,
;
3H) [C4-(CH3)2], 1.48 (br s, 2H, NH2), 3.01 (dd, J = 9.6, 1.5 Hz, 1H)
and 3.11 (d, J = 9.6 Hz, 1H) (5-H2), 3.15 (s, 1H, 3-H), 5.70 (br s,
1H, N-H); 13C NMR (75.4 MHz) 20.1 (CH3) and 25.1 (CH3) [4-
(CH3)2], 40.3 (C, C4), 52.5 (CH2, C5), 61.5 (CH, C3), 178.6 (C, C2).
Anal. Calcd for C6H12N2Oꢀ0.5H2O: C, 52.53; H, 9.55; N, 20.42.
Found: C, 52.76; H, 9.20; N, 20.07. HRMS (ESI) calcd for
([M+H]+): 129.1022; found 129.1019.
1203, 1057, 1042, 1012, 717, 662 cmꢁ1 1H NMR (DMSO-d6) 1.11
;
[s, 6H, 4-(CH3)2], 3.30 (s, 2H, 5-H2), 9.57 (s, 1H, NH); 13C NMR
(DMSO-d6) 23.2 [CH3, 4-(CH3)2], 40.8 (C, C4), 50.2 (CH2, C5),
161.0 (C, C2), 206.3 (C, C3). Anal. Calcd for C6H9NO2ꢀ0.1H2O: C,
55.89; H, 7.19; N, 10.86. Found: C, 55.93; H, 7.07; N, 10.84. HRMS
(ESI) calcd for ([M+H]+) 128.0706; found 128.0704.
4.16.2. By hydrogenation of the benzylimine 25
A mixture of the above-mentioned benzylimine 25 (1.41 g,
6.52 mmol) and 5% Pd/C (3.90 g) in EtOH (30 mL) was hydroge-
nated at 1 atm and room temperature for 24 h. The mixture was fil-
tered through a pad of CeliteÒ and the residue was washed with
EtOH (10 mL). The combined filtrate and washing were concen-
trated under reduced pressure to give rac-6 (810 mg, 97% yield)
as a white solid.
4.15. rac-3-(Benzylamino)-4,4-dimethylpyrrolidin-2-one rac-26
A solution of 24 (1.28 g, 10.1 mmol) and freshly distilled benzyl-
amine (1.10 mL, 1.08 g, 10.1 mmol) in toluene (50 mL) was heated
at reflux for 24 h in Dean–Stark equipment. Evaporation of the sol-
vent under reduced pressure gave the corresponding imine 25
(2.18 g, quantitative yield) as a yellow solid, which was used as
such in the next step. A part of the above mentioned imine 25
(1.00 g, 4.62 mmol) was taken in anhydrous MeOH (40 mL), and
a solution of NaBH3CN (95% purity, 650 mg, 9.84 mmol) in anhy-
4.17. rac-3-(Dimethylamino)-1-(hydroxymethyl)-4,4-dimethyl-
pyrrolidin-2-one rac-27
To an ice-cold stirred suspension of rac-6 (1.69 g, 13.2 mmol) in
water (10 mL), formaldehyde (2.5 mL, 37% aqueous solution,
33.6 mmol) and formic acid (1.2 mL, 31.8 mmol) were added and
the reaction mixture was heated at reflux for 4 h. Then, it was al-
lowed to cool to room temperature, after which more formalde-
hyde (1.2 mL, 37% aqueous solution, 16.1 mmol) and formic acid
(0.6 mL, 15.9 mmol) were added and the mixture was heated at re-
flux for 19 h. The solution was allowed to cool to room tempera-
ture, was basified with aqueous 5 M NaOH, and extracted with
CH2Cl2 (3 ꢂ 150 mL). The combined organic extracts were washed
with water, dried (anhydrous MgSO4), and concentrated in vacuo
to give a residue (2.40 g) that was crystallized from hexane/Et2O
10:1 (50 mL) to give rac-27 (1.57 g, 64% yield), mp 46–47 °C (hex-
ane/Et2O 10:1); Rf 0.22 (silica gel, 6.0 cm, EtOAc/MeOH/Et3N
100:1:0.1); IR 3312 and 3294 (OH), 2966, 2956, 2937, 1660
(C@O), 1462, 1453, 1431, 1313, 1295, 1275, 1206, 1176, 1094,
drous MeOH (5 mL) and AcOH (350 lL, 263 mg, 6.12 mmol) were
added and the reaction mixture was stirred at room temperature
for 4 h. Then, more NaBH3CN (125 mg, 1.89 mmol) was added
and stirring was continued for 45 min. Water (20 mL) was added
and the organic solvent was evaporated under reduced pressure.
