Synthesis, resolution and absolute configuration of trans 4,5-diphenyl-pyrrolidin-2-one: A possible chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(03)00097-1

β-Lactam (±)-N-benzyl-4-phenyl-azetidin-2-one rac-6a was converted into the γ-lactam (±)-trans-4,5-diphenyl-pyrrolidin-2-one rac-5 which was resolved via the preparation of diastereomers with N-phthalyl-L-alanine chloride or D-alanine chloride and its absolute configuration was determined by X-ray crystallographic analysis. This heterocycle has potential as a chiral γ-lactam in asymmetric induction due to the steric effects of its phenyl groups.

Full text of DOI:10.1016/S0957-4166(03)00097-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 981–985
Synthesis, resolution and absolute configuration of trans
4,5-diphenyl-pyrrolidin-2-one: a possible chiral auxiliary
Jaime Escalante* and Miguel A. Gonza´lez-Tototzin
Centro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Morelos, Av. Universidad 1001, 62210 Cuernavaca,
Mor., Mexico
Received 15 August 2002; revised 6 September 2002; accepted 11 November 2002
Abstract—b-Lactam ( )-N-benzyl-4-phenyl-azetidin-2-one rac-6a was converted into the g-lactam ( )-trans-4,5-diphenyl-pyrro-
lidin-2-one rac-5 which was resolved via the preparation of diastereomers with N-phthalyl-L-alanine chloride or D-alanine chloride
and its absolute configuration was determined by X-ray crystallographic analysis. This heterocycle has potential as a chiral
g-lactam in asymmetric induction due to the steric effects of its phenyl groups. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Among the methods available to synthesize 5, the
methodologies based on employing an acyclic compound
to form the heterocycle are very common; In particular,
cyclization of g-amino acids7 or g-amino esters8 has been
used frequently. In this context, we describe an alterna-
tive route for the preparation of the racemic trans
4,5-diphenyl-pyrrolidin-2-one 5.9 We subsequently devel-
oped a process for the resolution of the racemate and
determined the configuration of this heterocycle.
g-Lactams have potential to act as chiral auxiliaries in
the asymmetric synthesis of many kinds of products.1
Some of the most explored chiral g-lactams are the
pyrrolidinones 1a–d developed by Davies et al.2 that have
some advantages over the classic oxazolidinones
described by Evans3 2a–b or by Sibi et al. 2c.4 Another
related auxiliary is pyroglutamate 3 developed by
Ezquerra et al.5 which has been shown to control the
stereoselectivity of N-acyl fragments in aldol condensa-
tions or in conjugate additions. Further application was
reported by Juaristi et al.6 in cis- and trans-hexahy-
drobenzoxazolidinones 4 to control the stereoselectivity
in N-acyl fragments in alkylation and aldol reactions.
The chiral g-lactam-5 also might be considered as an
effective chiral auxiliary for asymmetric synthesis in
which the asymmetric induction may be realized by the
steric effects of phenyl groups (Fig. 1).
2. Results and discussion
2.1. Synthesis of g-lactam ( )-trans 4,5-diphenyl-pyrro-
lidin-2-one rac-5
The g-lactam rac-5 was prepared from b-lactam ( )-N-
benzyl-4-phenyl-azetidin-2-one rac-6a by lateral chain
incorporation in a ring expansion process10 with 1.1
Figure 1.
* Corresponding author. E-mail: escalante jaime@hotmail.com
–
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00097-1

982
J. Escalante, M. A. Gonza´lez-Tototzin / Tetrahedron: Asymmetry 14 (2003) 981–985
plane. The most interesting feature of the crystal struc-
ture is that the phenyl groups are located in a trans
arrangement in pseudo equatorial positions. The practi-
cal consequences are significant, since one of the phenyl
groups can be regarded as sterically hindered for attack
on one face in the course of stereoselective alkylation,
acylation and aldol condensation similar to the classic
oxazolidinones by Evans.3
Scheme 1.
We have demonstrated that the expansion mechanism
proposed11 in Fig. 3 proceeds via benzylic anion inter-
mediate I (see Section 2.1.1) and, because of ring strain,
a rearrangement to give the imine anion II (which is
stabilized by resonance, see Section 2.1.2) occurs to
release the ring strain of the small four-membered
ring.12 Finally, a Michael type reaction occurs for the
ring closure to give the more stable trans g-lactam rac-5
(see Section 2.1.3).
