Stereoselective synthesis of pyrrolidine derivatives via reduction of substituted pyrroles

Article abstract of DOI:10.1021/ol701962w

The heterogeneous catalytic hydrogenation of highly substituted pyrrole systems was studied. These aromatic systems could be fully reduced with excellent diastereoselectivfty to afford functionalized pyrrolidines with up to four new stereocenters. It is likely that the reaction is a two-step hydrogenation sequence, and that initial reduction of the C=X bond provides a stereocenter that directs the subsequent reduction of the pyrrole.

Full text of DOI:10.1021/ol701962w

ORGANIC
LETTERS
2007
Vol. 9, No. 24
4939-4942
Stereoselective Synthesis of Pyrrolidine
Derivatives via Reduction of Substituted
Pyrroles
Chao Jiang and Alison J. Frontier*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
frontier@chem.rochester.edu
Received August 10, 2007
ABSTRACT
The heterogeneous catalytic hydrogenation of highly substituted pyrrole systems was studied. These aromatic systems could be fully reduced
with excellent diastereoselectivity to afford functionalized pyrrolidines with up to four new stereocenters. It is likely that the reaction is a
two-step hydrogenation sequence, and that initial reduction of the C
of the pyrrole.
d
X bond provides a stereocenter that directs the subsequent reduction
Hydrogenative reduction of pyrroles to pyrrolidines using
heterogeneous catalyst systems is a well-known process,1 and
it has been shown that hydrogen is typically delivered from
just one face of the aromatic system. In this way, 2,5-
disubstituted pyrroles are converted into cis-2,5-dialkyl-
pyrrolidines.2-4 One might expect that pyrroles with sub-
stituents containing stereogenic centers might undergo
diastereoselective reduction, leading to a convenient method
for stereoselective synthesis of substituted pyrrolidines of
high complexity. A number of studies toward this goal have
been conducted, with varying degrees of success with respect
to diastereoselective pyrrole reduction.5-9 Jefford,5 Taylor6
and Angle7 have shown that, in bicyclic pyrroles, existing
stereocenters can exert a strong directing effect to allow
reduction to occur with high diastereoselectivity. However,
only one study was found describing hydrogenation of
pyrroles with a stereogenic centers on an acyclic chain. In
this report, one pyrrole was reduced with high diastereo-
selectivity, while reduction of a closely related structure was
unselective.10
Scheme 1. Diastereoselective Reduction of Pyrrole 1a
(1) Gribble, G. W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 603-634.
(2) Bates, H. A.; Rapoport, H. J. Am. Chem. Soc. 1979, 101, 1259-
1265.
(3) Kaiser, H.-P.; Muchowski, J. M. J. Org. Chem. 1984, 49, 4203-
4209.
(4) Gilchrist, T. L.; Lemos, A.; Ottaway, C. J. J. Chem. Soc., Perkin
Trans. 1 1997, 3005-3008.
During studies toward the synthesis of pyrrolidine-contain-
ing targets, our group found that hydrogenation of substituted
pyrrole 1a, with an R-ketoester substituent at the 2-position
(see Scheme 1), led to reduction of both the ketone and the
pyrrole ring with high diastereoselectivity. The hydrogenation
reaction of the pyrrole 1a was achieved with rhodium-on-
(5) (a) Jefford, C. W. Curr. Org. Chem. 2000, 4, 205-230. (b) Jefford,
C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991, 113, 3513-3518.
(c) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 3119-3122.
(d) Jefford, C. W.; Thornton, S. R.; Sienkiewicz, K. Tetrahedron Lett. 1994,
35, 3905-3908. (e) Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R.
Tetrahedron Lett. 1994, 35, 4759-4762. (f) Jefford, C. W.; Sienkiewicz,
K.; Thornton, S. R. HelV. Chim. Acta 1995, 78, 1511-1524.
10.1021/ol701962w CCC: $37.00
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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.
4940
Org. Lett., Vol. 9, No. 24, 2007

