Asymmetric Michael addition mediated by novel cinchona alkaloid-derived bifunctional catalysts containing sulfonamides

Article abstract of DOI:10.1021/ol802486m

(Chemical Equation Presented) Novel cinchona alkaloid-derived bifunctional organocatalysts containing sulfonamide groups were utilized to promote Michael addition of bicyclic α-substituted β-ketoesters to nitroolefins. The desired Michael adducts with all

Full text of DOI:10.1021/ol802486m

ORGANIC
LETTERS
2009
Vol. 11, No. 2
437-440
Asymmetric Michael Addition Mediated
by Novel Cinchona Alkaloid-Derived
Bifunctional Catalysts Containing
Sulfonamides
Jie Luo,† Li-Wen Xu,†,§ Robyn Aik Siew Hay,† and Yixin Lu*,†,‡
Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute,
National UniVersity of Singapore, 3 Science DriVe 3, Republic of Singapore, 117543
and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry
of Education, Hangzhou Normal UniVersity, Hangzhou 310012, P. R. China
chmlyx@nus.edu.sg
Received October 28, 2008
ABSTRACT
Novel cinchona alkaloid-derived bifunctional organocatalysts containing sulfonamide groups were utilized to promote Michael addition of
bicyclic r-substituted ꢀ-ketoesters to nitroolefins. The desired Michael adducts with all-carbon quaternary centers were constructed in high
yield and with excellent enantioselectivity, demonstrating the great potential of cinchona alkaloid-derived sulfonamides in asymmetric catalysis.
The past two decades have witnessed a terrific advancement
of chiral bifunctional catalysts.1 Over the years, chemists
have designed and developed many elegant and remarkably
effective bifunctional catalytic systems for asymmetric
synthesis, such as Corey’s CBS catalysts,2 Noyori’s DAIB
for dialkyl zinc addition,3 Shibasaki’s hetero- and homobi-
metallic catalysts,4 Jacobsen’s metal-salen complexes,5 and
Trost’s dinuclear zinc complex,6 among others.
Asymmetric organocatalysis has progressed astonishingly
in the past few years,7 and many impressive bifunctional
organocatalysts have emerged. In particular, the utilization
of thiourea in bifunctional oragnocatalysts has been shown
to be extremely effective,8 presumably due to the favorable
† Department of Chemistry, National University of Singapore.
‡ Medicinal Chemistry Program, Life Sciences Institute, National
University of Singapore.
§ Hangzhou Normal University.
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10.1021/ol802486m CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society

