Highly enantioslective synthesis of multisubstituted polyfunctional dihydropyrrole via an organocatalytic tandem Michael/cyclization sequence

Article abstract of DOI:10.1021/ol201299u

A unique approach to asymmetric synthesis of various optically pure multisubstituted 2,3-dihydropyrroles catalyzed by a novel rosin-derived tertiary amine-thiourea via a tandem Michael/cyclization sequence with high yield (up to 97%) and good to excellent

Full text of DOI:10.1021/ol201299u

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3806–3809
Highly Enantioslective Synthesis of
Multisubstituted Polyfunctional
Dihydropyrrole via an Organocatalytic
Tandem Michael/Cyclization Sequence
Gen Zhang,† Yaohu Zhang,† Xianxing Jiang,† Wenjin Yan,† and Rui Wang*,†,‡
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of
Biochemistry and Molecular Biology, State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou, China, and State Key Laboratory of
Chiroscience, Department of Applied Biology and Chemical Technology, The Hong
Kong Polytechnic University, Kowloon, Hong Kong
wangrui@lzu.edu.cn
Received May 13, 2011
ABSTRACT
A unique approach to asymmetric synthesis of various optically pure multisubstituted 2,3-dihydropyrroles catalyzed by a novel rosin-derived
tertiary amineÀthiourea via a tandem Michael/cyclization sequence with high yield (up to 97%) and good to excellent enantioselectivities (up to
97% ee) is present. This strategy provides an efficient and convenient method to access enantioenrich nitrogen heterocycles.
Multisubstituted dihydropyrroles bearing a stereogenic
center at the 3-position represent an important class of
nitrogen heterocycles, which are encountered in a wide
range of biologically active natural alkaloids, pharmaceu-
tically active compounds and optoelectronic materials.1
Optically active 2,3-dihydropyrroles, in particular, can
not only be used as a versatile intermediate in the total
synthesis of these active compounds but also be readily
converted to valuable chiral proline and pyrrolidine
derivatives.2 As such, much effort has been devoted to the
synthesis of these privileged heterocyclic motifs.3 However,
(2) (a) Schomaker, J. M.; Bhattacharjee, S.; Yan, J.; Borhan, B. J.
Am. Chem. Soc. 2007, 129, 1996. (b) Jackson, S. K.; Karadeolian, A.;
Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (c) Barluenga,
ꢀ
J.; Sanz, R.; Granados, A.; Fananas, F. J. J. Am. Chem. Soc. 1998, 120,
4865.
(3) (a) Zhu, Q.; Jiang, H.; Li, J.; Liu, S.; Xia, C.; Zhang, M. J. Comb.
Chem. 2009, 11, 685. (b) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (c) Ruano, J. L. G.; Tito,
A.; Peromingo, M. T. J. Org. Chem. 2002, 67, 981. (d) Dong, C.; Mo, F.;
Wang, J. J. Org. Chem. 2008, 73, 1971. (e) Feldman, K. S.; Mareska,
D. A. J. Org. Chem. 1999, 64, 5650. (f) Jiang, C.; Frontier, A. J. Org.
Lett. 2007, 9, 4939. (g) Unthank, M. G.; Tavassoli, B; Aggarwal, V. K.
Org. Lett. 2008, 10, 1501.
† Lanzhou University.
‡ The Hong Kong Polytechnic University.
(1) (a) Wiedeman, P. E.; Trevillyan, J. M. Curr. Opin. Invest. Drugs
2003, 4, 412. (b) Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am.
Chem. Soc. 2002, 124, 7324. (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17,
435. (d) Mroczek, T.; Glowniak, K. Proc. Phytochem. Soc. Eur. 2002, 4,
1. (e) Chen, Y.; Zeng, D. X.; Xie, N.; Dang, Y. Z. J. Org. Chem. 2005, 70,
5001.
