Organocatalytic asymmetric multi-component [C+NC+CC] synthesis of highly functionalized pyrrolidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.07.031

The highly chemo- and enantioselective organocatalytic [C+NC+CC] coupling process between aldehydes, dialkyl 2-aminomalonates and α,β-unsaturated aldehydes is presented. The reaction gives access to highly functionalized pyrrolidine derivatives in good yi

Full text of DOI:10.1016/j.tetlet.2007.07.031

Tetrahedron Letters 48 (2007) 6252–6257
Organocatalytic asymmetric multi-component
[C+NC+CC] synthesis of highly functionalized
pyrrolidine derivatives
*
´
Ismail Ibrahem, Ramon Rios, Jan Vesely and Armando Cordova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 4 June 2007; revised 25 June 2007; accepted 5 July 2007
Abstract—The highly chemo- and enantioselective organocatalytic [C+NC+CC] coupling process between aldehydes, dialkyl 2-
aminomalonates and a,b-unsaturated aldehydes is presented. The reaction gives access to highly functionalized pyrrolidine deriva-
tives in good yields with >10:1 dr and 90–98% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
The pyrrolidine ring is an important structural motif
found in several bioactive molecules. For example, it is
present in the neuroprotective agent kaitocephalin,1
the influenza drug A-192558,2 and the antitumor antibi-
otic bioxalomycin b1.3 Pyrrolidines also serve as useful
molecular scaffolds for the exploration and exploitation
of pharmacophore space via diversity-oriented synthesis
(DOS),4–6 which has led to the findings of new drug
leads for the treatment of cancer7 and hepatitis C viral
infections.8 Thus, intense research is ongoing for the
development of new stereocontrolled routes to chiral
pyrrolidines. For example, asymmetric methods that
rely on 1,3-dipolar cycloaddition reactions have been
developed for their preparation.9,10 In this area, organo-
electron-deficient alkenes (normal electron demand reac-
tion) have been successfully employed for the synthesis
of functional pyrrolidines.4,11 In the rapidly growing re-
search field of organocatalysis, MacMillan first reported
a catalytic enantioselective synthesis of isoxazolidines
based on the chiral imidazolidinone catalyzed 1,3-di-
polar cycloaddition between preformed nitrones and
enals.12–18 The iminium activation mechanism, which
is central in this type of catalysis, has been successfully
applied in several asymmetric reactions. In this context,
we recently reported a catalytic, highly enantioselective
isoxazolidine synthesis based on an organocatalytic
asymmetric multi-component 1,3-dipolar cycloaddition
(Eq. 1).19
R1
O
O
O N
N
R1 OH
H
ð1Þ
R2
H
N
R
+
H
R2
+
R
H
O
metallic complex-catalyzed enantioselective cycloaddi-
tion transformations between azomethine ylides and
Recently, Garner et al. reported a stereoselective synthe-
sis of functional pyrrolidines based on the union of an
aldehyde (‘C’), an amino acid derivative (‘NC’), and
an electron-deficient alkene (‘CC’) using a chiral
auxiliary in what they termed a three-component
*
Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908; e-mail
addresses: acordova@organ.su.se; acordova1a@netscape.net
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.031

I. Ibrahem et al. / Tetrahedron Letters 48 (2007) 6252–6257
6253
CO2R2
CO2R2
O
R1
N
CO2R2
CO2R2
H2N
R1
H
+
1
2
H
O
+
R1
N
OR2
OR2
R1
+
N
-
O
+
N
+
O
N
H
H
R2O
H
O
R
R2O
R
O
R
3
R1
N
+ N
H
CO2R2
CO2R2
O
H2O
1
R
R1
N
CO2R2
CO2R2
H
H
R1
N
H
4
Scheme 1. Organocatalytic asymmetric aldehyde ! imine ! dipole ! cycloadduct reaction cascade.
