Asymmetric synthesis of multifunctionalized pyrrolines by a ruthenium porphyrin-catalyzed three-component coupling reaction

Article abstract of DOI:10.1021/ol050819n

(Chemical Equation Presented) Chiral multifunctionalized pyrrolines have been synthesized by a ruthenium porphyrin catalyzed three-component coupling reaction. In a one-pot reaction, ruthenium porphyrins catalyzed in situ generation of chiral azomethine ylides from chiral diazo esters and imines. Asymmetric 1,3-dipolar cycloaddition reactions of the chiral azomethine ylides with dipolarophiles afforded the corresponding pyrrolines in good yields and high diastereoselectivity (up to 92% de).

Full text of DOI:10.1021/ol050819n

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5349-5352
Asymmetric Synthesis of
Multifunctionalized Pyrrolines by a
Ruthenium Porphyrin-Catalyzed
Three-Component Coupling Reaction
Hai-Wei Xu,† Gong-Yong Li,† Man-Kin Wong,‡ and Chi-Ming Che*,†,‡
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of
Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road,
Shanghai 200032, China, and Department of Chemistry and Open Laboratory of
Chemical Biology of the Institute of Molecular Technology for Drug DiscoVery and
Synthesis, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong, China
cmche@hku.hk
Received April 14, 2005
ABSTRACT
Chiral multifunctionalized pyrrolines have been synthesized by a ruthenium porphyrin catalyzed three-component coupling reaction. In a
one-pot reaction, ruthenium porphyrins catalyzed in situ generation of chiral azomethine ylides from chiral diazo esters and imines. Asymmetric
1,3-dipolar cycloaddition reactions of the chiral azomethine ylides with dipolarophiles afforded the corresponding pyrrolines in good yields
and high diastereoselectivity (up to 92% de).
Chiral multifunctionalized pyrrolidines are versatile synthetic
building blocks for organic synthesis and important structural
elements of many therapeutic drug molecules. Generally,
such nitrogen-containing heterocycles are synthesized by
asymmetric 1,3-dipolar cycloadditions1 that employ chiral
azomethine ylides,2 chiral olefinic dipolarophiles,3 or chiral
metal catalysts.4 The cycloadditions of chiral azomethine
ylides generated in situ from N-metalation of imines,2a the
desilylation of imines,2b,e,f the deprotonation of iminium
salts,2c,g,h,j and the thermolysis of aziridines2d,i have been
particularly well studied. However, these synthetic strategies
do not readily afford a sufficient variety of structurally
diverse pyrrolidines for high-throughput biological screening
in a time- and cost-effective manner. Application of multi-
component coupling approaches5 to this area could facilitate
future drug discovery efforts in both academic and industrial
laboratories.
(2) For examples, see: (a) Dogan, O¨ .; O¨ ner, I.; U¨ lku¨, D.; Arici, C.;
Tetrahedron: Asymmetry 2002, 13, 2099. (b) Karlsson, S.; Ho¨gberg, H.-E.
J. Chem. Soc., Perkin Trans. 1 2002, 1076. (c) Chinchilla, R.; Falvello, L.
R.; Galindo, N.; Na´jera, C. Eur. J. Org. Chem. 2001, 3133. (d) Garner, P.;
Dogan, O¨ .; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.; Zaniewski,
R. Tetrahedron 2001, 57, 71. (e) Karlsson, S.; Ho¨gberg, H.-E. Tetrahe-
dron: Asymmetry 2001, 12, 1975. (f) Karlsson, S.; Ho¨gberg, H.-E.
Tetrahedron: Asymmetry 2001, 12, 1977. (g) Enders, D.; Meyer, I.; Runsink,
J.; Raabe, G. Tetrahedron 1998, 54, 10733. (h) Grigg, R. Tetrahedron:
Asymmetry 1995, 6, 2475. (i) Garner, P.; Dogan, O. J. Org. Chem. 1994,
59, 4. (j) Deprez, P.; Royer, J.; Husson, H.-P. Tetrahedron: Asymmetry
1991, 2, 1189.
(3) For examples, see: (a) Ruano, J. L. G.; Tito, A.; Peromingo, M. T.
J. Org. Chem. 2003, 68, 10013. (b) Kagoshima, H.; Okamura, T.; Akiyama,
T. J. Am. Chem. Soc. 2001, 123, 7182. (c) Barluenga, J.; Ferna´ndez-
Rodr´ıguez, M. A.; Aguilar, E.; Ferna´ndez-Mar´ı, F.; Salinas, A.; Olano, B.