The remaining aqueous phase was treated with aqueous 2 M NaOH
until pH 12–13 and extracted with CH2Cl2 (3 ꢂ 50 mL). The com-
bined organic extracts were dried (anhydrous MgSO4) and concen-
trated under reduced pressure to give rac-26 (850 mg, 84% yield).
The analytical sample was obtained as a white solid by crystalliza-
tion from EtOAc, mp 97–98 °C (EtOAc); IR (KBr) 3315 and 3192
(NH), 2959 and 2868 (CH), 1698 and 1661 (CO), 1492, 1451,
1363, 1311, 1201, 1152, 730, 696 cmꢁ1
;
1H NMR 1.06 (s, 3H) and
1076, 1059, 1036, 1018, 972, 854, 709, 639, 628 cmꢁ1 1H NMR
;
1.14 (s, 3H) [4-(CH3)2], 1.88 (br s, 1H, N–H), 2.95 (dd, J = 9.6,
1.6 Hz, 1H) and 3.02 (d, J = 9.6 Hz) (5-H2), 3.05 (s, 1H, 3-H), 3.95
(d, J = 13.6 Hz, 1H) and 4.01 (d, J = 13.6 Hz, 1H) (CH2-Ph), 6.00 (s,
1H, 1-H), 7.24 (t, J = 7.2 Hz, 1H, Ar-Hpara), 7.32 (tm, J = 7.2 Hz, 2H,
Ar-Hmeta), 7.38 (d, J = 7.2 Hz, 2H, Ar-Hortho); 13C NMR 21.0 (CH3)
(300 MHz) 1.10 (s, 3H) and 1.13 (s, 3H) [C4-(CH3)2], 2.43 [s, 6H,
N-(CH3)2], 2.81 (s, 1H, 3-H), 3.14 (d, J = 9.6 Hz, 1H) and 3.11 (d,
J = 9.6 Hz, 1H) (5-H2), 4.70 (d, J = 11.0 Hz, 1H) and 4.82 (d,
J = 11.0 Hz, 1H) (N–CH2OH); 13C NMR (75.4 MHz) 21.4 (CH3) and
29.0 (CH3) [4-(CH3)2], 36.8 (C, C4), 43.7 [CH3, N(CH3)2], 57.9 (CH2,

P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
2133
C5), 66.4 (CH2, N–CH2OH), 74.6 (CH, C3), 173.6 (C, C2). Anal. Calcd
for C9H18N2O2: C, 58.04; H, 9.74; N, 15.04. Found: C, 57.92; H,
10.09; N, 15.10. HRMS (ESI) calcd for ([M+H]+): 187.1441; found
187.1441.
11.93. Found: C, 71.82; H, 8.03; N, 11.72. HRMS (ESI) calcd for
([M+Na]+) 253.1311; found 253.1313.
4.20. (3S,10R)-4,4-Dimethyl-3-[(1-phenylethyl)amino]pyrrolidin-
2-one (3S,10R)-30 and (3R,10R)-4,4-dimethyl-3-[(1-phenylethyl)-
amino]pyrrolidin-2-one (3R,10R)-31
4.18. rac-3-(Dimethylamino)-4,4-dimethylpyrrolidin-2-one rac-
28
To a cold (ꢁ78 °C) solution of (R)-29 (1.05 g, 4.56 mmol) in
4.18.1. From rac-27
anhydrous MeOH (30 mL), a solution of NaBH3CN (95% purity,
To an ice-cold stirred suspension of rac-27 (884 mg, 4.75 mmol)
in water (20 mL), methylamine (1.0 mL, 40% aqueous solution,
11.6 mmol) and formic acid (600 lL, 15.9 mmol) were added and
the mixture was heated at reflux for 19 h. The solution was allowed
to cool to room temperature, then basified with aqueous 5 M
NaOH, and extracted with CH2Cl2 (3 ꢂ 150 mL). The combined or-
ganic extracts were washed with water, dried (anhydrous MgSO4),
and concentrated in vacuo to give a residue (967 mg) that was
crystallized from hexane to give rac-28 (600 mg, 80% yield).