[C+NC+CC] coupling reaction.20 Notably, Schreiber
reported one example of a one-pot, three-component
synthesis of a highly substituted pyrrolidine derivative
catalyzed by a chiral silver complex.4 Inspired by these
findings and the importance of asymmetric multi-com-
ponent reactions,4,19–21 we envisioned that a small chiral
amine would be able to catalyze an asymmetric three-
component cascade imine ! azomethine ylide ! 1,3-
dipolar cycloaddition [C+NC+CC] sequence according
to Scheme 1. To the best of our knowledge, no report
of an organocatalytic highly enantioselective pyrrolidine
synthesis based on an asymmetric multi-component 1,3-
dipolar cycloaddition has been disclosed to date.22
pyrrolidines such as 8–12 also catalyzed the asymmetric
formation of 4a. In addition, MacMillan’s amino acid
derivative 13 catalyzed the formation of 4a in low con-
version and with excellent diastereoselectivity (19:1
endo/exo) but low enantioselectivity under our reaction
conditions (entry 8). To our delight, the protected
diarylprolinol 1123 catalyzed the formation of 4a with
high efficiency and excellent enantioselectivity in CHCl3
(entry 6).24 The chiral pyrrolidine 4a was the only prod-
uct observed by proton NMR analyses of the crude
reaction mixture, however, the chiral pyrrolidine 4a is
rather unstable and decomposed upon isolation and
storage. The highest diastereo- and enantioselectivity
for the reaction was achieved when CHCl3 or toluene
was used as the solvent. For example, the highest dr
(endo/exo) was accomplished in toluene when the ali-
phatic enal 3a was used as the substrate (entry 9). More-
over, the addition of a stoichiometric amount of
triethylamine (TEA) improved the diastereoselectivity
of the reaction.
Herein, we present a highly chemo- and enantioselective
one-pot, three-component organocatalytic route to the
synthesis of valuable pyrrolidine derivatives in good
yields with 3:1–>10:1 dr and 90–98% ee.
In an initial catalyst screen for the reaction between
benzaldehyde 1a (0.375 mmol), diethyl 2-aminomalo-
nate 2a (0.375 mmol), and 2-heptenal 3a (0.25 mmol),
we found that proline 6 and primary amino acids such
as valine 7 catalyzed the chemoselective formation of
functionalized pyrrolidine 4a in high conversion and
moderate enantioselectivity (Table 1). Simple chiral
Thus, we decided to investigate the scope of the cata-
lytic asymmetric one-pot, three-component reaction
using toluene and CHCl3 as the solvent, TEA as
an additive and chiral amine 11 as the catalyst
(Table 2).

6254
I. Ibrahem et al. / Tetrahedron Letters 48 (2007) 6252–6257
Table 1. Catalyst screen for the one-pot reaction between 1a, 2a, and 3a
O
Catalyst
H
CO2Et
CO2Et
O
O
(20 mol%)
CO2Et
EtO2C
+
N
H
Ph
H
Bu
H
Ph
+
NH2
2a
Solvent, rt
Et3N (1 equiv)
4a
1a
3a
Ph
COOH
Ph
N
COOH
N
H
N
H
H N
2
N
H
N
OH
H
OH
Ar
6
8
7
9
10
O
N
Ph
Ar
OTMS
Ph
OTMS
N
N
N
Ph
H
H
H
12: Ar=di(3,5-CF3)C6H3 13
11
Entry
Catalyst
Solvent
Time (h)
Conv.a (%)
drb
eec (%)
1
2
3
4
5
6
7
8
9
6
7
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
DMF
20
66
20
20
20
44
20
20
20
20
20
100
66
76
<10
90
100
52
8:1
2:1
5:1
n.d.
2:1
3:1
3:2
19:1
10:1 (10:1)d
3:2
50
17
33
n.d.
33
97
39
13
8
9
10
11
12
13
11
11
11
19
100 (51)d
52
95 (95)d
29
10
11
CH3CN
70
3:2
26
a Conversion of 3a as determined by NMR analyses of the crude reaction mixture.
b endo/exo-Ratio determined by NMR analyses of the crude reaction mixture.
c Determined by chiral-phase HPLC analyses of 4a.
d The results for the isolated product after silica-gel column chromatography.
The organocatalytic enantioselective three-component
reactions were highly chemo- and enantioselective. The
corresponding chiral pyrrolidine derivatives 4 were
obtained in 50–63% yields with 3:1–>10:1 dr and 90–
98% ee. For example, the reaction between benzaldehyde
1a, 2-aminomalonate 2a, and cinnamic aldehyde 3b gave
the corresponding product 4d in 63% yield with 10:1 dr
and 95% ee (entry 4). Several different aromatic and ali-
phatic enals 3 could be used as acceptors for the reaction.
