Enantiodivergent synthesis of 3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one and derivatives: amino analogues of pantolactone

Article abstract of DOI:10.1016/j.tetasy.2007.11.013

An enantiodivergent preparation of (+)-(R)- and (-)-(S)-3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one, (R)- and (S)-9, and several derivatives, from 4,4-dimethyl-1-phenylpyrrolidin-2,3-dione, 4, and (R)- or (S)-1-phenylethylamine, (R)- or (S)-5, as the chirality transfer agents, is described. Amine (S)-9 has also been used as a chiral auxiliary in a diastereoselective Michael reaction.

Full text of DOI:10.1016/j.tetasy.2007.11.013

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2947–2958
Enantiodivergent synthesis of 3-amino-4,4-dimethyl-1-
phenylpyrrolidin-2-one and derivatives: amino analogues
of pantolactone
a,
a
b
Pelayo Camps,a, Diego Munoz-Torrero, Jordi Rull, Merce Font-Bardia
*
*
`
˜
and Xavier Solansb
a
`
`
Laboratori de Quı´mica Farmaceutica (Unitat Associada al CSIC), Facultat de Farmacia and Institut de Biomedicina de la
Universitat de Barcelona (IBUB), Universitat de Barcelona, Av. Diagonal, 643, E-08028 Barcelona, Spain
b
` `
´
Serveis Cientı´fico-Tecnics, Universitat de Barcelona, Av. Martı Franques, s/n, E-08028 Barcelona, Spain
Received 5 November 2007; accepted 13 November 2007
Available online 3 December 2007
In memoriam of Professor Dr. Xavier Solans
Abstract—An enantiodivergent preparation of (+)-(R)- and (ꢀ)-(S)-3-amino-4,4-dimethyl-1-phenylpyrrolidin-2-one, (R)- and (S)-9, and
several derivatives, from 4,4-dimethyl-1-phenylpyrrolidin-2,3-dione, 4, and (R)- or (S)-1-phenylethylamine, (R)- or (S)-5, as the chirality
transfer agents, is described. Amine (S)-9 has also been used as a chiral auxiliary in a diastereoselective Michael reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
pyrrolidin-2-one, (R)- and (S)-N-phenylpantolactam, (R)-
and (S)-2 (Fig. 1),2,3 as chiral auxiliaries closely related to
pantolactone with improved properties: (i) non-hygro-
scopic crystalline compounds; (ii) easily UV-detectable;
and (iii) both enantiomers equally available. These novel
chiral auxiliaries have been successfully used in different
diastereoselective reactions including the deracemization
of a-arylpropionic acids, asymmetric Diels–Alder reac-
tions, dynamic kinetic resolutions of a-halo esters and as
resolution agents.1,4–6 As a continuation of our work on
chiral auxiliaries related to pantolactone, we herein report
the preparation of (R)- and (S)-3-amino-4,4-dimethyl-1-
phenylpyrrolidin-2-ones of general structure 3 (Fig. 1)
and other derivatives, such as (S,S)-15 (Scheme 3) and
(S,S)-18 (Scheme 4), as potential new chiral auxiliaries or
chiral ligands.
(R)-Pantolactone, (R)-1 (Fig. 1), is a chiral auxiliary, which
has been widely used in the past in different diastereoselec-
tive transformations.1 As chiral auxiliaries, (R)- and (S)-
pantolactone have several drawbacks: (i) they are highly
hygroscopic compounds, which makes their recovery diffi-
cult; (ii) they lack a good chromophore for easy UV detec-
tion; and (iii) the (S)-pantolactone is about 9-times more
expensive than its (R)-enantiomer. Several years ago, we
developed (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-
OH
NRR'
O
OH
O
N
N
O
O
(
R
)-1
2. Results and discussion
(
R
)-2
(
R
)-3
Figure 1. Structures of (R)-pantolactone, (R)-1, (R)-N-phenylpanto-
lactam, (R)-2, and substituted (R)-3-amino-N-phenylpantolactams, (R)-3.
To prepare these amines in enantiopure form, we chose
(R)- and (S)-1-phenylethylamine, (R)- and (S)-5, as the chi-
rality transfer agents, since both enantiomers are inexpen-
sive and easily available (Scheme 1). The reaction of the
known,3 4,4-dimethyl-1-phenylpyrrolidine-2,3-dione 4 with
*
Corresponding authors. Tel.: +34 93 4024536/4024533; fax: +34 93
4035941; e-mail addresses: camps@ub.edu; dmunoztorrero@ub.edu
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.013

2948
P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
CH3
Ph
PrOH/Et2O mixture in the ratio of 1:3 (approximately
20 mL/g). From this salt, the free amine was obtained in
a conventional way.
Ph
CH3
O
N
H2N
H
)-5
)-5]
(
R
O
O
N
N
[(S
Curiously, attempts to apply the same procedure for isola-
tion of the main diastereoisomer (3R,10R)-8 from the NaB-
H(OAc)3 reduction of (R)-6 failed to give any solid salt. In
this case, the isolation of the more polar (3R,10R)-8 was
carried out by silica gel column chromatography (hep-
tane/AcOEt mixtures).
toluene, Δ
96%
4
(
R
)-6
)-6]
[(S
H
N
H
N
CH3
Ph
CH3
Ph
NaBH3CN,
The same set of transformations was carried out by using
(S)-5 as the chirality transfer agent.
AcOH, MeOH,
–78 ºC, 4 h
94% (83:17)
O
O
+
N
N
Since we were unable to obtain a single crystal of the
(3S,10R)-7 monomaleate salt for X-ray diffraction analysis,
to establish its absolute configuration it was transformed
into amine (S)-9 by hydrogenation using 5% Pd/C as the
catalyst10 (Scheme 2). For characterization purposes,
amine (S)-9 was transformed into its p-nitrobenzoate salt.
Moreover, in this case, we could obtain a single crystal of
a 1:1 salt of (S)-9 and (ꢀ)-O,O-di-p-toluoyl-L-tartaric acid
and perform an X-ray diffraction analysis (Fig. 2).11 By
knowing the absolute configuration of (S)-9 we could de-
duce those of amines 7 and 8.
or NaBH(OAc)3,
DCE,
rt, 64 h
(3
[(3
R
,1'
S
R
)-8
-8]
(3
S
,1'
,1'S
R
)-7
74% (18:82)
[(3R
)
-7]
S,1'
)
Scheme 1. Diastereoselective preparation of amines (3S,10R)-7 and
(3R,10R)-8 and their enantiomers (conditions and yields are only given
for the firstly indicated enantiomeric series).
(R)-5 in toluene at reflux with azeotropic distillation of the
water formed in a Dean–Stark equipment7 gave almost
quantitatively the corresponding imine (R)-6. It is notewor-
thy that no racemization of (R)-6 was observed, a process
that could have taken place by tautomerization under
acidic or basic catalysis. Reduction of imine (R)-6 was
studied under different conditions (Table 1). Hydrogena-
tion using different catalysts and conditions gave poor
diastereoselectivities (entries 1–4), while sodium cyano-
borohydride reduction8 of (R)-6 in MeOH at ꢀ78 ꢁC gave
a mixture of (3S,10R)-7 and (3R,10R)-8 in the ratio of 83:17
(entry 5). The use of this reducing agent at higher temper-
atures gave lower diastereoselectivities (entries 6 and 7).
N(CH3)2
O
NH2
O
37.5% aq CH2O,
HCOOH,
80 ºC, 18 h
95%
N
N
TsCl, Et3N,
CH2Cl2,
rt, 15 h
80%
(
[(R
S
)-10
)-10]
(
[(R
S
)-9
)-9]
H2, 5% Pd/C,
MeOH, concd HCl,
1 atm, rt, 138 h
87%
NHTs
Table 1. Conditions, yields and diastereoselectivities in the reductions of
(R)-6a
O
(3
S
,1'
,1'S
R
)-7
)-7]
N
[(3R
Entry Reducing
agent
Solvent
t
P
T
dra
Yield
(%)
(h)
(atm) (ꢁC)
37.5% aq CH2O,
HCOOH,
1
2
3
4
5
6
7
8
H2/PtO2
EtOHb 10
1
1
30
1
1
1
25 60:40 61
25 60:40 70
25 60:40 62
25 70:30 56
ꢀ78 83:17 94
25 70:30 56
ꢀ20 73:27 77
25 18:82 74
80 ºC, 20 h
86%
H2/10% Pt/C EtOHb 22
H2/10% Pt/C EtOHb 20
H2/Raney Ni EtOHb 18
(S)-11
H3C
CH3
NHCH3
O
NaBH3CN
NaBH3CN
NaBH3CN
MeOHc
MeOHc 20
MeOHc
1.5
64
4
H2, 5% Pd/C,
MeOH, concd HCl,
1 atm, rt, 96 h
95%
N
Ph
O
1
1
N
N
NaBH(OAc)3 DCEc
a The dr was established by integration of the signal of 3-H in the 1H
NMR spectra of the mixtures.
b Absolute EtOH was used.
(3
[(3
S
R
,1'
,1'
R
S
)-12
)-12]
(S)-13
c Anhyd MeOH and DCE were used.
Scheme 2. Preparation of (S)- and (R)-9, and derivatives from (3S,10R)-
and (3R,10S)-7 (conditions and yields are only given for the first indicated
enantiomeric series).
Interestingly, the reduction of (R)-6 with sodium triacet-
oxyborohydride9 in DCE at room temperature gave a mix-
ture of (3S,10R)-7 and (3R,10R)-8 in the ratio of 18:82.
Isolation of the main diastereoisomer (3S,10R)-7 from the
NaBH3CN reduction of (R)-6 was carried out very conve-
niently on a gram scale in 66% yield by crystallization of
the corresponding mixture of monomaleates from an i-
Similarly, amine (R)-9 was obtained by hydrogenation of
(3R,10S)-7. Also, we obtained (R)-9 by hydrogenation of
(3R,10R)-8. The preparation of (S)- and (R)-9 via
(3S,10R)-7 and (3R,10R)-8, respectively, both obtained as

P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
2949
NaBH3CN,
N
AcOH, MeOH,
rt, 24 h
HN
O
NH
H
H
quantitative
N
O
O
O
N
N
17
+
S
( )-9
S,S
( )-18
Scheme 4. Preparation of amine (S,S)-18.
