Organocatalytic asymmetric synthesis of chiral pyrrolizines by cascade conjugate addition-aldol reactions

Article abstract of DOI:10.1021/ol101811c

Figure Presented. As the first N-centered heteroaromatic nucleophile for organocatalytic cascade reactions, pyrroles underwent the enantio- and diastereoselective organocatalytic cascade conjugate addition-aldol reactions of α,β-unsaturated aldehydes that

Full text of DOI:10.1021/ol101811c

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4352-4355
Organocatalytic Asymmetric Synthesis
of Chiral Pyrrolizines by Cascade
Conjugate Addition-Aldol Reactions
Ju-Yeon Bae, Hyo-Jun Lee, Seok-Ho Youn, Su-Hyun Kwon, and Chang-Woo Cho*
Department of Chemistry, Kyungpook National UniVersity,
Daegu 702-701, Republic of Korea
cwcho@knu.ac.kr
Received August 3, 2010
ABSTRACT
As the first N-centered heteroaromatic nucleophile for organocatalytic cascade reactions, pyrroles underwent the enantio- and diastereoselective
organocatalytic cascade conjugate addition-aldol reactions of r,ꢀ-unsaturated aldehydes that afford the highly functionalized chiral pyrrolizines
bearing three consecutive stereocenters in good yields, high enantioselectivities (90-98% ee), and excellent diastereoselectivities (>20:1 dr
in all cases).
Nitrogen-containing heterocycles and their derivatives have
broad applications in organic, biological, and materials
chemistry,1 and accordingly, synthesis of N-heteroaromatic
compounds, especially optically pure ones, via catalytic
routes has been a subject of active research.2,3 Recently,
intensive efforts have been devoted to the development of
organocatalytic asymmetric cascade reactions4,5 because they
provide powerful tools for the rapid and efficient construction
of complex structures from simple precursors. In organo-
catalytic asymmetric cascade reactions, the use of N-centered
heteroaromatic nucleophiles remains unexplored in contrast
to the widely studied C-centered nucleophiles. Specifically,
pyrroles have never been used as N-centered nucleophiles
in the cascade reactions,6 in spite of the importance of
pyrroles as optically pure N-heteroaromatic pharmacophores
in biologically active natural products.3a,7 Here, we report
(4) For recent reviews of organocatalytic asymmetric cascade reactions,
see: (a) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010, 2, 167.
(b) Alba, A.-N.; Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem.
2009, 13, 1432. (c) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
(d) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570.
(5) For synthesis of chiral heterocycles via organocatalytic cascade
Michael-aldol reactions, see: (a) Luo, G.; Zhang, S.; Duan, W.; Wang,
W. Tetrahedron Lett. 2009, 50, 2946, and references cited therein. (b)
Sundén, H.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Córdova, A.
AdV. Synth. Catal. 2007, 349, 827. (c) Sundén, H.; Ibrahem, I.; Zhao, G.-
L.; Eriksson, L.; Córdova, A. Chem. Eur. J. 2007, 13, 574. (d) Hong, L.;
Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem. Eur. J. 2010, 16, 440.
(6) For examples of pyrroles as C-centered nucleophiles for enantiose-
lective organocatalyses, see the following. (a) R-Heteroarylation of alde-
hydes: Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582. (b) Friedel-Crafts alkylation with imines:
Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett. 2007, 9,
4065. (c) Friedel-Crafts alkylation with heteroarenes: Shirakawa, S.; Berger,
R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858. (d) Friedel-Crafts
alkylation with R,ꢀ-unsaturated aldehydes: Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2001, 123, 4370.
(1) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd
ed.; Wiley-VCH: New York, 2003. (b) Katritzky, A. R.; Pozharskii, A. F.
Handbook of Heterocyclic Chemistry, 2nd ed.; Pergamon: Oxford, 2002.
(c) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science:
Oxford, 2000.
(2) For examples of enantioselective organocatalyses using N-centered
heteroaromatic nucleophiles, see: (a) Dine´r, P.; Nielsen, M.; Marigo, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1983. (b) Wang, J.; Li,
H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391
.
(3) For examples of enantioselective transition-metal catalyses using
N-centered heteroaromatic nucleophiles, see: (a) Trost, B. M.; Dong, G.
J. Am. Chem. Soc. 2006, 128, 6054. (b) Gandelman, M.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2005, 44, 2393
.
10.1021/ol101811c  2010 American Chemical Society
Published on Web 08/26/2010

