An easy access to (S)-pyrrolidinones and -pyrrolidines from chiral benzylic malonates

Article abstract of DOI:10.1016/S0957-4166(99)00425-5

From chiral benzylic malonic acid esters (R)-(+)-4, available with high enantiomeric excesses by enzymatic hydrolysis (PLE acetonic powder), enantiomerically enriched pyrrolidinones 1 and pyrrolidines 2 were prepared. This rapid and competitive method was

Full text of DOI:10.1016/S0957-4166(99)00425-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3877–3881
An easy access to (S)-pyrrolidinones and -pyrrolidines from
chiral benzylic malonates
Philippe Arzel, Vincent Freida, Philippe Weber and Antoine Fadel ∗
Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d’Orsay, Bât. 420, Université de Paris-Sud,
91405 Orsay, France
Received 10 September 1999; accepted 23 September 1999
Abstract
From chiral benzylic malonic acid esters (R)-(+)-4, available with high enantiomeric excesses by enzymatic
hydrolysis (PLE acetonic powder), enantiomerically enriched pyrrolidinones 1 and pyrrolidines 2 were prepared.
This rapid and competitive method was developed via enol ether formation, and subsequent one-pot cyclisation, in
good overall yield. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
A new series of benzylic quaternary substituted γ-lactams 1 presents a phosphodiesterase type
IV (PDE IV) inhibitory activity.1,2 Their analogues, 3-arylpyrrolidines 2, exhibit dual histamine
H1/tachykinin NK1 receptor antagonist properties.3,4 Such molecules have also attracted special attention
due to their analgesic effects.5–7 To our knowledge only a few methods for the synthesis of this class of
compounds have been described, moreover rarely in non-racemic form.5b,8,9
In previous papers, we have described the asymmetric construction of quaternary carbons from chiral
malonates and their subsequent transformation into sesquiterpenes10 and alkaloids.11 Herein, we report
that this strategy can be applied to the synthesis of γ-lactams 1 and analogous pyrrolidines 2, via the enol
ether 3, readily available from chiral malonates 4 (Scheme 1).
∗
Corresponding author. Fax: +33(1)69156278; e-mail: antfadel@icmo.u-psud.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00425-5

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Scheme 1.
2. Results and discussion
The prochiral dimethyl malonates 5a–c were prepared in good yields from methyl arylacetate by
successive alkylations with methyl iodide (or allyl bromide) and methyl chloroformate. Then these
malonates 5a–c were submitted to enantioselective enzymatic hydrolysis using pig liver esterase (PLE)
to provide the acid esters† (R)-(+)-4a–c12 in good yields and high enantiomeric excesses.‡ In the case of
the acid ester 4a, the ee was increased to 97% by crystallisation (ether:pentane). Formation of β-hydroxy
ester 6a–c was then achieved using our previously reported procedure (Scheme 2).10b
Scheme 2.
Thus, reaction of (R)-(+)-4a–c, with (COCl)2–cat. DMF,13 followed by reduction of the resulting acyl
chlorides (NaBH4, THF then MeOH, 15 equiv.)14 gave the β-hydroxy esters (R)-6a–c in excellent yields.
These hydroxy esters (R)-6 were then oxidised with the Dess–Martin reagent15 to lead quantitatively to
aldehydes 7a–c, which under Wittig reaction gave the enol ethers (S)-3a–c16 as a mixture of E–Z isomers.
Good yields were obtained for all these reactions (Scheme 3).
Scheme 3.
The enol ethers 3 were transformed quantitatively, under acidic conditions, into aldehydes 8a–c. These
latter were directly used in the next step without purification. In the case of 3a we observed that the
hydrolysis over silica gel in CH2Cl2 in the presence of a catalytic amount of HCl gave the methoxy
lactone 9a (Scheme 4).
