Highly enantioselective inverse-electron-demand hetero-diels-alder reactions catalyzed by modularly designed organocatalysts

Article abstract of DOI:10.1002/chem.201300168

MDO rocks! Proline and (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid are both poor catalysts for the inverse-electron-demand hetero-Diels-Alder reactions between aldehydes and electron-deficient enones. However, forming modularly designed organocatal

Full text of DOI:10.1002/chem.201300168

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DOI: 10.1002/chem.201300168
Highly Enantioselective Inverse-Electron-Demand Hetero-Diels–Alder
Reactions Catalyzed by Modularly Designed Organocatalysts
Debarshi Sinha, Sandun Perera, and John Cong-Gui Zhao*[a]
With the exponential developments of organocatalytic
methods in recent years, organocatalysis has now been es-
tablished as a very powerful tool for the synthesis of func-
tional molecules.[1] Most recently, there was considerable in-
terest in applying self-assembled organocatalysts in catalytic
reactions.[2] Compared to conventional organocatalysts, the
structure of self-assembled organocatalysts is easy to modify
and optimize due to the fact that synthesis is not involved in
the final catalyst formation step. Moreover, it is very con-
venient to build a large catalyst library of these self-assem-
bled organocatalysts for high-throughput screenings.[2,3] Sev-
eral self-assembled organocatalysts have been reported
since the seminal work of Clarke and co-workers;[2a] none-
theless, the reactions catalyzed by these catalysts are still
very limited. Most of the reported catalytic systems can only
catalyze Michael and/or aldol reactions through the enamine
mechanism.[2,3]
sembled in the final self-assembled catalyst. Herein we wish
to disclose our recent finding that novel MDOs self-assem-
bled from proline derivatives and cinchona alkaloid derived
thioureas are also highly efficient catalysts for inverse-elec-
tron-demand hetero-Diels–Alder reactions.[5] Our new re-
sults not only demonstrated that forming an MDO may dra-
matically improve the catalytic activity and asymmetric in-
duction of those poor catalysts, such as proline, so that these
readily available but otherwise useless catalysts may be still
applied in this important reaction, but also reveals the most
likely structure for these self-assembled catalysts through a
new NOESY study of the MDO.
Previously, Jørgensen,[5a] Ma,[5c] and our group[5b] have re-
ported that pyrolidine derivatives are good catalysts for the
hetero-Diels–Alder reactions between aldehydes and elec-
tron-deficient enones. In the presence of silica gel or an
acid, these catalysts catalyze the desired reaction through an
enamine intermediate.[5a–c] We envisioned that MDOs of
proline derivatives should serve the same purpose since
these catalysts are known to form enamines with alde-
In 2008, we developed the modularly designed organoca-
talysts (MDOs) through the self-assembly of amino acids
and cinchona alkaloids through ionic interactions
A
hydes.[4a] To test our hypothesis, an electron-poor enone 3a
ACHTUNGTRENNUNG
and propanal (4a) were adopted as the model substrates for
screening the MDOs self-assembled from the selected cata-
lyst modules (Figure 1). The most interesting results of the
screening are summarized in Table 1.[6]
As the results in Table 1 show, when l-proline (1a) and
quinidine thiourea 2a (10 mol% loading each) were used as
the catalyst in toluene at RT, the reaction generated a mix-
ture of the aldol product 5a and the desired hetero-Diels–
Alder product 6a in a ratio of about 1:4 with over 90% con-
version of 3a after 3 h (Table 1, entry 1). Prolonging the re-
action time to 5 h led to almost exclusive formation of 6a
(entry 2), which was isolated in 92% yield. It should be
pointed out that, unlike those pyrolidine-derived organo-
Scheme 1. Formation of MDOs through self-assembly.
MDOs are very efficient catalysts for Michael and aldol re-
actions.[4] Formation of MDOs from these precatalyst mod-
1
ules has been confirmed by our previous H NMR spectro-
catalysts,[5a–c] no silica gel or acid is necessary for the MDO
ACHTUNGTRENNUNG
scopic study[4a] and a recent HRMS study[2m] of the self-as-
sembled organocatalyst. Nevertheless, these studies were
not able to reveal how these two precatalyst modules are as-
to achieve an efficient conversion of the substrates. As ex-
pected for this type of compound,[5a–c] 6a was obtained as a
mixture of two anomers (ratio 80:20).[7] To facilitate the de-
termination of the enantiomeric excess (ee) value, product
6a was oxidized with pyridinium chlorochromate (PCC) to
give the dihydropyranone derivative 7a as a single trans dia-
[a] Dr. D. Sinha, S. Perera, Prof. J. C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio
One UTSA Circle, San Antonio, Texas 78249-0698 (USA)
Fax : (+1)-210-458-7428
ACHUTNGERNsNUG tereoACHTUNGTERNmNUGN er in 90% ee (entry 2), which should be very useful
in organic synthesis.[8] Increasing the loading of aldehyde 4a
slows down the formation of 6a, but does not affect the
product ee value (entries 3 and 4). These results indicate
that the aldol reaction is reversible under the reaction con-
E-mail: cong.zhao@utsa.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300168.