(4) (a) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313. (b) Viso,
A.; Pradilla, R. F.; de la; Urena, M.; Colomer, I. Org. Lett. 2008, 10,
4775.
r
10.1021/ol201299u
Published on Web 07/06/2011
2011 American Chemical Society

to date, the asymmetric catalytic approaches to construct
these heterocycles in enantiomerically pure form are
still surprisingly rare and less exploited.4 Thus, the devel-
opment of a fascinating and powerful strategy that
allowed the rapid construction of enantioenriched and
structurally diverse 2,3-dihydropyrroles is particularly
appealing.
In recent years, organocatalytic5 domino reactions
where multiple carbonÀcarbon bond formation is carried
out in a “green” process without any troublesome experi-
mental procedures have become one of the most powerful
methods for the synthesis of useful and versatile organic
molecules. In contrast to the extensive and fruitful studies
in this area by using R,β-unsaturated aldehydes, ketones,
esters, imides, and nitroolefins as electrophiles,6 fewer
cases have been reported in which R,R-dicyanoolefins
serve as the electrophiles, probably because of their
high chemical reactivity.7 Considering R,R-dicyanoolefins
could be readily prepared from a simple Knoevenagel
condensation of aldehydes with malononitrile,8 the
nitrile as a useful functional group could be easily trans-
formed to other important groups such as carbonyl
derivatives or imines.9 Therefore, an organocatalytic
domino reaction using R,R-dicyanoolefins as starting
material could provide a direct access to optically
active compounds, such as chiral multisubstituted 2,3-
dihydropyrroles.
As part of our ongoing interest in developing
new methods for the synthesis of useful compounds,10
we recently succeeded in developing a novel class of
bifunctional thiourea catalysis based on rosin11 and
applied it to facilitate various transformations, for in-
stance, the Michael reaction of 1,3-dicarbonyls with
nitroalkenes,10a aza-Henry reactions with in situ genera-
tion of N-Boc imines,10b Mannich reaction of lactones
with N-Boc-aldimines,10c and aldol reaction of R-iso-
thiocyanato imides to R-ketoesters and isatins.10d,e En-
couraged by these successful efforts and aimed to
demonstrate the efficiency and generality of this rosin-
derived thiourea bifunctional catalysis, therefore, we turned
our recent attention to employing this novel catalysis for the
asymmetric synthesis of optically active 2,3- dihydropyrroles
prepared from simple and easily available starting materials
under a mild domino reaction.
(5) Selected recent reviews and examples on asymmetric organoca-
talysis: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Xu, X.; Wang,
W. Org. Biomol. Chem. 2008, 6, 2037. (c) List, B. Chem. Commun. 2006,
819. (d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520. (e) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (f) Marigo,
M.; Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 15710. (g) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (h) Oisaki, K.; Zhao, D.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 15051. (i) Weber,
M.; Jautze, S.; Frey, W.; Peters, R. J. Am. Chem. Soc. 2010, 132, 12222.
(j) Dong, S.; Liu, X.; Chen, X.; Mei, F.; Zhang, Y.; Gao, B.; Lin, L.;
Feng, X. J. Am. Chem. Soc. 2010, 132, 10650. (k) Ma., A.; Ma, D. Org.
Lett. 2010, 12, 3634. (l) Bui, T.; Barbas, C. F., III. Tetrahedron Lett.
2000, 41, 6951.
(6) For recent reviews and examples, see: (a) Enders, D.; Grondal, C.;
€
Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Dondoni, A.;
Before attempting this novel strategy, we presumed its
possibility for the synthesis of chiral 2,3-dihydropyrroles.
We envisioned that in the presence of a chiral tertiary
amineÀthiourea, dibenzyl 2-aminomalonate 2 might be
activated through a hydrogen bond: the nitrogen atom of
the chiral tertiary amineÀthiourea with the carbonyl of 2
to form the enolate intermediate12 Then the electron-rich
R-carbon atom of 2 attacks the electron-deficient cyanoo-
lefins 1 to generate the Micheal adducts A, subsequently,
through intramolecular cyclization of A to afford the
cyclized adducts B, then through tautomerization of C to
obtain the desired final product 3 (Scheme 1).