the first use of pyrroles as the N-centered heteroaromatic
nucleophiles in the organocatalytic asymmetric cascade
conjugate addition-aldol reactions of R,ꢀ-unsaturated alde-
hydes that provide highly functionalized chiral pyrrolizines
containing three consecutive stereogenic centers (Scheme 1).
Scheme 2. Proposed Catalytic Cycle of the Cascade Conjugate
Addition-Aldol Reactions Using a Chiral Diarylprolinol Ether
Catalyst
Scheme 1. Organocatalytic Asymmetric Cascade Conjugate
Addition-Aldol Reactions of Pyrroles to R,ꢀ-Unsaturated
Aldehydes
Although pyrrolizines have potent cytostatic effects and thus
are potentially useful for the development of antitumor and
antiviral agents,8 synthesis of chiral pyrrolizines has been
sparsely reported. Chiral auxiliary-mediated diastereoselec-
tive intramolecular cycloadditions of pyrrole-based nitrone
intermediates have been reported only for the synthesis of
chiral pyrrolizines.9 Therefore, the development of a new
route for the efficient synthesis of chiral pyrrolizines from
simple starting materials in a single step is highly desirable.
To develop the catalytic cascade reaction, the NH of the
pyrrole should be acidic enough to be deprotonated by a base
such as the carboxylate anion; the resulting pyrrole anions
then can act as nucleophiles for the initial conjugate addition
to R,ꢀ-unsaturated aldehydes in the catalytic cycle (Scheme
2, step II). At the same time, the nucleophilic pyrrole species
should be compatible with an electrophilic carbonyl func-
tionality in one pyrrole entity, which serves as the electro-
phile for the subsequent aldol reaction (Scheme 2, step III).
To explore the feasibility of pyrroles as the N-centered
nucleophiles in the organocatalytic asymmetric cascade
conjugate addition-aldol reactions of R,ꢀ-unsaturated alde-
hydes, we optimized the cascade reactions stepwise: first,
optimization for the conjugate step and, second, optimization
for the whole cascade reaction (Table 1). All of the products
were obtained after in situ reduction of the cascade aldehyde
products into the alcohols using NaBH4 in EtOH. The results
from the first optimization, the enantioselective organocata-
lytic conjugate addition of pyrroles to R,ꢀ-unsaturated
aldehydes, are listed in Table 1 as entries 1-8. The
organocatalytic conjugate additions using pyrroles as N-
centered heteroaromatic nucleophiles are not known.10 The
enantioselective conjugate addition of 2,4-dicyanopyrrole 2a,
whose pKa is lower than those of pyrrole and 2-cyanopyrrole,
to crotonaldehyde 1 using PhCO2H (20 mol %) as the acid
additive in toluene at ambient temperature was performed
in the presence of several chiral organocatalysts (Table 1,
entries 1-4).11 Among the organocatalysts assayed, the
catalyst IV proved superior, providing the corresponding
conjugate product 3a in 72% yield and 67% enantiomeric
excess (ee). However, in the case of 2-cyanopyrrole, the
conjugate addition afforded the corresponding product in a
very poor yield under the same conditions. We speculated
that the benzoate anion was not sufficiently basic to depro-
tonate the 2-cyanopyrrole.12 At -10 °C, the conjugate
addition product 3a showed an increased ee of 81%, but a
decreased yield of 45% (Table 1, entry 6 vs entry 4). The
yield increased to 58% with a slight increase in the
(7) (a) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.;
Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095. (b) When, P. M.; Bois,
J. D. Angew. Chem., Int. Ed. 2009, 48, 3802. (c) Imaoka, T.; Iwamato, O.;
Noguchi, K.-i.; Nagasawa, K. Angew. Chem., Int. Ed. 2009, 48, 3799. (d)
Jacquot, D. E. N.; Lindel, T. Curr. Org. Chem. 2005, 9, 1551. (e) Poullennec,
K. G.; Romo, D. J. Am. Chem. Soc. 2003, 125, 6344.
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Werz, O.; Laufer, S. A. J. Med. Chem. 2009, 52, 4968. (b) Michael, J. P.
Nat. Prod. Rep. 2005, 22, 603. (c) Liddell, J. R. Nat. Prod. Rep. 2002, 19,
773. (d) Atwell, G. J.; Fan, J.-Y.; Tan, K.; Denny, W. A. J. Med. Chem.
1998, 41, 4744. (e) Das, P. C.; Roberts, J. D.; White, S. L.; Olden, K.
Oncology Res. 1995, 7, 425. (f) Laufer, S. A.; Augustin, J.; Dannhardt, G.;
Kiefer, W. J. Med. Chem. 1994, 37, 1894. (g) Gruters, R. A.; Neefjes, J. J.;
Tersmette, M.; de Goede, R. A. Y.; Tulp, A.; Huisman, H. G.; Miedema,
F.; Ploegh, H. L. Nature 1987, 330, 74. (h) Zalkow, L. H.; Glinski, J. A.;
Gelbaum, L. T.; Fleischmann, T. J.; McGowan, L. S.; Gordon, M. M.
J. Med. Chem. 1985, 28, 687.
(10) For recent reviews of organocatalytic asymmetric conjugate addition
reactions, see: (a) Sulzer-Mosse´, S.; Alexakis, A. Chem. Commun. 2007,
3123. (b) Alamas¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry
2007, 18, 299. (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(11) For the first development of diarylprolinol silyl ethers as organo-
catalysts, see: (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Marigo, M.; Fielenbach,
D.; Braunton, A.; Kjœrsgaad, A.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 3703. (c) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212.
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Chem. 2008, 2808. (b) Beccalli, E. M.; Broggini, G.; Farina, A.; Malpezzi,
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A.; Broggini, G.; Passarella, D.; Terraneo, A.; Zecchi, G. J. Org. Chem.
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(12) In addition to PhCO2H, we also surveyed a series of acid additives
having various pKa values such as Ph3CCO2H, 3,5-(NO2)2PhCO2H,
CH3CO2H, Cl2CHCO2H, and Cl3CCO2H. Among the additives surveyed,
PhCO2H was the best reagent.
Org. Lett., Vol. 12, No. 19, 2010
4353