The crude aldehydes 8a–c were transformed by a one-pot procedure (reaction with benzylamine,
reduction with NaBH3CN, then heating at 66°C in THF), to a mixture of γ-lactams (S)-1a–c17 (50–60%
yield) and γ-lactams 10a–c (10–13% yield) (Scheme 5). These latter were formed by cyclisation of
11a–c during the heating before reduction with NaBH3CN, since heating of imine 11a, formed in situ,
†
The absolute configuration of (+)-4a–c was assigned to be (R) by comparison with aryl malonic acid esters reported
previously.10,11
‡
The enantiomeric excesses of (R)-(+)-4a–c were determined from the 1H NMR spectra of their salts with (R)-(+)-1-
naphthylethylamine.

P. Arzel et al. / Tetrahedron: Asymmetry 10 (1999) 3877–3881
3879
Scheme 4.
with methanol in THF without the reducing reagent gave quantitatively lactam 10a. Treatment of 10a–c
with an excess of NaBH3CN (4 equiv.) did not give the expected lactaams (S)-1a–c. The amines 12a–c
were isolated only as HCl salts. In the case of aldehydes 8b,c we tested this one-pot transformation using
methylamine. This led to a 2:1 mixture of the two γ-butyrolactams 13b,c:14b,c, but in lower overall
yields (30% for 13b,c and 15% for 14b,c).
Scheme 5.
On the other hand, the reaction of the lactone 9a with benzylamine (110°C)9a gave quantitatively the
lactam 10a (Scheme 6).
Scheme 6.
The reduction of lactams (S)-1a–c or 10a–c by DIBAL-H (−78→20°C) gave the desired pyrrolidines
(S)-2a–c18 in 95% yields. It is interesting to note that this one-pot procedure starting from enol ethers
3a–c, by successive hydrolysis (H+), condensation with amine (H2NBn), heating (90°C) and then
reduction with an excess of DIBAL-H (5 equiv.), gave the expected pyrrolidines (S)-2a–c in 84% overall
yield from 3a–c (Scheme 7). This procedure thus allows easy and rapid access to a wide variety of
pyrrolidines in high yields.
Scheme 7.
In conclusion, from readily available chiral malonates 4 (ee >80%), we have developed, via enol ether
formation and subsequent one-pot cyclisation (H+, H2NR, ∆, then DIBAL-H), a rapid and competitive
method to the pyrrolidines (S)-2 (three steps, 57% overall yield). These compounds constitute potential
precursors to a wide variety of analgesic pyrrolidines. Synthetic applications of this method to total
synthesis of analgesic pyrrolidines are currently under way.

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References
1. For a review, see: Palfreyman, M. N.; Souness, J. E. Progress in Medicinal Chemistry 1996, 33, 1.
2. Carpenter, D. O.; Briggs, D. B.; Knox, A. P. J. Neurophysiol. 1988, 59, 358.
3. Kane, J. M.; Carr, A. A.; Hay, D. A.; Staeger, M. A. J. Org. Chem. 1990, 55, 1399.
4. Vaz, R. J.; Maynard, G. D.; Kudlacz, E. M.; Bratton, L. D.; Kane, J. M.; Shatzer, S. A.; Knippenberg, R. W. Bioorg. Med.
Chem. Lett. 1977, 7, 2825, and references cited therein.
5. (a) Cavalla, J. F. (Parke, Davis and Co) Ger. patent 1.303.096, 1962; Chem. Abst. 1972, 76, 85690s. (b) Lockhart, I. M.;
Webb, N. E.; Wright, M.; Winder, C. V.; Varner, P. J. Med. Chem. 1972, 15, 935, and references cited therein.
6. (a) Zimmerman, D. US patent 4.081.450, 1978; Chem. Abst. 1978, 89, 109113c. (b) Martinelli, M.; Peterson, B.
Tetrahedron Lett. 1990, 31, 5401.
