Stereoselective synthesis of chiral 3,4,5-trisubstituted 1,5- dihydropyrrol-2-ones from azadienes

Article abstract of DOI:10.1016/S0957-4166(99)00130-5

A new access to enantiopure 3-phthalimido-4-amino-5-(1-hydroxyalkyl) 1,5-dihydropyrrol-2-ones has been developed from 1,3-azadienes. Stereoselective Lewis acid catalyzed addition of a cyano group to an azadiene, followed by intramolecular ring closure, in a four-step one-pot synthesis, results in the formation of γ-lactams in satisfactory yields.

Full text of DOI:10.1016/S0957-4166(99)00130-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1445–1449
Stereoselective synthesis of chiral 3,4,5-trisubstituted
1,5-dihydropyrrol-2-ones from azadienes
Elisa Bandini,a Giorgio Martelli,a Giuseppe Spunta,a Alessandro Bongini,b,∗
Mauro Panunzio b,∗ and Giovanni Piersanti b
aI.Co.C.E.A.-C.N.R. Via Gobetti 101, 40129 Bologna, Italy
bCSFM-CNR and University Dipartimento di Chimica ‘G. Ciamician’ Via Selmi 2, 40126 Bologna, Italy
Received 20 March 1999; accepted 5 April 1999
Abstract
A new access to enantiopure 3-phthalimido-4-amino-5-(1-hydroxyalkyl) 1,5-dihydropyrrol-2-ones has been
developed from 1,3-azadienes. Stereoselective Lewis acid catalyzed addition of a cyano group to an azadiene,
followed by intramolecular ring closure, in a four-step one-pot synthesis, results in the formation of γ-lactams in
satisfactory yields. © 1999 Elsevier Science Ltd. All rights reserved.
The γ-lactam skeleton is commonly found in molecules of great value in medicinal chemistry such
as psychotropic agents,1,2 tetramic acid antibiotics,3–5 and muscarinic acid antagonists.6,7 Furthermore,
numerous chiral non-racemic substituted pyrrolidines and pyrrolidinones are used as intermediates, chiral
ligands or auxiliaries in asymmetric synthesis.8–11 The development of new methods for the preparation
of enantiomerically pure, highly substituted pyrrolidinones is of great interest.12
Recently, in our laboratory we have developed the synthesis of a new class of stable and highly
functionalized azadienes starting from N-trialkylylsilyl imines.13 Such compounds have been cyclized
under reflux to give four-membered β-lactam rings,14–17 or reacted with dienophilic aldehydes to
give the corresponding six-membered perhydrooxazinones18–20 which are useful starting materials for
the synthesis of α-amino-β-hydroxy-acids. In conjunction with a programme aimed at the de novo
asymmetric synthesis of antibiotics, including β-lactam antibiotics and polyoxamic acids, we chose
tetramic acid and its analogues as suitable synthetic targets.
We wish to report our preliminary results on the synthesis of 1,5-dihydropyrrol-2-ones, which are
key compounds for the preparation of tetramic acid analogues, using our homochiral-glycine-derived
azadienes according to Scheme 1. The azadiene 4 was prepared from the corresponding aldehyde in
almost quantitative yield (as judged by 1H and 13C NMR) according to the reported procedure.14 The next
step was the introduction of a cyano group and subsequent ring closure to obtain the pyrrolidinone ring.
After testing a number of Lewis acids [BF3Et2O, Sc(OTf)3, ZnCl2] under different reaction conditions,
∗
Corresponding author. E-mail: panunzio@ciam.unibo.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00130-5