Moreover, various benzaldehyde derivatives were used
as the aldehyde moiety. The reactions were also readily
performed in parallel. Thus, the one-pot, three-compo-
nent organocatalytic cascade [C+NC+CC] coupling
process should be useful as a platform in diversity-ori-
ented synthesis (DOS) of pyrrolidine derivatives with
three contiguous chiral centers. The chiral pyrrolidine
catalyzed asymmetric cascade [C+NC+CC] reaction
could also be extended to a one-pot in situ oxidation to
obtain the more stable acid functionalized chiral pyrrol-
idine derivative 14 (Scheme 2).25 For example, the one-
pot organocatalytic asymmetric tandem 1,3-reaction
dipolar/oxidation sequence between aldehyde 1a, amino-
malonate 2a, and enal 3b gave the corresponding acid
14d in 52% yield with 10:1 dr and 95% ee. Next, pure acid
14d was converted quantitatively to the corresponding
chiral proline derivative 15d (1:1 mixture of two diastereo-
isomers) under acidic conditions.26 Quantitative methyl-
ation of diacid 15d gave proline derivatives 16d27 and
16d0 as single diastereomers after isolation. Thus, the chi-
ral pyrrolidine catalyzed one-pot reaction can be used as
a novel route for the preparation of useful chiral proline
derivatives with four contiguous stereocenters.
Comparison with the literature revealed the relative con-
figuration of 16d and established the stereochemistry of
pyrrolidine derivatives 4.27 This is in accordance with
previous chiral pyrrolidine 11 catalyzed 1,3-dipolar cyc-
loadditions.12d,19 Thus, efficient shielding of the Si-face
of the chiral iminium intermediate by the bulky aryl
groups of 11 leads to stereoselective Re-facial endo-addi-
tion to the activated olefin via the plausible transition
state depicted in Scheme 1.
In summary, we have described a simple highly chemo-
and enantioselective organocatalytic one-pot, three-
component, cascade [C+NC+CC] reaction sequence
between aldehydes, dialkyl aminomalonate, and a,b-unsat-
urated aldehydes. The reaction represents a versatile
asymmetric entry to a variety of valuable highly func-
tionalized pyrrolidine derivatives in good yields with
3:1–>10:1 dr and 90–98% ee. Mechanistic studies, syn-
thetic applications of this transformation in DOS as well
as the development of other enantioselective multi-com-
ponent reactions are ongoing in our laboratory.

I. Ibrahem et al. / Tetrahedron Letters 48 (2007) 6252–6257
Table 2. Scope of the organocatalytic three-component reaction
6255
O
R
O
O
H
CO2Et
CO2Et
11
CO2Et
EtO2C
(20 mol%)
R1
H
+
R
H
R1
+
N
H
NH2
2a
Solvent, rt
Et3N (1 equiv)
1
3
4
Entry
R
R1
Ph
Product
Time (h)
Yielda (%)
drb
10:1
8:1
5:1
eec (%)
1
2
3
4
5
n-Bu
n-Bu
n-Bu
Ph
4a
4b
4c
4d
4e
20
20
20
20
20
51d
58d
59d
63e
61e
95
92
93
95
98
4-BrC6H4
4-NO2C6H4
Ph
10:1
3:1
n-Bu
4-MeOC6H4
6
Ph
Ph
4f
20
58d
>10:1
90
7
8
9
10
11
12
13
14
15
16
4-BrC6H4
4-ClC6H4
2-Naphth
n-Pr
4-ClC6H4
Ph
n-Pr
n-Hex
n-Et
Ph
Ph
Ph
4g
4h
4i
20
20
20
44
44
44
44
44
20
20
60e
52e
60e
57e
50e
52e
58e
55e
55e
62e
10:1
8:1
8:1
5:1
8:1
6:1
6:1
5:1
5:1
4:1
92
97
96
98
97
92
96
95
92
98
4-BrC6H4
4-ClC6H4
4-CNC6H4
4-ClC6H4
4-CNC6H4
4-ClC6H4
4-MeC6H4
4j
4k
4l
4m
4n
4o
4p
n-Pr
a Isolated yield of the pure product 4 after silica-gel chromatography.
b endo/exo-Ratio determined by NMR analyses of the crude reaction mixture.
c Determined by chiral-phase HPLC analyses.
d Reaction run in toluene.
e Reaction run in CHCl3.