7. Casy, A.; Dewar, G.; Al Deeb, O. Chirality 1989, 1, 202.
8. (a) Takano, S.; Sato, T.; Inomata, K.; Ogasawara, K. Heterocycles 1990, 31, 411. (b) Takano, S.; Moriya, M.; Ogasawara,
K. J. Org. Chem. 1991, 56, 5982.
9. (a) Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641. (b) Node, M.; Itoh, A.; Masaki,
Y.; Fuji, K. Heterocycles 1991, 32, 1705.
10. (a) Fadel, A.; Canet, J.-L.; Salaün, J. Tetrahedron: Asymmetry 1993, 4, 27. (b) Canet, J.-L.; Fadel, A.; Salaün, J. J. Org.
Chem. 1992, 57, 3463, and references cited therein.
11. (a) Fadel, A.; Arzel, Ph. Tetrahedron: Asymmetry 1995, 6, 893. (b) Fadel, A.; Garcia-Argote, S. Tetrahedron: Asymmetry
1996, 7, 1159. (c) Fadel, A.; Arzel, Ph. Tetrahedron: Asymmetry 1997, 8, 371. (d) Fadel, A.; Vandromme, L. Tetrahedron:
Asymmetry 1999, 10, 1153.
12. Selected data: Compound 4b: [α]2D0=+16.5 (c 1, CHCl3); (ee=71%); IR (neat): 1750 (C_O), 1730 (C_O ester); 1H NMR
(CDCl3, 250 MHz): δ=7.00–6.79 (m, 3H), 5.90–5.65 (m, 1H), 5.30–5.10 (m, 2H), 3.89 (s, 6H), 3.83 (s, 3H, Meester), 3.18
[ABX system, ∆νAB=47.8 Hz, 3.30 (A part, dd, JAB=13.6 Hz, JAX=8.8 Hz, 1H), 3.06 (B part, dd, JAB=13.6 Hz, JBX=8.1
Hz, 1H)]; 13C NMR (CDCl3, 62.86 MHz): δ=173.4 (C1), 173.3 (C3) [6 arom C: 148.9, 148.7, 128.5, 119.6, 110.8, 110.7],
132.3 (d), 119.5 (t), 61.5 (C2), 55.9, 55.8, 53.2, 39.6.
13. Wissner, A.; Grudzinskas, C. V. J. Org. Chem. 1978, 43, 3972.
14. Soai, K.; Yokoyoma, S.; Moshida, K. Synthesis 1987, 647.
15. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
16. Selected spectroscopic data: Compound 3a trans: [α]2D0=−27.5 (c 1, CHCl3); (ee=97%); IR (neat): 1720 (C_O), 1640
(C_C); 1H NMR (CDCl3, 200 MHz): δ=7.28–7.18 (m, 2H), 6.92–6.80 (m, 2H), 6.34 (d, J=13.5 Hz, 1H), 5.83 (d, J=13.5
Hz, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.60 (s, 3H), 1.60 (s, 3H); 13C NMR (CDCl3, 62.86 MHz): δ=175.9 (C1) [6 arom
C: 158.2, 136.5, 127.2 (2C), 113.5 (2C)], 148.4 (C3), 107.4 (C4), 56.0, 55.0, 52.2, 49.8 (C2), 24.8; HRMS calcd for
C14H18O4: 250.1205. Found: 250.1205. Compound 3b trans: [α]2D0=−7 (c 1, CHCl3); (ee=71%); H NMR (CDCl3, 250
1
MHz): δ=6.95–6.72 (m, 3H), 6.20 (d, J=13.5 Hz, 1H), 5.80–5.53 (m, 1H), 5.27 (d, J=13.5 Hz, 1H), 5.15–4.98 (m, 2H),
3.86 (s, 3H), 3.85 (s, 3H), 3.68 (s, 3H), 3.55 (s, 3H), 3.10–2.70 (m, 2H); 13C NMR (CDCl3, 62.86 MHz): δ=175.0 (C1),