2.1.1. Benzylic anion I formation. The b-lactam rac-6a
was treated with n-BuLi in THF at −78°C (expansion
conditions), after 1 min pivaloyl chloride was added to
obtain rac-7 with one pivaloyl group in the benzylic
position in 83% yield (Scheme 2). This experiment
indicates that the formation of the benzylic anion I9 can
be considered as the first step in the expansion
mechanism.
Figure 2. X-Ray diffraction study of ( )-trans-4,5-diphenyl-
pyrrolidin-2-one rac-5.
2.1.2. Imine anion II formation. To probe the second
step and to explore the effect of substitution at the C(4)
position in the starting material, we carried out the
expansion reaction under the same conditions with
b-lactams rac-6b and 6c (Scheme 3).
mol equiv. of n-butyllithium in THF at −78°C under a
nitrogen atmosphere in 87% yield. The expansion reac-
tion was carried out from −78°C to room temperature
during 1 h giving 72% yield, while at rt the expansion
proceeded in only 55% yield. We obtained exclusively
the trans product and did not observe the formation of
With these substrates no reaction has been observed
probably because of the absence of any resonance as in
II (induced by the phenyl group) assisting the stabiliz-
ing of the carbanion intermediate IV.
1
the cis isomer by H NMR (Scheme 1).
An X-ray crystallographic analysis was performed with
a suitable crystal of rac-5, and a view of the solid-state
structure is shown in Fig. 2. The heterocyclic ring is
rather flat and has the five atoms approximately in a
2.1.3. Ring strain as the ‘driving force’. Finally, to probe
if the ring strain in the b-lactam rac-6a is the driving
force for the rearrangement, we prepared the analogous
heterocycle N-benzyl g-lactam rac-8. rac-8 was treated
Figure 3. Reaction mechanism for the ring expansion.
Scheme 2.

J. Escalante, M. A. Gonza´lez-Tototzin / Tetrahedron: Asymmetry 14 (2003) 981–985
983
Scheme 3.
with n-BuLi following the established procedure for the
expansion conditions. Also in these cases, no detectable
conversion of the reactant was observed. We interpret
this observation as the five member heterocycle ring
now being stable, thus not promoting the expansion.
This observation is in agreement with our mechanistic
explanation (Scheme 4).
were able to determine the relative configuration S at
C(4) and R at C(5) in the heterocyclic system for
diastereomer 10a, and consequently the opposite
configuration for diastereomer 10b [R at C(4) and S at
C(5)].
Figure 4. Structure and solid-state conformation for
(4S,5R,aS)-10a.
Scheme 4.
2.2. g-Lactam-5, resolution and absolute configuration
Finally, as shown in Scheme 6, conversion of
diastereoisomer 10a to the enantiomerically pure g-lac-
tam (4S,5R)-5 was completed by hydrolysis with LiOH
in 86% yield.
determination
The resolution was achieved by the preparation of the
diastereomers 10a and 10b via condensation between
the g-lactam anion, formed with n-BuLi from −78°C to
rt, and N-phthalyl- -alanine chloride (S)-11 as the res-
L
oluting agent. Separation of the diastereomers was
accomplished by fractional crystallization from hexane/
AcOEt (Scheme 5).
Scheme 6.
Enantiomerically pure (4R,5S)-5 g-lactam was obtained
from 10c by the use of N-phthalyl-D-alanine chloride as
the resolving agent (Scheme 7) since attempts to recrys-
tallize diastereomer 10b had failed.
Scheme 5.
The assignment of the absolute configuration of the
main products was achieved by X-ray diffraction analy-
sis with the diastereomer 10a (Fig. 4). In this way, we
Scheme 7.

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J. Escalante, M. A. Gonza´lez-Tototzin / Tetrahedron: Asymmetry 14 (2003) 981–985
3. Conclusions
4.2.2.
( )-1-(3,3-Dimethyl-2-oxo-1-phenyl-butyl)-4-
phenyl-azetidin-2-one rac-7. The general procedure was
followed for ring expansion, and after 1 min 1.1 mol
equiv. of pivaloyl chloride was added. Purification of
the crude product by flash chromatography (hex/
AcOEt, 10:0“0:10) afforded 83% yield of rac-7. Color-
In this paper, we present a new method for the prepara-
tion of enantiomerically pure g-lactams (4S,5R)-5 and
(4R,5S)-5. The interest for these g-lactams as chiral
auxiliaries is given by their potential to be used in the
intramolecular protective formation of g-amino acids.