650 mg, 9.88 mmol) and AcOH (350 lL, 367 mg, 6.10 mmol) in
anhydrous MeOH (5 mL) was added dropwise and the reaction
mixture was stirred at this temperature for 4 h. Then more
NaBH3CN (95% purity, 350 mg, 5.29 mmol) was added and stirring
was continued for 1 h. Water (20 mL) was then added and the or-
ganic solvent was evaporated under reduced pressure. The remain-
ing aqueous phase was treated with aqueous 2 M NaOH until pH
12–13 and extracted with CH2Cl2 (3 ꢂ 50 mL). The combined or-
ganic extracts were dried (anhydrous MgSO4) and concentrated
under reduced pressure to give a diastereomeric mixture of
(3S,10R)-30 and (3R,10R)-31 (987 mg, 93% yield) in a ratio of
80:20 (1H-NMR). The mixture was taken in Et2O/hexane 5:4
(9 mL) and the solution was cooled to ꢁ20 °C for 24 h. The precip-
itated solid was collected by filtration and washed with Et2O/hex-
ane 1:1 (2 mL) to give (3R,10R)-31 (110 mg, 10% yield) as a white
solid. The mother liquors were kept at ꢁ20 °C for 48 h precipitating
an equimolar mixture of amines (3S,10R)-30 and (3R,10R)-31
(78 mg, 7% yield). The mother liquors were concentrated to dry-
ness to give a viscous solid [790 mg, (3S,10R)-30 >95% de] that
was crystallized from Et2O/pentane 7:2 (10 mL). Filtration of the
precipitate gave (3S,10R)-30 (350 mg) as a white solid. The filtrate
was concentrated to dryness and the residue (440 mg) was crystal-
lized from a mixture of Et2O/pentane 5:2 (4 mL), obtaining a new
crop of (3S,10R)-30 (330 mg, 64% total yield).
In another operation, starting from (R)-29 (10.21 g, 44.3 mmol),
the obtained mixture of (3S,10R)-30 and (3R,10R)-31 (9.69 g, 94%
yield) was separated by column chromatography (silica gel,
158 g, hexane/EtOAc/NH4OH mixtures). On elution with hexane/
EtOAc/concentrated NH4OH 3:1:0.1, (3S,10R)-30 (3.33 g, 32% yield)
as a white solid and a mixture of (3S,10R)-30 and (3R,10R)-31
(3.85 g, 86:14) were obtained. On elution with hexane/EtOAc/con-
centrated NH4OH 2:1:0.1, a mixture of (3S,10R)-30 and (3R,10R)-31
(1.92 g, 1:1) and (3R,10R)-31 as a white solid (590 mg, 6% yield)
were isolated. Column chromatography (silica gel, 72 g, hexane/
EtOAc/concentrated NH4OH mixtures) of the mixture of (3S,10R)-
30 and (3R,10R)-31 (3.85 g, 86:14) gave, on elution with hexane/
4.18.2. From rac-6
To an ice-cold stirred suspension of rac-6 (508 mg, 3.96 mmol)
in water (5 mL), formaldehyde (620 lL, 37% aqueous solution,
8.32 mmol) and formic acid (5 mL, 132 mmol) were added and
the reaction mixture was heated at reflux for 15 h. Then, it was al-
lowed to cool to room temperature, was basified with aqueous 2 M
NaOH, and extracted with CH2Cl2 (3 ꢂ 100 mL). The combined or-
ganic extracts were washed with water, dried (anhydrous MgSO4),
and concentrated in vacuo to give a residue (560 mg), mixture of
rac-27 and rac-28 (about 2:1 by 1H NMR). The mixture was taken
in water (5 mL), cooled (ice-water bath), and methylamine
(1.0 mL, 40% aqueous solution, 11.6 mmol) and formic acid
(800 lL, 21.2 mmol) were added and the mixture was heated at re-
flux for 20 h. The mixture was allowed to cool to room tempera-
ture, then basified with aqueous 5 M NaOH, and extracted with
CH2Cl2 (3 ꢂ 100 mL). The combined organic extracts were washed
with water, dried (anhydrous MgSO4), and concentrated in vacuo
to give a residue (600 mg), that was crystallized from hexane
(15 mL) to give rac-28 (455 mg, 74% yield). The analytical sample
was obtained as a white solid by crystallization from hexane/EtOAc
3:1 (20 mL), mp 118–120 °C (hexane/EtOAc 3:1). The IR, 1H and 13
C
NMR are coincidental with those of rac-28. Anal. Calcd for
C8H16N2Oꢀ0.15H2O: C, 60.46; H, 10.34; N, 17.63. Found: C, 60.44;
H, 10.30; N, 17.51. HRMS (ESI) calcd for ([M+H]+) 157.1335; found
157.1335.
4.19. (R)-4,4-Dimethyl-3-[(1-phenylethyl)imino]pyrrolidin-2-
one (R)-29
EtOAc/concentrated NH4OH 5:1:0.1, a new portion of pure
(3S,10R)-30 (1.52 g, 47% total yield).