(Table 1, entry 9). By lowering the reaction temperature to
-20 °C, the ee of 4b increased to 92% (Table 1, entry 10).
Similarly, pyrrole 2c containing a 2-trichloroacetyl group also
underwent the cascade reaction at -10 °C to afford 4c in
62% yield and 96% ee as a single diastereomer (Table 1,
entry 11).14
Table 1. Optimization of Enantio- and Diastereoselective
Organocatalytic Cascade Conjugate Addition-Aldol Reactions
of Pyrroles 2 with Crotonaldehyde 1a
Next, we examined the scope of pyrroles as nucleophiles
in the enantio- and diastereoselective organocatalytic cascade
conjugate addition-aldol reaction of crotonaldehyde 1 under
the optimized conditions. A series of 2-trichloroacetylpyrroles
bearing various substituents, such as 4-cyano, 4-nitro, 4,5-
dihalo, and 3,4,5-trihalo, were examined (Figure 1). In all
Nu
PhCO2H temp
yieldb eec drd
entry
2
cat. (mol %) (°C) product
(%)
(%) [4:5]
1
2a
I
none
20
20
20
20
20
20
40
40
40
40
rt
rt
3a
3a
3a
3a
3a
3a
3a
3a
4b
4b
4c
n.r.e
23
31
72
67
45
58
73
67
61
62
2
2a II
2a III
2a IV
2a IV
2a IV
2a IV
2a IV
2b IV
2b IV
2c IV
51
3
rt
5
4
rt
0
67
5
76
6
-10
-10
-10
-10
-20
-10
81
7f
8f
9f
10f
11f
83
82
88 >20:1
92 >20:1
96 >20:1
a Procedure: To a mixture of pyrrole 2 (100 mol %), catalyst (20 mol
%), and PhCO2H (20 or 40 mol %) in toluene (0.1 M) was added
crotonaldehyde 1 (100 or 200 mol %) in one portion. The reaction mixture
was allowed to stir at rt, 0, -10, or -20 °C for 18 h, at which point the
aldehyde was directly reduced to the alcohol with NaBH4 (100 mol %) in
EtOH (0.1 M). The reaction mixture was adsorbed onto silica gel by
evaporation of the solvent, and the product was isolated by silica gel
chromatography. b Isolated yield for two steps. c Determined by chiral HPLC
analysis (Chiralcel OD-H or Chiralpak AD-H). d Determined by 1H NMR.
e No reaction. f 200 mol % 1 and 100 mol % 2 were used.
Figure 1. Enantio- and diastereoselective organocatalytic cascade
conjugate addition-aldol reactions of crotonaldehyde 1 with various
pyrroles. See the Supporting Information for detailed experimental
procedures. Cited yields are of isolated material for two steps.
Enantiomeric excess was determined by chiral HPLC analysis
enantioselectivity (83% ee) by increasing the loading of 1
to 200 mol %, which suggests that crotonaldehyde 1 may
decompose gradually as the reaction proceeds (Table 1, entry
7). When we increased the loading of PhCO2H to 40 mol
%, the addition yield of product 3a increased to 73% with
82% ee (Table 1, entry 8). These optimized reaction
conditions for the enantioselective organocatalytic conjugate
addition were directly applied to the next optimization for
the whole cascade conjugate addition-aldol reaction with
4-cyano-2-trihaloacetylpyrroles 2b and 2c as pronucleophiles,
whose carbonyl groups act as the electrophilic site for the
subsequent aldol reaction after the conjugate addition (Table
1, entries 9-11). Gratifyingly, when pyrrole 2b containing
a trifluoromethyl group, an important pharmacophore,13 was
used as the pronucleophile in the cascade reaction of 1 under
the optimized reaction conditions, the highly functionalized
chiral pyrrolizine 4b was obtained in 67% yield and 88% ee
as a single diastereomer, as determined by 1H NMR analysis
1
(Chiralpak AD-H). Diastereomeric ratio was determined by H
NMR.
cases, chiral pyrrolizines 4c-k were obtained as single
diastereomers in good yields and excellent enantioselectivi-
ties. The halo groups on the pyrrole moiety in pyrrolizines
4e-k can be used for carbon-carbon coupling reactions to
synthesize a variety of chiral pyrrolizine derivatives.15 In
particular, the dibromopyrrole moiety in 4e occurs in a large
(13) For general reviews in this area, see: (a) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. ReV. 2008, 37, 320. (b) Mu¨ller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Isanbor, C.;
O’Hagan, D. J. Fluorine Chem. 2006, 127, 303. (d) Schlosser, M. Angew.
Chem., Int. Ed. 2006, 45, 5432.
(14) Under the optimized reaction conditions, the cascade reaction did
not proceed with pyrroles bearing less electrophilic carbonyl substituent
such as 2-acetylpyrrole and 2-acetyl-4-cyanopyrrole.
4354
Org. Lett., Vol. 12, No. 19, 2010