Chem. Eur. J. 2001, 7, 3533. (d) Kanemasa, S.; Hayashi, T.; Tanaka, J.;
Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56, 4473. (e) Coulter, T.;
Grigg, R.; Malone, J. F.; Sridharan, V. Tetrahedron Lett. 1991, 32, 5417.
(f) Barr, D. A.; Dorrity, M. J.; Grigg, R.; Malone, J. F.; Montgomery, J.;
Rajviroongit, S.; Stevenson, P. Tetrahedron Lett. 1990, 31, 6569. (g)
Kanemasa, S.; Yamamoto, H.; Tetrahedron Lett. 1990, 31, 3633.
† The Chinese Academy of Sciences.
‡ The University of Hong Kong.
(1) For reviews on asymmetric 1,3-dipolar cycloaddition reactions, see:
(a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.;
Wiley: Huboken, NJ, 2003. (b) Gothelf, K. V.; Jørgensen, K. A. Chem.
ReV. 1998, 98, 863. (c) Karlsson, S.; Ho¨gberg, H. E. Org. Prep. Proced.
Int. 2001, 33, 105. (d) Na´jera, C.; Sansano, J. M. Curr. Org. Chem. 2003,
7, 1105.
10.1021/ol050819n CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/29/2005

Over the years, we6 and others7 have demonstrated that
ruthenium porphyrins are effective catalysts for highly stereo-
and enantioselective carbenoid transfer reactions. We have
also shown that ruthenium porphyrins are effective at
catalyzing a three-component coupling reaction between
R-diazo esters, imines, and olefinic dipolarophiles in a one-
pot reaction8 for pyrrolidine synthesis.9-10
Figure 1. Proposed mechanism.
azomethine ylides. Subsequently, these chiral azomethine
ylides undergo 1,3-dipolar cycloaddition reactions with
dipolarophiles to afford chiral pyrrolines in good yields and
high diastereoselectivities (up to 92% de). In addition, we
provide experimental evidence for the proposed mechanism
of the three-component coupling reaction.
Herein is described the first asymmetric synthesis of chiral
pyrrolines based on the aforementioned ruthenium porphyrin
catalyzed three-component coupling process (Figure 1). In
this work, we show that ruthenium porphyrins catalyze the
decomposition of chiral 8-phenylmenthol R-diazo esters to
give metallocarbenoids that react with imines to afford chiral
At the outset, we examined the cycloaddition of chiral 8-
phenylmenthanol R-diazo ester 3a with imine 1a and di-
methyl acetylenedicarboxylate (DMAD) 2a using [Ru(2,6-
Cl2TPP)(CO)] as catalyst. Slow addition of 3a in CH2Cl2 to
a mixture of 1a, 2a, and [Ru(2,6-Cl2TPP)(CO)] (0.1 mol %)
in CH2Cl2 at 40 °C via a syringe pump afforded cycloadduct
(4) For examples, see: (a) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem.
Soc. 2003, 125, 10174. (b) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.;
Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043. (c)
Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.
(d) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 4236. (e) Allway, P.; Grigg, R. Tetrahedron Lett.
1991, 32, 5817.
1
4 in 70% isolated yield. On the basis of H NMR analysis
of the crude reaction mixture, two diastereomers were judged
to be present in a ratio of 2.1:1 (i.e., 36% de) (Table 1,
entry 1).
(5) (a) Jacobi von Wangelin, A.; Neumann, H.; Go¨rdes, D.; Klaus, S.;
Stru¨bing, D.; Beller, M. Chem. Eur. J. 2003, 9, 4286. (b) Bienayme´, H.;
Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (c) An,
H.; Dan Cook, P. Chem. ReV. 2000, 100, 3311. (d) Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem.
Res. 1996, 29, 123.
Table 1. Effect of Solventa
(6) Works by us: (a) Zhou, C.-Y.; Yu, W.-Y.; Chan, P. W. H.; Che,
C.-M. J. Org. Chem. 2004, 69, 7072. (b) Zhang, J.-L.; Chan, P. W. H.;
Che, C.-M. Tetrahedron Lett. 2003, 44, 8733. (c) Zhou, C.-Y.; Chan, P.
W. H.; Yu, W.-Y.; Che, C.-M. Synthesis 2003, 9, 1402. (d) Cheung, W.-
H.; Zheng, S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-M. Org. Lett. 2003, 5,
2535. (e) Zhou, C.-Y.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 4, 3235. (f)
Zhang, J.-L.; Che, C.-M. Org. Lett. 2002, 4, 1911. (g) Zheng, S.-L.; Yu,
W.-Y.; Che, C.-M. Org. Lett. 2002, 4, 889. (h) Li, Y.; Huang, J.-S.; Zhou,
Z.-Y.; Che, C.-M. J. Am. Chem. Soc. 2001, 123, 4843. (i) Che, C.-M.;
Huang J.-S.; Lee, F.-W.; Li, Y.; Lai, T.-S.; Kwong, H.-L.; Teng, P.-F.;
Lee, W.-S.; Lo, W.-C.; Peng, S.-M.; Zhou, Z.-Y. J. Am. Chem. Soc. 2001,
123, 4119. (j) Lo, W.-C.; Che, C.-M.; Cheng, K.-F.; Mak, T. C.-W. J. Chem.