Compound (3S,10R)-30: Rf 0.44 (silica gel, 6.1 cm, hexane/EtOAc/
concentrated NH4OH 1:1:0.1); Mp 79–80 °C (Et2O/pentane 5:4);
A solution of 24 (530 mg, 4.17 mmol) and (R)-1-phenylethyl-
amine, (R)-13 (540
lL, 508 mg, 4.17 mmol) in toluene (30 mL)
½
a 2D3
ꢃ
¼ þ26 (c 1.30, CH2Cl2); IR (KBr) 3600–2800 (max at 3247,
was heated at reflux for 20 h in a Dean–Stark equipment. Evapora-
3110, 3061, 3025, 2961, 2928, 2867, 2808), 1703 (CO), 1602,
tion of the solvent under reduced pressure gave (R)-29 (1.05 g,
1485, 1462, 1451, 1384, 1368, 1316, 1262, 1237, 1204, 1154,
quantitative yield) as a colorless oil. ½a D23
ꢃ
¼ þ44 (c 0.80, CH2Cl2);
1084, 1055, 1017, 909, 807, 762, 701, 666 cmꢁ1 1H NMR
;
IR (NaCl) 3212 (NH), 3062, 2970, 2927, 2890, 2868, 1701 and
1678 (CO), 1601, 1492, 1464, 1450, 1382, 1362, 1313, 1208,
(300 MHz) 1.08 (s, 3H) and 1.16 (s, 3H) [C4-(CH3)2], 1.37 (d,
J = 6.9 Hz, 3H, CH3CH), 1.4–2.2 (br s, 1H, 3-NH), 2.88 (dd, J = 9.6,
1.8 Hz, 1H) and 2.92 (d, J = 9.6 Hz, 1H) (5-H2), 2.94 (s, 1H, 3-H),
3.93 (q, J = 6.9 Hz, 1H, CH3CH), 5.79 (s, 1H, 1-H), 7.23 (m, 1H, Ar-
1069, 1044, 763, 700 cmꢁ ; 1H NMR (300 MHz) d 1.22 (s, 3H)
1
and 1.27 (s, 3H) [4-(CH3)2], 1.44 (d, J = 6.4 Hz, 3H, CH3–CH), 3.24
(dd, J = 9.9, 6.4 Hz, 1H) and 3.28 (dd, J = 9.9, 6.4 Hz, 1H) (5-H2),
6.47 (q, J = 6.4 Hz, 1H, CH3–CH), 7.20 (tm, J = 7.5 Hz, 1H, Ar-Hpara),
7.31 (tm, J = 7.5 Hz, 2H, Ar-Hmeta), 7.47 (dm, J = 7.5 Hz, 2H, Ar-
H
para), 7.30–7.33 (m, 4H, Ar-Hmeta and Ar-Hortho); 13C NMR
(75.4 MHz) 21.2 (CH3), 24.9 (CH3) and 26.2 (CH3) [4-(CH3)2 and
CH3–CH], 41.1 (C, C4), 52.2 (CH2, C5), 56.9 (CH, CH3–CH), 64.1
(CH, C3), 126.6 (CH, Ar-Cortho), 126.9 (CH, Ar-Cpara), 128.5 (CH,
Ar-Cmeta), 145.0 (C, Ar-Cipso), 177.7 (C, C2). Anal. Calcd for
H
ortho), 7.70 (br s, 1H, N-H); 13C NMR (75.4 MHz) 25.1 (CH3, CH3–
CH), 25.9 (CH3) and 26.7 (CH3) [4-(CH3)2], 40.0 (C, C4), 52.5 (CH2,
C5), 56.0 (CH, CH3-CH), 126.3 (CH, Ar-Cpara), 126.5 (CH, Ar-Cortho),
128.1 (CH, Ar-Cmeta), 146.2 (C, Ar-Cipso), 163.8 (C), 164.3 (C) (C2
and C3). Anal. Calcd for C14H18N2Oꢀ0.25H2O: C, 71.61; H, 7.94; N,
C
14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.25; H, 8.76;
N, 11.87. HRMS (ESI) calcd for ([M+H]+) 233.1648; found
233.1649.

