Synthesis of cis-2-aryl-3-pyrrolidine carboxylic esters via diastereoselective cyclization of γ-imino esters using a TiCl 4/Et3N reagent system

Article abstract of DOI:10.1016/j.tetlet.2004.06.080

Facile synthesis of cis-2-aryl-3-pyrrolidine carboxylates from readily accessible γ-imino esters by intramolecular cyclization mediated by a TiCl₄/Et₃N reagent system is described.

Full text of DOI:10.1016/j.tetlet.2004.06.080

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6291–6293
Synthesis of cis-2-aryl-3-pyrrolidine carboxylic esters via
diastereoselective cyclization of c-imino esters using a
TiCl /Et N reagent system
4
3
Surisetti Suresh and Mariappan Periasamy*
School of Chemistry, University of Hyderabad, Central University PO, Gachibowli, Hyderabad 500 046, India
Received 22 April 2004; revised 5 June 2004; accepted 21 June 2004
Abstract—Facile synthesis of cis-2-aryl-3-pyrrolidine carboxylates from readily accessible c-imino esters by intramolecular cycliza-
tion mediated by a TiCl /Et N reagent system is described.
ꢀ
4
3
2004 Elsevier Ltd. All rights reserved.
Pyrrolidines are an important class of structural motifs
1
reaction of the c-imino esters, which are readily accessi-
ble from the c-aminobutyric esters. We found that the
imino ester 1a reacted with TiCl /Et N to give 2a
present in many biologically active compounds. For
2
instance, several drug candidates displaying anticancer,
6
4
3
3
4
5
13
antibacterial, anti-HIV, antiviral, antifungal, and
7
(Scheme 1).
analgesic activities contain the pyrrolidine ring system,
8
as do several biologically important alkaloids and amino
9
Interestingly, only one stereoisomer was formed in the
1
13
acids. Further, many chiral ligands containing the
pyrrolidine ring system are useful in asymmetric synthe-
reaction. Comparison of the H NMR and C NMR
spectral data of the product 2a with the previously re-
ported data for 2a indicated that the phenyl and ester
1
0
sis. Hence, there has been continuing interest in the
development of new methods for the construction of
1
4
groupings are cis.
1
1
the pyrrolidine ring system. We wish to report a novel
and facile synthesis of cis-2,3-disubstituted pyrrolidines
by the intramolecular cyclization of c-imino esters medi-
ated by TiCl /Et N.
The structural assignment was further confirmed by a
single crystal X-ray analysis of the oxalic acid salt of
1
5
the amino ester 2a (Fig. 1).
4
3
During the course of investigations on the synthetic util-
1
We have examined this transformation with various
imino esters prepared using substituted aromatic
2
ity of the TiCl /Et N reagent system, we examined the
3
4
1
. SOCl /MeOH/reflux, 8 h
2
R
N
COOMe
H N
2
COOH
2
. RCHO, Et N, CH Cl , MS 4Å, rt, 48 h
3 2 2
1
a-g
COOMe
R
TiCl /Et N
4
3
R
N
COOMe
CH Cl 0 oC-rt, 3 h
2
2,
N
1
a-g
H
2
a-g
Scheme 1. Intramolecular coupling of c-imino esters mediated by the TiCl
Keywords: Imino esters; Intramolecular cyclization; Pyrrolidines.
4 3
/Et N reagent system.
*
Corresponding author. Tel.: +91-40-2313-0500-4814; fax: +91-40-2301-2460; e-mail: mpsc@uohyd.ernet.in
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.080

6292
S. Suresh, M. Periasamy / Tetrahedron Letters 45 (2004) 6291–6293
1
8
dines, the selective formation of cis-2,3-disubstituted
1
9
pyrrolidines is not common. Accordingly, the method
described here for the highly diastereoselective synthesis
of cis-2,3-disubstituted pyrrolidine derivatives has good
synthetic potential.
Acknowledgements
We thank the DST for financial support. S.S. thanks the
UGC and CSIR for a fellowship. We are also grateful to
the UGC for support under the ÔUniversity with Poten-
tial for ExcellenceÕ program.
Figure 1. ORTEP representation of the crystal structure of the
hydrated complex of 2a with oxalic acid (thermal ellipsoids are drawn
at 25% probability).
Table 1. Reaction of c-imino esters 1 with TiCl
disubstituted pyrrolidines 2
4
/Et
3
N to give cis-2,3-
References and notes
b
Entry
R
Substrate
Product
Yield
of 2 (%)
1
. (a) Shao, Z.; Chen, J.; Tu, Y.; Li, L.; Zhang, H. Chem.