Reaction of ketopantolactam 4 and amine (S)-9 in toluene
at reflux with azeotropic distillation of the water formed
and in the absence of any catalyst quantitatively gave imine
(S)-14 with a high value of its specific rotation, which sug-
gested that no racemization had taken place. Reduction of
this imine with NaBH3CN, as previously described for (R)-
6, gave a mixture of (S,S)-15 and meso-16, in a ratio of
80:20 (1H NMR) in good yield. Column chromatography
(aluminum oxide) of this mixture gave pure (S,S)-15, which
was fully characterized as such including an X-ray diffrac-
tion analysis (Fig. 3).11 Not enough of meso-16 could be
isolated for complete characterization.
Figure 2. ORTEP representation of (S)-9 mono-O,O-di-p-toluoyl-L-
tartrate.
main products from 4 and the same chiral auxiliary, (R)-5,
constitutes an example of enantiodivergent synthesis. Alto-
gether, we have developed an easy access to both enantio-
mers of amines 7, 8 and 9 on a gram scale.
These amines were transformed into several simple deriva-
tives. Thus, (S)-9 was dimethylated by reaction with 37.5%
aqueous formaldehyde and formic acid12 to give amine (S)-
10 in high yield. The corresponding monomethylated
amine, (S)-13, was obtained by methylation of (3S,10R)-7
as before to give (3S,10R)-12, followed by Pd/C hydrogena-
tion. Also, tosylamide (S)-11 was obtained in good yield by
reaction of (S)-9 with tosyl chloride.13 Similarly from
(3R,10S)-7 or (R)-9, amines (R)-10 and (3R,10S)-12 were
obtained in good yields.
In connection with the preparation of chiral ligands able to
polycoordinate with cations to give potential catalysts for
enantioselective transformations, we planned the prepara-
tion of derivatives of (S)-9 such as (S,S)-15 (Scheme 3) or
(S,S)-18 (Scheme 4).
Figure 3. ORTEP representation of (S,S)-15.
Finally, reductive amination of pyridine-2,6-dicarboxalde-
hyde, 17, with (S)-9 using NaBH3CN as the reducing agent,
gave triamine (S,S)-18 in high yield, which was character-
ized as its dihydrochloride.
N
toluene, Δ
4
+
quantitative
The new amine (S)-9 has successfully been used as a chiral
auxiliary in a Michael reaction. Thus, the reaction of ethyl
2-oxocyclohexanecarboxylate, 19, with (S)-9 under acidic
catalysis gave the corresponding enamine (S)-20, which
was reacted with methyl vinyl ketone to give the Michael
adduct (R)-21 in 82% yield and 80% ee, established by chi-
ral GC/MS (Scheme 5). This result is comparable to those
described by Guingant and d’Angelo using the enamine
derived from 19 and (R)-1-phenylethylamine.14–16
N
N
N
N
O
O
(S)-9
(S
)-14
H
N
NaBH3CN,
O
O
AcOH, MeOH,
–78 ºC, 5 h
86% (80:20)
(
S,S)-15
+
Conversely, all attempts to use the in situ generated com-
plexes of amines (S)-10, (S,S)-15, and (S,S)-18 with
Cu(OTf)2, Sc(OTf)3, and Yb(OTf)3, as enantioselective cat-
alysts in the Diels–Alder reaction of N-acryloyloxazolidin-
2-one and cyclopentadiene in the absence of additives or in
the presence of 2,6-lutidine at temperatures from ꢀ78 to
0 ꢁC, following the procedure described by Evans et al.,17
gave good yields of essentially racemic adducts in all cases.
H
N
N
N
O
O
meso-16
Scheme 3. Preparation of (S,S)-15.

2950
P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
umn (25 · 0.46 cm) containing the chiral stationary phase
cellulose tris(3,5-dimethylphenylcarbamate) was used.
Conditions A (mixture of hexane/EtOH/Et2NH 98:2:0.1
as eluent, flow 0.3 mL/min, k = 254 nm). For chiral GC/
MS analyses, a 30-m (0.25 mm internal diameter) chiral
O
N
COOEt
TsOH·H2O
O
toluene,
4Å mol sieves,
60 ºC, 16 h
H
N
column
[containing
permethylated
b-cyclodextrine
19
COOEt
)-20
(0.25 lm) as the chiral stationary phase; Conditions A:
10 psi, initial temperature: 80 ꢁC (1 min), then heating at
a range of 10 ꢁC minꢀ1 till 125 ꢁC, after 2 min at this tem-
perature, heating at a range of 0.5 ꢁC minꢀ1 till 240 ꢁC,
then isothermic] was used. Optical rotations were deter-
mined on a polarimeter using 1-dm cells. Column chromato-
graphy was performed on silica gel 60 A C.C (35–70
mesh) or basic aluminum oxide. For the thin layer chroma-
tography (TLC), aluminum-backed sheets with silica gel 60
F254 or aluminum oxide ALOX N/UV254 were used and
spots were visualized with UV light and/or 1% aqueous
KMnO4.
+
89%
(S)-9
(S
H3C
O
CH2=CHCOCH3, MgCl2,
4Å mol sieves,
Et2O, –78 ºC, 1 h
O
COOEt
82%, 80% ee
(
R
)-21
Scheme 5. Diastereoselective Michael addition using (S)-9 as a chiral
auxiliary.
4.2. (R)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)imino]-
pyrrolidin-2-one (R)-6
Attempts to use tosylate (S)-11 in conjunction with
[RuCl2(g6(mesitylene)2]2 as a transfer hydrogenation cata-
lyst in the enantioselective reduction of p-chloroacetophe-
none with isopropanol, following a similar procedure to
that described by Noyori and co-workers,18 required the
use of a 1–5% molar ratio of catalyst and room tempera-
ture for acceptable conversions, always yielding essentially
racemic 1-(4-chlorophenyl) ethanol.
A solution of 4,4-dimethyl-1-phenylpyrrolidine-2,3-dione,
4 (4.00 g, 19.7 mmol), and (R)-1-phenylethylamine, (R)-5
(2.55 mL, 2.40 g, 19.7 mmol) in toluene (120 mL) was
heated at reflux for 24 h in a Dean–Stark equipment. Evap-
oration of the solvent under reduced pressure gave imine
(R)-6 (5.81 g, 96% yield), as a brownish oil. Rf 0.61 (alumi-
20
num oxide, 7.8 cm, hexane/AcOEt 9:1); ½aꢁD ¼ þ159 (c
0.57, CH2Cl2); IR (NaCl) 3082, 3062, 3029, 2970, 2927,
2889, 2867, 1693 (C@O st), 1674 (C@N st), 1597, 1495,
1483, 1458, 1452, 1400, 1377, 1364, 1342, 1319, 1283,
3. Conclusion
1245, 1187, 1128, 1070, 1048, 760, 700, 690 cmꢀ1 1H
;
In conclusion, we have developed an enantiodivergent
preparation of amines (R)- and (S)-9 from ketopantolac-
tam 4 using (R)-1-phenylethylamine as the chirality trans-
fer agent. Several derivatives of (R)- or (S)-9 have also
been prepared, two of which contain two units of (S)-9.
Amine (S)-9 has shown to be an efficient chiral auxiliary
in a Michael reaction. However, Cu(II), Sc(III), or Yb(III)
complexes of amines (S)-10, (S,S)-15, and (S,S)-18 failed to
induce noticeable enantioselectivity in a Diels–Alder reac-
tion, as it was also the case in a transfer hydrogenation
reaction catalyzed by a Ru(II) complex of amine (S)-11.
Hopefully, these new amines could be useful as chiral
auxiliaries or chiral ligands in other asymmetric
transformations.
NMR 1.31 (s, 3H) and 1.36 (s, 3H) [C4–(CH3)2], 1.48 (d,
J = 6.3 Hz, 3H, CH3–CHPh), 3.70 (s, 2H, 5-H2), 6.53 (q,
J = 6.3 Hz, 1H, CH3–CHPh), 7.18–7.27 (complex signal,
2H, Hpara N–Ph and Hpara C–Ph), 7.32 (ddm,
J = J0 = 7.5 Hz, 2H) and 7.41 (ddm, J = J0 = 8.1 Hz, 2H)
(Hmeta N–Ph and Hmeta C–Ph), 7.50 (dm, J = 8.1 Hz, 2H)
and 7.70 (dm, J = 7.5 Hz, 2H) (Hortho C–Ph and Hortho
N–Ph); 13C NMR 25.3 (CH3), 25.8 (CH3) and 26.7 (CH3)
[C4–(CH3)2 and CH3CHPh], 37.8 (C, C4), 56.4 (CH,
CH3CHPh), 58.2 (CH2, C5), 119.7 (CH, Cortho N–Ph),
125.6 (CH) and 126.4 (CH) (Cpara N–Ph and Cpara C–
Ph), 126.6 (CH, Cortho C–Ph), 128.2 (CH) and 128.9 (CH)
(Cmeta N–Ph and Cmeta C–Ph), 139.1 (C, Cipso N–Ph),
146.4 (C, Cipso C–Ph), 159.3 (C, C3), 164.2 (C, C2). Anal.
Calcd for C20H22N2OÆ0.5H2O: C, 76.16; H, 7.35; N, 8.88.
Found: C, 76.35; H, 7.02; N, 8.86.
4. Experimental
4.1. General experimental detail
4.3. (S)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)imino]-
pyrrolidin-2-one (S)-6
Melting points were determined in open capillary tubes.
Unless otherwise stated, NMR spectra were recorded in
CDCl3: 1H NMR (300 MHz), 13C NMR (75.4 MHz).
Chemical shifts (d) are reported in ppm related to internal
tetramethylsilane (TMS). Assignments given for the NMR
spectra are based on DEPT sequence and comparison with
3-hydroxy-4,4-dimethyl-1-phenylpyrrolidin-2-one, 2. Un-
less otherwise stated, IR spectra were performed in KBr
pellets and the absorption values are given as wavenumbers
(cmꢀ1). For chiral HPLC analyses, a Chiralcel OD-H col-
This compound was prepared as described before for (R)-6.
From 4,4-dimethyl-1-phenylpyrrolidine-2,3-dione, 4 (5.00 g,
24.6 mmol), and (S)-1-phenylethylamine, (S)-5 (3.20 mL,
2.99 g, 24.6 mmol), (S)-6 (7.51 g, quantitative yield)
1
was obtained as a brownish oil. The Rf, IR, H, and 13C
NMR data are coincidental with those of (R)-6.