Soc., Chem. Commun. 1997, 1205.
(7) Works by others: (a) Mirafzal, G. A.; Cheng, G.; Woo, L. K. J. Am.
Chem. Soc. 2002, 124, 176. (b) Hamaker, C. G.; Djukic, J.-P. Smith, D.
A.; Woo, L. K. Organometallics 2001, 20, 5189. (c) Simonneaux, G.;
Galardon, E.; Paul-Roth, C.; Gulea, M.; Masson, S. J. Organomet. Chem.
2001, 617-618, 360. (d) Galardon, E.; Maux, P. L.; Simonneaux, G.
Tetrahedron 2000, 56, 615. (e) Gross, Z.; Galili, N.; Simkhovich, L.
Tetrahedron Lett. 1999, 40, 1571. (f) Galardon, E.; Roue´, S.; Maux, P. L.;
Simonneaux, G. Tetrahedron Lett. 1998, 39, 2333. (g) Galardon, E.; Maux,
P. L.; Simonneaux, G. J. Chem. Soc., Perkin Trans. 1 1997, 2455. (h)
Galardon, E.; Maux, P. L.; Simonneaux, G. Chem. Commun. 1997, 927. (i)
Frauenkron, M.; Berkessel, A. Tetrahedron Lett. 1997, 38, 7175. (j) Smith,
D. A.; Reynolds, D. N.; Woo, L. K. J. Am. Chem. Soc. 1993, 115, 2511.
(8) (a) Li, Y.; Chan, P. W. H.; Zhu, N.-Y.; Che, C.-M.; Kwong, H.-L.
Organometallics 2004, 23, 54. (b) Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong,
W.; Che, C.-M. Org. Lett. 2003, 5, 2153.
entry
solvent
CH2Cl2
ClCH2CH2Cl
CHCl3
toluene
benzene
ethylbenzene
xylene
chlorobenzene
THF
yieldb (%)
70
dec (%)
1
2
3
4
5
6
7
8
9
36
33
-
79
50
66
67
71
-
27
no reaction
70
27
40
54
49
no reaction
a Ru catalyst/1a/2a/3a ) 0.001:1.2:2:1. b Isolated yield. c Determined by
1H NMR analysis of the crude products.
We next examined the effect of different solvents on the
Ru-catalyzed cycloaddition reaction of 1a, 2a, and 3a. As
shown in Table 1, remarkable solvent effects were observed
on the diastereoselectivity of cycloaddition. Significant
improvements in diastereoselectivity (50-79% de) could be
achieved using aromatic solvents (toluene, benzene, ethyl-
benzene, xylene, and chlorobenzene), when compared with
halogenated solvents (CH2Cl2 and ClCH2CH2Cl) (33-36%
de). Notably, up to 79% de and 70% yield of 4 could be
attained by using toluene as the reaction solvent, and this
(9) For a copper-catalyzed three-component coupling reaction for pyr-
rolidine synthesis, see: Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.;
Scheidt, K. A. Org. Lett. 2003, 5, 3487.
(10) For examples on three-component 1,3-dipolar cycloaddition reac-
tions, see: (a) Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L.
Tetrahedron Lett. 1998, 39, 2235. (b) Hamper, B. C.; Dukesherer, D. R.;
South, M. S. Tetrahedron Lett. 1996, 37, 3671. (c) Murphy, M. M.; Schullek,
J. R.; Gordon, E. M.; Gallop, M. A. J. Am. Chem. Soc. 1995, 117, 7029.
5350
Org. Lett., Vol. 7, No. 24, 2005

was employed for the subsequent studies. No reaction was
observed when the reactions were performed in CHCl3 or
THF.