2134
P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
Compound (3R,10R)-31: Rf 0.30 (silica gel, 6.1 cm, hexane/EtOAc/
concentrated NH4OH 1:1:0.1); Mp 164–165 °C (Et2O/hexane 7:2);
¼ þ136 (c 0.70, CH2Cl2); IR (KBr) 3600–2800 (max at 3297,
3238, 2961, 2865, 2850, 1693 (CO), 1462, 1452, 1351, 1308,
1277, 1214, 1148, 728, 700, 673 cmꢁ1 1H NMR (300 MHz) 0.82
(s, 3H) and 0.98 (s, 3H) [C4-(CH3)2], 1.39 (d, J = 6.8 Hz, 3H, CH3CH),
1.60 (br s, 1H, 3-NH), 2.83 (s, 1H, 3-H), 2.87 (dd, J = 9.6, 2.1 Hz, 1H)
and 2.93 (d, J = 9.6 Hz, 1H) (5-H2), 4.30 (q, J = 6.8 Hz, 1H, CH3CH),
5.90 (s, 1H, 1-H), 7.22 (tm, J = 7.2 Hz, 1H, Ar-Hpara), 7.30 (tm,
J = 7.2 Hz, 2H, Ar-Hmeta) 7.39 (dm, J = 7.2 Hz, 2H, Ar-Hortho); 13C
NMR (75.4 MHz) 20.7 (CH3) and 24.7 (CH3) [4-(CH3)2], 25.2 (CH3,
CH3CH), 40.5 (C, C4), 52.3 (CH2, C5), 57.5 (CH, CH3CH), 65.4 (CH,
C3), 126.9 (CH, Ar-Cpara), 127.4 (CH, Ar-Cortho), 128.2 (CH, Ar-Cmeta),
145.9 (C, Ar-Cipso), 179.2 (C, C2). Anal. Calcd for C14H20N2O: C,
72.38; H, 8.68; N, 12.06. Found: C, 72.48; H, 8.75; N, 11.95. HRMS
(ESI) calcd for ([M+Na]+) 255.1468; found 255.1467.
concentrated in vacuo to give a residue (210 mg), mixture of (R)-
27 and (R)-28 (about 2:1 by 1H NMR). The mixture was taken in
½
a 2D3
ꢃ
water (2 mL), cooled (ice-water bath); methylamine (500
lL, 40%
aqueous solution, 5.80 mmol) and formic acid (400 L, 10.6 mmol)
l
;
were added and the mixture was heated at reflux for 20 h. Then it
was allowed to cool to room temperature, basified with aqueous
5 M NaOH, and extracted with CH2Cl2 (3 ꢂ 100 mL). The combined
organic extracts were washed with water, dried (anhydrous MgSO4),
and concentrated in vacuo to give a residue (350 mg) that was crys-
tallized from hexane (15 mL) to give (R)-28 (158 mg, 75% yield). The
analytical sample was obtained as a white solid by crystallization
from hexane/EtOAc 3:1 (6 mL), mp 118–119 °C (hexane/EtOAc
3:1). ½a 2D3
¼ þ19 (c 0.52, CH2Cl2); IR 3354 (NH), 2958, 2937, 2870,
ꢃ
2787, 1672 (CO), 1453, 1434, 1366, 1296, 1266, 1176, 1033,
641 cmꢁ1 1H NMR 1.11 (s, 3H) and 1.15 (s, 3H) [C4-(CH3)2], 2.47
;
[s, 6H, N(CH3)2], 2.76 (s, 1H, 3-H), 2.97 (dd, J = 10.0, 1.2 Hz, 1H) and
3.06 (d, J = 10.0 Hz, 1H) (5-H2), 6.54 (br s, 1H, 1-H); 13C NMR 21.5
(CH3) and 29.3 (CH3) [4-(CH3)2], 39.2 (C, C4), 43.6 [CH3, N(CH3)2],
54.3 (CH2, C5), 73.4 (CH, C3), 176.1 (C, C2). Anal. Calcd for
C8H16N2Oꢀ0.2H2O: C, 60.12; H, 10.34; N, 17.53. Found: C, 59.98; H,
10.18; N, 17.36. HRMS (ESI) calcd for ([M+H]+) 157.1335; found
157.1338.
