Chemzymes: A new class of structurally rigid tricyclic amphibian organocatalyst inspired by natural product

Article abstract of DOI:10.1021/ol9029758

"Chemical Equation Presented" A new class of structurally rigid tricyclic amphibian chiral catalyst was rationally designed based on the hexahydropyrrolo[2,3-b]indole skeleton as a new type of chemzyme. This new type of chemzyme possesses a structurally rigid tricyclic skeleton and a chiral pocket which provides a well-organized chiral environment for asymmetric induction, as well as a hydrophobic pocket to enable organocatalytic reactions to proceed smoothly both in organic solvents and in water.

Full text of DOI:10.1021/ol9029758

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1220-1223
Chemzymes: A New Class of Structurally
Rigid Tricyclic Amphibian Organocatalyst
Inspired by Natural Product
Jian Xiao, Feng-Xia Xu, Yun-Peng Lu, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received January 7, 2010
ABSTRACT
A new class of structurally rigid tricyclic amphibian chiral catalyst was rationally designed based on the hexahydropyrrolo[2,3-b]indole skeleton
as a new type of chemzyme. This new type of chemzyme possesses a structurally rigid tricyclic skeleton and a chiral pocket which provides
a well-organized chiral environment for asymmetric induction, as well as a hydrophobic pocket to enable organocatalytic reactions to proceed
smoothly both in organic solvents and in water.
Designing molecular robots or chemzymes that behave like
small molecules of enzymes is greatly valued as enzymatic
catalysis promotes stereoselective processes with very high
fidelity. Such a glorious goal was first achieved by Corey
through his “CBS catalyst”.1 In this system, the two reactants
are brought together and mutually activated for chemical
reactions. However, the existing chemzymes work mainly in
organic solvents and many of these catalysts are unstable in
water unlike the actual enzymatic reactions which take place
in water.2 Therefore, the rational design of new types of
molecular robots which possess a chiral pocket that could
function in water is highly sought-after.
The hexahydropyrrolo[2,3-b]indole motif is frequently
found as a key unit in many indole alkaloids with diverse
biological activities that have attracted much attention from
synthetic chemists (Figure 1).3 It has been brought to our
attention that the tricyclic rigid ring system with a stable
bowl-shaped conformation could potentially act as a novel
chiral skeleton for asymmetric catalysis and novel template
for designing new chemzymes. The chiral pocket of this
skeleton could serve as a catalytic site by assembling
hydrophobic reactants in water and plays an important role
in the function of chemzymes.
On the basis of this novel skeleton, we rationally designed
chiral amino acid I (Figure 1). We highly anticipated that
this newly designed organocatalyst I could function as a
molecular robot or chemzyme which may accomplish the
task that proline cannot. Although proline has been ascribed
as a “universal catalyst” due to its widespread application
(1) (a) Corey, E. J.; Chen, C. P.; Reichard, G. A. Tetrahedron Lett. 1989,
30, 5547. (b) Waldrop, M. M. Science 1989, 245, 354. (c) Corey, E. J.;
Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(2) (a) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am.
Chem. Soc. 1995, 117, 6194. (b) Yao, S.; Johannsen, M.; Audrain, H.;
Hazell, R. G.; Jorgensen, K. A. J. Am. Chem. Soc. 1998, 120, 8599. (c)
Ooi, T.; Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. 1997, 36, 1183.
(d) Woeltinger, J.; Bommarius, A. S.; Drauz, K.; Wandrey, C. Org. Process
Res. DeV. 2001, 5, 241. (e) Pirrung, M. C.; Liu, H.; Morehead, A. T. Jr.
J. Am. Chem. Soc. 2002, 124, 1014. (f) Bjerre, J.; Rousseau, C.; Marinescu,
L.; Bols, M. Appl. Microbiol. Biotechnol. 2008, 81, 1. (g) Nanda, V.; Koder,
R. L. Nature Chem. 2010, 2, 15.
(3) (a) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37, 1487. (b) Bourne,
G. T.; Crich, D.; Davies, J. W.; Horwell, D. C. J. Chem. Soc., Perkin Trans.
1 1991, 1693. (c) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151.
(d) Xiao, J.; Loh, T. P. Tetrahedron Lett. 2008, 49, 7184.
10.1021/ol9029758  2010 American Chemical Society
Published on Web 02/16/2010