O
Ph
CO2Et
CO2Et
HO
Ph
O
O
(a)
CO2Et
EtO2C
N
H
+
Ph
H
Ph
Ph
H
+
NH2
2a
14d
1a
3b
O
(b)
MeO
Ph
O
CO2Me
Ph
N
H
(c)
HO
Ph
16d
CO2H
N
H
+
O
Ph
15d
MeO
Ph
CO2Me
N
H
16d'
Scheme 2. Reagents and conditions: (a) (i) (S)-11 (20 mol %), Et3N, CHCl3, rt, 20 h, 85%; (ii) NaClO2, isobutene, KHPO4, t-BuOH–H2O 2:1, 52%.
(b) HCl (6 N), AcOH, reflux, 16 h, >99%. (c) TMSCHN2, benzene–MeOH, rt, 1.5 h, >99%.
Acknowledgments
References and notes
1. (a) Kobayashi, H.; Shin-ya, K.; Furihata, K.; Hayakawa,
Y.; Seto, H. Tetrahedron Lett. 2001, 42, 4021; (b) Ma, D.;
Yang, J. J. Am. Chem. Soc. 2001, 123, 9706; (c) Kawasaki,
We gratefully acknowledge the Swedish National
Research Council, Wenner-Gren, and Carl-Trygger
Foundations for financial support.

6256
I. Ibrahem et al. / Tetrahedron Letters 48 (2007) 6252–6257
M.; Shinada, T.; Hamada, M.; Ohfune, Y. Org. Lett. 2005,
7, 4165.
K. A. Chem. Commun. 2006, 2001; (e) Enders, D.;
Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
¨
2. (a) Hanessian, S.; Bayrakdarian, M.; Luo, X. J. Am.
Chem. Soc. 2002, 124, 4716; (b) DeGoey, D. A.; Chen,
H.-J.; Flosi, W. J.; Grampovnik, D. J.; Yeung, C. M.;
Klein, L. L.; Kempf, D. J. J. Org. Chem. 2002, 67,
5445.
3. (a) Zaccardi, J.; Alluri, M.; Ashcroft, J.; Bernan, V.;
Korshalla, J. D.; Morton, G. O.; Siegel, M.; Tsao, R.;
Williams, D. R.; Maeiese, W.; Ellestad, G. A. J. Org.
Chem. 1994, 59, 4045; (b) Scott, J. D.; Williams, R. M.
Chem. Rev. 2002, 102, 1669.
4. Lo, M. M.-C.; Neimann, C. S.; Nagayama, S.; Perlstein,
E. O.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077.
5. (a) Hanessian, S.; Bayrakdarian, M. Bioorg. Med. Chem.
Lett. 2000, 10, 427; (b) Hanessian, S.; Bayrakdarian, M.
Tetrahedron Lett. 2002, 43, 9441.
6. MacClean, D.; Schullek, J. R.; Murphy, M. M.; Ni, Z.-J.;
Gordon, E. M.; Gallop, M. A. Proc. Natl. Acad. Sci.
U.S.A. 1997, 94, 2805.
2007, 46, 1570.
14. For selected examples of C-nucleophiles see: (a) Ahrendt,
K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243; (b) Northrup, A. B.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2002, 124, 2458; (c) Kunz, R. K.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240;
(d) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370; (e) Halland, N.; Aburell, P. S.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2004, 43, 1272; (f) Brandau,
S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305; (g) Halland, N.;
Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003,
42, 4955; (h) Halland, N.; Aburel, P. S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661; (i) Carlone, A.;
Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 1101, and references therein; (j) Gotoh,
H.; Masui, R.; Ogino, M.; Shoji, H.; Hayashi, Y. Angew.
Chem., Int. Ed. 2006, 45, 6853; (k) Hanessian, S.; Pham, V.
7. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding,
Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J.
Am. Chem. Soc. 2005, 127, 10130.
8. Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R.
