A new class of structurally rigid tricyclic chiral secondary amine organocatalyst: Highly enantioselective organocatalytic Michael Addition of aldehydes to vinyl sulfones

Article abstract of DOI:10.1021/ol102933q

A new class of chiral secondary amine organocatalyst was rationally designed as an efficient catalyst to catalyze the elusive Michael addition of aldehydes to vinyl sulfones. High yield and excellent enantioselectivities could be obtained at room temperature without having to resort to high catalyst loading, anhydrous solvents, and low temperatures. Efficient control of enamine conformation and face shielding as well as the rigid nature of the tricyclic skeleton, with an inherent chiral pocket, provide a well-organized chiral environment to effect this elusive reaction efficiently.(Figure Presented)

Full text of DOI:10.1021/ol102933q

ORGANIC
LETTERS
2011
Vol. 13, No. 5
876–879
A New Class of Structurally Rigid Tricyclic
Chiral Secondary Amine Organocatalyst:
Highly Enantioselective Organocatalytic
Michael Addition of Aldehydes
to Vinyl Sulfones
Jian Xiao,†,‡ Yun-Peng Lu,† Yan-Ling Liu,† Poh-Shen Wong,† and Teck-Peng Loh*,†
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, and Dalian Institute of
Chemical Physics, The Chinese Academy of Sciences, Dalian 116023, People’s Republic
of China
teckpeng@ntu.edu.sg
Received December 3, 2010
ABSTRACT
A new class of chiral secondary amine organocatalyst was rationally designed as an efficient catalyst to catalyze the elusive Michael addition of
aldehydes to vinyl sulfones. High yield and excellent enantioselectivities could be obtained at room temperature without having to resort to high
catalyst loading, anhydrous solvents, and low temperatures. Efficient control of enamine conformation and face shielding as well as the rigid
nature of the tricyclic skeleton, with an inherent chiral pocket, provide a well-organized chiral environment to effect this elusive reaction
efficiently.
In recent years, we have witnessed an exponential growth
in the field of organocatalysis. This is due to the many
advantages they can offer.1 Among the organocatalysts,
chiral secondary amines which involve enamine catalysis
have been used widely in many different organic transfor-
mations to generate products in high optical purities.
In addition to the widely employed naturally occurring
† Nanyang Technological University.
‡ The Chinese Academy of Sciences.
(1) (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, 2005. (b) Dalko, P. I., Ed. Enantioselective Organocata-
lysis; Wiley-VCH: Weinheim, 2007. (c) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138. (d) List, B. Chem. Commun. 2006, 819. (e)
Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001. (f) Barbas,
C. F., III. Angew. Chem., Int. Ed. 2008, 47, 42. (g) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
6138. (h) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (i) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev.
2009, 38, 2178. (j) MacMillan, D. W. C. Nature 2008, 455, 304. (k)
Westermann, B.; Ayaz, M.; Berkel, S. Angew. Chem., Int. Ed. 2010, 49,
846. (l) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
(2) For reviews, see: (a) List, B. Synlett 2001, 1675. (b) List, B.
Tetrahedron 2002, 58, 5573. (c) List, B. Acc. Chem. Res. 2004, 37, 548.
(d) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
580. (e) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904. For
pioneering work using proline as catalyst, see: (f) Eder, U.; Sauer, G.;
Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496. (g) Hajos, Z. G.;
Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (h) List, B.; Lerner, R. A.;
Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (i) Notz, W.; List,
B. J. Am. Chem. Soc. 2000, 122, 7386. (j) List, B.; Pojarliev, P.; Castello,
C. Org. Lett. 2001, 3, 573. (k) Sakthivel, K.; Notz, W.; Bui, T.; Barbas,
C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (l) Pidathala, C.; Hoang,
L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785.
r
10.1021/ol102933q
Published on Web 01/27/2011
2011 American Chemical Society

Scheme 1. Rationally Designed New Class of Chiral Secondary
Amine Organocatalyst 4 with a Chiral Pocket
Figure 1. Typical chiral secondary amine organocatalysts 1-3.
proline,2 chemists have also rationally designed several
other impressive chiral secondary amines as organocatalysts.