Figure 2. X-ray crystal structure of methyl ester derivative II.
With chiral catalyst I in hand, we proceeded to test our
hypothesis for asymmetric catalysis. To demonstrate the
efficiency of I, the enantioselective Michael addition of
aldehydes to nitroalkenes4b,7 was selected as the testing
ground since nitroalkanes are versatile synthetic intermedi-
ates. We were delighted to find that the desired product could
be obtained in 86% yield and 96% ee in the presence of 10
mol % catalyst I using 2 equiv of propanal at room
temperature in MeOH (Table 1, entry 1). In contrast, catalysts
Figure 1. Rationally designed chiral amino acid catalyst I based
on hexahydropyrrolo[2,3-b]indole.
in organocatalysis, it is usually not an effective catalyst in
terms of yield and enantioselectivity for electrophiles that
are poor hydrogen bond acceptors such as nitroalkene.4 We
also noticed that only few organocatalysts without additional
assistance could work in water,5 and among these, catalysts
based on amino acids for asymmetric reactions in water is a
rather special case due to their inherent involvement in
enzymatic catalysis.6 Therefore, the design and identification
of novel water-compatible chiral amino acid catalysts, particu-
larly those embedded in a new chiral skeleton is a challenging
task. Herein, we report a new class of organocatalyst I having
the hexahydropyrrolo[2,3-b]indole skeleton as a new type of
chemzyme which works in both organic solvent and water. The
efficiency of this catalyst is demonstrated in the asymmetric
Michael addition of aldehydes to nitrostyrenes.
Table 1. Catalytic Asymmetric Michael Addition of Propanal to
Nitrostyenea
The desired catalyst I was easily synthesized in 4 steps
from cheap commercially available NR-carbobenzyloxy-
L-tryptophan 1 on a large scale with a total yield of 74%
(Scheme 1). The unique rigid tricyclic skeleton and
loading yield
solvent (mol %)
ee
(%)d
entry
catalyst
(%)b
drc
Scheme 1. Synthesis of Chiral Catalyst I
1
2
3
4
5
6
7
8
I
III
IV
V
I/DMAP
I/DMAP
I/DMAP
I/DMAP
I
III/DMAP
IV/DMAP
V/DMAP
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
H2O
brine
H2O
H2O
10
10
10
10
5
86
30
<10
<10
96
92
90
10
N.R.
N.R.
N.R.
N.R.
91: 9
85:15 -20
86:14 -20
N.D.
91: 9
75:25 >99
91:9 >99
86:14 96
N.R.
N.R.
N.R.
N.R.
96
N.D.
>99
2
5
10
10
10
10
10
9
N.R.
10
11
12
N.R.
N.R.
N.R.
H2O
H2O
a Reactions were conducted with 2 equiv of aldehyde, 1 equiv of
nitrostyene at room temperature in the presence of catalyst with 1:1
catalyst:DMAP. b Isolated yield. c Dr (syn/anti) was determined by chiral
HPLC analysis. d Reported values refer to the syn isomer and were
determined by chiral HPLC on a chiral stationary phase.
stereochemistry of I have been confirmed by X-ray
analysis of its methyl ester derivative II (Figure 2).
III, IV and V gave much less desirable results in MeOH
(Table 1, entries 2-4). The vast differences in efficiencies
Org. Lett., Vol. 12, No. 6, 2010
1221