Commun. 2003, 1918–1919; (b) Lewis, J. R. Nat. Prod.
Rep. 2001, 18, 95–128; (c) OÕHagen, D. Nat. Prod. Rep.
2000, 17, 435–446.
2. Inad, A.; Nishino, H.; Kuchide, M.; Takayasu, J.;
Mukainaka, T.; Nobukuni, Y.; Okuda, M.; Tokuda, H.
Biol. Pharm. Bull. 2001, 24, 1282–1285.
3. Hong, C. Y.; Kim, Y. K.; Chang, J. H.; Kim, S.-H.; Choi,
H.; Nam, D. H.; Kim, Y. Z.; Kwak, J. H. J. Med. Chem.
1997, 40, 3584–3593.
. Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.;
Finke, P. E.; Caldwell, C. G.; Mills, S. G.; MacCoss, M.;
Shen, D. M.; Chapman, K. T.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.;
Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.;
Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Emini, E. Org. Lett. 2003, 5,
a
5
a
2a
1
2
3
4
5
6
7
C
6
H
1a
1b
1c
1d
1e
1f
75
64
76
71
69
66
32
p-H
p-H
3
CC
6
H
4
2b
2c
2d
2e
2f
3
COC
6
H
4
p-ClC
p-O NC
1-Naphthyl
(CH CH
6
H
4
2
6 4
H
3
)
2
1g
2g
a
1
13
Compound 2a was confirmed by spectral data (IR, H NMR,
NMR) and X-ray analysis and by comparison with reported data.
C
1
4
4
Compounds 2b–g were identified by the comparison of their spectral
data with 2a.
Yields are for isolated products.
b
aldehydes. The products were obtained in 64–76% yields
Table 1). The product obtained using the imino ester
prepared from iso-butyraldehyde was formed only in
(
2
473–2475.
5
6
. Gaudernak, E.; Seipelt, J.; Triendl, A.; Grassauer, A.;
Kuechler, E. J. Virol. 2002, 76, 6004–6015.
. Raj, A. A.; Raghunathan, R.; SrideviKumari, M. R.;
Raman, N. Bioorg. Med. Chem. 2003, 11, 407–419.
7. Chang, A.-C.; Cowan, A.; Takemori, A. E.; Portoghese,
1
poor yield (32%). Comparison of the H NMR spectral
data obtained for the substituted derivatives 2b–g with
those obtained for 2a indicated that 2b–g all had the
cis stereochemistry.
P. S. J. Med. Chem. 1996, 39, 4478–4482.
. (a) Burgers, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57,
656–1662; (b) Daly, J. W.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1986; Vol. 4, Chapter 1.
. Silverman, R. B.; Nanavati, S. J. Med. Chem. 1990, 33,
8
The high level of stereoselectivity observed in this trans-
formation can be tentatively explained by postulating
the formation of a pseudo six-membered chair-like tran-
sition state A (Fig. 2), assuming that the geometry of the
1
9
1
6
titanium enolate is Z and that the imine has an E con-
9
31–936.
1
7
figuration. The chelated six-membered titanocycle A
would then undergo ring closure leading to the 2,3-cis
configuration in the newly constructed pyrrolidine ring
1
1
0. (a) Kagan, H. B. In Asymmetric Synthesis; Morrison, J.
D., Ed.; Academic: New York, 1975; Vol. 5, Chapter 1; (b)
Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.;
Oalmann, C. J.; Muller, P. J. Am. Chem. Soc. 1991, 113,
(
Fig. 2).
1
423–1424, and references cited therein.
1. (a) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S.
J. Chem. Soc., Perkin Trans. 1, 2002, 2747–2762, (con-
temporary review) and other reviews on ÔSynthesis of
heterocycles by radical cyclizationÕ cited therein; (b)
Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996,
Though several methods have been reported for the
selective synthesis of trans-2,3-disubstituted pyrroli-
7
, 927–964.
L
n
Ti
12. (a) Periasamy, M.; Srinivas, G.; Karunakar, G. V.;
Bharathi, P. Tetrahedron Lett. 1999, 40, 7577–7580; (b)
Periasamy, M.; Srinivas, G.; Suresh, S. Tetrahedron Lett.
