Rational design of organocatalyst: Highly stereoselective michael addition of cyclic ketones to nitroolefins

Article abstract of DOI:10.1021/ol900330p

A remarkable organocatalyst that facilitates the asymmetric Michael addition of cyclic ketones to nitroolefins in excellent stereoselectivities (98:2 to > 99:1 dr, 92% to > 99% ee) has been developed and afforded various types of optically active nitroalk

Full text of DOI:10.1021/ol900330p

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1927-1930
Rational Design of Organocatalyst:
Highly Stereoselective Michael Addition
of Cyclic Ketones to Nitroolefins
Bin Tan, Xiaofei Zeng, Yunpeng Lu, Pei Juan Chua, and Guofu Zhong*
DiVision of Chemistry & Biological Chemistry, School of Physical & Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link, Singapore 637371, Singapore
guofu@ntu.edu.sg
Received February 14, 2009
ABSTRACT
A remarkable organocatalyst that facilitates the asymmetric Michael addition of cyclic ketones to nitroolefins in excellent stereoselectivities
(98:2 to >99:1 dr, 92% to >99% ee) has been developed and afforded various types of optically active nitroalkane derivatives of synthetic and
biological importance. The extremely simple and practical operational procedure at room temperature increases the attractiveness of this
reaction.
The important advances made in enantioselective catalytic
C-C and C-H bond-forming reactions generally depend on
the careful and time-consuming optimization of the structure
of the chiral catalyst so as to achieve good to excellent
selectivity and catalytic activity. Very subtle changes to the
catalyst structure can often lead to large and unpredictable
differences to the performance of the catalyst, especially in
terms of the enantioselectivity.1
ture, an additive and a large excess of organic solvents.2,3
Since the beginning of the new millennium, a great number
of pyrrolidine-type asymmetric organocatalysts have been
reported.4-6 The cyclic five-membered secondary amine
structure of these compounds is now regarded as one of the
“privileged” backbones for asymmetric catalysis. The general
strategies used in designing a set of new catalyts are
represented below.
The Michael addition reaction, being one of the most
general and versatile methods for formation of C-C bonds
in organic synthesis, has received much attention in the
development of enantioselective catalytic protocols. Most of
the efforts aimed at achieving asymmetric versions of this
process by using chiral organocatalysts not only showed
moderate enantioselectivity but also required low tempera-
(2) (a) Coquiere, D.; Feringa, B. L.; Roelfes, G. Angew. Chem., Int.
Ed. 2007, 46, 9308. (b) Lubkoll, J.; Wennemers, H. Angew. Chem., Int.
Ed. 2007, 46, 6841. (c) Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O.
Org. Lett. 2006, 8, 6099. (d) Sasamoto, N.; Dubs, C.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 14010. (e) Mekonnen, A.;
Carlson, R. Eur. J. Org. Chem. 2006, 2005. (f) List, B.; Pojarliev, P.; Martin,
H. J. Org. Lett. 2001, 3, 2423. (g) Tsogoeva, S. B.; Wei, S. Chem. Commun.
2006, 1451. (h) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
7170. (i) Clarke, M. L.; Fuentes, J. A. Angew. Chem., Int. Ed. 2007, 46,
930. (j) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701
.
(1) For a review, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138. (b) Gaunt, M. J.; Johansson, C. C.; McNally, A.; Vo,
N. T. Drug DiscoVery Today 2007, 12, 8. (c) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719. (d) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638. (e) Barbas, C. F., III. Angew. Chem., Int. Ed. 2007,
46, 42. (f) Asymmetric Organocatalysis; Berkessel, A., Gro¨ger, H., Eds.;
Wiley-VCH: Weinheim, 2005. (g) EnantioselectiVe Organocatalysis; Dalko,
P. I., Ed.;Wiley-VCH: Weinheim, 2007.
(3) Enamine-based Michael reaction of carbonyl compounds with
nitroolefins: (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260. (b) Ishii, T.; Fujioka, S.; Sekiguchi, Y.;
Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558. (c) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808.
(d) Xu, Y.; Co´rdova, A. Chem. Commun. 2006, 460. (e) Pansare, S. V.;
Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624. (f) Enders, D.; Chow, S.
Eur. J. Org. Chem. 2006, 4578
.
10.1021/ol900330p CCC: $40.75
Published on Web 04/03/2009
 2009 American Chemical Society