Table 4. Cycloaddition with Various N-Benzylidene Iminesa
The effect of ligand structure on the ruthenium porphyrin
catalyzed cycloaddition reactions of 1a, 2a, and 3a was also
examined (Table 2). [Ru(2,6-Cl2TPP)CO] was found to
dec
cycloadduct yieldb (%) (%)
entry imine
R1
R2
1
2
1a
1b
1c
1d
1e
1f
Ph
Ph
4
70
79
70
77
74
73
85
74
60
70
72
Table 2. Effect of Porphyrin Structurea
m-MeOPh Ph
p-MeOPh Ph
6
58
3
7
68
entry
catalyst
yieldb (%)
dec (%)
4
p-MePh
p-ClPh
p-NO2Ph
Ph
Ph
Ph
Ph
p-MeOPh
p-BrPh
p-ClPh
m-ClPh
o-ClPh
8
67
5
9
45
1
2
3
4
5
[Ru(2,6-Cl2TPP)(CO)]
[Ru(4-ClTPP)(CO)]
[Ru(TPP)(CO)]
[Ru(2,6-(OMe)2TPP)(CO)]
[Ru(TMP)(CO)]
70
73
71
trace
trace
79
72
71
-
6
10
11
12
13
14
39
7
1g
1h
1i
61
8
Ph
30
9
Ph
47
10
11
1j
1k
Ph
32
-
Ph
no reaction
a Ru catalyst/1a/2a/3a ) 0.001:1.2:2:1. b Isolated yield. c Determined by
a Ru catalyst/1/2a/3a ) 0.001:1.2:2:1. b Isolated yield. c Determined by
1H NMR analysis of the crude products.
1H NMR analysis of the crude products.
exhibit the best diastereoselectivity (79%) and good yield
(70%) in the cycloaddition reaction. With [Ru(4-ClTPP)-
(CO)] or [Ru(TPP)(CO)] as catalyst, comparable yields (71-
73%) and diastereoselectivities (71-72%) were obtained.
While [Ru(2,6-(OMe)2TPP)(CO)] and [Ru(TMP)(CO)] dis-
played poor catalytic activity, only a trace amount of
cycloaddition product was detected.
When the 8-phenyl ring of chiral R-diazo ester 3a was
replaced by a hydrogen atom, a significant decrease in
diastereoselectivity (from 79% to 33%) resulted (Table 3).
imines 1a-f. Notably, up to 85% diastereoselectivity was
attained for imine 1f with a p-NO2 substituent (entry 6).
Similarly, a higher yield (61%) was obtained for imine
1g bearing an electron-donating substituent (R2 ) p-MeOPh)
while 30-47% yields were obtained for imines 1h-j bearing
electron-withdrawing substituents (R2 ) p-BrPh, p-ClPh, and
m-ClPh). Interestingly, imines 1i (with p-Cl) and 1j with (m-
Cl) substituents on the phenyl ring gave the corresponding
cycloaddition products 13 and 14 with high diastereoselec-
tivities (70 and 72%, respectively). Notwithstanding this, no
reaction was observed for the o-Cl-substituted imine 1k,
probably due to the steric bulkiness of the o-Cl substituent.
With [Ru(2,6-Cl2TPP)CO] as catalyst, the cycloadditions
of 3a with dipolarophiles of different steric bulkiness and
electronic properties were also examined (Table 5). Remark-
Table 3. Effect of Chiral Auxiliarya
entry R-diazo ester
X
cycloadduct yieldb (%) dec (%)
Table 5. Effect of Various Dipolarophilesa
1
2
3a
3b
Ph
H
4
5
70
90
79
33
a Ru catalyst/1a/2a/3 ) 0.001:1.2:2:1. b Isolated yield. c Determined by
1H NMR analysis of the crude products.
dipolar-
entry ophile
cyclo-
R3
R4
adduct yieldb (%) dec (%)
The bulky 8-phenyl ring was therefore crucial to achieving
high diastereoselectivity in the cycloaddition reaction.
To define the scope of the Ru-catalyzed cycloaddition
process, we extended our studies to a range of N-benzylidine
imines with different substituents on the two aromatic rings
(i.e., R1 and R2). Using chiral R-diazo ester 3a as the
carbenoid source, DMAD (2a) as dipolarophile, and [Ru-
(2,6-Cl2TPP)(CO)] as catalyst, with a series of N-benzylidine
imines 1a-k, the chiral pyrrolines were obtained in good
yields and high diastereoselectivity (Table 4).