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Table 1. Catalyst screening for the MDO-catalyzed hetero-Diels–Alder
reaction[a]
Entry
Modules [mol%]
t [h]
3a/5a/6a[b]
6a [%][c]
ee [%][d]
1
2
1a/2a (10:10)
1a/2a (10:10)
1a/2a (10:10)
1a/2a (10:10)
1a (10)
3
5
5
5
5
5
5
5
5
2
3
2
4
3
5
5
24
06:19:75
02:02:96
03:20:77
03:25:72
94:05:01
93:06:01
80:11:09
76:04:20
nd[e]
92
75
70
nd
nd
nd
18
90
91
89
91
90
88
91
91
89
–
90
90
90
–
3[f]
4[g]
5
6
7
8
9
10
11
12
13
14
15
16
17
2a (10)
–
–
1a/2g (10:10)
1a/2h (10:20)
1b/2a (10:10)
1j/2a (10:10)
1j/2b (10:10)
1j/2c (10:10)
1j/2d (10:10)
38
88[h]
94
94
94
94
94
94
94
94
1j/2e
N
1j/2 f (10:10)
1j/2a (5:5)
1j/2a (3:3)
[a] Unless otherwise indicated, all reactions were carried out with 3a
(0.20 mmol), 4a (0.24 mmol, 1.2 equiv), and the specified catalyst mod-
ules in toluene at room temperature (ca. 258C). Upon the completion of
1
the reaction (monitored by TLC analysis and H NMR spectroscopy), the
product 6a was isolated (anomeric ratio 80:20) and subjected to oxida-
tion by PCC to 7a to facilitate the ee value determination. [b] The ratio
was determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [c] Yield of the isolated compound 6a after column chromatog-
raphy. [d] Determined by HPLC analysis on the oxidative product 7a by
using a ChiralPakIB column. Only a single trans diastereomer was ob-
served for compound 7a according to 1H NMR spectroscopy and HPLC
analysis. Absolute configuration of the major enantiomer was assigned
by comparing the observed optical rotation value with the literature data.
[e] Not determined. [f] 2.0 equiv 4a were used. [g] 5.0 equiv 4a were
used. [h] The opposite enantiomer was obtained as the major product.
Figure 1. Structure of the catalyst modules used in the asymmetric
À
hetero-Diels–Alder reaction (Ar=(3,5-CF3)2C6H4 ).
ditions and that the hetero-Diels–Alder product is thermo-
dynamically more stable. In contrast, when l-proline
(entry 5) or 2a (entry 6) were used alone, low conversion of
3a and almost no formation of 6a were observed. These re-
sults clearly demonstrate that the MDOs of 1a and 2a are
much superior to the individual precatalyst modules. To fur-
ther clarify the role of quinidine thiourea 2a in this reaction,
the reactions were also attempted with the mixtures of 1a
The reaction gave the desired product 6a in 91% yield and
94% ee in just 2 h (entry 10).[10] Further screening of other
cinchona alkaloid thioureas (2b–e) and Takemoto thiourea
2 f as the stereocontrolling modules reveals that all these
modules led to similar product yields and identical product
ee values with 2j as the reaction-center module (entries 11–
15), except that a few of these modules took a slightly
longer time to complete the reaction.
The reaction conditions were further optimized with the
MDO of 1j and 2a. Normal organic solvents were found to
have only minimal influences on the asymmetric induction,
except that poor results were obtained with a very polar sol-
vent DMF (Table S1 in the Supporting Information). When
the reaction was carried out at 08C, the reaction proceeded
much slower, while there was no improvement on the prod-
uct ee value (Table S1 in the Supporting Information). It
was also found that reducing the precatalyst loading to
5 mol% each did not affect the reactivity and asymmetric
and an achiral thiourea 2g as well as 1a and triACHTNUTRGNEeUNG thylamine
(2h) as the catalysts (entries 7 and 8). Again poor results
were obtained in both cases. Thus, the concurrent presence
of a base and a thiourea moiety in 2a is crucial for the ob-
served reactivity and enantioselectivity. These data lend fur-
ther support to the formation of an MDO under the reac-
tion conditions. Next other amino acids were screened as
the reaction-center module in this reaction with 2a as the
stereocontrolling module. The MDO of d-proline (1b) and
2a yield the opposite enantiomer in 90% yield and 88% ee
(entry 9). In contrast, the MDOs of 2a with primary amino
acids 1c and 1d, l-pipecolic acid (1e), and proline deriva-
tives 1 f–i all showed very poor reactivities (Table S1 in the
Supporting Information). Nonetheless, (2S,3aS,7aS)-octahy-
dro-1H-indole-2-carboxylic acid (OHIC, 1j)[9] was identified
as a slightly better reaction-center module than l-proline.