20
½aꢁD ¼ ꢀ161 (c 0.57, CH2Cl2). Anal. Calcd for C20H22N2OÆ
0.5H2O: C, 76.16; H, 7.35; N, 8.88. Found: C, 76.38; H,
7.12; N, 8.85.

P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
2951
4.4. (3S,10R)-4,4-Dimethyl-1-phenyl-3-[(1-phenyl-
ethyl)amino]pyrrolidin-2-one monomaleate (3S,10R)-7
monomaleate
1H, N–H), 3.14 (s, 1H, 3-H), 3.30 (d, J = 9.4 Hz, 1H)
and 3.39 (d, J = 9.4 Hz, 1H) (5-H2), 3.99 (q, J = 6.6 Hz,
1H, CH3CHPh), 7.11 (tm, J = 7.4 Hz, 1H, Hpara N–Ph),
7.23 (tm, J = 7.4 Hz, 1H, Hpara C–Ph), 7.31–7.37 (complex
signal, 6H, Hmeta N–Ph, Hortho and Hmeta C–Ph), 7.56 (dm,
J = 8.4 Hz, 2H, Hortho N–Ph); 13C NMR (100.6 MHz) 21.3
(CH3), 24.6 (CH3) and 25.7 (CH3) [C4–(CH3)2 and
CH3CHPh], 38.6 (C, C4), 57.2 (CH, CH3CHPh), 58.1
(CH2, C5), 66.1 (CH, C3), 119.3 (CH, Cortho N–Ph),
124.4 (CH), 126.7 (CH), 127.0 (CH), 128.6 (CH) and
128.8 (CH) (Cmeta and Cpara N–Ph, Cortho, Cmeta and Cpara
C–Ph), 139.5 (C) and 144.7 (C) (Cipso N–Ph and Cipso C–
Ph), 173.7 (C, C2).
To a cold (ꢀ78 ꢁC) solution of (R)-6 (1.07 g, 3.50 mmol) in
anhydrous MeOH (100 mL), a solution of NaBH3CN
(470 mg, 7.48 mmol) and AcOH (0.25 mL, 4.4 mmol) in
MeOH (30 mL) was added dropwise and the reaction mix-
ture was stirred at this temperature for 4 h. Water (100 mL)
was then added. The organic solvent was evaporated under
reduced pressure and the remaining aqueous phase was
treated with aqueous 2 M NaOH till pH 12–13 and ex-
tracted with CH2Cl2 (3 · 100 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to give a diastereomeric mix-
ture of (3S,10R)-7 and (3R,10R)-8 in a ratio of 83:17 (1H
NMR) (1.01 g, 94% yield). HPLC (conditions A),
(3S,10R)-7, tR 18.5 min; (3R,10R)-8, tR 22.1 min.
4.5. (3R,10S)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)-
amino]pyrrolidin-2-one monomaleate (3R,10S)-7
monomaleate
This compound was prepared as described before for
(3S,10R)-7 monomaleate. From imine (S)-6 (7.50 g,
24.5 mmol), NaBH3CN (3.32 g, 52.8 mmol) and AcOH
(1.70 mL, 29.7 mmol), a diastereomeric mixture (3R,10S)-
7 and (3S,10S)-8 in a ratio of 82:18 (1H NMR) (7.03 g,
93% yield) was obtained. HPLC (conditions A), (3R,10S)-
7, tR 18.6 min; (3S,10S)-8, tR 22.2 min. The monomaleate
of this mixture was formed as before by the addition of a
solution of maleic acid (2.91 g, 25.1 mmol) in i-PrOH to
a solution of the above mixture of (3R,10S)-7 and
(3S,10S)-8 in the same solvent. After concentration to dry-
ness in vacuo, the mixture of maleates was crystallized
from i-PrOH/Et2O in the ratio of 1:3 to give (3R,10S)-7
monomaleate (6.47 g, 67% yield). The mp, IR, 1H, and
An aliquot of the above mixture (588 mg, 1.91 mmol) was
taken in i-PrOH (0.75 mL), treated with a solution of
maleic acid (243 mg, 2.09 mmol) in i-PrOH (1.5 mL) and
the mixture was concentrated to dryness in vacuo. The
solid obtained was taken in i-PrOH (3 mL), Et2O (9 mL)
was added, and the mixture was cooled to 3 ꢁC for 24 h.
The precipitated solid was collected by filtration and washed
with a mixture i-PrOH/Et2O 1:3 (3 · 5 mL) to give, after
drying, (3S,10R)-7 monomaleate (536 mg, 66% yield), mp
20
126–127 ꢁC (i-PrOH/Et2O 1:3); ½aꢁD ¼ ꢀ21 (c 0.61, EtOH);
IR 3500–2400 (max at 3406, 2981, 2836, 2663, 2555, 2476,
O–H st, +N–H st and C–H st), 1710 (C@O st), 1622, 1592,
1522, 1484, 1457, 1411, 1391, 1354, 1324, 1308, 1279, 1205,
1
1050, 869, 760, 700, 692, 644 cmꢀ1; H NMR 1.27 (s, 3H)
13C NMR data of this compound are coincidental with
and 1.30 (s, 3H), [C4–(CH3)2], 1.72 (d, J = 6.9 Hz, 3H,
CH3CHPh), 3.48 (d, J = 9.6 Hz, 1H) and 3.56 (d,
J = 9.6 Hz, 1H) (5-H2), 3.60 (s, 1H, 3-H), 4.68 (q,
J = 6.9 Hz, 1H, CH3CHPh), 6.25 [s, 2H, 2(3)-H maleate],
7.18 (t, J = 7.5 Hz, 1H, Hpara N–Ph), 7.32–7.40 (complex
signal, 5H, Hmeta N–Ph, Hmeta C–Ph, Hpara C–Ph), 7.50
(dm, J = 8.1 Hz, 2H) and 7.54 (br d, J = 7.8 Hz, 2H)
(Hortho N–Ph, Hortho C–Ph), 11.3 (br signal, +NH2 and
COOH); 13C NMR 19.5 (CH3), 21.0 (CH3) and 25.0
(CH3) [C4–(CH3)2 and CH3CHPh], 38.0 (C, C4), 58.6
(CH, CH3CHPh), 58.9 (CH2, C5), 65.3 (CH, C3), 119.9
(CH, Cortho N–Ph), 125.5 (CH), 127.7 (CH), 129.0 (CH)
and 129.1 (CH) (Cmeta and Cpara N–Ph, Cortho, Cmeta and
Cpara C–Ph), 135.2 [CH, C2(3) maleate], 137.9 (C) and
138.3 (C) (Cipso N–Ph and Cipso C–Ph), 168.7 (C) and
169.0 (C) (C2 and COO). Anal. Calcd for C20H24N2OÆ-
C4H4O4Æ0.1H2O: C, 67.62; H, 6.67; N, 6.57. Found: C,
67.44; H, 6.76; N, 6.47.
20
those of (3S,10R)-7 monomaleate. ½aꢁD ¼ þ19 (c 0.54,
EtOH). Anal. Calcd for C20H24N2OÆC4H4O4Æ0.05H2O: C,
67.76; H, 6.66; N, 6.59. Found: C, 67.47; H, 6.64; N,
6.44. A sample of (3R,10S)-7 as the free base was obtained
from (3R,10S)-7 monomaleate as described before (98.5%
ar). The Rf, 1H and 13C NMR data of this base are coinci-
25
dental with those of its enantiomer, ½aꢁD ¼ þ57:7 (c 1.0,
CH2Cl2).
4.6. (3R,10R)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)-
amino]pyrrolidin-2-one hydrochloride (3R,10R)-8ÆHCl
AcOH (100 lL, 1.75 mmol) was added dropwise to a sus-
pension of NaBH4 (22 mg, 0.58 mmol) in anhydrous
DCE (2 mL) and the mixture was heated at reflux for
30 min. The solution of NaBH(OAc)3 thus obtained was
allowed to cool to room temperature, a solution of (R)-6
(100 mg, 0.33 mmol) in anhydrous DCE (1.5 mL) was
added and the reaction mixture was stirred at room tem-
perature for 64 h. The resulting mixture was cooled in an
ice-water bath and aqueous 5 M HCl (2 mL) was slowly
added. When gas evolution ceased, the mixture was basi-
fied with aqueous 2 M NaOH (10 mL), the organic phase
was separated and washed with aqueous 2 M NaOH
(3 · 15 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo to give a diastereomeric mixture of amines
(3S,10R)-7 and (3R,10R)-8 in a ratio of 18:82 (75 mg, 74%
yield).
A sample of (3S,10R)-7 as the free base was obtained as fol-
lows: (3S,10R)-7 monomaleate (536 mg, 1.26 mmol) was
taken in CH2Cl2 (10 mL), the solution was washed with
aqueous 2 M NaOH (3 · 10 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo to give (3S,10R)-7
[339 mg, 87% yield, 98.4% area ratio (ar) by HPLC] as a
colorless oil. Rf 0.75 (aluminum oxide, 6.5 cm, hexane/
25
AcOEt 9:1); ½aꢁD ¼ ꢀ57:2 (c 1.2, CH2Cl2); 1H NMR
(400 MHz) 1.11 (s, 3H) and 1.24 (s, 3H), [C4–(CH3)2],
1.42 (d, J = 6.6 Hz, 3H, CH3CHPh), 2.2–2.6 (br signal,

2952
P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
A diastereomeric mixture of amines (3S,10R)-7 and
(3R,10R)-8 in a ratio of 23:77 (2.45 g), from several reduc-
tions of (R)-6 with NaBH(OAc)3 under different reaction
conditions, was subjected to column chromatography (sil-
ica gel, 125 g, heptane/AcOEt mixtures). On elution with
heptane/AcOEt in the ratio of 10:1, in the order of elution
were obtained (3S,10R)-7 (290 mg), a diastereomeric mix-
ture of (3S,10R)-7 and (3R,10R)-8 (ratio 1:1, 440 mg), and
pure (3R,10R)-8 (1.38 g, 73% recovery). A solution of
HCl in MeOH (1.81 N, 4 mL) was added to a solution of
(3R,10R)-8 (1.00 g, 3.25 mmol) in MeOH (5 mL) and the
solution was concentrated in vacuo to give a yellow solid
(1.12 g), which was crystallized from a mixture MeOH/
Et2O 1:2 (5 mL) to give (3R,10R)-8ÆHCl as a yellow solid.
of (3R,10S)-7 and (3S,10S)-8 in a ratio of 19:81 (1H NMR)
(790 mg, 75% yield) was obtained. Column chromatogra-
phy (silica gel, 80 g, heptane/AcOEt 15:1) of the above
mixture (1.56 g, 5.06 mmol, from two reduction runs) gave
in the order of elution (3R,10S)-7 (184 mg), a mixture of
(3R,10S)-7 and (3S,10S)-8 in a ratio of 1:1 (280 mg) and
(3S,10S)-8 [872 mg, 69% recovery, 98.3 ar by HPLC (condi-
1
13
tions A)]. The H and C NMR data of (3S,10S)-8 are
25
coincidental with those of its enantiomer, ½aꢁD ¼ ꢀ130 (c
1.3, CH2Cl2).