Representative examples are MacMillan’s imidazolidi-
nones catalyst 1,3 Hayashi and Jørgensen’s R,R-diarylpro-
linol ether catalyst 24 and Maruoka’s binaphthyl-based
chiral secondary amine catalyst 3,5 which were found to
induce high enantioselectivities in a large number of reac-
tions that proline failed (Figure 1). Despite these significant
progresses, there are still many limitations such as high
catalytic loading, low temperature, low enantioselectivity
and reactivity in many other reactions which could not be
resolved using existing organocatalysts. Therefore, there is
a tremendous amount of effort directed at the design of
more efficient organocatalysts.1 Toward solving some of
these limitations, we rationally designed a new class of
Scheme 2. Synthesis of Chiral Organocatalyst 4
(3) (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582. (b) Jang, H.-Y.; Hong, J.-
B.; MacMillan, D.W. C. J. Am. Chem. Soc. 2007, 129, 7004. (c) Kim, H.;
MacMillan, D.W. C. J. Am. Chem. Soc. 2008, 130, 398. (d) Lelais, G.;
MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79.
chiral secondary amine 4 (Scheme 1) based on the naturally
occurring hexahydropyrrolo[2,3-b]indole skeleton,6 which
has been identified as a new privileged chiral skeleton for
asymmetric catalysis in our group.7 In our new design of 4,
in addition to the intrinsic chiral pocket brought about by
the conformation of the tricyclic skeleton, the ethyl carba-
mate group serves to control the conformation of the
enamine while the bulky naphthyl group efficiently shields
the top face of the pocket. It is anticipated that the unique
rigid tricyclic structure, together with the inherent hydro-
phobic pocket, will bestow upon catalyst 4 more promising
and superior properties as compared to other chiral sec-
ondary amine catalysts. In this paper, we report a new class
of organocatalyst 4 with high potential as demonstrated in
the highly enantioselective organocatalytic Michael reac-
tion of aldehydes to vinyl sulfones.
Catalyst 4 could be easily prepared in four steps from 5
as shown in Scheme 2. DCC coupling of 5 with 1-naphthol
furnished 6, which was treated with TFA to afford an endo
and exo mixture of 7. Reaction of 7 with ethyl chlorofor-
mate in the presence of sodium carbonate, followed by
hydrogenation, gave the desired catalyst 4 in good yield.
The unique structure and stereochemistry of 4 has been
unambiguously confirmed by X-ray crystallography.
X-ray crystallographic analysis indicates that there is a
face tilted-T orientation of the naphthyl and phenyl rings
(4) For reviews, see: (a) Palomo, C.; Mielgo, A. Angew. Chem., Int.
Ed. 2006, 45, 7876. (b) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3,
922. For the pioneering work, see: (c) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (d) Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794. (e) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjasgaard,
ꢀ
A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (f) Franzen,
J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.;
Jørgensen, A. K. J. Am. Chem. Soc. 2005, 127, 18296.
(5) For reviews, see: (a) Maruoka, K. Bull. Chem. Soc. Jpn. 2009, 82,
917. (b) Kano, T.; Maruoka, K. Chem. Commun. 2008, 5465. For
selected examples, see: (c) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K.
Angew. Chem., Int. Ed. 2005, 44, 3055. (d) Kano, T.; Tokuda, O.; Takai,
J.; Maruoka, K. Chem. Asian J. 2006, 1, 210. (e) Kano, T.; Yamaguchi,
Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1738. (f) Kano, T.;
Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127,
16408. (g) Kano, T.; Yamaguchi, Y.; Maruoka, K. Angew. Chem., Int.
Ed. 2009, 48, 1838.
(6) For reviews of natural products containing hexahydropyrrolo
[2,3-b]indole, see: (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40,
151. (b) Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.; Alvarez, M.