double-hydrogen-bonding interactions between thiourea moi-
eties and the substrates. Very recently, Rawal and co-workers
disclosed the use of a novel cinchona alkaloid-based squara-
mide as an effective hydrogen bond donor catalyst for the
conjugate addition of 1,3-dicarbonyl compounds to nitroole-
fins.9 N-Sulfonamides, containing an acidic hydrogen, rep-
resent a versatile structural scaffold that can be used for fine-
tuning the structures of organocatalysts. Validity of single-
hydrogen-bonding interactions of N-sulfonamide in asymmetric
organocatalysis has been demonstrated recently. Wang and
co-workers reported that pyrrolidine sulfonamide was an
efficient catalyst in R-aminoxylation, aldol and Mannich
reactions, R-sulfenylations, R-selenenylation, and Michael
addition of aldehydes to nitrostyrenes.10 Berkessel11 and
Adolfsson12 also reported the use of proline N-sulfonamide
catalyst in aldol and amination reactions, respectively.
Given the proven ability of thiourea-containing bifunc-
tional catalysts and efficient catalysis involving hydrogen
bonding interaction in N-sulfonamides, we became interested
in developing novel bifunctional organocatalysts combining
a tertiary amino group and N-sulfonamide moiety. Cinchona
alkaloids are privileged organic catalysts,13 which are
remarkably effective and versatile in asymmetric
catalysis;8b,14 quinidine was therefore chosen as a chiral
structural scaffold in our studies. We hypothesize that
incorporating N-sulfonamides into quinidine structural scaf-
fold could result in bifunctional organocatalysts with novel
and interesting activities.15
Table 1. Screening of Organocatalysts for the Asymmetric
Michael Additions to Nitrostyrene 2a
Construction of quaternary stereocenters is considered to
be one of the most challenging tasks in organic synthesis,
(7) For general reviews on asymmetric organocatalysis, see: (a) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Berkessel, A.;
Groger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (c)
EnantioselectiVe Organocatalysis, Reactions and Experimental Procedures;
Dalko. P. I., Ed.; Wiley-VCH: Weinheim, 2007.
(8) For recent reviews on thiourea catalysts, see: (a) Doyle, A. G.;
Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (b) Connon, S. J. Chem.
Commun. 2008, 2499. For selected examples of thiourea-containing
bifunctional catalysts, see: (c) Huang, H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2006, 128, 7170. (d) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 6366. (e) Okino, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2003, 125, 12672. (f) Wang, J.; Li, H.; Yu, X.; Zu, L.;
Wang, W. Org. Lett. 2005, 7, 4293. (g) Li, B.-J.; Jiang, L.; Liu, M.; Chen,
Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (h) Vakulya, B.; Varga, S.;
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45, 7235. (b) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7243.
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a Reactions were performed with 0.05 mmol of 1, 0.055 mmol of
nitrostyrene, and 0.005 mmol of catalyst in 0.15 mL of toluene at room
temperature, unless otherwise specified. See Supporting Inforamtion for the
assignment of absolute configurations of the products. b QD, quinidine; Q,
quinine; CD, cinchonidine; C, cinchonine. c Isolated yield. d Determined by
1H NMR analysis of the crude products. e Reactions were performed in CH2Cl2
at room temperature. f Reactions were performed in CH2Cl2 at -40 °C.
(13) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
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126, 9906. (d) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem.
Soc. 2008, 130, 8134
.
(15) While we were preparing our manuscript, Chin and Song reported
a cinchona alkaloid-based sulfonamide catalyst-promoted methanolytic
desymmetrization of cyclic anhydride; see: Oh, S. H.; Rho, H. S.; Lee,
J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed.
2008, 47, 7872.
and significant progress has been made in this field over the
years.16 The conjugate addition of R-substituted dicarbonyl
compounds to suitable acceptor represents an important
438
Org. Lett., Vol. 11, No. 2, 2009

Table 2. QD-4-Catalyzed Direct Michael Addition of Bicyclic ꢀ-Ketoesters to Aryl Nitroolefinsa
a Reactions were performed with 0.05 mmol of ketoester, 0.055 mmol of nitroolefin, and 0.005 mmol of QD-4 in 0.15 mL of CH2Cl2. b Isolated yield.
c
Determined by H NMR analysis of the crude products. d Enantiomeric excess of the major isomer, determined by chiral HPLC analysis.
1
approach to generate all-carbon quaternary stereocenters.
Recently, Takemoto and co-workers applied their bifunc-
tional thiourea catalyst in enantio- and diastereoselective
Michael addition of dicarbonyl compounds to nitroolefins.17
In another elegant organocatalytic approach, Deng et al.
reported the construction of quaternary stereocenters by
conjugate addition of ꢀ-ketoesters mediated by cinchona
alkaloid catalyst.18 Herein, we wish to report a highly
enantioselective organocatalytic Michael addition of bicyclic
R-substituted ꢀ-ketoesters19 to nitroolefins for the asymmetric
construction of all-carbon quaternary stereocenters promoted
by novel cinchona alkaloid-derived N-tosylsulfonamide-
containing organocatalysts.
In our initial study, the Michael addition of R-substituted
cyclic ꢀ-ketoester (1) to nitrostyrene (2) was selected as a
model reaction (Table 1). Natural quinidine, quinine, cin-
chonidine, and cinchonine were not effective, affording
products with very low enantioselectivity (entries 1-4).
When quinidine-derived thiourea (QD-1) was used as the
(16) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591. (c) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (d)
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R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969.
(18) (a) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman,
B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (b) Wu, F.; Li, H.;
Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947.
(19) Michael additions of bicyclic R-substituted ꢀ-ketoesters to nitroole-
fins are rare in the literature, and only a couple of examples were reported
in ref 17.
(17) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
Org. Lett., Vol. 11, No. 2, 2009
439