The hydrochloride of (3S,10S)-8 was formed as before by
addition of a solution of HCl in MeOH (1.81 M, 2.5 mL)
to a solution of (3S,10S)-8 (600 mg, 1.95 mmol) in MeOH
(3 mL). After concentration to dryness in vacuo, the prod-
uct was crystallized from MeOH/Et2O 1:2 to give (3S,10S)-
8ÆHCl (610 mg, 91% yield), mp 151–152 ꢁC (MeOH/Et2O
(3R,10R)-8: Rf 0.67 (aluminum oxide, 6.5 cm, hexane/
AcOEt 9:1); HPLC (conditions A), tR 22.09 min, 98.4%
25
1
1
ar; ½aꢁD ¼ þ128 (c 1.3, CH2Cl2); H NMR 0.91 (s, 3H)
and 1.01 (s, 3H), [C4–(CH3)2], 1.43 (d, J = 6.6 Hz, 3H,
CH3CHPh), 1.70 (br signal, 1H, N–H), 3.00 (s, 1H, 3-H),
3.29 (d, J = 9.3 Hz, 1H) and 3.38 (d, J = 9.3 Hz, 1H) (5-
H2), 4.39 (q, J = 6.6 Hz, 1 H, CH3CHPh), 7.12 (tm,
J = 7.5 Hz, 1H, Hpara N–Ph), 7.20–7.43 (complex signal,
7H) and 7.59 (dm, J = 7.8 Hz, 2H) (Hortho and Hmeta N–
1:2). The IR, H, and 13C NMR data of this compound
are coincidental with those of (3R,10R)-8ÆHCl.
20
½aꢁD ¼ ꢀ125 (c 0.54, MeOH). Anal. Calcd for
C20H24N2OÆHClÆ0.75H2O: C, 67.03; H, 7.45; N, 7.82; Cl,
9.89. Found: C, 67.23; H, 7.56; N, 7.59; Cl, 9.68.
4.8. (S)-3-Amino-4,4-dimethyl-1-phenylpyrrolidin-2-one
p-nitrobenzoate (S)-9 p-nitrobenzoate
Ph, Hortho
,
Hmeta and Hpara C–Ph); 13C NMR
(100.6 MHz) 20.8 (CH3), 24.3 (CH3) and 25.1 (CH3) [C4–
(CH3)2 and CH3CHPh], 37.8 (C, C4), 57.6 (CH,
CH3CHPh), 58.1 (CH2, C5), 67.2 (CH, C3), 119.4 (CH,
Cortho N–Ph), 124.3 (CH, Cpara N–Ph), 127.0 (CH), 127.5
A mixture of (3S,10R)-7 (132 mg, 0.43 mmol), concd HCl
(150 lL), and 5% Pd/C (370 mg) in MeOH (12 mL) was
hydrogenated at 1 atm and room temperature for 138 h.
The mixture was filtered through a pad of Celiteꢂ washing
the filter with MeOH (25 mL). The filtrate was basified
with aqueous 2 M NaOH (12 mL) and extracted with
CH2Cl2 (3 · 25 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give (S)-9 (76 mg, 87% yield) as a color-
less oil. ½aꢁD ¼ ꢀ24:5 (c 1.1, CH2Cl2); H NMR 1.04 (s,
3H) and 1.29 (s, 3H), [C4–(CH3)2], 1.53 (br s, 2H, NH2),
3.34 (s, 1H, 3-H), 3.43 (d, J = 9.6 Hz, 1H) and 3.56 (d,
J = 9.6 Hz, 1H) (5-H2), 7.15 (tm, J = 6.9 Hz, 1H, Hpara),
7.35–7.40 (m, 2H, Hmeta), 7.62 (dm, J = 7.8 Hz, 2H, Hortho);
13C NMR 20.1 (CH3) and 24.7 (CH3) [C4–(CH3)2], 37.6 (C,
C4), 58.3 (CH2, C5), 62.3 (CH, C3), 119.3 (CH, Cortho),
124.3 (CH, Cpara), 128.8 (CH, Cmeta), 139.5 (C, Cipso),
174.8 (C, C2).
(CH), 128.2 (CH) and 128.8 (CH) (Cmeta N–Ph, Cortho
,
Cmeta and Cpara C–Ph), 139.7 (C, Cipso N–Ph), 144.8 (C,
Cipso C–Ph), 173.9 (C, C2).
(3R,10R)-8ÆHCl: mp 153–154 ꢁC (MeOH/Et2O 1:2);
20
½aꢁD ¼ þ126 (c 0.51, MeOH); IR 3500–2400 (max at
24
1
3396, 3033, 2958, 2930, 2873, 2783, 2725, 2680, 2658,
2523, 2437, +N–H st and C–H st), 1708 (C@O st), 1597,
1499, 1458, 1422, 1410, 1391, 1327, 1209, 1121, 1067,
1
764, 703 cmꢀ1; H NMR (D2O) 1.12 (s, 3H) and 1.28 (s,
3H), [C4–(CH3)2], 1.81 (d, J = 6.9 Hz, 3H, CH3CHPh),
3.56 (d, J = 9.9 Hz, 1H) and 3.67 (d, J = 9.9 Hz, 1H) (5-
H2), 3.79 (s, 1H, 3-H), 4.78 (s, mobile H), 5.15 (q,
J = 6.9 Hz, 1H, CH3CHPh), 7.36 (m, 1H, Hpara N–Ph),
7.46–7.58 (complex signal, 9H, Hmeta and Hortho N–Ph,
Hmeta, Hortho and Hpara C–Ph); 13C NMR (D2O) 19.0
(CH3), 19.7 (CH3) and 21.9 (CH3) [C4–(CH3)2 and
CH3CHPh], 37.2 (C, C4), 58.9 (CH, CH3CHPh), 58.9
(CH2, C5), 64.0 (CH, C3), 121.7 (CH, Cortho N–Ph),
126.7 (CH, Cpara N–Ph), 127.8 (CH), 129.2 (CH) and
129.6 (CH) (Cmeta N–Ph, Cortho and Cmeta C–Ph), 129.9
(CH, Cpara C–Ph), 135.0 (C, Cipso N–Ph), 137.1 (C,
Cipso C–Ph), 168.1 (C, C2). Anal. Calcd for C20H24N2OÆ
HClÆH2O: C, 66.19; H, 7.50; N, 7.72; Cl, 9.77. Found: C,
66.21; H, 7.52; N, 7.75; Cl, 9.53.
An analytical sample of (S)-9 p-nitrobenzoate was obtained
as follows: amine (S)-9 (118 mg, 0.58 mmol) was taken in
MeOH (3 mL) and a solution of p-nitrobenzoic acid
(101 mg, 0.60 mmol) in MeOH (5 mL) was added. The
resulting solution was concentrated to dryness in vacuo
and the solid residue was recrystallized from MeOH
(4 mL) to give (S)-9 p-nitrobenzoate as a white solid
(167 mg from two crops, 78% yield). Mp 191–192 ꢁC
25
(MeOH); ½aꢁD ¼ ꢀ15 (c 0.51, MeOH); IR 3500–2500
(max at 3437, 3110, 2981, 2960, 2938, 2882, 2664, O–H
st, +N–H st and C–H st), 1718 (C@O st), 1595, 1564,
1537 (N@O st), 1497, 1482, 1414, 1388, 1344 (N@O st),
4.7. (3S,10S)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)-
amino]pyrrolidin-2-one hydrochloride (3S,10S)-8ÆHCl
1
1280, 824, 802, 761, 728 cmꢀ1; H NMR (CD3OD) 1.16
This compound was prepared as described before for
(3R,10R)-8. From imine (S)-6 (1.05 g, 3.43 mmol) and
NaBH(OAc)3 [prepared from AcOH (1.10 mL, 19.2 mmol)
and NaBH4 (228 mg, 6.03 mmol)] a diastereomeric mixture
(s, 3H) and 1.38 (s, 3H), [C4–(CH3)2], 3.60 (d,
J = 9.6 Hz, 1H) and 3.79 (d, J = 9.6 Hz, 1H) (5-H2), 3.93
(s, 1H, 3-H), 4.86 (s, mobile H), 7.21 (tm, J = 7.5 Hz,
1H, Hpara), 7.40 (dd, J = 8.4 Hz, J0 = 7.5 Hz, 2H, Hmeta),

P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
2953
25
1
7.62 (dm, J = 8.4 Hz, 2H, Hortho), 8.15 (dm, J = 9.0 Hz,
2H) and 8.26 (dm, J = 9.0 Hz, 2H) [2(6)-H and 3(5)-H p-
nitrobenzoate]; 13C NMR (CD3OD) 21.0 (CH3) and 24.5
(CH3) [C4–(CH3)2], 38.0 (C, C4), 59.9 (CH2, C5), 62.4
(CH, C3), 121.4 (CH, Cortho), 126.6 (CH, Cpara), 124.2
[CH, C3(5) p-nitrobenzoate], 129.3 (CH, Cmeta), 131.5
[CH, C2(6) p-nitrobenzoate], 140.1 (C, Cipso), 142.8 (C,
C1 p-nitrobenzoate), 150.9 (C, C4 p-nitrobenzoate), 170.7
(C) and 171.0 (C) (C2 and COO). Anal. Calcd for
C12H16N2OÆC7H5NO4Æ0.5H2O: C, 59.99; H, 5.83; N,
10.55. Found: C, 60.08; H, 5.85; N, 10.61.
½aꢁD ¼ þ14 (c 0.50, MeOH). The IR, H, and 13C NMR
data of this compound are coincidental with those of (S)-
9 p-nitrobenzoate. Anal. Calcd for C12H16N2OÆC7H5-
NO4Æ0.5H2O: C, 59.99; H, 5.83; N, 11.05. Found: C,
59.96; H, 5.49; N, 10.84.