Further studies to explore these g-lactams as new chiral
auxiliaries in the synthesis of amino acids are in
progress.
1
less crystals, mp 77–79°C. H NMR (200 MHz, CDCl3)
l 1.33 (s, 9H), 2.78 (dd, Jgem=17.6 Hz, Janti=6.2 Hz,
1H), 3.13 (dd, Jgem=17.6 Hz, Jsy4n=8.4 Hz, 1H), 3.38
(ddd, Janti=6.2 Hz, Jsyn=8.4 Hz, J=5.2 Hz, 1H), 5.30
4
(d, J=5.2 Hz, 1H), 7.10–7.35 (m, 10H). 13C NMR (50
MHz, CDCl3) l 26.3, 39.9, 42.2, 46.5, 70.1, 125.4,
126.2, 127.0, 127.6, 127.9, 128.2, 129.0, 129.1, 140.9,
141.2, 173.4, 180.9.
4. Experimental
4.1. General
4.3. ( )-1-Benzyl-trans-4,5-diphenyl-pyrrolidin-2-one
rac-8
TLC: Merck-DC-F254 plates; detection by UV light.
Flash column chromatography:13 Merck silica gel
(0.040–0.063 mm). Mp: Mel-Temp apparatus; not cor-
rected. Optical rotations were determined in a Perkin–
A mixture 1:1 of solvents THF/DMF was added to the
trans-4,5-diphenyl-pyrrolidin-2-one (rac-5) at 0°C in an
ice-water bath. This suspension was treated with 2.2
mol equiv. of NaH and 1.1 mol equiv. of benzyl
bromide. The ice-water bath was removed and stirring
continued at room temperature over night. The mixture
was filtered, evaporated and purified by flash chro-
matography (hex/AcOEt, 10:0“0:10) afforded 84%
yield of rac-8. Colorless oil. 1H NMR (200 MHz,
CDCl3), l 2.71 (dd, Jgem=17.1 Hz, Janti=7.8 Hz, 1H),
1
Elmer 241 polarimeter at the sodium D-line. H NMR
spectra: Varian Oxford 400 MHz, Varian Mercury 200
MHz. 13C NMR spectra: Varian Oxford 100 MHz,
Varian Mercury 50 MHz. Chemical shifts (l) in ppm
downfield from the integral TMS reference; the cou-
pling constants (J) in Hz. X-Ray: APEX-Bruker dif-
fractometer. The structures were solved by direct
methods using the program SHELXS.14
3.06 (dd, Jgem=17.1 Hz, Jsyn=9.1 Hz, 1H), 3.34 (ddd,
Flasks, stirring bars and hypodermic needles used for
the generation and reactions of organolithiums were
dried for 12 h at 120°C and allowed to cool in a
desiccator over anhydrous CaSO4. Anhydrous solvents
were obtained by distillation from benzophenone
ketyl.15 The n-BuLi employed was titrated according to
the method of Juaristi et al.16
3
Janti=7.8 Hz, Jsyn=9.1 Hz, J=6.1 Hz, 1H), 4.30 (d,
3J=6.1 Hz, 1H), 3.51, 5.20 (AB, J=J%=14.3, 2H),
6.95–7.45 (m, 15H). 13C NMR (50 MHz, CDCl3) l
38.6, 44.8, 47.7, 69.5, 127.1, 127.2, 127.2, 127.7, 128.4,
128.7, 128.8, 128.9, 129.1, 136.2, 139.4, 141.7, 174.2.
4.4. General procedure for the g-lactam-5 resolution
4.2. General procedure for the ring expansion
A solution of rac-5 in THF was cooled to −78°C before
slowly adding 1.1 mol equiv. of n-butyllithium in hex-
ane (2.4 M). The resulting solution was stirred at −78°C
for 10 min and further at room temperature for 15 min,
and treated successively with the resolution agent (N-
Under N2 a dry flask fitted with magnetic stirrer and a
solution of the appropriate b-lactam17 in anhydrous
THF was cooled to −78°C before the slow addition of
1.1 mol equiv. of n-BuLi in hexane (2.4 M). The
resulting solution was stirred at −78°C for 30 min and
then quenched with a saturated ammonium chloride
solution and then with 10 mL of water. The aqueous
phase was extracted with three 10 mL portions of
CH2Cl2. The combined organic extracts were dried
(Na2SO4), filtered and evaporated to give the crude
product. The crude material was recrystallized from
mixtures of MeOH and CH2Cl2 to yield the pure g-
lactam.
phthalyl-L-alanine or D
-alanine chloride).19 The mixture
was stirred at the same temperature for 1 h and treated
with saturated ammonium chloride solution and then
with water. The aqueous phase was extracted with
CH2Cl2. The combined extracts were dried (Na2SO4),
filtered and evaporated to give the crude product.