between catalyst I and catalysts III, IV and V fully highlight
the importance of this new skeleton for the success of this
reaction and also demonstrate that it is proline’s skeleton
and not the hydrogen bonding interaction which account for
its failure in this reaction. In line with the concept of the
self-assembly of organocatalysts proposed recently,8 more
than 99% ee was achieved when DMAP was added and The
catalyst loading could be decreased to as low as 2 mol % (Table
Table 2. Catalytic Asymmetric Michael Addition of Unmodified
Aldehydes to Nitroalkenesa
1
1, entries 5-6). H NMR revealed that the salt was formed
rapidly and quantitatively, with significant chemical shift of all
the protons. Both I and I/DMAP are soluble in water and are
1
stable as shown by H NMR (see Supporting Information).
More importantly, the I/DMAP catalyst could also catalyze this
reaction in water (Table 1, entry 7). Very low yield was obtained
when brine was used as solvent (Table 1, entry 8). However,
no reaction was observed when the reaction was carried out
using either III/DMAP, or IV/DMAP, or V/DMAP or I itself
in pure water (Table 1, entries 9-12).
Next, various substrates were examined and the reactions
were found to exhibit broad substrate scope with regard to
both the Michael acceptor and the donor (Table 2). The
adducts were obtained in excellent enantioselectivity (up to
>99% ee) and with good syn diastereoselectivity. The
stereochemistry was confirmed by X-ray crystal structure of
product 7b (see Supporting Information). Both aromatic and
aliphatic aldehydes, aryl- and alkyl-substituted nitroalkenes
gave the desired products in good yields and excellent enanti-
oselectivities (Table 2, entries 1-11). For the more bulky
isobutyraldehyde, which was found to be a poor nucleophile
giving only 68% ee using 20 mol % diarylprolinol ether catalyst
alone,7c our catalyst afforded the product in 94-95% ee with
various nitrostyrenes using 10 mol % of our catalyst (Table 2,
entries 12-14). Most of the earlier reports for this reaction were
carried out at 0 °C or even lower temperature with large excess
of aldehyde,7 while in our cases, only slight excess of aldehyde
(4) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (b)
Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737. (c) Enders,
D.; Seki, A. Synlett 2002, 26.
(5) For reviews, see: (a) Gruttadauria, M.; Giacalone, F.; Notoa, R. AdV.
Synth. Catal. 2009, 351, 33. (b) Raj, M.; Singh, V. K. Chem. Commun.
2009, 6687. For leading references, see: (c) Mase, N.; Nakai, Y.; Ohara,
N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 734. (d) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958.
(6) Paradowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem., Int. Ed.
2009, 48, 4288.
a Reactions were conducted with 0.2 mmol nitroalkene, 0.4 mmol
aldehyde at room temperature or 0.2 mmol nitroalkene, 0.8 mmol aldehyde
at 60 °C (for bulky aldehydes, entries 12-14) in the presence of catalyst
with 1:1 catalyst I:DMAP. b Isolated yield. c Syn/anti was determined by
(7) For reviews, see: (a) Vicario, J. L.; Bada, D.; Carrillo, L. Synthesis
2007, 2065. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c) Mossé,
S.; Alexakis, A. Chem. Commun. 2007, 3123. For some selected examples,
see: (d) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas,
C. F., III. J. Am. Chem. Soc. 2006, 128, 4966. (e) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (f) Wang,
W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (g) Palomo,
C.; Vera, S.; Mielgo, A.; Go´mez-Bengoa, E. Angew. Chem., Int. Ed. 2006,
45, 5984. (h) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47,
545. (i) Uehara, H.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2009, 48,
9848. (j) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132,
50.
chiral HPLC analysis or by H NMR after purification. d Reported values
1
refer to the syn isomer and were determined by chiral HPLC on a chiral
stationary phase.
was employed and excellent enantioselectivity could be obtained
at room temperature.
Therefore, our catalytic system I/DMAP could be defined
as “artificial enzyme”, considering the high efficiency and high
catalytic activity observed in both organic solvents and water.
(8) For examples of self-assembly between amines and acids, see: (a)
Clarke, M. L.; Fuentes, J. A. Angew. Chem., Int. Ed. 2007, 46, 930. (b)
Mandal, T.; Zhao, C. G. Angew. Chem., Int. Ed. 2008, 47, 7714. (c)
Schmuck, C.; Wienand, W. J. Am. Chem. Soc. 2003, 125, 452. (d) Gac,
S. L.; Luhmer, M.; Reinaud, O.; Jabin, I. Tetrahedron 2007, 63, 10721.
For addition of DMAP to improve the catalyst efficiency, see: (e) Sohtome,
Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004,
45, 5589. (f) Gu, L.; Zhao, G. AdV. Synth. Catal. 2007, 349, 1629. (g) Zhang,
X. J.; Liu, S. P.; Li, X. M.; Yan, M.; Chan, A. S. C. Chem. Commun.
2009, 833.
To probe the mechanism of this reaction, different possible
conformers of the enamine intermediate were subjected to
DFT calculation to determine the lowest energy conforma-
1222
Org. Lett., Vol. 12, No. 6, 2010