ꢀ
Chem.-Eur. J. 2011, DOI: 10.1002/chem.201001451. For cinchona alkaloids-
derived catalysts, see: (c) Tian, S. K.; Chen, Y.; Hang, J.; Tang, L.; McDaid,
ꢀ
P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (d) Kacprzak, K.; Gawronski,
J. Synthesis 2001, 961. For the pioneering work using natural product
nornicotine as a catalyst, see: (e) Dickerson, T. J.; Janda, K. D. J. Am.
Chem. Soc. 2002, 124, 3220. (f) Brogan, A. P.; Dickerson, T. J.; Janda, K.
D. Chem. Commun. 2007, 4952. (g) Rogers, C. J.; Dickerson, T. J.;
Brogan, A. P.; Janda, K. D. J. Org. Chem. 2005, 70, 3705. (h) Dickerson,
T. J.; Lovell, T.; Meijler, M. M.; Noodleman, L.; Janda, K. D. J. Org.
Chem. 2004, 69, 6603. (i) Rogers, C. J.; Dickerson, T. J.; Janda, K. D.
Tetrahedron 2006, 62, 352.
(7) (a) Xiao, J.; Xu, F. X.; Lu, Y. P.; Loh, T. P. Org. Lett. 2010, 12,
1220. (b) Xiao, J.; Wong, Z. Z.; Lu, Y. P.; Loh, T. P. Adv. Synth. Catal.
2010, 352, 1107. (c) Xiao, J.; Liu, Y. L.; Loh, T. P. Synlett 2010, 2029. (d)
Xiao, J.; Loh, T. P. Org. Lett. 2009, 11, 2876. (e) Xiao, J.; Loh, T. P.
Synlett 2007, 815. (f) Xiao, J.; Loh, T. P. Tetrahedron Lett. 2008, 49,
7184. For a discussion of “privileged” chiral catalyst, see: (g) Yoon,
T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
˚
with Ha lying 2.77 A perpendicularly under the face of the
phenyl ring with an inter-ring angle of 77° (Figure 2). This
Org. Lett., Vol. 13, No. 5, 2011
877

Table 1. Evaluation of 4 as a Catalyst for the Asymmetric
Michael Addition of Isovaleraldehyde to Vinyl Sulfonea
yield (%)b
ee (%)c
Figure 2. Crystal structure of organocatalyst 4.
entry
loading (mol %)
solvent
1
10
10
10
10
10
10
10
5
MeOH
THF
10
42
39
-
-
-
98
preferred conformation is primarily driven by the relief of
torsional strain, further enhanced by attractive edge-to-
face π-π interactions.8
2
3
CHCl3
MeCN
CH2Cl2
<10
16
4
5
53
Asa representativeexample, wefocus on the asymmetric
Michael addition of aldehydes to vinyl sulfones. If success-
ful, this method will provide facile access to various
optically pure sulfones, which are featured widely in many
bioactive molecules,9 and after desulfonylation, a wide
range of optically pure aldehydes will be obtained, which
offer analternative solution tothe problematic asymmetric
alkylation of aldehydes.10 Despite its apparent importance
in organic synthesis, the highly enantioselective Michael
addition of aldehydes to vinyl sulfones still remains a great
challenge.11 Only limited examples afford high enantio-
selectivities and most of them suffered from using high
catalystloading (up to25mol %), low temperature (-60to
0 °C) and anhydrous solvents, which limit their applic-
ability to organic synthesis.
d
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
<10
66
-
7
99
99
99
95
-
e
8
63
9
5
99
f
10
11
12
5
71
g
5
<10
51
2
97
a Reactions were conducted with 3 equiv of aldehyde, 1 equiv of vinyl
sulfone at room temperature in the presence of catalyst. b Isolated yield.
c ee was determined by chiral HPLC on a chiral stationary phase. d 3-
NO2PhCO2H (10 mol %) was added. e Aldehyde (4 equiv) was used.
f Aldehyde (2 equiv) was used. g Anhydrous CH2Cl2 was used or
˚
molecular sieves (4 A) was added.
temperature in AR grade CH2Cl2 (Table 1, entry 5).