Purification of the crude product was accomplished by
flash chromatography (hexane/AcOEt) and then by
recrystallization from hexane/AcOEt yielding the corre-
sponding diastereomer.
4.2.1. ( )-trans 4,5-Diphenyl-pyrrolidin-2-one rac-5. 87%
1
yield as white crystals, mp 215–218°C. H NMR (400
4.4.1.
2-[1(S)-Methyl-2-oxo-2-(5-oxo-2(R),3(S)-
MHz, CDCl3) l 2.70 (dd, Jgem=16.5 Hz, Janti=8.8 Hz,
1H), 2.87 (dd, Jgem=16.5 Hz, Jsy3n=9.9 Hz, 1H), 3.40
(ddd, Janti=8.8 Hz, Jsyn=9.9 Hz, J=7.7 Hz, 1H), 4.70
diphenyl-pyrrolidin-1-yl)-ethyl]-isoindole-1,3-dione 10a.
90% Yield; mp 188–189°C; [h]2D5=−61.9 (c 1.1, CHCl3);
1H NMR (400 MHz, CDCl3) l 1.87 (d, J=7.2 Hz, 3H),
2.76 (dd, Jgem=18.4 Hz, Janti=2.4 Hz, 1H), 3.22 (dd,
3
(d, J=7.7 Hz, 1H), 6.36 (s, 1H), 7.15–7.35 (m, 10H).
13C NMR (100 MHz, CDCl3) l 39.2, 51.0, 65.3, 126.5,
127.1, 127.7, 127.9, 128.7, 128.8, 141.4, 141.8, 176.1.
MS, m/z 237 (M+). X-Ray crystallographic structure in
Fig. 2.18
Jgem=18.4 Hz, Jsyn=8.8 Hz, 1H), 3.41 (ddd, Janti=2.4
3
3
Hz, Jsyn=8.8 Hz, J=2.4 Hz, 1H), 5.32 (d, J=2.4 Hz,
1H), 6.02 (c, 1H), 7.16–7.40 (m, 10H), 7.68 (dd, J=2.8
Hz, J%=5.6 Hz, 2H), 7.82 (dd, J=2.8 Hz, J%=5.6 Hz,

J. Escalante, M. A. Gonza´lez-Tototzin / Tetrahedron: Asymmetry 14 (2003) 981–985
985
2H). 13C NMR (100 MHz, CDCl3) l 14.9, 38.7, 45.9,
References
51.2, 68.9, 123.5, 125.1, 126.5, 127.9, 128.0, 129.2,
129.5, 132.2, 134.1, 140.1, 142.3, 168.0, 170.7, 174.9.
X-Ray crystallographic structure in Fig. 4.18
1. (a) Na´jera, C.; Yus, M. Tetrahedron: Asymmetry 1999,
10, 2245; (b) Gonza´lez-Tototzin, M. A. To´picos de Inves-
tigacio´n en Qu´ımica 2000, 1, 24.
2. Davies, S. G.; Doisneau, G. J.-M.; Prodger, J. C.; Sanga-
nee, H. J. Tetrahedron Lett. 1994, 35, 2369.
3. Evans, D. A. Aldrichim. Acta 1982, 15, 23.
4. (a) Sibi, M. P. Aldrichim. Acta 1999, 32, 93; (b) Sibi, M.
P.; Deshpande, P. K.; Ji, J. Tetrahedron Lett. 1995, 36,
8965.
4.4.2.
2-[1(R)-Methyl-2-oxo-2-(5-oxo-2(S),3(R)-
diphenyl-pyrrolidin-1-yl)-ethyl]-isoindole-1,3-dione 10c.
80% Yield; mp 188–189°C; [h]2D5=+61.4 (c 1.1, CHCl3).
4.5. Procedure for remotion of the resolution agent
5. (a) Ezquerra, J.; Rubio, A.; Mart´ın, J.; Garc´ıa-Nav´ıo, J.