T.; Lin-Goerke, J.; Baker, A.; Earnshaw, D. L.; Hofmann,
G. A.; Keenan, R. M.; Dhanak, D. Bioorg. Med. Chem.
Lett. 2005, 15, 1553.
9. For reviews on 1,3-dipolar cycloadditions see: (a) Pellis-
sier, H. Tetrahedron 2007, 63, 3235; (b) Karlsson, S.;
Ho¨gberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103; (c)
Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; VCH: Weinheim, 1998; (d) Gothelf,
K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863; (e)
Gothelf, K. V. Synthesis 2002, 211; (f) Gothelf, K. V.;
Jørgensen, K. A. Chem. Commun. 2000, 1449.
Org. Lett. 2000, 2, 2975; (l) Enders, D.; Huttl, M. R. M.;
Grondal, C.; Raabe, G. Nature 2006, 441, 861.
¨
15. For selected examples of H-nucleophiles see: (a) Yang, J.
W.; Hechevarria Fonseca, M. T.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2005, 44, 108; (b) Guellet, S. G.;
Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 32; (c) Mayer, S.; List, B. Angew. Chem., Int.
Ed. 2006, 45, 4193; (d) Wilson, R. M.; Jen, W. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616;
´
(e) Zhao, G.-L.; Cordova, A. Tetrahedron Lett. 2006, 47,
7417.
16. For selected examples of S-nucleophiles see: (a) Marigo,
M.; Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 15710; (b) Wang, W.; Li, H.; Wang,
J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354; (c) Rios, R.;
Sunden, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.;
´
10. (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev.
2006, 106, 4484; (b) Najea, C.; Sansano, J. M. Angew.
Chem., Int. Ed. 2005, 44, 6272; (c) Husinec, S.; Savic, V.
Tetrahedron: Asymmetry 2005, 16, 2047.
Cordova, A. Tetrahedron Lett. 2006, 47, 8547; (d) Bran-
dau, S.; Maerten, E.; Jørgensen, K. A. J. Am. Chem. Soc.
2006, 128, 14986.
17. For selected examples of N-nucleophiles see: (a) Chen, Y.
K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 9328; (b) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao,
11. For selected examples see: (a) Saito, S.; Tsubogo, T.;
Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364; (b)
Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 4236; (c) Zeng, W.;
Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc.
2007, 129, 750; (d) Yan, X.-X.; Peng, Q.; Zhang, Y.;
Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew.
Chem., Int. Ed. 2006, 45, 1979; (e) Dogan, O.; Koyuncu,
H.; Garner, P.; Bulut, A.; Youngs, W. J.; Panzner, M.
Org. Lett. 2006, 8, 4687; (f) Cabrera, S.; Arrayas, R. G.;
Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394; (g)
Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett. 2005,
7, 4569; (h) Bonini, B. F.; Boschi, M.; Comes-Franchini,
M.; Fochi, M.; Fini, F.; Mazzanti, A.; Ricci, A. Synlett
2006, 543; (i) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis
2005, 1431.
´
G.-L.; Cordova, A. Chem. Commun. 2006, 849; (c) Vesely,
´
J.; Ibrahem, I.; Rios, R.; Zhao, G.-L.; Xu, Y.; Cordova,
´
A. Tetrahedron Lett. 2007, 48, 2193; (d) Diner, P.; Nielsen,
M.; Marigo, M.; Jørgensen, K. A. Angew. Chem. 2007, 46,
1983; (e) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.;
´
Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 778; (f)
Uria, U.; Vicario, J. L.; Badia, D.; Carillo, L. Chem.
Commun. 2007, 46, 1983.
18. For selected examples of O-nucleophiles see: (a) Bertelsen,
´
S.; Diner, P.; Johansen, R. L.; Jørgensen, K. A. J. Am.