4.11. (R)-3-Amino-4,4-dimethyl-1-phenylpyrrolidin-2-one
(R)-9 from (3R,10R)-8
A mixture of (3R,10R)-8 (140 mg, 0.45 mmol), concd HCl
(150 lL), and 5% Pd/C (394 mg) in MeOH (12 mL) was
hydrogenated at 1 atm and room temperature for 96 h.
The mixture was filtered through a pad of Celiteꢂ washing
the filter with MeOH (25 mL). The filtrate was basified
with aqueous 2 M NaOH (12 mL) and was extracted with
CH2Cl2 (3 · 25 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated under re-
4.9. (S)-3-Amino-4,4-dimethyl-1-phenylpyrrolidin-2-oneÆ-
mono-O,O-di-p-toluoyl-L-tartrate (S)-9 mono-O,O-di-p-
toluoyl-L-tartrate
To a solution of amine (S)-9 (157 mg, 0.77 mmol) in
MeOH (1 mL), a solution of (ꢀ)-O,O-di-p-toluoyl-L-tar-
taric acid (297 mg, 0.77 mmol) in MeOH (2 mL) was
added. The resulting mixture was concentrated to dryness
in vacuo and the residue was crystallized from MeOH/
Et2O 1:1 (6 mL) to yield (S)-9Æmono-O,O-di-p-toluoyl-L-
duced pressure to give (R)-9 (80 mg, 86% yield), as a color-
23
less oil. ½aꢁD ¼ þ25:0 (c 1.0, CH2Cl2). The 1H NMR
spectrum is coincidental with the previously described for
(S)-9.
tartrate (376 mg, from two crops, 83% yield) as a white so-
4.12. (S)-3-(Dimethylamino)-4,4-dimethyl-1-phenylpyrrol-
idin-2-one (S)-10
24
lid. Mp 195–196 ꢁC (MeOH/Et2O 1:1); ½aꢁD ¼ ꢀ99:8 (c
1.17, MeOH); IR 3500–2500 (max at 3443, 3177, 3061,
3029, 2949, 2884, 2636, O–H st, +N–H st and C–H st),
1721 and 1704 (C@O st), 1611, 1596, 1540, 1498, 1413,
1377, 1332, 1271, 1176, 1121, 1109, 1045, 1021, 900, 840,
Aqueous formaldehyde (37.5%, 8.5 mL, 106 mmol) was
added to (S)-9 (998 mg, 4.89 mmol). Formic acid
(8.50 mL, 10.4 g, 225 mmol) was added to the cold mixture
(ice-water bath) and then the reaction mixture was heated
at 80 ꢁC for 18 h. The mixture was allowed to cool to room
temperature, basified with aqueous 5 M NaOH (50 mL)
and was extracted with Et2O (3 · 50 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give (S)-10
(1.08 g, 95% yield) as a yellow solid. An analytical sample
750, 693 cmꢀ1 1H NMR (400 MHz, CD3OD) 1.15 (d,
;
J = 2.0 Hz, 3H) and 1.35 (s, 3H), [C4–(CH3)2], 2.40 [s,
6H, Ar–CH3], 3.57 (d, J = 9.8 Hz, 1H) and 3.76 (br d,
J = 9.8 Hz, 1H) (5-H2), 4.01 (s, 1H, 3-H), 4.91 (s, mobile
H), 5.89 (s, 2H, 2(3)-H tartrate), 7.21 (t, J = 7.4 Hz, 1H,
H
para N-phenyl), 7.28 (d, J = 8.0 Hz, 4H, 3(5)-H p-toluoyl],
7.40 (pseudo t, J = 8.2 Hz, 2H, Hmeta N-phenyl), 7.61 (dm,
J = 8.4 Hz, 2H, Hortho N-phenyl), 8.01 (d, J = 8.0 Hz, 4H,
2(6)-H p-toluoyl]; 13C NMR (CD3OD) 21.1 (CH3) and
24.4 (CH3) [C4–(CH3)2], 21.7 (CH3, toluoyl CH3), 37.8
(C, C4), 59.9 (CH2, C5), 61.9 (CH, C3), 74.9 [CH, C2(3)
tartrate], 121.3 (CH, Cortho N-phenyl), 126.6 (CH, Cpara
N-phenyl), 128.4 (C, C1 toluoyl), 130.1 (CH, Cmeta N-
phenyl), 130.2 [CH, C3(5) toluoyl], 131.1 [CH, C2(6)
toluoyl], 140.0 (C, Cipso N-phenyl), 145.4 (C, C4 toluoyl),
167.5 (C, CO toluoyl), 169.5 (C, C2), 171.6 [C, C1(4)
tartrate]. Anal. Calcd for C12H16N2OÆC20H18O8: C, 65.07;
H, 5.80; N, 4.74. Found: C, 64.96; H, 5.70; N, 4.71.
of (S)-10 was obtained by crystallization from Et2O, mp
20
56–57 ꢁC (Et2O); ½aꢁD ¼ ꢀ35 (c 0.61, CH2Cl2); IR 3050,
3024, 2960, 2935, 2871, 2833, 2785, 1763 and 1694 (C@O
st), 1598, 1500, 1460, 1400, 1379, 1315, 1291, 1213, 1175,
1
1121, 1078, 1063, 1041, 759, 691 cmꢀ1; H NMR 1.20 (s,
3H) and 1.23 (s, 3H), [C4–(CH3)2], 2.53 [s, 6H, N(CH3)2],
3.02 (s, 1H, 3-H), 3.41 (d, J = 9.6 Hz, 1H) and 3.56 (d,
J = 9.6 Hz, 1H) (5-H2), 7.14 (tm, J = 7.5 Hz, 1H, Hpara),
7.36 (m, 2H, Hmeta) 7.63 (dm, J = 8.7 Hz, 2H, Hortho);
13C NMR 21.6 (CH3) and 29.1 (CH3) [C4–(CH3)2], 36.2
(C, C4), 43.9 [CH3, N(CH3)2], 60.1 (CH2, C5), 75.3 (CH,
C3), 119.8 (CH, Cortho), 124.6 (CH, Cpara), 128.8 (CH, Cmeta),
139.3 (C, Cipso), 172.2 (C, C2). Anal. Calcd for
C14H20N2OÆ0.2H2O: C, 71.27; H, 8.72; N, 11.87. Found:
C, 71.19; H, 8.71; N, 11.63.
4.10. (R)-3-Amino-4,4-dimethyl-1-phenylpyrrolidin-2-one
p-nitrobenzoate (R)-9 p-nitrobenzoate
This compound was prepared as described before for (S)-9.
From (3R,10S)-7 (2.15 g, 6.98 mmol), concd HCl
(2.50 mL), and 5% Pd/C (6.00 g) in MeOH (195 mL), after
92 h hydrogenation at 1 atm and room temperature, (R)-9
4.13. (R)-3-(Dimethylamino)-4,4-dimethyl-1-phenylpyrrol-
idin-2-one (R)-10
(1.22 g, 86% yield) was obtained as a colorless oil,
This compound was prepared as described before for (S)-
10. From (R)-9 (1.01 g, 4.95 mmol), aqueous formaldehyde
(37.5%, 8.60 mL, 107 mmol), and formic acid (8.60 mL,
10.5 g, 228 mmol), (R)-10 (1.07 g, 93% yield) was obtained
as a yellow viscous oil. An analytical solid sample was ob-
tained by crystallization from Et2O, mp 54–55 ꢁC (Et2O);
24
½aꢁD ¼ þ24:0 (c 0.95, CH2Cl2). The 1H and 13C NMR spec-
tra of this compound are coincidental with those of its
enantiomer. A sample of (R)-9 (121 mg, 0.59 mmol) on
reaction with p-nitrobenzoic acid (104 mg, 0.62 mmol)
was transformed as before into the corresponding (R)-9
p-nitrobenzoate (175 mg from two crops, 78% yield), after
crystallization from MeOH, mp 190–191 ꢁC (MeOH);
20
1
½aꢁD ¼ þ36 (c 0.75, CH2Cl2). The IR, H, and 13C NMR
data are coincidental with those of (S)-10. Anal. Calcd

2954
P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
for C14H20N2OÆ0.4H2O: C, 70.20; H, 8.75; N, 11.70.
Found: C, 70.16; H, 8.38; N, 11.64.
(CH3) [C4–(CH3)2 and CH3CHPh], 36.5 (C, C4), 38.0
(CH3, N–CH3), 59.6 (CH2, C5), 63.1 (CH, CH3CHPh),
68.3 (CH, C3), 119.7 (CH, Cortho N–Ph), 124.4 (CH, Cpara
N–Ph), 126.8 (CH), 127.9 (CH) and 128.1 (CH) (Cmeta
N–Ph, Cortho and Cmeta C–Ph), 128.7 (CH, Cpara C–Ph),
139.5 (C) and 145.4 (C) (Cipso N–Ph and Cipso C–Ph),
173.2 (C, C2).