L. Tetrahedron: Asymmetry 1997, 8, 669; (b) Ezquerra, J.;
Prieto, L.; Avendan˜o, C.; Martos, J. L.; de la Cuesta, E.
Tetrahedron Lett. 1999, 40, 1575.
6. de Parrodi, C.; Clara-Sosa, A.; Pe´rez, L.; Quintero, L.;
Maran˜o´n, V.; Toscano, A.; Avin˜a, J.; Rojas-Lima, S.;
Juaristi, E. Tetrahedron: Asymmetry 2001, 12, 69.
7. Potapov, V. M.; Gracheva, R. A.; Sivov, N. A.; Savina,
S. A.; Sivova, L. A. Zh. Org. Khim. 1989, 25, 1876.
8. Yee, N. K. Tetrahedron Lett. 1997, 38, 5091.
9. Durst, T.; Van Den Elzen, R.; LeBelle, M. J. J. Am.
Chem. Soc. 1972, 94, 9261.
To the appropriate diastereomer in THF was added at
0°C an excess of 1N LiOH solution under stirring for 2
h. The resulting mixture was concentrated at reduced
pressure and purified by column chromatography (hex/
AcOEt 50:50“0:10) to give the product as a white
solid.
4.5.1. trans-(4S,5R)-Diphenyl-pyrrolidin-2-one, (4S,5R)-
5. 86% Yield. White solid, mp 104–106°C. [h]2D5=
1
−150.1 (c 1.1, MeOH). H NMR (400 MHz, CDCl3) l
2.69 (dd, Jgem=16.8 Hz, Janti=9.2 Hz, 1H), 2.87 (dd,
J
gem=16.8 Hz, Jsyn=8.8 Hz, 1H), 3.39 (ddd, Janti=9.2
3
3
10. Hesse, M. Ring Enlargement in Organic Chemistry, Ed.
VCH: Weinheim, Germany. ISBN 3-527-28182-7, 1991.
11. Ahn, Ch.; Shin, D.-S.; Park, J.-H. J. Korean Chem. Soc.
1999, 43, 489.
Hz, Jsyn=8.8 Hz, J=7.2 Hz, 1H), 4.69 (d, J=7.2 Hz,
1H), 6.48 (s, 1H), 7.15–7.38 (m, 10H). 13C NMR
(CDCl3, 100 MHz) l 38.6, 51.3, 66.2, 126.1, 127.5,
128.4, 129.0, 140.8, 141.0, 176.7.
12. Baeyer, A. Ber. 1885, 2269.
13. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
4.5.2. trans-(4R,5S)-Diphenyl-pyrrolidin-2-one, (4R,5S)-
5. 87% Yield. [h]D25=+149.2 (c 1.1, MeOH).
14. Sheldrick, G. M. SHELX97, Programs for Crystal Struc-
ture Analysis, release 97-2; Institute for Inorganic Chem-
istry der Universita¨t: Tommanstrasse 4, D-3400
Go¨ttingen, Germany, 1998.
4.6. Determination of absolute configuration of g-
lactams
15. Brown, H. C. Organic Synthesis via Boranes; Wiley: New
York, 1975; p. 256.
16. Juaristi, E.; Mart´ınez-Richa, A.; Cruz-Sa´nchez, J. S. J.
Org. Chem. 1983, 48, 2603.
Configurations in the C(4) and C(5) positions of
(4S,5R)- and (4R,5S)-g-lactams-5 were determined rela-
tive to (S) stereogenic center of
L-alanine or (R) for
D
-alanine mediated X-ray diffraction.
17. (a) Escalante, J.; Gonza´lez-Tototzin, M. A.; Avin˜a, J.;
Mun˜oz-Mun˜iz, O.; Juaristi, E. Tetrahedron 2001, 57,
1883; (b) Kim, S.; Lee, P. H.; Lee, T. A. Synth. Commun.
1988, 18, 247.
Acknowledgements
18. Crystallography data are deposited at Cambridge Crys-
tallographic Data Center (CDDC 191006 and 191007).
19. Camps, P.; Pe´rez, F.; Soldevilla, N.; Borrego, M. A.
Tetrahedron: Asymmetry 1999, 10, 493.
We are grateful to Dr. Thomas Buhse for many impor-
tant observations. The financial support from Conacyt-
Me´xico, via grants 38187-E and M.A.G.-T. Conacyt for
a scholarship.