catalyst, only moderate enantioselectivity was attainable
(entry 5). The 6′-demethylated quinidine (QD-2),20 proven
to be a powerful catalyst in a number of enantioselective
transformations, led to only moderate enantioselectivity
(entry 6). When the C9 hydroxy function in quinidine was
protected as a bulky tert-butyl ester, both the rate of reaction
and enantioselectivity dropped (entry 7). The fact that QD-1
and QD-2 were better catalysts in promoting asymmetric
Michael addition seemed to indicate the importance of
hydrogen bonding in the chiral induction. When N-tosylsul-
fonamide-containing catalyst QD-4 was tested, we were
delighted to find the desired Michael product was obtained
in quantitative yield and with good enantioselectivity (entry
8). Upon lowering the reaction temperature and performing
a solvent screening, good diastereoselectivity and excellent
enantioselectivity were achieved (entries 9 and 10). A number
of novel quinidine-based N-sulfonamides were prepared and
examined. Whereas QD-6 and QD-4 showed similar catalytic
effects, catalysts QD-5 and QD-7 were less effective (entries
11-13). Monocyclic ꢀ-ketoester 1b was an excellent sub-
strate, the Michael addition of which to nitroolefin yielded
adducts with exceptional diastereoselectivity and excellent
enantioselectivity (entries 14-16).21 The ester moiety in
ketoester seemed to have little influence on stereoselectivity
(entry 17). QD-6 could also effect the asymmetric additions
of ꢀ-ketonitrile and ꢀ-ketothioester to nitroolefin, although
only modest enantioselectivities were obtained (entries 18
and 20).
On the basis of the observed reactivity and experimental
results of the described reactions, we propose that the reaction
proceeds via a dual activation model. As shown in Figure 1,
the ketoester and nitroolefin may get activated simultaneously
through their interactions with cinchona alkaloid-derived
sulfonamides.
Figure 1. Proposed dual activation in the Michael addition.
In summary, new bifunctional organocatalysts (QD-4 to
QD-7) derived from cinchona alkaloid incorporating N-
sulfonamide were prepared. QD-4 was utilized to promote
the Michael addition of bicyclic R-substituted ꢀ-ketoesters
to nitroolefins, yielding highly functionalized all-carbon
quaternary Michael adducts with excellent enantioselectivity.
The studies carried out in this report demonstrated that single-
hydrogen-bonding activation is a powerful approach in
asymmetric organocatalysis, and we believe this finding can
contribute to the design of novel bifunctional catalysts.
Further development of relevant catalytic systems and the
full extension of the scope of this chemistry are in progress
in our laboratory and will be reported in due course.
After the initial screening of the catalysts and examination
of different reactions, we next focused on Michael reactions
involving bicyclic ꢀ-ketoesters of type 1a as donors, since
the Michael addition of such substrates to nitroolefin
remained to be largely unexplored. A wide range of aryl
nitroolefins and bicyclic R-substituted ꢀ-ketoesters were
employed in the QD-4-promoted organocatalytic Michael
reactions, and the Michael adducts were obtained in virtually
quantitative yield, with moderate to good diastereoselectivity
and excellent enantioselectivity (Table 2).
Acknowledgment. We thank the National University of
Singapore and the Ministry of Education (MOE) of Sin-
gapore (R-143-000-362-112) for generous financial support.
Supporting Information Available: Preparation and
characterization of novel cinchona-based sulfonamide cata-
lysts, representative experimental procedure for Michael
addition to nitroolefins, HPLC chromatogram, and analytical
data and NMR spectra of the Michael adducts. This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
126, 9906. (b) Marcelli, T.; Maarseveen, J. H. Van.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 7496, and refereces therein.
(21) The observed diasteroselectivity for this type of substrates is
consistent with the similar examples reported in ref 18a.
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