4.14. (S)-4,4-Dimethyl-1-phenyl-3-(p-toluenesulfonylamino)-
pyrrolidin-2-one (S)-11
Tosyl chloride (470 mg, 2.47 mmol) was added to a cold
(0 ꢁC) solution of (S)-9 (505 mg, 2.47 mmol) and anhyd
Et3N (0.68 mL, 4.88 mmol) in anhyd CH2Cl2 (10 mL)
and the mixture was stirred at room temperature for
15 h. The reaction mixture was cooled (ꢀ10 ꢁC, ice-NaCl
bath) and a mixture of ice/ 10% aqueous HCl (70 mL)
was added. The organic phase was separated and the aque-
ous one was extracted with CH2Cl2 (3 · 20 mL). The com-
bined organic extracts were washed with saturated aqueous
NaHCO3 solution (3 · 20 mL) and brine (40 mL) and were
dried over anhydrous Na2SO4 and concentrated in vacuo
An aliquot of the above product (384 mg, 1.19 mmol) was
taken in i-PrOH (3 mL) and a solution of maleic acid
(152 mg, 1.31 mmol) in i-PrOH (3 mL) was added and
the solution was concentrated to dryness in vacuo. The
solid residue was recrystallized from i-PrOH/Et2O 1:2
(9 mL) to give (3S,10R)-12 monomaleate (504 mg, 97% yield)
20
as a white solid, mp 92–93 ꢁC (i-PrOH/Et2O 1:2); ½aꢁD ¼ ꢀ24
(c 0.55, CH2Cl2); IR 3500–2400 (max at 3422, 3074, 3032,
2968, 2861, 2615, O–H st, +N–H st and C–H st), 1706
(C@O st), 1668, 1614, 1583, 1500, 1484, 1459, 1414, 1388,
1349, 1320, 1284, 1210, 1189, 1119, 1073, 1054, 1031,
to give (S)-11 (710 mg, 80% yield) as a white solid, mp
20
149–150 ꢁC (CH2Cl2); ½aꢁ ¼ ꢀ6 (c 0.51, CH2Cl2); IR
3323 and 3286 (N–H st),D3125, 3063, 3042, 2968, 2927,
2885, 1720 and 1709 (C@O st), 1595, 1495, 1478, 1460,
1401, 1382, 1350, 1314 (S@O st), 1278, 1235, 1217, 1162
(S@O st), 1132, 1109, 1091, 940, 923, 812, 760, 721, 692,
1013, 864, 762, 728, 702, 692 cmꢀ1; H NMR 1.09 (s, 3H)
1
and 1.37 (s, 3H), [C4–(CH3)2], 1.84 (d, J = 7.2 Hz, 3H,
CH3CHPh), 2.96 (s, 3H, NCH3), 3.49 (d, J = 9.6 Hz, 1H)
and 3.54 (d, J = 9.6 Hz, 1H) (5-H2), 3.93 (s, 1H, 3-H),
4.96 (q, J = 7.2 Hz, 1H, CH3CHPh), 6.40 [s, 2H, 2(3)-H
maleate], 7.24 (tm, J = 7.5 Hz, 1H, Hpara N–Ph), 7.38–
7.45 (complex signal, 5H) and 7.52–7.60 (complex signal,
4H) (Hortho and Hmeta N–Ph, Hortho, Hmeta and Hpara C–
Ph), 11.73 (br signal, +NH and COOH); 13C NMR 15.7
(CH3), 21.9 (CH3) and 25.1 (CH3) [C4–(CH3)2 and
CH3CHPh], 38.1 (C, C4), 38.4 (CH3, NCH3), 59.2 (CH2,
C5), 67.0 (CH, CH3CHPh), 68.7 (CH, C3), 120.1 (CH,
Cortho N–Ph), 125.9 (CH, Cpara N–Ph), 129.1 (2 CH) and
129.3 (CH) (Cmeta N–Ph, Cortho and Cmeta C–Ph), 129.9
(CH, Cpara C–Ph), 135.6 [CH, C2(3) maleate], 136.0 (C)
and 138.0 (C) (Cipso N–Ph and Cipso C–Ph), 166.4 (C),
168.9 (C) (C2 and COO). Anal. Calcd for C21H26N2OÆ-
C4H4O4Æ0.75H2O: C, 66.43; H, 7.02; N, 6.20. Found: C,
66.31; H, 6.80; N, 6.01.
1
665 cmꢀ1; H NMR 1.09 (s, 3H) and 1.36 (s, 3H), [C4–
(CH3)2], 2.40 (s, 3H, CH3 p-tosyl), 3.40 (d, J = 9.9 Hz,
1H) and 3.56 (d, J = 9.9 Hz, 1H) (5-H2), 3.66 (d,
J = 5.4 Hz, 1H, 3-H), 5.23 (d, J = 5.4 Hz, 1H, NH), 7.14
(tt, J = 7.2 Hz, J0 = 1.2 Hz, 1H, Hpara), 7.28–7.37 [complex
signal, 4H, Hmeta and 3(5)-H p-tosyl], 7.50 [dm, J = 9.0 Hz,
2H, 2(6)-H p-tosyl], 7.84 (dm, J = 8.7 Hz, 2H, Hortho); 13C
NMR 21.1 (CH3), 21.5 (CH3) and 26.0 (CH3) [C4–(CH3)2
and CH3 p-tosyl], 38.6 (C, C4), 58.2 (CH2, C5), 64.3
(CH, C3), 119.4 (CH, Cortho), 125.1 (CH, Cpara), 127.5
(CH), 128.9 (CH) and 129.7 (CH) [Cmeta, C2(6) and
C3(5) p-tosyl], 136.0 (C, C1 p-tosyl), 138.8 (Cipso), 143.7
(C, C4 p-tosyl), 169.8 (C, C2). Anal. Calcd for
C19H22N2O3S: C, 63.66; H, 6.19; N, 7.82; S, 8.95. Found:
C, 63.68; H, 6.13; N, 7.73; S, 8.81.
4.15. (3S,10R)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)-
methylamino]pyrrolidin-2-one monomaleate, (3S,10R)-12
monomaleate
4.16. (3R,10S)-4,4-Dimethyl-1-phenyl-3-[(1-phenylethyl)-
methylamino]pyrrolidin-2-one monomaleate (3R,10S)-12
monomaleate
Aqueous formaldehyde (37.5%, 1.94 mL, 24.3 mmol) was
added to (3S,10R)-7 (700 mg, 2.27 mmol). Formic acid
(1.94 mL, 2.37 g, 51.5 mmol) was added to the cold mixture
(ice-water bath) and then the reaction mixture was heated
at 80 ꢁC for 20 h. The mixture was allowed to cool to room
temperature, basified with aqueous 2 M NaOH and was
extracted with Et2O (3 · 35 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and con-
This compound was prepared as described before for (3S,10
R)-12 monomaleate. From (3R,10S)-7 (2.03 g, 6.59 mmol),
aqueous formaldehyde (37.5%, 5.60 mL, 69.9 mmol), and
formic acid (5.60 mL, 6.83 g, 148 mmol), (3R,10S)-12
(1.75 g, 82% yield) was obtained as a colorless oil,
25
1
½aꢁD ¼ þ74:0 (c 1.2, CH2Cl2). The H and 13C NMR data
of this compound are coincidental with those of its
enantiomer.
centrated under reduced pressure to give (3S,10R)-12
25
(629 mg, 86% yield) as a colorless oil, ½aꢁD ¼ ꢀ74:8 (c
1
1.1, CH2Cl2); H NMR (400 MHz) 0.87 (s, 3H) and 1.11
The above product was transformed into the correspond-
ing monomaleate as before. After recrystallization of the
crude salt (2.40 g) from i-PrOH/E2O 1:2 (40 mL) pure
(3R,10S)-12 monomaleate (2.20 g, 93% yield) was obtained
(s, 3H), [C4–(CH3)2], 1.48 (d, J = 6.8 Hz, 3H, CH3CHPh),
2.42 (s, 3H, NCH3), 3.39 (s, 1H, 3-H), 3.36 (d, J = 9.6 Hz,
1H) and 3.47 (d, J = 9.6 Hz, 1H) (5-H2), 4.06 (q,
J = 6.8 Hz, 1H, CH3CHPh), 7.13 (tm, J = 7.4 Hz, 1H,
Hpara N–Ph), 7.22 (tm, J = 7.2 Hz, 1H, Hpara C–Ph),
7.29–7.41 (complex signal, 6H, Hmeta N–Ph, Hortho and
Hmeta C–Ph), 7.61 (dm, J = 8.4 Hz, 2H, Hortho N–Ph);
13C NMR (100.6 MHz) 18.3 (CH3), 22.3 (CH3) and 27.7
as
a white solid, mp 90–92 ꢁC (i-PrOH/E2O 1:2);
20
1
½aꢁD ¼ þ25 (c 0.52, CH2Cl2). The IR, H, and 13C NMR
data are coincidental with those of (3S,10R)-12 monomal-
eate. Anal. Calcd for C21H26N2OÆC4H4O4Æ1.15H2O: C,
65.39; H, 7.09; N, 6.10. Found: C, 65.14; H, 6.86; N, 5.86.

P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
2955
4.17. (S)-4,4-Dimethyl-3-methylamino-1-phenylpyrrolidin-
2-one (S)-13
for C24H27N3O2: C, 74.01; H, 6.99; N, 10.69. Found: C,
73.88; H, 7.32; N, 10.35.
A mixture of (3S,10R)-12 (100 mg, 0.31 mmol), concd HCl
(80 lL) and 5% Pd/C (265 mg) in MeOH (10 mL) was
hydrogenated at 1 atm and room temperature for 96 h.
The mixture was filtered through a pad of Celiteꢂ, washing
the filter with MeOH (30 mL). The filtrate was basified
with aqueous 2 M NaOH (5 mL). The organic solvent
was eliminated under reduced pressure and the aqueous
residue was extracted with CH2Cl2 (3 · 20 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4
4.19. (S,S)-Bis(4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl)-
amine (S,S)-15
To a cold (ꢀ78 ꢁC) solution of (S)-14 (331 mg, 0.85 mmol)
in anhyd MeOH (15 mL), a solution of NaBH3CN
(114 mg, 1.82 mmol) and AcOH (60 lL, 1.05 mmol) in
MeOH (5 mL) was added and the reaction mixture was
stirred at this temperature for 5 h. Water (15 mL) was then
added. The organic solvent was evaporated under reduced
pressure and the remaining aqueous phase was treated with
aqueous 2 M NaOH till pH 12–13 and extracted with
CH2Cl2 (3 · 15 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated under re-
duced pressure to give a diastereomeric mixture of (S,S)-
15 and meso-16 in a ratio of 80:20 (1H NMR) (285 mg,
86% yield). The above mixture was subjected to column
chromatography (aluminum oxide, 41 g, hexane/AcOEt
9:1). In the order of elution were obtained (S,S)-15
(171 mg, 51% isolated yield) as a white solid, a mixture
of (S,S)-15 and meso-16 (ratio 1:1, 11 mg) and meso-16
(8 mg, 2% isolated yield) as a yellowish oil. Crystallization
of (S,S)-15 (138 mg) from hexane/AcOEt 6:1 (1.75 mL)
gave the analytical sample (120 mg, 87% recovery). (S,S)-
and concentrated in vacuo to give (S)-13 (64 mg, 95% yield)
20
as a light yellow solid, mp 52–53 ꢁC (CH2Cl2); ½aꢁD ¼ ꢀ35
(c 0.59, CH2Cl2); IR 3321 (N–H st), 3082, 2972, 2945, 2876,
2848, 2793, 1700 (C@O st), 1598, 1502, 1486, 1459, 1407,
1381, 1367, 1340, 1323, 1284, 1222, 1211, 1175, 1136,
1122, 1012, 899, 759, 691 cmꢀ1 1H NMR 1.06 (s, 3H)
;
and 1.32 (s, 3H), [C4–(CH3)2], 1.67 (br s, 1H, NH), 2.62
(s, 3H, NCH3), 3.09 (s, 1H, 3-H), 3.38 (d, J = 9.6 Hz,
1H) and 3.52 (d, J = 9.6 Hz, 1H) (5-H2), 7.14 (tm,
J = 7.2 Hz, 1H, Hpara), 7.37 (m, 2H, Hmeta), 7.61 (dm,
J = 8.7 Hz, 2H, Hortho); 13C NMR 21.0 (CH3) and 26.0
(CH3) [C4–(CH3)2], 37.2 (CH3, NCH3), 38.2 (C, C4), 58.4
(CH2, C5), 71.6 (CH, C3), 119.5 (CH, Cortho), 124.4 (CH,
Cpara), 128.8 (CH, Cmeta), 139.5 (Cipso), 173.7 (C, C2). Anal.
Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found:
C, 71.50; H, 8.51; N, 12.75.
15: Rf 0.21 (aluminum oxide, 9.4 cm, hexane/AcOEt 9:1),
25
mp 144–145 ꢁC (hexane/AcOEt 6:1); ½aꢁD ¼ ꢀ53 (c 0.51,
CH2Cl2); IR 3357 (N–H st), 3060, 3044, 2966, 2935,
2876, 2812, 1706 and 1697 (C@O st), 1596, 1498, 1478,
1461, 1402, 1379, 1368, 1335, 1309, 1278, 1203, 1170,
4.18. (S)-3-[(4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl)-
imino]-4,4-dimethyl-1-phenylpyrrolidin-2-one (S)-14
1
1118, 756, 692 cmꢀ1; H NMR 1.16 (s, 6H) and 1.35 (s,
6H), [2 · C4–(CH3)2], 3.46 (d, J = 9.3 Hz, 2H) and 3.54
(d, J = 9.3 Hz, 2H) (2 · 5-H2), 3.64 (s, 2H, 2 · 3-H), 7.14
(tm, J = 7.2 Hz, 2H, 2 · Hpara), 7.37 (dd, J = 8.4 Hz,
J0 = 7.5 Hz, 4H, 2 · Hmeta), 7.63 (dm, J = 7.5 Hz, 4H,
2 · Hortho); 13C NMR 20.7 (CH3) and 25.0 (CH3)
[2 · C4–(CH3)2], 38.3 (C, 2 · C4), 58.2 (CH2, 2 · C5),
68.9 (CH, 2 · C3), 119.4 (CH, 2 · Cortho), 124.3 (CH,
2 · Cpara), 128.8 (CH, 2 · Cmeta), 139.6 (C, 2 · Cipso),
174.2 (C, 2 · C2). Anal. Calcd for C24H29N3O2: C, 73.63;
H, 7.47; N, 10.73. Found: C, 73.41; H, 7.56; N, 10.66.
Meso-16: Rf 0.14 (aluminum oxide, 9.4 cm, hexane/AcOEt
9:1); 1H NMR 1.12 (s, 6H) and 1.33 (s, 6H), [2 · C4–
(CH3)2], 3.41 (d, J = 9.3 Hz, 2H) and 3.53 (d, J = 9.3 Hz,
2H) (2 · 5-H2), 3.72 (s, 2H, 2 · 3-H), 7.13 (tm,
J = 7.5 Hz, 2H, 2 · Hpara), 7.36 (dd, J = 8.7 Hz,
J0 = 7.2 Hz, 4H, 2 · Hmeta), 7.65 (dm, J = 7.5 Hz, 4H,
2 · Hortho).
A solution of 4,4-dimethyl-1-phenylpyrrolidine-2,3-dione 4
(0.98 g, 4.83 mmol), and amine (S)-9 (0.98 g, 4.80 mmol) in
toluene (30 mL) was heated at reflux for 24 h in a Dean–
Stark equipment. Evaporation of the solvent under re-
duced pressure gave imine (S)-14 (1.87 g, quantitative
yield) as a yellow solid. Crystallization of (S)-14 (205 mg)
from hexane/AcOEt 6:1 (2 mL) provided the analytical
sample (176 mg, 86% recovery). Mp 133–134 ꢁC (hexane/
AcOEt 6:1); Rf 0.52 (aluminum oxide, 7.3 cm, hexane/
25
AcOEt 4:1); ½aꢁD ¼ ꢀ187 (c 0.50, CH2Cl2); IR 3062,
3045, 2958, 2927, 2869, 1701 and 1692 (C@O st), 1677
(C@N st), 1597, 1495, 1481, 1458, 1398, 1376, 1319,
1189, 1057, 767, 758, 723, 690, 627 cmꢀ1 1H NMR
;
(400 MHz) 1.24 (s, 3H), 1.26 (s, 3H), 1.36 (s, 3H) and
1.40 (s, 3H) [C4–(CH3)2 and C40-(CH3)2], 3.62 (d,
J = 9.4 Hz, 1H) and 3.65 (d, J = 9.4 Hz, 1H) (5-H2), 3.73
(d, J = 9.6 Hz, 1H) and 3.79 (d, J = 9.6 Hz, 1H) (50-H2),
6.12 (s, 1H, 30-H), 7.12 (t, J = 7.4 Hz, 1H) and 7.21 (t,
4.20. (S,S)-2,6-Bis[(4,4-dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl)aminomethyl]pyridine dihydrochloride (S,S)-18Æ2HCl
J = 7.4 Hz,
1H)
(2 · Hpara),
7.34
(pseudo
t,
J = J0 = 8.0 Hz, 2H) and 7.39 (pseudo t, J = J0 = 8.0 Hz,
2H) (2 · Hmeta), 7.64 (d, J = 7.6 Hz, 2H) and 7.70 (d,
J = 8.0 Hz, 2H) (2 · Hortho); 13C NMR (100.6 MHz) 21.5
(CH3), 25.6 (CH3), 25.8 (CH3) and 27.0 (CH3) [C4–
(CH3)2 and C40-(CH3)2], 38.5 (C) and 38.9 (C) (C4 and
C40), 58.1 (CH2) and 59.0 (CH2) (C5 and C50), 68.7 (CH,
C30), 119.5 (CH) and 119.8 (CH) (2 · Cortho), 124.2 (CH)
and 125.7 (CH) (2 · Cpara), 128.7 (CH) and 128.9 (CH)
(2 · Cmeta), 139.1 (C) and 139.9 (C) (2 · Cipso), 159.5 (C,
C3), 170.4 (C) and 170.7 (C) (C2 and C2’). Anal. Calcd
To a solution of (S)-9 (500 mg, 2.45 mmol) in anhydrous
MeOH (30 mL), a solution of NaBH3CN (231 mg,
3.68 mmol) and AcOH (0.92 mL, 16.1 mmol) in MeOH
(5 mL) and pyridine-2,6-dicarboxaldehyde, 17 (165 mg,
1.22 mmol) was added and the reaction mixture was stirred
at room temperature for 24 h. Water (15 mL) was then
added. The organic solvent was evaporated under reduced
pressure and the remaining aqueous phase was treated with
aqueous 2 M NaOH until pH 12–13 and extracted with

2956
P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
CH2Cl2 (3 · 15 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated under re-
duced pressure to give crude (S,S)-18 (636 mg, quantitative
yield) as a yellowish oil. The above product was taken in
anhydrous MeOH (5 mL), treated with a solution of HCl
in MeOH (0.4 M, 30 mL) and the solution was concen-
trated under reduced pressure to give a white solid
(802 mg), which was crystallized from MeOH/Et2O 3:4
16 h. The mixture was allowed to cool to room temperature
and was filtered through a basic aluminum oxide pad (10 g,
1.5 cm internal diameter) washing the pad with CH2Cl2
(100 mL). After concentration of the fractions containing
the desired product, (S)-20 (1.41 g, 89% yield) was obtained
as a yellow oil. Rf 0.47 (aluminum oxide, 7.1 cm, hexane/
25
AcOEt 5:1); ½aꢁD ¼ þ56:9 (c 0.65, CH2Cl2); IR (NaCl)
3255 (N–H st), 3169, 3061, 2938, 2900, 2874, 2831, 1701
(10 mL) to give (S,S)-18Æ2HCl (453 mg, 56% yield). Mp
(C@O st), 1640, 1598, 1499, 1485, 1469, 1402, 1379, 1321,
22
168–170 ꢁC (MeOH/Et2O 3:4); ½aꢁ ¼ ꢀ87:2 (c 0.51,
MeOH); IR 3500–2400 (max at 342D0, 2964, 2929, 2781,
2708, 2596, O–H st, +N–H st and C–H st), 1703 (C@O
st), 1633, 1596, 1498, 1458, 1425, 1392, 1323, 763,
1233, 1165, 1106, 1080, 1063, 830, 776, 757, 690,
621 cmꢀ1; 1H NMR 1.22 (s, 3H) and 1.31 (s, 3H) [pyrrolid-
inone C4–(CH3)2], 1.27 (t, J = 7.0 Hz, 3H, OCH2CH3),
1.56–1.72 (m, 4H, cyclohexene 4-H2 and 5-H2), 2.17–2.42
(m, 3H) and 2.52–2.62 (m, 1H) (cyclohexene 3-H2 and 6-
H2), 3.48 (d, J = 9.6 Hz, 1H) and 3.64 (d, J = 9.6 Hz,
1H) (pyrrolidinone 5-H2), 4.10 (d, J = 9.9 Hz, 1H, pyrro-
lidinone 3-H), 4.14 (m, 2H, OCH2CH3), 7.14 (t,
J = 7.2 Hz, J0 = 1.5 Hz, 1H, Hpara), 7.36 (m, 2H, Hmeta),
7.61 (m, 2H, Hortho), 9.33 (d, J = 9.9 Hz, 1H, NH); 13C
NMR 14.6 (CH3, OCH2CH3), 21.4 (CH3) and 25.0 (CH3)
[pyrrolidinone C4–(CH3)2], 22.3 (CH2), 22.6 (CH2), 23.9
(CH2) and 26.4 (CH2) (cyclohexene C3, C4, C5 and C6),
37.6 (C, pyrrolidinone C4), 58.1 (CH2, pyrrolidinone C5),
58.8 (CH2, OCH2CH3), 63.4 (CH, pyrrolidinone C3),
92.7 (C, cyclohexene C1), 119.3 (CH, Cortho), 124.5 (CH,
Cpara), 128.8 (CH, Cmeta), 139.4 (C, Cipso), 158.6 (C, cyclo-
hexene C2), 170.9 (C, pyrrolidinone C2), 171.8 (C, COO).