4.21. (R)-3-Amino-4,4-dimethylpyrrolidin-2-one (R)-6
A mixture of (3R,10R)-31 (200 mg, 0.86 mmol), concentrated HCl
(100 lL), and 5% Pd/C (600 mg) in MeOH (10 mL) was hydroge-
nated at 1 atm and room temperature for 24 h. The mixture was fil-
tered through a pad of CeliteÒ and the residue was washed with
MeOH (10 mL). The combined filtrate and washings were concen-
trated to dryness under reduced pressure. The residue was basified
with aqueous 2 M NaOH (5 mL) and extracted with CH2Cl2
(3 ꢂ 40 mL). The combined organic extracts were dried (anhydrous
MgSO4) and concentrated under reduced pressure to give (R)-6
(104 mg, 94% yield) as a white solid. The analytical sample was ob-
tained by crystallization from a mixture of EtOAc/MeOH 11:1
4.24. (S)-3-(Dimethylamino)-4,4-dimethylpyrrolidin-2-one (S)-
28
To an ice-cold stirred suspension of (S)-6 (1.03 g, 8.04 mmol) in
water (15 mL), formaldehyde (1.27 mL, 37% aqueous solution,
16.9 mmol) and formic acid (783 lL, 19.5 mmol) were added and
the reaction mixture was heated at reflux for 20 h. Then it was al-
lowed to cool to room temperature, basified with aqueous 5 M
NaOH, and extracted with CH2Cl2 (3 ꢂ 150 mL). The combined or-
ganic extracts were washed with water, dried (anhydrous MgSO4),
and concentrated in vacuo to give a residue (1.45 g), mixture of (S)-
27 and (S)-28 (about 2:1 by 1H NMR). The mixture was taken in
water (10 mL), cooled (ice-water bath); methylamine (3 mL, 40%
aqueous solution, 34.2 mmol) and formic acid (2.4 mL, 63.6 mmol)
were added and the mixture was heated at reflux for 15 h. Then it
was allowed to cool to room temperature, basified with aqueous
5 M NaOH solution, and extracted with CH2Cl2 (3 ꢂ 150 mL). The
combined organic extracts were washed with water, dried (anhy-
drous MgSO4), and concentrated in vacuo to give a residue
(1.73 g) that was crystallized from hexane (30 mL) to give (S)-28
(978 mg, 78% yield). The analytical sample was obtained as a white
solid by crystallization from hexane/EtOAc 3:1 (40 mL), mp 119–
(6 mL), mp 96–97 °C (AcOEt/MeOH 11:1). ½a D23
¼ þ17 (c 0.45,
ꢃ
CH2Cl2); IR 3204 (NH), 2948, 2894, 2868, 1701 and 1677 (CO),
1617, 1591, 1480, 1464, 1355, 1309, 1140, 1018, 995, 948, 841,
775, 713, 659 cmꢁ1 1H NMR (300 MHz) 1.02 (s, 3H) and 1.21 (s,
;
3H) [C4ꢁ(CH3)2], 1.48 (br s, 2H, NH2), 3.01 (dd, J = 9.6, 1.5 Hz,
1H) and 3.11 (d, J = 9.6 Hz, 1H) (5-H2), 3.15 (s, 1H, 3-H), 5.80 (br
s, 1H, 1-H); 13C NMR (75.4 MHz) 20.1 (CH3) and 25.1 (CH3) [4-
(CH3)2], 40.3 (C, C4), 52.5 (CH2, C5), 61.5 (CH, C3), 178.6 (C, C2).
Anal. Calcd for C6H12N2Oꢀ0.5H2O: C, 52.53; H, 9.55; N, 20.42.
Found: C, 52.76; H, 9.20; N, 20.07. HRMS (ESI) calcd for ([M+H]+)
129.1022; found 129.1027.
4.22. Compound (S)-6 from (3S,10R)-30
A mixture of (3S,10R)-30 (4.03 g, 17.4 mmol), concentrated HCl
(6.5 mL), and 5% Pd/C (10 g) in MeOH (100 mL) was hydrogenated
at 1 atm and room temperature for 20 h. The mixture was filtered
through a pad of CeliteÒ and the residue was washed with MeOH
(50 mL). The combined filtrate and washings were concentrated to
dryness under reduced pressure. The residue was basified with
aqueous 5 M NaOH (20 mL) and extracted with CH2Cl2 (3 ꢂ
100 mL). The combined organic extracts were dried (anhydrous
MgSO4) and concentrated under reduced pressure to give (S)-6
(2.13 g, 96% yield) as a white solid, whose analytical data are coinci-
dental with those of the sample previously prepared from (S)-7.
120 °C (hexane/EtOAc 3:1). ½a D23
¼ ꢁ20 (c 0.78, CH2Cl2); The IR,
ꢃ
1H, and 13C NMR data are coincidental with those of (R)-28. Anal.
Calcd for C8H16N2Oꢀ0.3H2O: C, 59.45; H, 10.35; N, 17.33. Found:
C, 59.42; H, 10.08; N, 17.23. HRMS (ESI) calcd for ([M+H]+)
157.1335; found 157.1333.