Chem. Soc. 2007, 129, 1536; (b) Govender, T.; Hojabri, L.;
Moghaddam, F. M.; Arvidsson, P. I. Tetrahedron: Asym-
´
metry 2006, 17, 1763; (c) Sunden, H.; Ibrahem, I.; Zhao,
´
G.-L.; Eriksson, L.; Cordova, A. Chem. Eur. J. 2007, 13,
12. (a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2000, 122, 9874; For other studies see: (b)
Karlsson, S.; Ho¨gberg, H.-E. Eur. J. Org. Chem. 2003, 15,
2782; (c) Karlsson, S.; Ho¨gberg, H. E. Tetrahedron:
Asymmetry 2002, 13, 923; (d) Chow, S. S.; Nevalainen,
M.; Evans, C. A.; Johannes, C. W. Tetrahedron Lett. 2007,
48, 277; (e) Chen, W.; Yuan, X.-H.; Li, R.; Du, W.; Wu,
Y.; Ding, L.-S.; Chen, Y.-C. Adv. Synth. Catal. 2006, 348,
1818.
13. For reviews see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2001, 40, 3726; (b) List, B. Chem.
Commun. 2006, 819; (c) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (d) Marigo, M.; Jørgensen,
574.
´
19. Rios, R.; Ibrahem, I.; Vesely, J.; Zhao, G.-L.; Cordova, A.
Tetrahedron Lett. 2007, 48, 5701.
20. (a) Garner, P.; Kaniskan, H. U.; Hu, J.; Youngs, W. J.;
¨
Panzner, M. Org. Lett. 2006, 8, 3647; For other examples
of this approach see: (b) Garner, P.; Kaniskan, H. U. J.
¨
Org. Chem. 2005, 70, 10868, and references therein.
21. For an excellent review on the importance of developing
asymmetric multi-component reactions see: Ramon, D. J.;
Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
22. After completion of this manuscript an excellent paper by
Vicario et al. (Vicario, J. L.; Reboredo, S.; Badia, D.;
Carrillo L. Angew. Chem., Int. Ed. 2007, early view)

I. Ibrahem et al. / Tetrahedron Letters 48 (2007) 6252–6257
6257
appeared on the web on 30th May describing an organo-
catalytic reaction between a preformed azomethine ylide
derived from diethyl 2-aminomalonate and enals. Nota-
bly, catalyst 11 did not catalyze the reaction under their
reaction conditions.
temperature. After vigorous stirring overnight, the crude
was purified by column chromatography on silica-gel
(pentane/EtOAc mixtures) to afford the desired acid 14d.
Colorless oil. H NMR (400 MHz, CDCl3): d = 7.40–7.05
(m, 10H), 5.21 (d, J = 9.2Hz, 1H), 4.65 (d, J = 11.2 Hz,
1
23. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgen-
sen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794; (b)
Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212.
1H), 4.32–4.20 (m, 2H), 3.94–3.85 (m, 2H), 3.58–3.49 (m,
1H), 1.25 (t, J = 7.2 Hz, 3H), 0.77 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): 174.2, 171.7, 169.4, 140.4,
136.5, 128.5, 128.2, 128.1, 127.7, 127.5, 127.2, 76.5, 62.4,
23
24. Typical experimental procedure for the organocatalytic
three-component synthesis of chiral pyrrolidines. To a
stirred solution of aldehyde 1 (0.375 mmol, 1.5 equiv) in
CHCl3 or toluene, diethyl aminomalonate 2 (0.375 mmol,
1.5 equiv) was added. The reaction was stirred at room
temperature for 1 h and then catalyst 11 (0.05 mmol,
20 mol %), TEA (0.25 mmol, 1.0 equiv), and a,b-unsatu-
rated aldehyde 3 (0.25 mmol, 1.0 equiv) were added. The
reaction was then stirred at room temperature for the time
shown in Table 2. Next, the crude was purified by silica-gel
column chromatography to afford the pyrrolidine deriv-
61.8, 58.8, 49.8, 14.0, 13.3. ½aꢀD +28.3 (c 1.0, CHCl3).
HRMS (ESI): calcd for [M+H]+ (C23H26NO6) requires
m/z 412.1755, found 412.1740.
26. Experimental procedure for the synthesis of highly func-
tionalized proline derivatives: Compound 14d (0.073 mmol)
was dissolved in AcOH (0.15 mL) and HCl (6 N, 0.6 mL).
The reaction was stirred at reflux for 16 h. Next, the crude
mixture was diluted with water and washed with EtOAc.
The aqueous layer was dried under reduced pressure to
afford the proline derivative 15d in a 1:1 diastereomeric
mixture in quantitative yield. Compound 15d (1:1 mixture
of diastereoisomers): colorless solid. Mp 214–216 °C.