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E. Bandini et al. / Tetrahedron: Asymmetry 10 (1999) 1445–1449
Scheme 1. Reagents and conditions: (i) TMS-N(Li)-STBDM, heptane, 0°C; (ii) phthaloylglycine chloride 3, TEA; (iii) TMSCN,
TiCl4, 12 h; (iv) HCl 6 N, 12 h (80%)
we found that satisfactory yields of 10 and 11, and almost complete diastereoselectivity, were obtained
through the use of 2 equiv. of TiCl4 and 2 equiv. of TMSCN. No reaction occurred in the absence of the
Lewis acid. The use of 1 equiv. of TiCl4 resulted in an incomplete ring closure, since cyanoamides 14
and 15 were isolated from the reaction mixture after aqueous work-up (Scheme 2). The configurations
of the new stereogenic centres in 10 and 11 were established by 1H NMR analysis of the corresponding
0
1,5-dihydropyrrol-2-one hydrochlorides 12a and 13a (vide infra) on the basis of C5H–C5 H coupling
constants.
Scheme 2. Reagents and conditions: (i) TiCl4 (1 equiv.); (ii) TMSCN (1 equiv.); (iii) NH4Claq
1. Synthesis of pyrrolidinones as an example
1.1. Synthesis of azadiene 4a
n-Butyllithium (1 mmol, 0.4 ml of a 2.5 M solution in hexane) was added to a solution of N,N-
trimethylsilyl-tert-butyldimethylsilylamine (1 mmol, 0.20 g) in anhydrous heptane (3 ml) under an inert
atmosphere at 0°C. The mixture was allowed to react for 30 min, then triisopropylsilyloxy-lactaldehyde
(1 mmol, 0.23 g) was added at the same temperature. After 30 min, the reaction mixture was allowed
to reach r.t. and stirred for 1 h. TMSCl (1 mmol, 0.13 ml) was added at 0°C, followed, after 1 h at the
same temperature, by the addition of triethylamine (2 mmol, 0.27 ml) and acid chloride 3. A copious
precipitate occurred during 1 h at r.t. The mixture was filtered and the solvent evaporated at low pressure.
The NMR analysis of an aliquot of the crude mixture showed only the azadiene 4a.

E. Bandini et al. / Tetrahedron: Asymmetry 10 (1999) 1445–1449
1447
Table 1
Synthesis of 1,5-dihydropyrrol-2-ones 10 and 11
1.2. Synthesis of pyrrolidin-2-ones 10a and 11a
A solution of 4a, obtained as above in DCM (10 ml), was cooled to −78°C and TiCl4 (2 equiv., 0.22
ml) in DCM (10 ml) was slowly added, followed by TMSCN (2 mmol, 0.27 ml) in DCM (1 ml). The
reaction mixture was allowed to slowly warm to r.t. while stirring for 12 h. The mixture was poured
into a saturated solution of NH4Cl, extracted with DCM, the solvent removed and the residue flash-
chromatographed on silica gel to give 10a and 11a (in equilibrium with the enaminic forms 8a and 9a)
in yields and diastereomeric ratio reported in Table 1.
The high diastereoselectivity obtained with chelating Lewis acids such as TiCl4 can be ascribed to a
cyclic Cram-type transition state (Scheme 2) by analogy to the results obtained by Cainelli et al. on the
addition of the cyano group to N-trimethylsilyl imines.21 In this model the cyano group is forced to attack
from the side of the diastereotopic plane opposite to that of the alkyl group of the alkylsilyloxy side chain.
The configurations of the new stereogenic centres in 10a and 11a were established by 1H NMR analyses
on the the basis of the coupling constants of the derived deprotected dihydropyrrol-2-ones hydrochlorides
12a and 13a (Scheme 3).
Scheme 3.
A full AM1 conformational analysis23 shows that in both the compounds the system is best described
by the two conformations in which the lactic hydroxide is close to the ammonium group. This is due to a
strong electrostatic interaction between the positively charged ammonium group and the hydroxyl group
and also to a weak H-bond (2.1 Å) between the acid protons of the ammonium group and the hydroxyl
oxygen. The coupling constant of the (R,S)-diastereomer 13a, in which the preferred conformation has
the two hydrogens in an anti relationship, is expected to be greater than that of the (S,S)-isomer 12a in