1.9901 Å, and the CdC bond of the nitrostyrene is elongated
to 1.4205 Å; the hydrogen bond distance mediated by water
is reasonable. In the gas phase, the energy of TS1 is 4.36
kcal/mol lower than that of TS2 due to the fact that the bulky
phosphine group has less steric interaction with the six-
membered ring in the syn-enamine.
Thus far, the design and development of more efficient
chiral organocatalysts and practical approaches in Michael
additions to achieve higher enantio- and diastereoselec-
tivities remains a major challenge in synthetic organic
chemistry. Therefore, we have developed and designed a
set of new catalysts. Our design of catalyst II comprises
of this “privileged” chiral pyrrolidine unit covalently
adhered to a phosphine oxide moiety,7 so that the former
can serve as catalytic site and the latter as chiral-induction
group that contains a very polar PdO bond. In order to
test the feasibility of the above-mentioned catalyst,
nitroolefins were chosen as Michael acceptors due to the
polar nitro group and cyclohexanone as a donor for
forming enamine. The strong polar PdO group may
interact favorably with the nitro group via dipole interac-
tions mediated by water to allow greater control in enantio-
and diastereoselectivities (Figure 1).
Model experiments were conducted with nitrostyrene and
cyclohexanone.8 Initially, the conjugated addition reaction
was examined in a few solvents at room temperature with
catalyst II. Only moderate yields of the desired adduct were
observed in polar solvents (Table 1, entries 4-6), whereas
Table 1. Effects of Solvents and Catalysts on the Addition of
Cyclohexanone to trans-Nitrostyrenea
entry catalyst solvent time (h) yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
II
II
II
II
II
II
II
I
CH2Cl2
benzene
hexane
DMSO
MeOH
THF
neat
neat
neat
neat
24
24
24
24
24
24
16
16
16
6
67
86
98
41
62
61
99
99
77
98
99:1
>99:1
>99:1
97:3
97:3
98:2
>99:1
97:3
95:5
99
>99
>99
90
94
98
>99
91
17
9
III
II
10 e
97:3
96
a Unless otherwise noted, all reactions were conducted using nitroolefin
(0.3 mmol, 1.0 equiv) and cyclohexanone (1.5 mmol, 5.0 equiv) in the
presence of 15 mol % of catalyst at room temperature. b Isolated yield.
c Determined by 1H NMR of the crude mixture or HPLC. d Determined by
chiral HPLC analysis (chiralpak AS-H, hexane/2-propanol ) 85/15, 1.0
mL/min). e 30 mol % of catalyst II.
Figure 1. Structures and action of designed catalysts.
On the basis of this hypothesis, DFT calculations were
carried out. Two transition-state geometries are reported to
demonstrate the fact that hydrogen bonds formed with water
molecules are important factors in controlling the stereo-
chemistry (Figure 2). TS1 is a transition state from syn-
moderate to excellent yields with excellent enantioselectivi-
ties of the product were obtained in nonpolar solvents such
as benzene and hexane (entries 2 and 3). Although the up to
30 mol % of catalyst loading could dramatically increase
the reaction rate (entry 10), the diastereoselectivity and
enantioselectivity dropped. When the reaction was tested
under solvent-free conditions, we achieved almost quantita-
tive yield with over 99% enantiomeric excess (ee) and over
99:1 diastereomeric ratio (dr).
This initial finding strengthened our suggestion that the
polar bond PdO of the new catalyst is an important role for
the addition reaction. To further investigate the effects of
dipole interaction, we tested chiral catalysts I (without polar
bond) and III (bearing a PdS bond). Although moderate
yield and dr were obtained when nonpolar bond catalyst I
was used (Table 1, entry 9), there was almost no ee detected
in the product. When catalyst III containing a weaker polar
bond (PdS) was utilized, the yield was excellent but the dr
and ee were slightly decreased (Table 1, entry 8). These
results further demonstrated that the PdO bond in catalyst
Figure 2. DFT-calculated transition state TS1 (left) and TS2 (right).
enamine, while TS2 is anti-enamine. In TS1, the forming
C-C bond length between enamine and nitrostyrene is
1928
Org. Lett., Vol. 11, No. 9, 2009