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Inverse-Electron-Demand Hetero-Diels–Alder Reactions
COMMUNICATION
induction of this MDO (entry 16). However, further drop-
ping the loading to 3 mol% each slowed down the desired
reaction, although there was no effect on the asymmetric in-
duction (entry 17). The ratio of these two modules was
found to have some influence on the reaction: Slightly lower
product ee values were observed with a 2:1 loading of 2a
and 1j (Table S1 in the Supporting Information).
Once the reaction conditions were optimized, the scope
of this MDO-catalyzed hetero-Diels–Alder reaction was
evaluated and the results are summarized in Table 2. As the
data in Table 2 show, besides propanal (Table 2, entry 1),
various aldehydes, including long-chain and branched alde-
hydes, were found to be excellent substrates for this reaction
(entries 2–6), except for phenylacetaldehyde, with which the
opposite enantiomer[11] was obtained with a poor ee value of
35% (entry 7). This was most likely due to electronic ef-
fects,[12] since high ee values were obtained for the products
of the more sterically hindered isovaleraldehyde (entry 5)
and isobutyraldehyde (entry 6). Upon moving the phenyl
group further away from the reaction center, such as in hy-
drocinnamaldehyde, the high reactivity and enantioselectivi-
ty of this reaction was restored (95% yield and 95% ee,
entry 4). The ester alkyl group of the b,g-unsaturated a-
ketoACTHUNRTGNEUNGesters has almost no influence on either the reactivity
or enantioselectivity (entries 4, 8, and 9). Similarly, the sub-
stituent on the phenyl ring of the enones has minimal effects
on the reactivity and the asymmetric induction of this reac-
tion (entries 1 and 10–14), except that the 4-methoxyphenyl-
substituted enone is less reactive (entry 10). Excellent re-
sults were also achieved for a g-alkyl b,g-unsaturated a-
ketoACTHNUGRTENUNGester (entry 11). Besides b,g-unsaturated a-ketoesters,
b,g-unsaturated a-ketophosphonates may also applied in
this reaction[5b,9c] if a slightly higher loading of the precata-
lyst modules (10 mol% each) was used. Again high yields
and enantioselectivities were obtained (entries 17–21).
As aforementioned, although previous studies have con-
firmed the formation of MDO from the precatalyst modules,
such as l-proline (1a) and quinidine thiourea (2a),[2m,4a] they
were not able to reveal the possible structure of the MDO.
To find out how these two precatalyst modules are self-as-
sembled in the MDO, we conducted a NOESY study of the
MDO of 1a/2a. On the basis of these new results (Fig-
AHCTUNGTREGuNNNU res S2–S4 in the Supporting Information), a more plausible
Table 2. Substrate scope of the MDO-catalyzed hetero-Diels–Alder reac-
tion.[a]
structure of the MDO is proposed (Figure S5 in the Sup-
porting Information), in which 1a sits right under the quinu-
clidine ring of 2a, with its amine group facing the front and
its carboxylic acid group forming an ammonium salt with
2a. On the other hand, the absolute configuration of the
hetero-Diels–Alder products 6 was assigned as 4S,5R by
comparing the measured optical rotation data of compounds
7d and 7e with the reported values.[5a] Except for compound
7g,[11] the absolute configuration of the other compounds
was similarly assigned according to the reaction mechanism.
On the basis of the product stereochemistry and the pro-
posed MDO structure, a plausible transition state is pro-
posed. As shown in Scheme 2, the aldehyde reacts with the
OHIC moiety of the MDO to form an E enamine. Simulta-
neously, the thiourea moiety of the MDO forms hydrogen
bonds with the enone and directs the enone to approach en-
amine from the front. The attack of the enone onto the Re
face of the enamine in an endo fashion[5a] leads to the for-
mation of the observed (4S,5R)-product after hydrolysis.