tion.9 As expected, the ethyl carbamate group controls the
geometry of the enamine to adopt the syn enamine confor-
mation (Figure 3). From this conformer, we can see that at
is supported by the following experimental results: (1) methyl
ester derivative II or phenyl ester derivative could not
catalyze the reaction with or without acid additive in MeOH
or H2O, which indicate the possible activation of nitrostyrene
by the carboxylic acid. (2) the reaction was much slower in
aprotic solvent such as DMSO and DMF which implies that
H2O may be involved in the reaction through hydrogen-
bonding interaction. Although the role of DMAP is not clear
at this moment, the DMAP salt was found to improve the
solubility of the catalyst and could also function as phase
transfer catalyst when the reaction was carried out in water.
This structurally rigid tricyclic skeleton proVides a well-
organized enVironment for asymmetric induction as well as
a hydrophobic pocket to enable this reaction to proceed
smoothly in water. For catalyst III, IV and V, they could
not satisfy the above criteria.
Figure 3. Most stable syn enamine conformation by DFT calculation.
In summary, a new class of structurally rigid tricyclic
amphibian chiral catalyst based on the hexahydropyrrolo[2,3-
b]indole skeleton has been developed. The special features
of this catalyst include: (1) bowl-shaped conformation; (2)
high geometry control of enamine and efficient face shield-
ing; (3) involvement of a chiral pocket; (4) easy preparation
in large scale; (5) I/DMAP catalyst has been shown to effect
high yields and excellent enantioselectivities in the Michael
addition of aldehydes to nitroalkenes both in organic solvents
and in water with slight excess of aldehyde, low catalyst
loading and broad substrate scope. These advantages render
this chiral catalyst more suitable for practical use and will
certainly find wide application in asymmetric synthesis. The
success of this novel catalyst design will open up new
perspectives in chiral catalyst or ligand design.12 Further
applications to other asymmetric reactions using this new
catalyst as well as more detailed mechanistic insight are
ongoing in our group.
the Si face of the enamine, there are several highly electro-
negative atoms such as O and N which could function as
hydrogen bond acceptors. Therefore when the enamine is
immersed into protic solvents such as methanol and water,
the Si face is expected to develop strong hydrogen-bond
networks which eventually block the attack of nitrostyrene
from this side.10 On this basis, nitrostyrene will attack the
enamine from the less hindered Re face via transition state
4A, where a water molecule is probably involved by forming
hydrogen bonds with the CO2H group and NO2, which will
lead to the desired (S,R) product (Figure 4).11 The activation
Acknowledgment. We thank Dr Yongxin Li (Nanyang
Technological University) for X-ray analyses. We thank Prof.
Liuzhu Gong (University of Science and Technology of
China) and Prof. Guofu Zhong (Nanyang Technological
University) for helpful discussions. We gratefully acknowl-
edge Nanyang Technological University and Ministry of
EducationAcademicResearchFundTier2(No.T207B1220RS)
for the funding of this research.
Supporting Information Available: Additional experi-
ment procedures, spectrum data for reactions products and
two CIF files. This material is available free of charge via
the Internet at http://pubs.acs.org.
Figure 4. Lowest energy TS 4A by DFT calculation.
OL9029758
(11) (a) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W.
Chem.-Eur. J. 2006, 12, 4321. (b) Chen, X. H.; Luo, S.-W.; Tang, Z.;
Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Chem.-Eur. J. 2007, 13,
689.
energy of TS 4A is 64.61 kJ/mol lower than that of TS 4B
without the water molecule as hydrogen-bond bridge. The
whole system is stabilized by hydrogen bonds. This proposal
(12) For our efforts on novel chiral catalyst or ligand design, see: (a)
Xiao, J.; Loh, T. P. Synlett 2007, 815. (b) Xiao, J.; Loh, T. P. Org. Lett.
2009, 3, 3737. (c) Loh, T. P.; Chua, G. L. Chem. Commun. 2006, 2739,
and references cited therein.
(9) See the Supporting Information for DFT calculation details.
(10) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492.
Org. Lett., Vol. 12, No. 6, 2010
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