2001, 42, 7123–7125; (c) Periasamy, M.; Srinivas, G.;
Bharathi, P. J. Org. Chem. 1999, 64, 4204–4205; (d)
Periasamy, M. Unpublished results; (e) Periasamy, M.;
Srinivas, G. Tetrahedron Lett. 2002, 43, 2785–2788.
O
COOMe
R
OMe
N
R
N
H
H
A
1
3. General experimental procedure: To the imino ester
(5mmol), and triethylamine (5mmol) in dichloromethane
Figure 2. Proposed pathway for the cis diastereoselectivity.

S. Suresh, M. Periasamy / Tetrahedron Letters 45 (2004) 6291–6293
6293
(
CH Cl ) in CH
40mL), TiCl
4
(10mmol, 2.2mL of a 1:1 solution of TiCl
Cl
4
/
122.9, 123.1, 125.1, 125.3, 125.9, 127.7, 128.7, 131.4, 133.5,
135.2, 174.2. 2g: IR (Neat): 2964, 1726 cm ; MS (EI) m/z:
À1
2
2
2
2
(15mL) was added dropwise at 0ꢁC
under N over 15min. The reaction mixture was stirred at
1
171; H NMR (200 MHz, CDCl ): 0.80–1.32 (m, 6H),
2
3
room temperature for 3h, then quenched with saturated
aq K CO (15mL) and filtered through a B u¨ chner funnel.
2 3
1.37–1.51 (m, 1H), 1.76–2.01 (m, 2H), 2.10–2.22 (m, 1H),
2.27–2.43 (m, 1H), 3.27–3.48 (m, 2H), 3.68 (s, 3H), 3.92 (s,
1
3
The organic layer was separated and the aqueous layer
was extracted with CH Cl (2·25mL). The combined
organic extract was washed with brine (15mL), dried over
br, NH); C NMR (50 MHz, CDCl
30.9, 46.1, 46.3, 51.1, 71.7, 175.7.
3
): 20.9, 21.6, 30.1,
2
2
14. Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35,
593–601.
anhydrous Na
residue was purified by chromatography on a silica gel
column using CHCl /MeOH (99.5/0.5) as eluent.
Spectral data for products 2a–2g: 2a: IR (Neat): 3342,
2 4
SO , filtered, and concentrated. The crude
15. Methyl 2-phenyl-3-pyrrolidine carboxylate 2a (5mmol)
and oxalic acid dihydrate (5mmol) were dissolved in dry
acetone (10mL), and the solution stirred for 6h. The
precipitate was filtered off and crystallized from methanol.
Crystal Data: Complex of the amine 2a and oxalic acid
3
À1
1
3
MHz, CDCl ): 2.07–2.22 (m, 2H), 2.26 (br, NH), 2.96–
028, 2949, 1732 cm ; MS (EI) m/z: 205; H NMR (200
3
3
Hz, 1H), 7.23–7.27 (m, 5H); C NMR (50 MHz, CDCl
.12 (m, 2H), 3.21 (s, 3H), 3.27–3.43 (m, 1H), 4.36 (d, J=8
28 36 2
C H N O13, MW=608.58, monoclinic, space group:
1
3
˚ ˚ ˚
3
3
):
P21, a=5.7341(9)A, b=30.789(5)A, c=8.577(2)A,
˚
À3
=1.393mgm ,
l=0.111mm , T=298K. Of the 3410 reflections col-
lected, 3391 were unique (Rint =0.0000). Refinement on all
2
1
9.6, 46.6, 49.6, 50.9, 66.3, 126.7, 127.2, 128.0, 139.6,
74.3. 2b: IR (Neat): 3348, 3055, 2954, 1720 cm ; MS
b=106.63(2)ꢁ, V=1450.9(5)A , Z=4, q
c
À1
À1
1
(
EI) m/z: 219; H NMR (200 MHz, CDCl
3
): 2.11 (br, NH),
2
3
.18–2.26 (m, 2H), 2.31 (s, 3H), 2.94–3.07 (m, 2H), 3.25 (s,
H), 3.36–3.46 (m, 1H), 4.33 (d, J=8 Hz, 1H), 7.07–7.27
data converged at R
number CCDC 236003).
1 2
=0.0384, wR =0.0883. (Deposition
1
3
(
m, 4H); C NMR (50 MHz, CDCl ): 21.0, 29.6, 46.5,
3
16. (a) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118,
2527–2528; (b) Lorthiois, E.; Marek, I.; Normant, J. F.