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E. Bandini et al. / Tetrahedron: Asymmetry 10 (1999) 1445–1449
which the two hydrogens are in two gauche relationships. The experimentally observed J values for the
two compounds are 3.5 Hz for 12a and 4.8 Hz for 13a, which allows the assignment of the configurations
as S and R, respectively. By analogy stereochemical assignments for compounds 10b, 10c, 10d and 10e
were deduced.
In conclusion, the facile conversion of azadienes 4 into the cyano derivatives, and subsequently
into the pyrrolidinones, provides a particularly flexible asymmetric synthesis of highly functionalized
pyrrolidinone intermediates and may be extended to other targets.
Acknowledgements
This work was partially supported by ‘Progetto Strategico sulle applicazioni delle Micronde-CNR-
Rome’. Thanks are due to MURST, Cofin ’98 (Roma) for financial support and to Dr. Gordon Kennedy
of Exploratory Chemistry, GlaxoWellcome, Verona, Italy for fruitful discussions.
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12. Baussanne, I.; Royer, J. Tetrahedron Lett. 1998, 39, 845 and references cited therein.
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16. Bacchi, S.; Bongini, A.; Panunzio, M.; Marzia, V. Synlett 1998, 843.
17. Martelli, G.; Spunta, G.; Panunzio, M. Tetrahedron Lett. 1998, 39, 6257.
18. Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio, M.; Piersanti, G. Tetrahedron: Asymmetry 1997, 8, 3717.
19. Bongini, A.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. J. Org. Chem. 1997, 62, 8911.
20. Panunzio, M.; Villa, M.; Missio, A.; Seneci, P. Tetrahedron Lett. 1998, 39, 6585.
21. Cainelli, G.; Giacomini, D.; Treré, A.; Galletti, P. Tetrahedron: Asymmetry 1995, 6, 1593.
22. All the products described gave spectroscopic data consistent with the assigned structures. Data for selected compounds
follow: 4a: [α]D20=−28.4 (c 1.16, CH2Cl2); H NMR (200 MHz, CDCl3) 8.00 (d, 1H, J=4.40), 7.86 (m, 2H), 7.72 (m,
1
2H), 5.50 (s, 1H), 4.48 (dq, 1H, J=4.40, 6.40), 1.35 (d, 3H, J=6.40), 1.05 (s, 21H), 0.78 (s, 9H), 0.04 (s, 6H); 13C NMR
(50 MHz, CDCl3) 168.1, 166.9, 156.8, 133.9, 132.3, 122.2, 90.4, 70.4, 25.5, 21.7, 17.7, 12.3, −4.1; 10a: mp 86–88°C;
[α]D20=−42.0 (c 0.55, CHCl3); IR (CHCl3) 3490, 3448, 3383, 1723, 1665; H NMR (200 MHz, CDCl3) 7.90–7.70 (m,
1
4H), 6.05 (s, 1H), 5.21 (s, 2H), 4.30 (m, 2H), 1.25 (d, 3H, J=6.04), 1.08 (s, 21H); 13C NMR (50 MHz, CDCl3) 170.90,
166.60, 159.10, 134.10, 132.30, 123.50, 95.40, 69.50, 59.80, 18.00, 16.00, 12.04; MS m/z 400 (M+−43), 356, 243; 11a:
mp 89–91°C; [α]D20=−6.6 (c 0.61, CHCl3); IR (CHCl3) 3490, 3448, 3383, 1723, 1665; H NMR (200 MHz, CDCl3)
1
7.90–7.70 m, 4H), 5.08 (s, 1H), 4.77 (s, 2H), 4.22 (m, 2H), 1.26 (d, 3H, J=5.80), 1.08 (s, 21H); 13C NMR (50 MHz,
CDCl3) 170.84, 166.75, 158.01, 133.99, 132.19, 123.42, 95.44, 69.83, 60.49, 18.02, 17.95, 17.32, 12.40; MS m/z 400
(M+−43), 356, 243; 10b: mp 247°C; [α]D20=−97.7 (c 1.08, CHCl3); IR (CHCl3) 3491, 3450, 3386, 1720, 1663; 1H NMR
(200 MHz, CDCl3) 7.85–7.65 (m, 4H), 6.25 (s, 1H), 5.21 (s, 2H), 4.40 (d, 1H, J=4.64), 4.04 (m, 1H), 2.03 (m, 1H), 1.10