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (c) Nicolaou, K. C.;
Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (d) Wasilke, J.-C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (e) Toure,
B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (f) Wang, C.; Han, Z.-Y.;
Luo, H.-W.; Gong, L.-Z. Org. Lett. 2010, 12, 2266. (g) Zhang, F.-L.; Xu,
A.-W.; Gong, Y.-F.; Wei, M.-H.; Yang, X.-L. Chem.;Eur. J. 2009, 15,
6815. (h) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787.
(i) Zhao, G.-L.; Vesely, J.; Rios, R.; Ibrahem, I.; Sunden, H.; Cordova,
A. Adv. Synth. Catal. 2008, 350, 237. (j) Hazelard, D.; Ishikawa, H.;
Hashizume, D.; Koshino, H.; Hayashi, Y. Org. Lett. 2008, 10, 1445.
(k) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem.;Eur. J. 2008, 14, 4788. (l) Carlone,
A.; Cabrera, S.; Marigo, M.; Jørgenson, K. A. Angew. Chem., Int. Ed.
€
2007, 46, 1101. (m) Enders, D.; Huttl, M. R. M.; Runsink, J.; Raabe, G.;
Wendt, B. Angew. Chem., Int. Ed. 2007, 46, 467. (n) Zhou, J.; List, B. J.
Am. Chem. Soc. 2007, 129, 7498. (o) Beeson, T. D.; Mastracchio, A.;
Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582.
(p) Tan, B.; Candeias, N. R.; Barbas, C. F., III. Nat. Chem. 2011, 3, 473.
(7) (a) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928.
(b) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen,
Y.-C. J. Am. Chem. Soc. 2007, 129, 1878. (c) Li, X.-M.; Wang, B.; Zhang,
J.-M.; Yan, M. Org. Lett. 2011, 13, 374. (d) Nikishkin, N. I.; Huskens, J.;
Verboom, W. Eur. J. Org. Chem. 2010, 35, 6820.
(8) Guo, K.; Thompson, M. J; Chen, B. J. Org. Chem. 2009, 74, 6999.
(9) (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed.
2005, 44, 4032. (b) Hazell, H. N. G.; Jorgensen, K. A. J. Org. Chem.
2002, 67, 8331. (c) Mitchell, C. E.; Brenner, T. S. E.; Ley, S. V. Chem.
Commun. 2005, 5346. (d) Hojabri, L.; Hartikka, A.; Moghaddam, M. F.;
Arvidsson, P. I. Adv. Synth. Catal. 2007, 349, 740. (e) Bernardi, L.; Fini,
F.; Fochi, M.; Ricci, A. Synlett 2008, 1857.
(10) Selected for rosin-derived thiourea catalyzed reactions: (a)
Jiang, X. X.; Zhang, Y. F.; Liu, X.; Zhang, G.; Lai, L. H.; Wu, L. P.;
Zhang, J. N.; Wang, R. J. Org. Chem. 2009, 74, 5562. (b) Jiang, X. X.;
Zhang, Y. F.; Wu, L. P.; Zhang, G.; Liu, X.; Zhang, H. L.; Fu, D.; Wang,
R. Adv. Synth. Catal. 2009, 351, 2096. (c) Jiang, X. X.; Fu, D.; Zhang, G.;
Cao, Y. M.; Liu, L. P.; Song, J. J.; Wang, R. Chem. Commun. 2010, 46,
4294. (d) Jiang, X. X.; Zhang, G.; Fu, D.; Cao, Y. M.; Shen, F. F.; Wang,
R. Org. Lett. 2010, 12, 1544. (e) Jiang, X. X.; Cao, Y. M.; Wang, Y. Q.;
Liu, L. P.; Shen, F. F.; Wang., R. J. Am. Chem. Soc. 2010, 132, 15328.
(f) Liu, X. D.; Deng, L. J.; Jiang, X. X.; Yan, W. J.; Liu, C. L.; Wang, R.