Entry R1/R2/R3/R4
6/7
t
Yield[b] ar[c]
[%]
ee[d]
[%]
[h]
1
2
3
4
5
6
7
8
CO2Me/Ph/Me/H
CO2Me/Ph/nPr/H
CO2Me/Ph/nC10H21/H
CO2Me/Ph/Bn/H
CO2Me/Ph/iPr/H
CO2Me/Ph/Me/Me
CO2Me/Ph/Ph/H
CO2Et/Ph/Bn/H
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
5
6
6
91
91
90
95
72
51
64
92
93
88
90
92
91
96
94
93
95
92
99
82
97
80:20 94
90:10 93
87:13 94
91:09 95
76:24 93
85:15 91
64:36 35[e]
91:09 95
90:10 96
85:15 94
86:14 91
88:12 94
88:12 92
82:18 92
79:21 98
62:38 85
67:33 94
66:34 92
70:30 93
56:44 86
66:34 94
6
48
48
5
6
6
24
5
5
6
6
4
8
5
4
5
24
2
9
CO2iPr/Ph/Bn/H
10
11
12
13
14
15
16
17
18
19
20
21
CO2Me/4-OMeC6H4/Bn/H
CO2Me/4-MeC6H4/Bn/H
CO2Me/4-CF3C6H4/Bn/H
CO2Me/4-ClC6H4/Bn/H
CO2Me/2-ClC6H4/Bn/H
CO2Et/Me/Bn/H
P(O)
P(O)
P(O)
P(O)
P(O)
P(O)
N
p[f]
q[f]
r[f]
s[f]
t[f]
[a] Unless otherwise indicated, all reactions were carried out with enone
3 (0.20 mmol) and aldehyde 4 (0.24 mmol) by using the catalyst modules
1j (0.010 mmol, 5 mmol%) and 2a (0.010 mmol, 5 mmol%) at room
temperature in toluene. [b] Yield of the isolated product 6 after column
chromatography. [c] Anomeric ratio as determined by 1H NMR spectro-
scopic analysis of the crude 6. [d] Determined by HPLC analysis of the
oxidized product 7 (67–80% yield). Only a single diastereomer was ob-
tained after the oxidation according to the 1H NMR spectra of the crude
product. [e] The opposite enantiomer is obtained as the major product in
this case. [f] The loading of the catalyst modules (1j and 2a) was
10 mmol% each.
Scheme 2. Proposed transition state of the MDO-catalyzed hetero-Diels–
Alder reaction.
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J. C.-G. Zhao et al.
Xu, Chem. Eur. J. 2010, 16, 801; k) J. A. Fuentes, T. Lebl, A. M. Z.
Slawin, M. L. Clarke, Chem. Sci. 2011, 2, 1997; l) G. Ma, A. Bartos-
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2012, 18, 8008.
In summary, we have developed a highly enantioselective
hetero-Diels–Alder reaction of electron-deficient enones
and aldehydes by using MDOs. The reactivity and stereose-
lectivity of proline derivatives may be dramatically im-
proved through the formation of MDOs. A new NOESY
study also reveals the most likely structure for these self-as-
sembled catalysts.
[3] For reviews on self-assembled organocatalysts, see: a) J.-F. Briere, S.
Oudeyer, V. Dalla, V. Levacher, Chem. Soc. Rev. 2012, 41, 1696;
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Goldman, J. C.-G. Zhao, Chin. J. Chem. 2012, 30, 2624.
Experimental Section
General procedure: (2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid
(OHIC, 1j) (1.7 mg, 0.010 mmol, 5 mol%) and quinidine thiourea 2a
(5.9 mg, 0.010 mmol, 5 mol%) were added to a stirred solution of propa-
nal (4a) (13.9 mg, 0.24 mmol) in toluene (0.5 mL) at room temperature.
After the mixture had been stirred for 10 min, a solution of b,g-unsaturat-
ed-a-ketoester 3a (0.20 mmol) in toluene (0.5 mL) was added and the
stirring was continued at RT (for b,g-unsaturated a-ketophosphonate
substrates (0.10 mmol), propanal 4a (29.0 mg, 0.50 mmol) was used with
10 mol% of the two catalyst modules in toluene (0.1 mL)). The progress
of the reaction was monitored by TLC analysis. Upon completion, the
crude reaction mixture was transferred to a silica gel column and eluted
with a 15–20% ethyl acetate/hexane mixture. After the evaporation of
the solvent, the product 6a was obtained as a colorless gummy liquid
(45.1 mg, 0.18 mmol, 91% yield). It was then oxidized by PCC (196.1 mg,
0.91 mmol) in CH2Cl2 (1.0 mL) at RT for 48 h to the corresponding lac-
tone 7a. Product 7a was again purified by flash column chromatography
(32.3 mg, 0.13 mmol, 71% yield) and its ee value was determined to be
94% by HPLC analysis by using a ChiralPak IB column.