However, for other organic solvents, the results were not
satisfactory (Table 1, entries 1-4). The addition of acid
was not beneficial to this reaction (Table 1, entry 6). It was
found that excellent yield and enantioselectivity could be
obtained with only 5 mol % 4 and 3 equiv of isovaleralde-
hyde (Table 1, entries 7-10). Interestingly, use of anhy-
drous solvent or addition of molecular sieves impede this
reaction, which is different from the previous report
(Table 1, entry 11). Catalyst 4 still shows high reactivity
and retains the enantioselectivity even when the catalyst
loading was decreased to 2 mol % (Table 1, entry 12).
Next, various substrates were examined and the reaction
exhibited broad applicability in terms of the aldehyde
substrate. The adducts were obtained in good yields and
excellent enantioselectivities (up to 99% ee) in the presence
of 5 mol % or 10 mol % of catalyst 4 (Table 2).12 Further
experimentation showed that when the naphthyl group
was replaced by a methyl, phenyl and 2-(1-adamantyl)-4-
methylphenyl group in catalyst 4, the chiral product 10f
could be obtained in 81, 89, and 88% ee, respectively.
Under the same conditions, however, MacMillan’s imida-
zolidinones catalyst 1 gave the same product in low yield
and low ee.13
Attheonset, the Michael addition of isovaleraldehyde to
vinyl sulfone was chosen as the testing ground. To our
delight, the desired product could be obtained in 53% yield
and 98% ee in the presence of 10 mol % catalyst 4 at room
(8) (a) Jennings, W. B.; Farrell, B. M.; Malone, J. F. Acc. Chem. Res.
2001, 34, 885. (b) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew.
Chem., Int. Ed. 2003, 42, 1210.
(9) For reviews, see: (a) El-Awa, A.; Noshi, M. N.; Jourdin, X. M.;
Fuchs, P. L. Chem. Rev. 2009, 109, 2315. (b) Meadows, D. C.; Gervay-
Hague, J. Med. Res. Rev. 2006, 26, 793. (c) Trost, B. M. Bull. Chem. Soc.
ꢀ
Jpn. 1988, 61, 107. (d) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
For asymmetric organocatalysis with sulfones, see: (e) Nielsen, M.;
~
Jacobsen, C. B.; Holub, N.; Paixao, M. W.; Jøgensen, K. A. Angew. Chem.,
Int. Ed. 2010, 49, 2668. (f) Zhu, Q.; Lu, Y. Aust. J. Chem. 2009, 62, 951. (g)
ꢀ
Alba, A. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018.
(10) (a) Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 1360. (b)
Alba, A.-N.; Viciano, M.; Rios, R. ChemCatChem 2009, 1, 437.
ꢀ
ꢀ
(11) (a) Mosse, S.; Alexakis, A. Org. Lett. 2005, 7, 4361. (b) Mosse, S.;
Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559.
(c) Quintard, A.; Bournaud, C.; Alexakis, A. Chem.-Eur. J. 2008, 14,
ꢀ
7504. (d) Mosse, S.; Alexakis, A.; Mareda, J.; Bollot, G.; Bernardinelli,
G.; Filinchuk, Y. Chem.-Eur. J. 2009, 15, 3204. (e) Landa, A.; Maestro,
M.; Masdeu, C.; Puente, A.; Vera, S.; Oiarbide, M.; Palomo, C. Chem.-
Eur. J. 2009, 15, 1562. (f) Quintard, A.; Alexakis, A. Chem.-Eur. J.
2009, 15, 11109. (g) Zhu, Q.; Lu, Y. Org. Lett. 2008, 10, 4803. (h)
Quintard, A.; Belot, S.; Marchal, E.; Alexakis, A. Eur. J. Org. Chem.
2010, 5, 927. For generation of quaternary carbon centers, see: (i) Alba,
A.-N. R.; Companyo, X.; Valero, G.; Moyano, A.; Rios, R. Chem. -Eur.
