alumina to give a single diastereomer 2a (Scheme 1). The
relative stereochemistry of the four stereocenters formed in
this reaction was determined by an X-ray crystallography
study of amine 2a. The hydrobromide complex of 2a was
available via treatment of 2a with benzyl bromide in
refluxing ethanol,11 and the crystal structure is shown in
Figure 1. Since highly substituted pyrrolidines are valuable
unstable pyrrole 4,15 which was immediately treated with
ethyl or methyl oxalyl chloride to give R-ketoester 1a in 71%
yield.16
Different catalysts and reaction conditions were screened
based on literature procedures (Table 1). Hydrogenation of
Table 1. Catalyst Screening
Figure 1. ORTEP drawing of the hydrobromide complex of 2a.
products
%
building blocks for the synthesis of chiral ligands, drugs,
and other bioactive molecule,12 further examination of this
potentially general diastereoselective reduction of pyrroles
was conducted.13
Bicyclic pyrrole 1a was synthesized from pipecolic acid
methyl ester in a three-step sequence (Scheme 2). Treatment
entry
1
conditions
(ratio)a yield references
H2 (10 atm), Pt/Al2O3,
EtOH, 12 h
H2 (3.7 atm), Rh/Al2O3,
HOAc/MeOH, 16 h
H2 (20 atm), Rh/Al2O3,
TFA, 24 h
H2 (1 atm), Pd/C,
MeOH, 12 h
H2 (3.7 atm), Pd/C,
HOAc, 16 h
5a:2a
(2:1)
94
90
84
88
2
3
4
5
6
7
6a:2a
(1:10)
6a:2a
(1:6.7)
6a:2a
(1:3.3)
b
6b, 5c,d
4
6a,b, 17
5d-f, 6b
9
Scheme 2. Synthesis of Pyrrole 1a
H2 (10 atm), Rh/C,
EtOH, 24 h
H2 (10 or 1 atm), Rh/Al2O3,
MeOH, 2 h
2a
2a
87
92 2, 6a,b, 8, 10
a Ratio was determined by 1H NMR of crude mixture. b Only decomposi-
tion products were observed.
1a gave varying ratios of undesired products 5a and 6a along
with the desired pyrrolidines 2a. It was found that Pt/Al2O3
reduced only the ketone to give primarily 5a, along with
both diastereomers of 2a (entry 1). The major product of
of the ester with methoxycarbonylmethylene (triphenyl)
phosphorane in refluxing toluene gave tetronic acid derivative
3 in 80% yield.14 Reduction of 3 with DIBAL-H gave
(13) For a selection of recently reported methods for the stereoselective
synthesis of pyrrolidines, see: (a) Reference 12. (b) Enders, D.; Thiebes,
C. Pure Appl. Chem. 2001, 73, 573-578. (c) Vasse, J. L.; Joosten, A.;
Denhez, C.; Szymoniak, J. Org. Lett. 2005, 7, 4887-4889. (d) Gebauer,
J.; Dewi, P.; Blechert, S. Tetrahedron Lett. 2005, 46, 43-46. (e) Young, I.
S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953-955. (f) Galliford,
C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A. Org. Lett. 2003, 5,
3487-3490. (g) Coldham, I.; Hufton, R.; Price, K. N.; Rathmell, R. E.;
Snowden, D. J.; Vennall, G. P. Synthesis 2001, 1523-1531. (h) Schlummer,
B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471-1474. (i) Besev, M.; Engman,
L. Org. Lett. 2002, 4, 3023-3025.
(14) (a) Schobert, R.; Muller, S.; Bestmann, H.-J. Synlett 1995, 425-
426. (b) Lo¨ffler, J.; Schobert, R. J. Chem. Soc., Perkin Trans. 1 1996, 2799-
2802.
(15) Kochhar, K. S.; Pinnick, H. W. J. Org. Chem. 1984, 49, 3222-
3224.
(6) (a) Bond, T. J.; Jenkins, R.; Ridley, A. C.; Taylor, P. C. J. Chem.
Soc., Perkin Trans. 1 1993, 2241-2242. (b) Bond, T. J.; Jenkins, R.; Taylor,
P. C. Tetrahedron Lett. 1994, 35, 9263-9266.
(7) Angle, S. R.; Boyce, J. P. Tetrahedron Lett. 1995, 36, 6185-6188.
(8) Artis, D. R.; Cho, I.-S.; Jaime-Figueroa, S.; Muchowski, J. M. J.
Org. Chem. 1994, 59, 2456-2466.
(9) Castano, A. M.; Cuerva, J. M.; Echavarren, A. M. Tetrahedron Lett.
1994, 35, 7435-7438.
(10) Mori, M.; Hori, M.; Sato, Y. J. Org. Chem. 1998, 63, 4832-4833.
(11) Kantor, S. W.; Hauser, C. K. J. Am. Chem. Soc. 1951, 73, 4122-
4131.
(12) For a comprehensive discussion of the importance of pyrrolidines
and strategies for their synthesis, see: Schomaker, J. M.; Bhattacharjee,
S.; Yan, J.; Borhan, B. J. Am. Chem. Soc. 2007, 129, 1996-2003.
(16) Harrison, C.-A.; Jackson, P. M.; Moody, C. J.; Williams, J. M. J. J.
Chem. Soc., Perkin Trans. 1 1995, 1131-1136.
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