4.25. X-ray crystal-structure determination of (S)-7ꢀmono-
(2R,3R)-O,O0-di-(p-toluoyl)tartrate (Table 1)
A prismatic crystal (0.09 ꢂ 0.08 ꢂ 0.07 mm) was selected and
mounted on a MAR345 diffractometer with an image plate detec-
tor. Unit-cell parameters were determined from 1120 reflections
(3° < h < 31°) and refined by least-squares method. Intensities were
4.23. (R)-3-(Dimethylamino)-4,4-dimethylpyrrolidin-2-one (R)-
28
collected with graphite monochromatized Mo Ka radiation. 10,249
To an ice-cold stirred suspension of (R)-6 (174 mg, 1.36 mmol) in
reflections were measured in the range 2.62 6 h 6 32.41. 5977 of
which were non-equivalent by symmetry (Rint(on I) = 0.028).
4329 reflections were assumed as observed applying the condition
water (3 mL), formaldehyde (213
lL, 37% aqueous solution,
2.86 mmol) and formic acid (125 L, 3.31 mmol) were added and
l
the reaction mixture was heated at reflux for 23 h. Then it was al-
lowed to cool to room temperature, basified with aqueous 5 M NaOH
and extracted with CH2Cl2 (3 ꢂ 100 mL). The combined organic
extracts were washed with water, dried (anhydrous MgSO4), and
I >2
made.
The structure was solved by Direct methods, using SHELXS com-
puter program14 and refined by full-matrix least-squares method
r(I). Lorentz-polarization but no absorption corrections were

P. Camps et al. / Tetrahedron: Asymmetry 21 (2010) 2124–2135
2135
Table 1
The structure was solved by Direct methods, using SHELXS com-
puter program14 and refined by full-matrix least-squares method
with SHELX97 computer program15 using 7930 reflections, (very
negative intensities were not assumed). The function minimized
Experimental data of the X-ray crystal-structure determination of compound (S)-
7ꢀmono-(2R,3R)-O,O-di-(p-toluoyl)tartrate and (3R,10R)-31
Compound
(S)-7ꢀmono-O,O0-di-
(p-toluoyl)tartrate
(3R,10R)-31
was
R
w||Fo|2 ꢁ |Fc|2|2, where w = [
r ,
2(I) + (0.0793P)2 + 0.0660P]ꢁ1
and P = (|Fo|2 + 2|Fc|2)/3, f, f0 and f00 were taken from International
Tables of X-ray Crystallography.16 All H atoms were computed
and refined, using a riding model, with an isotropic temperature
factor equal to 1.2 times the equivalent temperature factor of the
atom to which are linked. The final R(on F) factor was 0.047, wR(on
|F|2) = 0.134, and goodness of fit = 1.121 for all observed reflections.
Number of refined parameters was 157. Max shift/esd = 0.00, mean
shift/esd = 0.00. Max and min peaks in final difference synthesis
were 0.260 and ꢁ0.358 eÅꢁ3, respectively.
Molecular formula
Molecular mass weight
Crystal system
Space group
Cell parameters
a (Å)
C34H38N2O10
634.66
Monoclinic
C2
C14H20N2O
232.32
Orthorhombic
P212121
25.711(13)
7.936(5)
19.739(6)
90
119.59(2)
90
6.262(4)
7.780(6)
27.410(12)
90
90
90
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
3502(3)
4
1335.4(15)
4
Z
F (000)
1344
1.204
0.09 ꢂ 0.08 ꢂ 0.07
10,249
5977
4329
0.089
0.084
0.171
504
Acknowledgments
dcalc [Mg m3]
Crystal size (mm)
Measured reflect.
Independent reflect.
1.156
0.2 ꢂ 0.09 ꢂ 0.02
7930
2529
2311
0.073
0.047
0.134
0.260
ꢁ0.358
157
Financial support from Ministerio de Ciencia e Innovación (Pro-
ject CTQ2008-03768/PPQ) and Comissionat per a Universitats i
Recerca (Project 2005-SGR-00180) is gratefully acknowledged.
We thank the Serveis Científico-Tècnics of the University of Barce-
lona for the NMR and MS facilities, and Ms. P. Domènech from the
IIQAB (CSIC, Barcelona, Spain) for carrying out the elemental
analyses.
Observed reflect.
a
l
(Mo K
a)
(mm1)
R
Rw
b
3
D
D
qmax (e Åꢁ )
0.205
c
3
qmin (e Åꢁ )
ꢁ0.216
Refined parameters
Max. shift/esd
416
0.00
0.00
References
a
b
c
l
(Mo K
a
) linear absorption coefficient. Radiation Mo K
a
(k = 0.71073 Å).
Maximum peaks in final difference synthesis.
Minimum peaks in final difference synthesis.
1. For a recent review, see: Camps, P.; Muñoz-Torrero, D. Curr. Org. Chem. 2004, 8,
1339–1380.