reduction using Rh/Al2O3 with HOAc or TFA was 2a, as a
mixture of two diastereomers, along with 6a (entries 2 and
3). Pd/C gave the same result in alcoholic solvents (entry
4). Reduction with Pd/C in acetic acid led to decomposition
(entry 5). Reduction with Rh/Al2O3 or Rh/C in alcohol gave
the best results, delivering a single diastereomer of 2a as
the only product with yields of 92 and 88% (entries 6 and
7). Rh/Al2O3-catalyzed reductions could also be carried out
under 1 atm of hydrogen pressure at room temperature: the
reaction was complete in 2 h and gave 2a with the same
yield and selectivity as the reductions under 10 atm of
hydrogen pressure.
hydrogenation reaction of indolizine 1e,18 with a TBSO group
at the 4-position, gave one diastereomer 2e (entry 5). The
hydrogenation reaction of pyrrole 1f, with a tertiary alcohol
substitution at the 2-position, gave 2f as a 9:1 ratio of two
diastereomers (entry 6).
Acyclic alkyl-substituted pyrroles were also studied under
the same conditions with rhodium-on-alumina (Table 3). The
Table 3. Stereoselective Reduction of Substituted Pyrrolesa
Bicyclic pyrrole substrates with different substitution
patterns were synthesized to study the scope of this hetero-
geneous catalytic reaction with rhodium-on-alumina (Table
2). The hydrogenation reaction of the pyrrole 1b, with a fused
Table 2. Stereoselective Reduction of Bicyclic Pyrrolesa
a Reaction conditions: 10 atm H2, 5% Rh/Al2O3 (w/w), room temper-
ature, MeOH or EtOH. b Stereochemistry of products in entries 1 and 2
was tentatively assigned based on structure determination of 2a.
hydrogenation of N-methyl pyrrole 1g, with a methoxy group
at the 3-position, gave one diastereomer 2g with three
stereocenters (entry 1). The hydrogenation of N-methyl
pyrrole 1h, with a methyl group at the 5-position, gave one
diastereomer 2h with four stereocenters (entry 2). Hydro-
genations of pyrroles with substitution other than methyl (i.e.,
1i and 1j) gave mixtures of two diastereomers (2i and 2j,
respectively, entries 3 and 4). Pyrrole 1k, which is unsub-
stituted at the 3-, 4-, and 5-positions, also gave a mixture of
two diastereomers 2k (entry 5). Hydrogenations of pyrroles
a Reaction conditions: 10 atm H2, 5% Rh/Al2O3 (w/w), room temper-
ature, MeOH or EtOH. b Stereochemistry of product in entry 5 was
tentatively assigned based on structure determination of 2a.
five-membered ring, gave a complex mixture that was hard
to analyze (entry 2). The hydrogenation reaction of the
pyrrole 1c, with an acetyl group at the 2-position instead of
an R-ketoester, gave a single diastereomer 2c (entry 3). The
hydrogenation reaction of pyrrole 1d, with an imino group
at the 2-position, gave only diastereomer 2d (entry 4). The
(17) Mori, M.; Hashimoto, A.; Shibasaki, M. J. Org. Chem. 1993, 58,
6503-6504.
(18) The indolizine substrates were synthesized according to the proce-
dure of: Gevorgyan, Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006,
128, 12050-12051. For details, see the Supporting Information.
Org. Lett., Vol. 9, No. 24, 2007
4941

with a vinyl group at the 3- and 4-positions (i.e., 1l and 1m)
gave one diastereomer (2l and 2m, respectively, entries 6
and 7).
not generated selectively during hydrogenation using Rh/
Al2O3 (Scheme 4). In contrast, partial reduction to 5k could
be achieved using Pt/Al2O3 as catalyst, and hydrogenation
of 5k was more diastereoselectiVe than hydrogenation of 1k.
It is important to emphasize that it was not possible to
determine the structures of pyrrolidines 2 by simple spec-
troscopic techniques. X-ray crystallographic analysis of 2a
was carried out, but other compounds 2 did not crystallize
readily. Therefore, the relative stereochemistry of compounds
2c-2h, 2l, and 2m has not yet been unambiguously assigned.
Tentative assignments have been made based on the stereo-
chemical result of the closely analogous hydrogenation of
1a (see Tables 2 and 3) because it seems reasonable to
propose that all of these highly selective reductions are likely
to produce products with the same relative stereochemistry.
Efforts to obtain data that confirm these assignments are
underway.
Scheme 4. Diastereoselectivity in the Hydrogenation of 1k
During optimization experiments, it was found that, using
either Rh/Al2O3 or Pt/Al2O3, hydrogenation of the ketone
occurs first to give unstable pyrrole 5a, which can be isolated
(Scheme 3). Further reduction delivers pyrrolidine 2a. While
Taken together, the results shown in Schemes 3 and 4 suggest
that (1) the pyrrole alcohol stereocenter must be present for
diastereoselective reduction to occur, but (2) the diastereo-
selectivity of the reduction is not completely controlled by
the alcohol stereocenter. Finally, it appears that (3) the
electron-donating methoxy group may slow the reduction rate
of the pyrrole ring relative to the ketone carbonyl.
In summary, an efficient and diastereoselective heteroge-
neous catalytic hydrogenation reaction of highly substituted
pyrrole systems has been developed to synthesize pyrrolidine
derivatives stereoselectively. Efforts to expand the scope of
the hydrogenation and develop a convenient enantioselective
protocol for the reduction of substituted pyrroles are under-
way.
Scheme 3. Stepwise Reduction of Pyrrole 1a
hydroxyl groups often direct hydrogenation of neighboring
olefins,19,20 it is difficult to assess directing effects in this
case because of the unknown orientation of the side chain
during reduction. Simple analysis suggests that hydrogen is
delivered to the face anti to the hydroxyl group, indicating
that the stereocenter on the side chain may hinder approach
to one face of the pyrrole rather than complexing to the
catalyst.
Acknowledgment. We thank the University of Rochester
for support of this work. The authors thank Tulay Aygan
Atesin (University of Rochester) for conducting preliminary
studies on the hydrogenation of pyrrole 1a. We also thank
Dr. William Brennessel (University of Rochester) for car-
rying out an X-ray crystallographic study of compound 2a,
and Dr. Alice Bergmann (SUNY at Buffalo) for the collection
of high-resolution mass spectra.
Another interesting observation was made during the
unselective reduction of 1k. Hydrogenation product 2k was
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
crystallographic data for 2a (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Bartok, M.; Czombos, J.; Felfoldi, K.; Gera, L.; Gondos, G.; Molnar,
A.; Notheisz, F.; Palinko, I.; Wittmann, G.; Zsigmond, A. G. Stereochemistry
of Heterogeneous Metal Catalysis; Wiley: Chichester, U.K., 1985.
(20) (a) Thompson, H. W. J. Org. Chem. 1971, 36, 2577-2581. (b)
Thompson, H. W.; Naipawer, R. E. J. Am. Chem. Soc. 1973, 95, 6379-
6386. (c) Thompson, H. W.; McPherson, E.; Lences, B. L. J. Org. Chem.
1976, 41, 2903-2906.
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