Org. Lett. 2010, 12, 876. (g) Hong., L.; Sun., W. S.; Liu, C. X.; Zhao,
D. P.; Wang, R. Chem. Commum. 2010, 46, 2856.
To explore the possibility of the proposed Michael/
cyclization sequence, initially, the reaction of 2-benzyli-
denemalononitrile with diethyl 2-formamidomalonate
was used as a model reaction, and a variety of bifunc-
tional organocatalysts (Figure 1) were screened at room
(11) Selected recent reviews and examples on asymmetric thiourea,
see: (a) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418. (b) Yu, X.; Wang,
W. Chem. Asian. J. 2008, 3, 516. (c) Zhang, Z.; Schreiner, P. Chem. Soc.
Rev. 2009, 38, 1187. (d) List, B.; Yang, J. W. Science 2006, 313, 1584.
(e) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132,
5030. (f) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131,
8758. (g) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc.
2007, 129, 6686. (h) Zu, L. S.; Wang, J.; Li, H.; Xie, H. X.; Jiang, W.;
Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (i) Wang, Y.; Li, H. M.;
Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007,
129, 6364. (j) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed.
2005, 44, 6367.
(12) (a) Zuend, S. J.; Jacøbsen, E. N. J. Am. Chem. Soc. 2007, 129,
15872. (b) Doyle, A. G.; Jacøbsen, E. N. Chem. Rev. 2007, 107, 5713.
(c) Ren, Q.; Gao, Y.; Wang, J. Chem.;Eur. J. 2010, 16, 13594. (d) Hu,
Z.-P.; Lou, C.-L.; Wang, J.-J.; Chen, C.-X.; Yan, M. J. Org. Chem. 2011,
76, 3797.
Org. Lett., Vol. 13, No. 15, 2011
3807

Table 1. Catalyst Screening and Optimization of Reaction
Conditionsa
Scheme 1. Strategy for Synthesis of Chiral 2,3-Dihydropyrrole
by Chiral Tertiary Amines
entry
catalyst
R/Pg
yieldb (%)
eec (%)
1
2
L1
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
H/CHO
CH3/CHO
H/H
3a/76
3a/78
3a/83
3a/84
3a/79
3a/75
3a/71
3a/73
3a/77
3a/72
3a/92
<10
À30d
50
L2
3
L3
À77d
4
L4
80
5
L5
À71d
55
6
L6
7
L7
17
8
L8
15
9
L9
À27d
À23d
96
10
11
12
13
14
15
16
17
L10
L11
L11
L11
L11
L11
L11
L11
nde
nde
trace
<10
H/Ac
nde
f
H/Tos
3b/70
3c/74
3d/62
f
H/Boc
H/Cbz
45
a Unless otherwise specified, the reaction was carried out with 1
(0.3 mmol) and 2 (0.2 mmol) in the presence of an organocatalyst L
(0.02 mmol) in toluene (2.0 mL) at rt for 12 h. b Isolated yield. c Determined
by chiral HPLC on a Chiralcel OD column. d The opposite configuration.
e Not determined. f Not determined by chiral HPLC.
With the optimized reaction conditions in hand, we then
examined the scope of the reaction for the construction
of various optically active 2,3-dihydropyrroles, and the
results are summarized in Table 2. In general, the reaction
proceeded smoothly to afford the desired products in good
yields and excellent enantioselectivities. For the reaction
with diethyl 2-formamidomalonate 2a, a wide range of
substituted aromatic R,R-dicyanoolefins 1 were examined
(entries 1À12). It was found that R,R-dicyanoolefins 1 with
either electron-withdrawing or electron-donating groups
on the phenyl ring provided good yields (81À96%) and
good to excellent enantioselectivities (83À97% ee values).
In addition, good results were also obtained by using
2-furyl as substituent of R,R-dicyanoolefins 1 (entry 13).