J. 2010, 16, 5354. (j) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 2235. (k) Liu,
T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen,
Y.-C. Org. Biomol. Chem. 2006, 4, 2097. (l) Moteki, S. A.; Xu, S.;
Arimitsu, S.; Maruoka, K. J. Am. Chem. Soc. 2010, 132, 17074. For a
tandem reaction, see: (m) Chua, P. J.; Tan, B.; Yang, L. M.; Zeng, X. F.; Zhu,
D.; Zhong, G. F. Chem. Commun. 2010, 46, 7611. For asymmetric Michael
addition of aldehydes to vinyl sulfones in water, see ref 7c.
(12) Epimerization of the aldehydes products was observed during
the purification step; therefore, the corresponding aldehydes adducts
were reduced to alcohols for determination of yield and ee.
(13) For instance, the product 10a was obtained only in 30% yield
and 31% ee in the presence of 10 mol % 1.
878
Org. Lett., Vol. 13, No. 5, 2011

Table 2. Asymmetric Michael Addition of Aldehydes to Vinyl
Sulfonea
Figure 3. Lowest energy enamine conformation 3A and 3B.
entry
R
product
yield (%)b
ee (%)c
1
CH3
CH3
10a
10a
10b
10b
10c
10c
10d
10d
10e
10e
10f
82
59
66
71
56
88d
49
93
55
60
71
99
95
66
92
96
93
94
94
95
92
92
90
93
91
99
93
97
2
3
C2H5
4
C2H5
5
C3H7
6
C3H7
7
C4H9
8
C4H9
9
C6H13
C6H13
C7H15
i-Pr
10
11
12
13
14
10g
10h
10i
PhCH2
BnO(CH2)2
Figure 4. Proposed Transition State C.
a Reactions were conducted with 0.1 mmol vinyl sulfone, 0.3 mmol
aldehyde and 5 mol % (entries 1,3,5,7,9) or 10 mol % 4 (entries
2,4,6,8,10-14) at room temperature. b Yield of the isolated products.
c ee was determined by HPLC analysis on chiral stationary phases after
purification. d The stereochemistry has been assigned R configuration
by X-ray crystallography, see the Supporting Information for details.
In summary, we have developed a new class of chiral
secondary amine organocatalyst 4 which can catalyze the
elusive Michael addition of aldehydes to vinyl sulfones in
good yields and excellent enantioselectivities. The desired
chiral products could be obtained with high stereocontrol
at room temperature without having to resort to high
catalyst loading, anhydrous solvents and low tempera-
tures. Efficient control of enamine conformation and face
shielding as well as the rigid nature of the tricyclic skeleton,
with an inherent chiral pocket provide a well-organized
chiral environment to enable this elusive reaction to pro-
ceed smoothly. This chiral pocket directed asymmetric
enamine catalysis opens new perspectiveand willfindmore
application in asymmetric catalysis.
To probe the mechanism of this reaction, eight possible
enamine geometries and the relative orientation of
naphthalene were subjected to DFT calculation. The most
stable conformation is syn enamine conformation 3A with
the naphthalene ring puckered in the chiral pocket, which
is more favored by 2.64 kcal/mol than the second lower
energy conformation 3B with the naphthalene ring stretch-
ing out (Figure 3).14 In addition to the relief of torsional
strain, a weak hydrogen bond interaction between hydro-
gen in the naphthalene ring and the oxygen in the ester
group was found to lock the naphthalene ring.
Acknowledgment. We thank Dr. Yongxin Li (Nanyang
Technological University) for X-ray analyses. We grate-
fully acknowledge Nanyang Technological University and
Ministry of Education Academic Research Fund Tier 2
(No. T207B1220RS) for the funding of this research.
On the basis of the above analysis and the observed
stereochemistry of the Michael product, we proposed a
plausible transition state model C. In this transition state
model, the ethyl carbamate group favors the enamine
conformation 3A and the bulky naphthyl group efficiently
shields the Si face of the enamine to force the vinyl
sulphone attack from the Re face to afford the product
in R configuration (Figure 4).
Supporting Information Available. Additional experi-
ment procedures, spectrum data for reactions products
and 2 CIF files. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) See Supporting Information for the calculation details.
Org. Lett., Vol. 13, No. 5, 2011
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