aliphatic, variously protected hydroxymethyl, and doubly
N-protected aminomethyl substituents afforded the desired
pyrrolizines 4e and 4l-p as single diastereomers in excellent
enantioselectivities. Similarly, dibromopyrrole 2e underwent
the cascade reactions with R,ꢀ-unsaturated aldehydes bearing
aliphatic, Me-protected hydroxymethyl, and doubly N-
protected aminoalkyl substituents to afford the desired
pyrolizines 4q-t as single diastereomers in good yields and
excellent enantioselectivities. The absolute stereochemical
assignment of all cascade products is based upon single
crystal X-ray diffraction analysis of the pyrrolizine 4e. From
the absolute stereochemistry of the pyrrolizines, the course
of asymmetric induction in the cascade reaction was con-
firmed to be as that already described in the proposed
catalytic cycle in Scheme 2.
In summary, the enantio- and diastereoselective cascade
conjugate addition-aldol reaction between R,ꢀ-unsaturated
aldehydes and 2-trihaloacetylpyrroles has been achieved
using (S)-R,R-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrro-
lidinemethanol trimethylsilyl ether as the organocatalyst and
benzoic acid as acid additive. The catalytic reaction provides
various chiral pyrrolizines containing three consecutive
stereogenic centers in good yields with high enantioselec-
tivities (90-98% ee) and excellent diastereoselectivities
(>20:1 dr in all cases). This is the first example of
organocatalytic cascade reactions in which pyrroles act as
N-centered heteroaromatic nucleophiles. This organocatalytic
process provides an efficient route for the synthesis of various
chiral pyrrolizines of biologically potent natural products and
drugs. Further investigations on the scope of the cascade
reaction and its application to the synthesis of biologically
active compounds are underway.
Figure 2. Enantio- and diastereoselective organocatalytic cascade
conjugate addition-aldol reactions of dibromopyrroles 2d and 2e
with various R,ꢀ-unsaturated aldehydes. See the Supporting Infor-
mation for detailed experimental procedures. Cited yields are of
isolated material for two steps. Enantiomeric excess was determined
by chiral HPLC analysis (Chiralcel OD-H or Chiralpak AD-H).
1
Diastereomeric ratio was determined by H NMR.
Acknowledgment. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (KRF-2008-313-
C00494).
class of marine natural products that show various interesting
biological properties.16
Therefore, we further explored the organocatalytic reaction
for dibromopyrroles 2d and 2e by varying the R,ꢀ-unsatur-
ated aldehyde at -30 °C, under otherwise identical condi-
tions, because -30 °C provided the cascade product in
slightly higher ee than the reaction conducted at -10 °C,
while still sustaining a good yield (Figure 2, 4e). The results
are summarized in Figure 2. The cascade reactions of
dibromopyrrole 2d with R,ꢀ-unsaturated aldehydes bearing
Note Added after ASAP Publication. This paper was
published on the Web on August 26, 2010. References
5b-5d were added. The corrected version was reposted on
September 1, 2010.
Supporting Information Available: Spectral data (1H
NMR, 13C NMR, IR, HRMS) and chiral HPLC analysis data
for all new compounds. Single-crystal X-ray diffraction data
of 4e. This material is available free of charge via the Internet
at http://pubs.acs.org.
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11, 1051. (b) Smith, J. A.; Ng, S.; White, J. Org. Biomol. Chem. 2006, 4,
2477.
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(b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1. (c) Hao, E.; Fromont, J.;
Jardine, D.; Karuso, P. Molecules 2001, 6, 130. (d) Gribble, G. W. J. Nat.
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