II is indispensable in achieving excellent diastereoselectivity
and enantioselectivity.
Under the optimized conditions, a variety of nitroolefins
with different structures were investigated, and the results
are summarized in Table 2. Various styrene-type nitroolefins
indicated that they are good Michael acceptors to cyclohex-
anone. Furthermore, other cyclic ketones (1b and 1c) also
react smoothly with nitroolefin and maintained excellent
stereoselectivities (Scheme 1).
Scheme 1. Different Ketones Reacted with trans-Nitrostyene
Table 2. Michael Addition of Cyclohexanone with Nitroolefins
Catalyzed by II under Neat Conditions at Room Temperaturea
Based on the experimental results described above, the
stereochemical outcome may be accounted for by a synclinal
transition state assembly. We propose that the pyrrolidine
ring will first react with a carbonyl compound to form an
enamine. Subsequently, the PdO group, via a strong H-bond
mediated by water, will orientate the nitro group so that the
enamine will attack the nitro olefin from the Re-face to give
the highly enantio- and diastereoselective product. This
explanation is consistent with the experimental results. The
absolute configuration of 3h was determined by X-ray
crystallography (Figure 3).
a Unless otherwise noted, all reactions were conducted using nitroolefin
(0.3 mmol, 1.0 equiv) and cyclohexanone (1.5 mmol, 5.0 equiv) in the
presence of 15 mol % of catalyst II under neat conditions at room
temperature. b Isolated yield. c Determined by 1H NMR of the crude mixture
or HPLC. d Determined by chiral HPLC analysis (see the Supporting
Information).
reacted smoothly with cyclohexanone and excellent yields,
diastereoselectivities, and enantioselectivities (entries 1-10)
were obtained. Generally, aryl compounds containing electron-
withdrawing and electron-donating substituents influenced
the result slightly, especially in dr (up to >99:1) and ee (up
to >99%). The excellent enantioselectivities achieved for
the heteroaryl substrates (Table 2, entries 5-7) have also
Figure 3. X-ray crystal structure of 3h.
Performing such reactions on water9 could potentially give
rise to ideal reactions from a green chemistry perspective.
In our first attempt on water, although the stereoselectivity
Org. Lett., Vol. 11, No. 9, 2009
1929

does not change too much, low conversion and yield were
observed using catalyst II. When brine was used as a solvent,
excellent yield and high diastereo- and enantioselectivities
were provided. In these electrolyte-rich aqueous solutions,
the anion intermediate is readily complexed by metal cations,
which may contribute to the result (Scheme 2).
92% to >99% ee), hence producing various types of optically
active nitroalkane derivatives of synthetic and biological
importance.10 The new catalyst containing a pyrrolidine unit
and a phosphine oxide moiety is proven to be very important
in controlling the stereochemistry of the adducts.The ex-
tremely practical operational procedure that involves the
mixing of reactants with catalyst at room temperature
increases the attractiveness of this reaction. We hope that
more efficient and practical catalysts can be designed based
on the nature of the reaction and that this strategy may lead
to a range of enantiomeric reactions that involves rationally
designed catalysts.
Scheme 2. Michael Reaction in Aqueous Medium
Acknowledgment. Research support from the Ministry
of Education in Singapore (ARC12/07, no. T206B3225) and
Nanyang Technological University (SEP, RG140/06) is
gratefully acknowledged. We thank Dr. Yongxin Li from
Nanyang Technological University for the X-ray crystal-
lographic analysis.
In summary, we have developed a remarkably efficient
organocatalyst that facilitates the asymmetric Michael ad-
dition of cyclic ketones to nitroolefins in excellent yields
(87% to 99%) and stereoselectivies (98:2 to >99:1 dr and
Supporting Information Available: Experimental pro-
cedures, characterization, spectra, chiral HPLC conditions,
and X-ray crystallographic data (CIF file of 3h). This material
is available free of charge via the Internet at http://pubs.acs.org.
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L. J. Am. Chem. Soc. 2005, 127, 9285. (e) Martin, H. J.; List, B. Synlett
2003, 1901.
OL900330P
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