2. (a) Camps, P.; Giménez, S.; Font-Bardia, M.; Solans, X. Tetrahedron: Asymmetry
1995, 6, 985–990; (b) Camps, P.; Pérez, F.; Soldevilla, N. Tetrahedron Lett. 1999,
40, 6853–6856.
3. (a) Camps, P.; Muñoz-Torrero, D.; Sánchez, L. Tetrahedron: Asymmetry 2004, 15,
2039–2044; (b) Boschi, F.; Camps, P.; Comes-Franchini, M.; Muñoz-Torrero, D.;
Ricci, A.; Sánchez, L. Tetrahedron: Asymmetry 2005, 16, 3739–3745; (c) Ayats, C.;
Camps, P.; Font-Bardia, M.; Solans, X.; Vázquez, S. Tetrahedron 2007, 63, 8027–
8036; (d) Camps, P.; Gómez, T.; Muñoz-Torrero, D.; Rull, J.; Sánchez, L.; Boschi,
F.; Comes-Franchini, M.; Ricci, A.; Calvet, T.; Font-Bardia, M.; De Clerq, E.;
Naessens, L. J. Org. Chem. 2008, 73, 6657–6665.
4. Camps, P.; Muñoz-Torrero, D.; Rull, J.; Font-Bardia, M.; Solans, X. Tetrahedron:
Asymmetry 2007, 18, 2947–2958.
5. Barrios, I.; Camps, P.; Comes-Franchini, M.; Muñoz-Torrero, D.; Ricci, A.;
Sánchez, L. Tetrahedron 2003, 59, 1971–1979.
6. Kopelevich, V. M.; Bulanova, L. N.; Gunar, V. I. Tetrahedron Lett. 1979, 20, 3893–
3894.
7. Camps, P.; Fernández, J. A.; Rull, J.; Vázquez, S. Eur. J. Org. Chem. 2009, 3081–
3087.
with SHELX97 computer program15 using 10,249 reflections (very
negative intensities were not assumed). The function minimized
was
R
w||Fo|2 ꢁ |Fc|2|2, where w = [
r ,
2(I) + (0.0529P)2 + 1.6160P]ꢁ1
and P = (|Fo|2 + 2|Fc|2)/3, f, f0 and f00 were taken from International
Tables of X-ray Crystallography.16 All H atoms were computed
and refined, using a riding model, with an isotropic temperature
factor equal to 1.2 times the equivalent temperature factor of the
atom to which are linked. The final R(on F) factor was 0.084, wR(on
|F|2) = 0.171, and goodness of fit = 1.233 for all observed reflections.
Number of refined parameters was 416. Max shift/esd = 0.00, mean
shift/esd = 0.00. Max and min peaks in final difference synthesis
were 0.205 and ꢁ0.216 eÅ3, respectively.
8. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
9. Yamaoka, H.; Noriya, N.; Ikunaka, M. Org. Process Res. Dev. 2004, 8, 931–938.
10. Dagne, E.; Castagnoli, N., Jr. J. Med. Chem. 1972, 15, 356–360.
11. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 774633 [(S)-7ꢀ(2R,3R)-O,O0-di(p-
toluoyl)tartrate] and CCDC 774634 [(3R,10R)-31]. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
12. Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith,
A. D.; Rodriguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007,
5, 1961–1969.
4.26. X-ray crystal-structure determination of (3R,10R)-4,4-
dimethyl-3-[(1-phenylethyl)amino]pyrrolidin-2-one (3R,10R)-
31 (Table 1)
A prismatic crystal (0.2 ꢂ 0.09 ꢂ 0.02 mm) was selected and
mounted on a MAR345 diffractometer with an image plate detec-
tor. Unit-cell parameters were determined from 2311 reflections
(3° < h < 31°) and refined by least-squares method. Intensities were
collected with graphite monochromatized Mo K
a radiation. 7930
13. Singh, S. B. Tetrahedron Lett. 1995, 36, 2009–2012.
14. Sheldrick, G. M. SHELXS: A Computer Program for Automatic Solution of Crystal
Structure Refinement; University of Göttingen: Germany, 1997.
15. Sheldrick, G. M. SHELX-97: A Computer Program for Crystal Structure Refinement;
University of Göttingen: Germany, 1999.
reflections were measured in the range 2.72 6 h 6 32.10. 2529 of
which were non-equivalent by symmetry (Rint(on I) = 0.060).
2311 reflections were assumed as observed applying the condition
16. International Tables of X-ray Crystallography; Kinoch Press: Birmingham, 1974;
Vol. IV, pp 99–100 and 149.
I >2
made.
r(I). Lorentz-polarization but no absorption corrections were