Anal. Calcd for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86.
Found: C, 70.78; H, 8.06; N, 7.61.
1
692 cmꢀ1; H NMR (400 MHz, CD3OD) 1.40 (s, 6H) and
1.50 (s, 6H), [2 · C4–(CH3)2], 3.64 (d, J = 9.8 Hz, 2H)
and 3.78 (d, J = 9.8 Hz, 2H) (2 · 5-H2), 4.27 (s, 2H,
2 · 3-H), 4.85 (s, mobile H), 4.91 (d, J = 15.0 Hz, 2H)
and 4.94 (d, J = 15.0 Hz, 2H) (2 · CH2N), 7.23 (t,
J = 7.2 Hz, 2H, 2 · Hpara), 7.40 (pseudo t, J = 8.0 Hz,
4H, 2 · Hmeta), 7.63 (d, J = 8.8 Hz, 4H, 2 · Hortho), 7.65
[overlapped d, 2H, pyridine 3(5)-H], 8.03 (t, J = 7.8 Hz,
1H, pyridine 4-H); 13C NMR (100.6 MHz, CD3OD) 21.4
(CH3), 24.7 (CH3) [2 · C4–(CH3)2], 38.8 (C, 2 · C4), 51.9
(CH2, 2 · C5), 60.0 (CH2, 2 · CH2N), 67.3 (CH, 2 · C3),
121.6 (CH, 2 · Cortho), 125.1 (CH, 2 · Cpara), 126.8 [CH,
pyridine C3(5)], 130.1 (CH, 2 · Cmeta), 139.8 (C, 2 · Cipso),
140.5 (CH, pyridine C4), 152.3 [C, pyridine C2(6)], 168.8
(C, 2 · C2). Anal. Calcd for C31H37N5O2Æ2.15HClÆ2H2O:
C, 59.47; H, 6.95; N, 11.19; Cl, 12.17. Found: C, 59.68;
H, 6.77; N, 11.25; Cl, 12.22.
4.22. Ethyl (R)-2-oxo-1-(2-oxobutyl)cyclohexanecarboxyl-
ate (R)-21
A sample of (S,S)-18 as the free base was liberated from the
above dihydrochloride as follows: (S,S)-18Æ2HCl (101 mg)
was treated with aqueous 2 M NaOH (5 mL) and the mix-
ture was extracted with AcOEt (3 · 10 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give (S,S)-18
To a cold (ꢀ78 ꢁC) mixture of enamine (S)-20 (357 mg,
˚
1.00 mmol), MgCl2 (95 mg, 1.00 mmol) and 4 A molecular
sieves (171 mg) in anhydrous Et2O (4 mL), freshly distilled
methyl vinyl ketone (179 mg, 207 lL, 2.55 mmol) was
added and the reaction mixture was stirred for 1 h at
ꢀ78 ꢁC. The molecular sieves were separated by decanta-
tion and the solvent and volatile components were elimi-
nated from the solution under reduced pressure to give a
residue (220 mg), which was subjected to column chromato-
graphy (silica gel, hexane/AcOEt 2:1) to give (R)-21
(84 mg, quantitative yield) as a colorless oil. (S,S)-18: Rf
22
0.71 (aluminum oxide, 7.0 cm, CH2Cl2); ½aꢁD ¼ ꢀ41:2 (c
1
0.45, CH2Cl2); H NMR 1.13 (s, 6H) and 1.27 (s, 6H),
[2 · C4–(CH3)2], 2.3–2.6 (br s, 2H, 2 · NH), 3.31 (s, 2H,
2 · 3-H), 3.39 (d, J = 9.6 Hz, 2H) and 3.49 (d,
J = 9.6 Hz, 2H) (2 · 5-H2), 4.13 (d, J = 14.7 Hz, 2H) and
4.18 (d, J = 14.7 Hz, 2H) (2 · CH2N), 7.13 (tm,
J = 7.2 Hz, 2H, 2 · Hpara), 7.32 [d, J = 7.8 Hz, 2H, pyri-
dine 3(5)-H], 7.35 (pseudo t, J = 8.1 Hz, 4H, 2 · Hmeta),
7.60 (d, J = 8.1 Hz, 4H, 2 · Hortho), 7.61 (overlapped t,
1H, pyridine 4-H); 13C NMR 21.1 (CH3), 25.8 (CH3)
[2 · C4–(CH3)2], 38.3 (C, 2 · C4), 54.5 (CH2, 2 · C5),
58.4 (CH2, 2 CH2N), 68.8 (CH, 2 · C3), 119.4 (CH,
2 · Cortho), 120.3 [CH, pyridine C3(5)], 124.3 (CH,
2 · Cpara), 128.8 (CH, 2 · Cmeta), 136.9 (CH, pyridine
C4), 139.5 (C, 2 · Cipso), 159.1 [C, pyridine C2(6)], 173.6
(C, 2 · C2).
(197 mg, 82% yield) as a yellow oil. Rf 0.55 (silica gel,
25
7.3 cm, hexane/AcOEt 2:1); ½aꢁD ¼ þ67:5 (c 2.5, CH2Cl2)
25
{lit.19 ½aꢁD ¼ þ84:5 (neat)}. Chiral GC (conditions A)/
MS: (R)-21, tR 67.6 min; (S)-21, tR 67.2 min; 80% ee.
4.23. X-ray crystal-structure determination of (S)-9 mono-
O,O-di-p-toluoyl-L-tartrate (Table 2)11
A prismatic crystal (0.1 · 0.1 · 0.2 mm) was selected and
mounted on a MAR345 diffractometer with an image plate
detector. Unit-cell parameters were determined from 1785
reflections (3 < h < 31ꢁ) and refined by least-squares meth-
od. Intensities were collected with graphite monochroma-
tized Mo Ka radiation. 16,883 reflections were measured
in the range 2.59 6 h 6 32.46. 9766 of which were non-
equivalent by symmetry [Rint (on I) = 0.021]. 5691 reflec-
tions were assumed as observed applying the condition
I > 2r(I). Lorentz-polarization but no absorption correc-
tions were made. The structure was solved by Direct meth-
4.21. Ethyl 2-{(S)-[(4,4-dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl)amino]}cyclohex-1-enecarboxylate (S)-20
A mixture of ethyl 2-oxocyclohexanecarboxylate, 19
(757 mg, 4.45 mmol), amine (S)-9 (1.00 g, 4.90 mmol), p-
˚
TsOHÆH2O (86 g, 0.45 mmol), and dried 4 A molecular
sieves (2.5 g) in toluene (10 mL) was heated at 60 ꢁC for

P. Camps et al. / Tetrahedron: Asymmetry 18 (2007) 2947–2958
2957
Table 2. Experimental data of the X-ray crystal-structure determination
of compounds of (S)-9 mono-O,O-di-p-toluoyl-L-tartrate and of (S,S)-
1511
2.64 6 h 6 29.96. 544 reflections were assumed as observed
applying the condition I > 2r(I). Three reflections were
measured every two hours as orientation and intensity con-
trol, significant intensity decay was not observed. Lorentz-
polarization but no absorption corrections were made. The
structure was solved by Direct methods, using SHELXS
computer program,20 and refined by full-matrix least-
squares method with SHELX97 computer program,21 using
1849 reflections (very negative intensities were not as-
Compound
(S)-9 (salt)
(S,S)-15
Molecular formula
Molecular mass
Crystal system
Space group
C12H16N2OÆC20H18O8
590.61
Orthorhombic
P212121
C24H29N3O2
391.50
Orthorhombic
P22121
Cell parameters
˚
2
2 2
a (A)
15.435(7)
15.738(6)
26.223(6)
90
90
90
6.070(5)
8.276(2)
21.562(4)
90
90
90
sumed). The function minimized was RwkFoj ꢀ jFcj j ,
˚
2
2
where w = [r2(I) + (0.0678P)2]ꢀ1, and P = (jFoj + 2jFcj )/
3, f, f0 and f00 were taken from International Tables of
X-ray Crystallography.22 All H atoms were computed
and refined, using a riding model, with an isotropic temper-
ature factor equal to 1.2 time the equivalent temperature
factor of the atom to which are linked. The final R (on
b (A)
˚
c (A)
˚
a (A)
˚
b (A)
˚
c (A)
3
˚
V (A )
6370(4)
8
1083.2(10)
2
Z
2
F) factor was 0.066, wR (on jFj ) = 0.125 and goodness
F(000)
2496
420
dcalcd [Mg mꢀ3
]
1.232
0.1 · 0.1 · 0.2
16,883
9766
1.200
0.1 · 0.1 · 0.2
1849
1849
544
0.077
0.066
0.125
0.114
ꢀ0.123
137
of fit = 0.950 for all observed reflections. Number of
refined parameters was 137. Max shift/esd = 0.00, Mean
shift/esd = 0.00. Max and min peaks in final difference
Size of crystal (mm)
Measured reflect.
Independent reflect.
Observed reflect.
synthesis was 0.114 and ꢀ0.123 e Aꢀ3, respectively.
˚
5691
l(Mo Ka) (mmꢀ1 a
)
0.091
0.055
0.122
0.220
ꢀ0.151
803
R
Rw
Acknowledgments
b
ꢀ3
)
˚
˚
Dqmax (e A
Dqmin (e A
c
ꢀ3
Financial support from Ministerio de Educacio´n y Ciencia
(Project CTQ2005-02192) and Comissionat per a Universi-
tats i Recerca (Project 2005-SGR-00180) is gratefully
)
Refined parameters
Max. shift/esd
0.00
0.00
`
acknowledged. We thank the Serveis Cientı´fico-Tecnics of
a l(Mo Ka) linear absorption coefficient. Radiation Mo Ka (k =
the University of Barcelona for the NMR and MS facili-
ties, and Ms. P. Domenech from the IIQAB (CSIC, Barce-
lona, Spain) for carrying out the elemental analyses.
˚
0.71073 A).
b Maximum peaks in final difference synthesis.
c Minimum peaks in final difference synthesis.
`
ods, using SHELXS computer program,20 and refined by
full-matrix least-squares method with SHELX97 computer
program,21 using 16,883 reflections (very negative intensi-
ties were not assumed). The function minimized was
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´
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˚
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2958
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