We note that higher yields (58-70%) were obtained for
imines 1a-d bearing electron-donating substituents (R1 )
Ph, m-MeOPh, p-MeOPh, and p-MePh) when compared
imines 1e,f with electron-withdrawing substituents (R1 )
p-ClPh and p-NO2Ph) (39-45% yield). Nevertheless, high
diastereoselectivities (70-85%) were achieved for all the
1
2
3
4
5
2a
2b
2c
2d
2e
CO2Me
CO2Et
CO2Me
CO2Et
4
70
79
67
92
15
16
59
CO2-i-Pr CO2-i-Pr
50
H
Me
CO2Me
CO2Me
no reaction
no reaction
a Ru catalyst/1a/2/3a ) 0.001:1.2:2:1. b Isolated yield. c Determined by
1H NMR analysis of the crude products.
ably, up to 92% de was achieved for the bulky dipolarophile
2c (R3 ) R4 ) CO2-i-Pr) while only 67% de was attained
for 2b (R3 ) R4 ) CO2Et). This result suggests that high
diastereoselectivity can be achieved via modification of the
steric bulk of the dipolarophiles. For the less electron-
deficient dipolarophile 2d,e, no reactions were observed.
Cycloaddition reactions with different olefinic dipolaro-
philes were conducted (Table 6). High diastereoselectivity
Org. Lett., Vol. 7, No. 24, 2005
5351

On the basis of X-ray crystallographic analysis of 24, the
ruthenium-carbene distance is 1.854(8) Å, which is com-
parable to the reported examples11 (see the Supporting
Information).
Table 6. Cycloaddition with Olefinic Dipolarophilesa
In a one-pot reaction, bicyclic pyrrolidine 25 was
obtained in 61% yield by reacting a stoichiometric amount
of Ru-carbene complex 24, imine 1d, and dipolarophile
2g in refluxing toluene for 16 h (Figure 3). This experi-
a Ru catalyst/1a/2/3a ) 0.001:1.2:1:1.1, at 60 °C. b Ru catalyst/1a/2/3a
) 0.001:1.2:1:4, at 90 °C. c Isolated yield. d Determined by 1H NMR
analysis of the crude products.
(up to 78%) and good yields (64-76%) were obtained for
cyclic imides 2f-h while less satisfactory results were found
for terminal alkenes 2i,j. However, attempts to use chalcone,
methyl crotonate, and trans-4-phenyl-3-buten-2-one failed
to give the corresponding cycloadducts under the same
reaction conditions. Instead, an unexpected 8-phenylmenthol
phenylamino ester 22 (45-56% yield) was obtained (see the
Supporting Information). Probably, the ester arose from an
N-H insertion of 8-phenylmenthol carbene into aniline,
which was generated from the decomposition of imine 1a.
No reactions were observed for maleic anhydride and
dimethyl maleate.
It is well-known that azomethine ylides undergo 1,3-
dipolar cycloaddition with dipolarophiles to give pyrrolidines.
However, there is sparse evidence on the generation of
azomethine ylides from metallocarbenes and imines for
cycloaddition. Here, we have found that pyrrolidines can be
prepared from the one-pot reaction of an isolated ruthenium-
carbene complex together with imine and dipolarophile.
An isolated Ru-carbene complex 24 was prepared from
the reaction of [Ru(2,6-Cl2TPP)CO] with diazo ester 23 in
1,2-dichloroethane at 60 °C for 0.5 h under an argon
atmosphere (Figure 2). Complex 24 was recrystallized from
1,2-dichloroethane/hexane.
Figure 3. Synthesis of 25.
ment offers an experimental evidence that ruthenium-
carbene complex can react with imines to generate azome-
thine ylides for 1,3-dipolar cycloaddition with cyclic
imides.
In conclusion, we have found that ruthenium por-
phyrins are effective catalysts for asymmetric synthesis of
multi-functionalized pyrrolines with remarkable stereoselec-
tivity via a three-component coupling reaction involving
chiral diazo esters, N-benzylidene imines, and dipolaro-
philes.12
Acknowledgment. We are thankful for the support of
the Areas of Excellence Scheme established under the
University Grants Committee of the Hong Kong Special
Administrative Region, China (AoE/P-10/01), The University
of Hong Kong (University Development Fund), and Hong
Kong Research Grants Council (HKU 7099/01P). H.W.X.
and G.Y.L. thank the Croucher Foundation of Hong Kong
for the postgraduate studentships.
Supporting Information Available: Detailed experi-
mental procedures, characterization data, X-ray crystal-
lographic data of 24, 1H NMR spectra, and HPLC analysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL050819N
(11) (a) Reference 6i. (b) Li, Y.; Huang, J.-S.; Xu, G.-B.; Zhu, N.; Zhou,
Z.-Y.; Che, C.-M.; Wong, K.-Y. Chem. Eur. J. 2004, 10, 3486.
(12) Several attempts failed to obtain crystalline solids of the cycload-
dition products for absolute configuration determination by X-ray crystal-
lography analysis. Current efforts are directed toward the preparation of
other pyrroline analogues for X-ray crystallography analysis.
Figure 2. Synthesis of 24.
5352
Org. Lett., Vol. 7, No. 24, 2005