[5] For examples of amine-catalyzed hetero-Diels–Alder reactions, see:
a) K. Juhl, K. A. Jørgensen, Angew. Chem. 2003, 115, 1536; Angew.
Chem. Int. Ed. 2003, 42, 1498; b) S. Samanta, L. Krause, T. Mandal,
C.-G. Zhao, Org. Lett. 2007, 9, 2745; c) J. Wang, F. Yu, X.-J. Zhang,
D.-W. Ma, Org. Lett. 2008, 10, 2561; d) B. Han, J.-L. Li, C. Ma, S.-J.
Zhang, Y.-C. Chen, Angew. Chem. 2008, 120, 10119; Angew. Chem.
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T.-Y. Liu, Y.-C. Chen, Angew. Chem. 2009, 121, 5582; Angew. Chem.
Int. Ed. 2009, 48, 5474; f) S. Kobayashi, T. Kinoshita, H. Uehara, T.
Sudo, I. Ryu, Org. Lett. 2009, 11, 3934; g) J.-H. Lao, X.-J. Zhang, J.-
J. Wang, X.-M. Li, M. Yan, H.-B. Luo, Tetrahedron: Asymmetry
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[6] For more details, please see the Supporting Information.
[7] Although the possibility of a tandem Michael-acetalization reaction
cannot be ruled out for the formation of the final product, we never
observed the expected Michael product in the 1H NMR spectra
during the reaction.
[8] a) S. J. Danishefsky, M. T. Bilodeau, Angew. Chem. 1996, 108, 1482;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1380; b) K. C. Nicolaou, H. J.
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[9] OHIC (1j) has never been used as a catalyst in hetero-Diels–Alder
reactions; for its application in Michael reactions, see: a) J.-W. Xie,
L. Yue, D. Xue, X.-L. Ma, Y.-C. Chen, Y. Wu, J. Zhu, J.-G. Deng,
Chem. Commun. 2006, 1563; b) R.-S. Luo, J. Weng, H.-B. Ai, G. Lu,
A. S. C. Chan, Adv. Synth. Catal. 2009, 351, 2449; c) D. Roca-Lopez,
P. Merino, F. J. Sayago, C. Cativiela, R. P. Herrera, Synlett 2011, 249;
for its application in aldol reactions, see: d) X. Tang, B. Liegault, J.-
L. Renaud, C. Bruneau, Tetrahedron: Asymmetry 2006, 17, 2187.
[10] Control experiments conducted with 1j alone as the catalyst gave
no conversion of the substrate. For details, please see the Supporting
Information.
[11] The absolute stereochemistry of compound 7g was determined by
comparing the measured optical rotation data with those reported
in: D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D.
Smith, J. Am. Chem. Soc. 2011, 133, 2714.
[12] A similar phenomenon was also observed in the hetero-Diels–Alder
reaction of b,g-unsaturated a-ketophosphonate, see ref. [5b].
Acknowledgements
The authors thank the National Science Foundation (grant no. CHE
0909954) and the Welch Foundation (grant no. AX-1593) for the financial
support of this research. The authors also thank Dr. J. Walmsley (UTSA)
for the fruitful discussions regarding the NOESY experiments.
Keywords: aldehydes · Diels–Alder reaction · ketoesters ·
ketophosphonate · organocatalsis
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Received: January 16, 2013
Published online: && &&, 0000
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Inverse-Electron-Demand Hetero-Diels–Alder Reactions
COMMUNICATION
Synthetic Methods
D. Sinha, S. Perera,
J. C.-G. Zhao* ................ &&&& — &&&&
MDO rocks! Proline and (2S,3aS,7aS)-
octahydro-1H-indole-2-carboxylic acid
are both poor catalysts for the inverse-
electron-demand hetero-Diels–Alder
reactions between aldehydes and elec-
tron-deficient enones. However, form-
ing modularly designed organocatalysts
(MDOs) through their self-assembly
Highly Enantioselective Inverse-Elec-
tron-Demand Hetero-Diels–Alder
Reactions Catalyzed by Modularly
Designed Organocatalysts
with cinchona alkaloid-derived thiour-
eas can dramatically improve the effi-
ciency of these unfunctional catalysts
(see scheme; PCC=pyridinium chloro-
chromate).
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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ÞÞ
These are not the final page numbers!