E. Bandini et al. / Tetrahedron: Asymmetry 10 (1999) 1445–1449
1449
(m, 27H); 13C NMR (50 MHz, CDCl3) 170.30, 166.74, 159.72, 134.02, 132.35, 123.46, 96.26, 77.84, 58.76, 30.39, 20.74,
18.67, 18.22, 18.18, 12.71; MS m/z 428 (M+−43), 386, 357, 300; (ꢀ)-10c: mp 246–248°C; IR (CHCl3) 3492, 3460, 3389,
1
1724, 1666; H NMR (CDCl3−CD3OD) 7.75–7.55 (m, 4H), 4.22 (d, 1H, J=2.94), 3.63 (d, 1H, J=2.94), 0.88 (s, 9H),
0.79 (s, 9H), 0.01 (s, 3H), −0.03 (s, 3H); 13C NMR (50 MHz, CDCl3) 171.39, 161.12, 161.05, 133.88, 132.00, 123.10,
94.10, 78.41, 57.69, 36.58, 26.81, 25.68, 17.86, −4.50, −4.95; MS m/z 443 (M+), 386 (M+−57), 357, 300; (ꢀ)-10d: mp
1
258–260°C; IR (CHCl3) 3489, 3452, 3386, 1723, 1664; H NMR (200 MHz, CDCl3) 7.85–7.65 (m, 4H), 5.40 (s, 1H),
4.22 (d, 1H, J=4.38), 3.75 (t, 1H, J=4.38), 3.25 (m, 2H), 1.82 (m, 1H), 1.60 (m, 5H), 1.12 (m, 5H), 0.86 (s, 9H), 0.09
(s, 3H), 0.06 (s, 3H); 13C NMR (50 MHz, CDCl3) 171.29, 167.13, 160.80, 134.02, 132.17, 123.35, 94.84, 76.73, 58.70,
39.48, 31.38, 28.68, 26.32, 26.15, 26.07, 25.73, 17.88, −4.72, −4.93; MS m/z 454 (M+−15), 4.12 (M+−57), 357, 337, 300;
10e: mp 235–237°C; [α]D20=−17.0 (c 0.5, CH2Cl2); IR (CHCl3) 3493, 3452, 3390, 1720, 1666; H NMR (200 MHz,
1
CDCl3) 7.70 (m, 4H), 7.40–7.25 (m, 5H), 6.40 (s, 1H), 5.03 (m, 3H), 4.50 (d, 1H, J=5.12), 1.02 (s, 21H), 0.95 (d, 3H,
J=5.86); 13C NMR (50 MHz, CDCl3) 169.90, 165.82, 157.28, 137.50, 133.94, 132.18, 128.49, 128.00, 127.46, 123.39,
96.77, 76.62, 59.92, 17.92, 17.78, 12.05; MS m/z 505 (M+), 462 (M+−43), 399, 356, 330, 284, 263; 12a: [α]D20=+19.7 (c
1.12, CH3OH); IR (Nujol) 3556, 3372, 3158, 1703, 1650. 1H NMR (400 MHz, CD3OD) 7.94–7.85 (m, 4H), 4.38 (d, 1H,
J=3.60), 4.22 (dq, 1H, J=3.60, 6.00), 1.29 (d, 3H, J=6.00); 13C NMR (100 MHz, CD3OD) 171.80, 168.61, 167.54, 134.45,
133.52, 124.25, 90.93, 67.85, 62.71, 17.89; MS m/z 323 (M+), 287, 269, 244, 243; 13a: [α]D20=+12.90 (c 0.85, CH3OH);
1H NMR (400 MHz, CD3OD) 7.95 (m, 4H), 4.32 (d, 1H, J=4.88), 4.11 (dq, 1H, J=4.88, 6.36), 1.23 (d, 3H, J=6.36); 13
NMR (100 MHz, CD3OD) 171.5, 168.94, 168.23, 135.31, 133.25, 124.19, 89.06, 68.79, 64.01, 16.80.
23. HyperChem Rel 4.5 from Hypercube, Inc. Waterloo, Ontario, Canada.
C