149.8 (C3) [6 arom C: 148.4, 147.8, 134.6, 118.1, 110.6, 110.5], 134.0 (d), 119.1 (t), 105.7 (C4), 56.0, 55.8, 55.7, 53.8
(C2), 52.2, 42.7. Compound 3c trans: [α]2D0=−12.5 (c 1, CHCl3); (ee=86%); H NMR (CDCl3, 250 MHz): δ=7.35–7.15
1
(m, 1H), 6.95–6.73 (m, 3H), 6.22 (d, J=13.7 Hz, 1H), 5.80–5.50 (m, 1H), 5.26 (d, J=13.7 Hz, 1H), 5.20–4.95 (m, 2H),
3.81 (s, 3H), 3.70 (s, 3H), 3.59 (s, 3H), 2.88 [AB system, ∆νAB=34.2 Hz, 2.94 (A part, dd, JAB=14.7 Hz, J=7.4 Hz, 1H),
2.82 (B part, dd, JAB=14.7 Hz, J=7.4 Hz, 1H)]; 13C NMR (CDCl3, 62.86 MHz): δ=174.8 (C1) [6 arom C: 159.3, 143.9,
129.1, 119.4, 113.5, 111.6], 149.8 (d), 133.9 (C3), 118.1 (t), 105.3 (C4), 56.0 (C2), 55.1, 54.1, 52.2, 42.5.
17. Selected spectroscopic data: Compound 1a: [α]D20=−8 (c 1, CHCl3); (ee=97%); IR (neat): 1690 (C_O); 1H NMR (CDCl3,
200 MHz): δ=7.40–7.15 (m, 7H), 6.95–6.80 (m, 2H), 4.53 (s, 2Hbenzyl), 3.80 (s, 3H), 3.25–3.15 (dd, J1=J2=7.4 Hz, 2H),
2.48–2.30 (m, 1H), 2.20–2.02 (m, 1H), 1.55 (s, 3H); 13C NMR (CDCl3, 52.29 MHz): δ=177.5 (C2) [12 arom C: 158.2,
136.5, 135.8, 128.6 (2C), 128.0 (2C), 127.5, 127.1 (2C), 113.7], 55.2, 48.0 (C3), 46.9 (t), 43.3 (C5), 35.2 (C4), 25.2.
Compound 1b: [α]D20=−8.5 (c 1, CHCl3); (ee=71%); IR (neat): 1690 (C=O); 1H NMR (CDCl3, 250 MHz): δ=7.40–7.15
(m, 6H), 7.10–6.75 (m, 2H), 5.76–5.55 (m, 1H), 5.16–5.00 (m, 2H), 4.49 (s, 2H), 3.87 (s, 6H), 3.22–3.10 (m, 2H), 2.65 (d,
J=7.8 Hz, 2H), 2.45–2.18 (m, 2H); 13C NMR (CDCl3, 62.86 MHz): δ=176.1 (C2) [12 arom C: 148.8, 147.8, 136.5, 134.3,
129.1, 128.6 (2C), 128.0 (2C), 127.5, 110.7, 110.2], 134.2 (CH_), 118.4 (CH2_), 55.8 (2C), 51.5 (C3), 46.9, 43.6 (C5),
43.5, 30.3 (C4). Compound 1c: [α]2D0=−21 (c 1, CHCl3); (ee=86%); IR (neat): 3080, 1690 (C_O), 1610, 1590; 1H NMR
(CDCl3, 250 MHz): δ=7.38–7.12 (m, 6H), 7.12–7.00 (m, 2H), 6.80 (dd, J1=7.9 Hz, J2=2.6 Hz, 1Hb), 5.79–5.59 (m, 1H),
5.18–5.02 (m, 2H), 4.56 (like AB system, d, J=14.7 Hz, 1Hbenzyl), 4.47 (d, J=14.7 Hz, 1Hbenzyl), 3.81 (s, 3H), 3.24–3.08
(m, 2H, CH2-N), 2.70 (br d, J=7.4 Hz, 2H, allyl), 2.45–2.17 (m, 2H); 13C NMR (CDCl3, 62.86 MHz): δ=175.8 (C2) [12

P. Arzel et al. / Tetrahedron: Asymmetry 10 (1999) 3877–3881
3881
arom C: 159.6, 143.6, 136.4, 129.3, 128.6 (2C), 128.0 (2C), 127.5, 118.8, 112.6, 112.0], 134.1 (d), 118.5 (t), 55.2, 52.0
(C3), 46.9, 43.5 (C5), 43.3, 30.4 (C4); Anal. calcd for C21H23N1O2: C, 78.47; H, 7.21; N, 4.36. Found: C, 78.07; H, 7.28;
N, 4.31.