1H NMR (400 MHz, D2O): d = 7.60–7.20 (m, 10H),
5.60–5.50 (m, 1H), 5.48–5.40 (m, 1H), 5.10–5.02 (m,
1H), 4.75–4.65 (m, 1H), 4.65–4.55 (m, 1H), 4.30–4.20 (m,
1H), 4.05–3.95 (m, 1H), 3.90–3.80 (m, 1H). HRMS (ESI):
calcd for [M+H]+ (C18H18NO4) requires m/z 312.1230,
found 312.1239.
1
ative 4. Compound 4a: colorless oil. H NMR (400 MHz,
CDCl3): d = 9.03 (d, J = 4.4 Hz, 1H), 7.35–7.20 (m, 5H),
5.13 (d, J = 9.2 Hz, 1H), 4.37–4.21 (m, 4H), 3.32–3.25 (m,
1H), 3.07–3.00 (br s, 1H), 2.95–2.87 (m, 1H), 1.80–1.70 (m,
2H), 1.36–1.20 (m, 10 H), 0.92–0.84 (m, 3H); 13C NMR
(100 MHz, CDCl3): 202.2, 171.8, 169.6, 138.9, 128.6,
127.7, 127.1, 75.1, 61.9, 61.7, 61.7, 59.6, 44.0, 30.4, 30.2,
23
22.7, 14.2, 14.0, 13.8. ½aꢀD ꢁ33.5 (c 1.0, CHCl3). HRMS
27. To a 5 mL round bottom flask containing compound 15d
(0.1 mmol) in benzene (1 mL) was added MeOH (0.2 mL)
and the reaction mixture was stirred for 5 min. Next,
TMSCHN2 (0.150 mL) was added dropwise. The reaction
mixture was stirred for 90 min followed by the removal of
the solvent under reduced pressure. The crude mixture was
purified by silica-gel column chromatography (pentane/
EtOAc mixtures) to afford the pure diastereomers. Com-
pound 16d: colorless solid. Mp 64–65 °C. 1H NMR
(400 MHz, CDCl3): d = 7.32–7.22 (m, 10H), 4.87 (d,
J = 8.8 Hz, 1H), 4.09 (d, J = 8.8 Hz, 1H), 3.90 (t, J =
8.4 Hz, 1H), 3.72 (s, 3H), 3.54 (t, J = 8.4 Hz, 1H), 3.16 (s,
3H); 13C NMR (100 MHz, CDCl3): 173.1, 172.0, 140.2,
139.3, 129.0, 128.5, 128.0, 127.8, 127.4, 127.2, 67.8, 65.5,
(ESI): calcd for [M+H]+ (C21H30NO5) requires m/z
376.2118, found 376.2108. The enantiomeric excess was
determined by HPLC with an AD column. (n-hexane–i-
PrOH = 98:2, k = 250 nm), 1.0 mL/min; tR = major enan-
tiomer 15.7 min, minor enantiomer 10.7 min.
25. Typical experimental procedure for the one-pot organocat-
alytic three-component synthesis of acid functionalized
pyrrolidine 14d: To a stirred solution of aldehyde 1a
(0.375 mmol) in CHCl3, diethyl aminomalonate 2a
(0.375 mmol) was added. The reaction was stirred at
room temperature for 1 h and then catalyst 11 (0.05 mmol,
20 mol %), TEA (0.25 mmol, 1.0 equiv), and cinnamic
aldehyde 3b (0.25 mmol) were added. After stirring for
20 h at room temperature, the reaction temperature was
decreased to 0 °C and then isobutene (0.1 mL), tert-
butanol (0.4 mL), H2O (0.2 mL), KH2PO4 (54.4 mg,
4 mmol), and NaClO2 (36 mg, 4 mmol) were added
sequentially. The reaction was allowed to reach room
23
59.0, 52.5, 52.4, 51.5. ½aꢀD +19.2 (c 1.0, CHCl3). HRMS
(ESI): calcd for [M+Na]+ (C20H21NO4Na) requires m/z
362.1363, found 362.1372. The data matched those for
previously reported 16d see: Tsuge, O.; Kanemasa, S.;
Yoshioka, M. J. Org. Chem. 1988, 53, 1384.