Then, dibenzyl 2-formamidomalonate 2b and dimethyl
2-formamidomalonate 2c were used for the synthesis of
desirable optically active 2,3-dihydropyrroles, and good
results were also obtained (85À97% yields and 86À94% ee
values, entries 15À19). The absolute configuration of pro-
ducts were determined to be R by using a single-crystal
X-ray diffraction of 3m (Figure 2).14
Figure 1. Organocatalysts used in this study.
temperature in toluene for the synthesis of the optically
active 2,3-dihydropyrroles; the results are summarized in
Table 1. It showed that the bifunctional thiourea catalysis
derived from quinineamine13 based on rosin exhibited good
activity and high enantioselectivity (up to 96% ee, entry 11),
while other thiourea catalyzes derived from diaminocyclo-
hexane (entries 1À5) and cinchonine or quinine derives
(entries 6À10) showed disappointing results. The optimiza-
tion results of N-terminal protection groups showed that
formyl is the best choice (entries 11À17).
(13) For selected reviews of chiral quinineÀthiourea catalysis, see:
(a) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int.
Ed. 2006, 45, 7496. (b) Chen, Y. G.; McDaid, P.; Deng, L. Chem. Rev.
2003, 103, 2965. For selected examples of chiral quinine-thiourea
catalysis, see: (c) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan,
W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (d) Saaby, S.; Bella,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (e) Yoon, T. P.;
Jacobsen, E. N. Science 2003, 299, 1691.
(14) CCDC808330 (3m) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/cgi-
bin/catreq.cgi.
3808
Org. Lett., Vol. 13, No. 15, 2011

Table 2. Asymmetric Synthesis of 2,3-Dihydropyrrolea
entry
R
R1
yieldb (%)
eec (%)
1
2
Ph
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2a/Et
2b/Bn
2b/Bn
2b/Bn
2b/Bn
2c/Me
2a/Et
3a/92
3e/91
3f/86
3g/82
3h/84
3i/80
3j/94
3k/95
3l/92
3m/96
3n/83
3o/81
3p/79
3q/97
3r/93
3s/94
3t/90
3u/85
3v/62
96
97
95
83
90
96
92
90
89
94
85
92
78
94
89
90
86
87
28
4-ClPh
4-BrPh
4-CNPh
4-MePh
4-MeOPh
3-ClPh
3-BrPh
2-ClPh
2-BrPh
2-MeOPh
2,5-MeOPh
2-furyl
Ph
3
4
5
Figure 2. X-ray crystal data of compound 3m.
6
7
8
tandem Michael/cyclization sequence with high yield
(up to 97%) and excellent enantioslectivities (up to
97% ee). These enantioenriched products will be ap-
pied in the synthesis of chiral nitrogen heterocyclic
compounds, and this simple operational, excellent
enantiocontrol and broad substrate scope transforma-
tion will be potentially applied in the synthesis of other
chiral nitrogen heterocycles. Further investigation on
these new heterocyclic compounds is ongoing in our
laboratories.
9
10
11
12
13
14
15
16
17
18
19
4-FPh
4-ClPh
4-BrPh
Ph
cyclohexyl
a Unless otherwise specified, the reaction was carried out with 1
(0.3 mmol) and 2 (0.2 mmol) in the presence of an organocatalyst L11
(0.02 mmol) and toluene (2.0 mL) at rt for 12 h. b Isolated yield.
c Determined by HPLC on a Chiralcel AD or OD column, and the
configuration was assigned by comparison of HPLC data and X-ray
crystal data of 3m.
Acknowledgment. We are grateful for the grants from
the National Natural Science Foundation of China
(20932003 and 90813012) and the Key National S & T
Project “Major New Drug Development” of the Ministry
of Science and Technology (2009ZX09503-017).
In conclusion, we have successfully developed a
unique approach to an asymmetric synthesis of various
optically pure 2,3-dihydropyrroles catalyzed by a
novel tertiary amineÀthiourea based on rosin under a
Supporting Information Available. Experimental de-
tails, compound characterization, and X-ray crystallo-
graphic data (CIF) for 3m. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3809