18. Selected data: Compound 2: [α]2D0=−59.6 (c 1, CHCl3); (ee=97%); 1H NMR (CDCl3, 200 MHz): δ=7.45–7.15 (m, 7H),
6.90–6.80 (m, 2H), 3.82 (s, 3H), 3.75 (s, 2Hbenzyl), 2.84 (s, 2H), 3.05–2.90 (m, 1H), 2.80–2.60 (m, 1H), 2.30–2.15 (m,
1H), 2.10–1.90 (m, 1H), 1.45 (s, 3H); 13C NMR (CDCl3, 52.29 MHz): δ=[12 arom C: 157.5, 142.3, 138.7, 128.8 (2C),
128.2 (2C), 127.0, 126.8 (2C), 113.5 (2C)], 67.1, 60.4 (C2), 55.2, 53.6 (C5), 45.0 (C3), 39.7 (C4), 30.5. Compound 2b:
[α]2D0=−21 (c 1, CHCl3); (ee=71%); H NMR (CDCl3, 250 MHz): δ=7.45–7.15 (m, 6H), 7.00–6.68 (m, 2H), 5.58–5.38
1
(m, 1H), 5.07–4.88 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.67 (m, 2Hbenzyl), 2.79 [AB system, ∆νAB=59.2 Hz, JAB=9.2 Hz,
2H), 2.98–2.36 (m, 2H)], 2.59–2.50 (m, 2H), 2.21–2.02 (m, 2H); 13C NMR (CDCl3, 62.86 MHz): δ=[12 arom C: 148.3,
146.8, 140.7, 139.6, 128.3 (2C), 128.0 (2C), 126.6, 118.5, 110.4, 110.35], 135.4 (CH_), 117.0 (CH2_), 64.2, 60.2 (C2),
55.7 (2C), 53.5 (C5), 48.8 (C3), 47.2, 37.3 (C4). Compound 2c: [α]2D0=−40 (c 1, CHCl3); (ee=86%); 1H NMR (CDCl3, 200
MHz): δ=7.42–7.15 (m, 6H), 6.85–6.68 (m, 3H), 5.60–5.35 (m, 1H), 5.05–4.87 (m, 2H), 3.80 (s, 3H), 3.67 [AB system,
∆νAB=21.1 Hz, 3.72 (A part, d, JAB=12.6 Hz, 1Hbenzyl), 3.62 (B part, d, JAB=12.6 Hz, 1Hbenzyl)], 3.04–2.87 (m, 1H), 2.81
[A0B0 system, ∆νA B =60.2 Hz, 2.96 (d, JA B =9.0 Hz, 1H), 2.65 (d, JA B =9.0 Hz, 1H)], 2.63–2.45 (m, 1H), 2.55 (br d,
J=8.0 Hz, 2Hallyl), 2.24–1.98 (m, 2H); 13C NMR (CDCl3, 52.29 MHz): δ=[12 arom C: 159.3, 149.8, 139.6, 128.8, 128.5
(2C), 128.2 (2C), 126.8, 119.3, 113.2, 110.4], 135.4 (d), 117.1 (t), 64.0, 60.4 (C2), 55.1, 53.4 (C5), 49.4 (C3), 47.3, 36.9
(C4); HRMS calcd for C21H25N1O1: 307.1936. Found: 307.1927.
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