J. Org. Chem. 1998, 63, 2442–2450; (c) van der Steen, F.
H.; Kleijn, H.; Britovsek, G. J. P.; Jastrzebski, J. T. B. H.;
van Koten, G. J. Org. Chem. 1992, 57, 3906–3916; (d)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.
J. Org. Chem. 1992, 57, 4155–4162.
4
3
9.5, 50.9, 60.0, 126.5, 128.6, 136.5, 174.2. 2c: IR (Neat):
338, 2950, 1732 cm ; MS (EI) m/z: 235; H NMR (200
À1
1
MHz, CDCl ): 2.06–2.26 (m, 2H), 2.93–3.07 (m, 2H), 3.19
3
(
br, NH), 3.26 (s, 3H), 3.38–3.47 (m, 1H), 3.78 (s, 3H),
.32 (d, J=8 Hz, 1H), 6.83 (d, J=10 Hz, 2H), 7.20 (d,
4
J=10 Hz, 2H); C NMR (50 MHz, CDCl
1
3
3
): 29.5, 46.4,
4
7.5, 51.1, 55.1, 66.7, 113.4, 127.5, 131.4, 158.7, 174.4. 2d:
17. (a) McCarty, C. G. In Chemistry of the Carbon–Nitrogen
Double Bond; Patai, S., Ed.; Wiley: New York, 1970; pp
364–372; (b) Curtin, D. Y.; Grubbs, E. J.; McCarty, C. G.
J. Am. Chem. Soc. 1966, 88, 2775–2786.
18. (a) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett.
2002, 4, 3147–3150; (b) Boto, A.; Hern a´ ndez, R.; de Le o´ n,
Y.; Su a´ rez, E. J. Org. Chem. 2001, 66, 7796–7803; (c) Kim,
Y.-A.; Oh, S.-M.; Han, S.-Y. Bull. Korean Chem. Soc.
2001, 22, 327–329; (d) Boto, A.; Hern a´ ndez, R.; de Le o´ n,
Y.; Su a´ rez, E. Tetrahedron Lett. 2000, 41, 2495–2498; (e)
Meyers, A. I.; Snyder, L. J. Org. Chem. 1992, 57,
3814–3819; (f) Carretero, J. C.; Array a´ s, R. G.; de Gracia,
I. S. Tetrahedron Lett. 1996, 37, 3379–3382.
À1
1
IR (Neat): 3332, 2954, 1730 cm ; MS (EI) m/z: 239; H
NMR (200 MHz, CDCl ): 1.94–2.00 (m, 2H), 2.08–2.22
m, 2H), 3.26 (s, 3H), 3.32 (br, NH), 3.36–3.46 (m, 1H),
3
(
1
3
4.34 (d, J=8 Hz, 1H), 7.20–7.30 (m, 4H); C NMR (50
MHz, CDCl
3
): 29.5, 46.5, 49.4, 51.1, 65.4, 128.1, 132.8,
À1
1
38.4, 174.0. 2e: IR (Neat): 3419, 2956, 1742 cm ; MS
1
(
EI) m/z: 250; H NMR (200 MHz, CDCl ): 1.89 (br, NH),
3
2
3
2
2
1
.09–2.31 (m, 2H), 3.02–3.25 (m, 1H), 3.27 (s, 3H), 3.34–
.52 (m, 2H), 4.49 (d, J=8 Hz, 1H), 7.50 (d, J=10 Hz,
H), 8.17 (d, J=10 Hz, 2H); C NMR (50 MHz, CDCl ):
3
9.4, 46.5, 49.4, 51.1, 65.1, 123.0, 127.8, 147.1, 148.1,
73.3. 2f: IR (Neat): 3336, 3049, 2947, 1732 cm ; MS (EI)
1
3
À1
1
m/z: 255; H NMR (200 MHz, CDCl
3
): 1.88 (br, NH),
19. (a) Pal, K.; Behnke, M. L.; Tong, L. Tetrahedron Lett.
1993, 34, 6205–6208; (b) Havairi, G.; C e´ l e´ rier, J. P.; Petit,
H.; Lhommet, G.; Gardette, D.; Gramain, J. C. Tetrahe-
dron Lett. 1992, 30, 4311–4312.
2
3
.23–2.34 (m, 2H), 2.87 (s, 3H), 3.08–3.14 (m, 1H), 3.48–
.57 (m, 2H), 5.08 (d, J=8 Hz, 1H), 7.27–8.06 (m, 7H);
1
3
3
C NMR (50 MHz, CDCl ): 29.7, 46.3, 48.9, 50.7, 62.6,