Desymmetrization of cyclohexadienones via bronsted acid-catalyzed enantioselective oxo-michael reaction

Article abstract of DOI:10.1021/ja100207s

Chemical Reaction Reprentation Desymmetrlzatlon of cyclohexadlenones via enantloselectlve oxo-Mlchael reaction catalyzed by chlral phosphoric add to afford highly enantloenrlched 1,4-dloxane and tetrahydrofuran derivatives In excellent yields has been realized. The newly established methodology allows the facile enantloselectlve synthesis of clerolndlclns C, D, and F.Copyright

Full text of DOI:10.1021/ja100207s

Published on Web 03/08/2010
Desymmetrization of Cyclohexadienones via Brønsted Acid-Catalyzed
Enantioselective Oxo-Michael Reaction
Qing Gu, Zi-Qiang Rong, Chao Zheng, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
Received January 10, 2010; E-mail: slyou@mail.sioc.ac.cn
Table 1. Screening of Chiral Phosphoric Acid Catalysts
The oxo-Michael addition reaction is one of the most important
methods for forming C-O bonds.1 In particular, intramolecular this
reaction provides a straightforward route to oxoheterocycles, which
are frequently encountered in biologically active natural products
and pharmaceuticals.2 However, the oxo-Michael reaction suffers
from drawbacks such as low reactivity and reversibility, which
impede the development of its corresponding asymmetric version.1
To date, only a few examples of highly enantioselective oxo-
Michael reactions, utilizing chiral secondary amines,3 thioureas,4
cinchona catalysts,5 or Lewis acids,6 have been described.
entrya
3, R
time (h)
conv. (%)b
ee (%)c
1
2
3
4
5
3a, phenyl
3b, SiPh3
3c, 1-naphthyl
3d, 2-naphthyl
0.6
2
0.5
0.5
0.6
1
3
10
3
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
4
-19
11
10
5
16
76
70
93
3e, 9-anthryl
6
7
3f, 9-phenanthryl
3g, 2,4,6-(iPr)3C6H2
3g, 2,4,6-(iPr)3C6H2
3g, 2,4,6-(iPr)3C6H2
3h, 2,6-(iPr)2-4-tBuC6H2
8d
9e
10e
Figure 1. Dearomatization/desymmetrization oxo-Michael reaction.
3
94
Desymmetrization reaction is one of the most common and powerful
methods for enantioselective synthesis of chiral molecules.7 When
coupled with a dearomatization process, it provides a facile construction
of optically active cyclic and polycyclic compounds from readily
available starting materials. Recently, this strategy was successfully
demonstrated in asymmetric desymmetrization of cyclohexadienone
using intramolecular Heck,8 Stetter,9 and Michael reactions,10 providing
efficient carbon-carbon bond-formation methods. Intrigued by these
elegant works, we envisaged that the desymmetrization and dearoma-
tization strategy might be suitable for the synthesis of enantioenriched
oxygen-containing polycyclic compounds by enantioselective oxo-
Michael reaction (Figure 1). We recently found that chiral phosphoric
acids11 can catalyze the enantioselective oxo-Michael reaction, provid-
ing highly enantioenriched 1,4-dioxane and tetrahydrofuran derivatives.
By this method, the natural products cleroindicin C, D, and F were
synthesized in a highly concise fashion. In this paper, we report our
study on this subject.
We began our studies by examining different chiral Brønsted
acids in the oxo-Michael reaction. Cyclohexadienone 2a, which is
readily prepared from p-cresol, was chosen as the model substrate.
As summarized in Table 1, with 10 mol % readily available chiral
phosphoric acid (3a-g) in CH2Cl2 at room temperature, the
reactions all proceeded smoothly to give the desired product 4a
with 4-76% ee (Table 1). Chiral phosphoric acid 3g bearing 2,4,6-
(iPr)3C6H2 groups proved to be an efficient catalyst, affording
product 4a with 76% ee (entry 7). Lowering the temperature to 0
°C did not improve the enantioselectivity of the reaction (70% ee;
entry 8). To our delight, an increase in ee was obtained by adding
4 Å molecular sieves (93% ee; entry 9). Chiral phosphoric acid 3h
bearing 2,6-(iPr)2-4-tBuC6H2 groups further improved the enanti-
oselectivity to 94% ee (entry 10). Varying the solvents disclosed
that CH2Cl2 was the optimal one (for details, see the Supporting
Information).
a Reaction conditions: 3 (10 mol %) and 2a (0.05 mol/L) in CH2Cl2
at room temperature. b Determined by 1H NMR analysis. c Determined
by HPLC analysis (Chiralpak OB-H). d At 0 °C. e With 4 Å molecular
sieves (activated) as an additive.
Under the above optimized reaction conditions, different substrates
were examined to test the generality of the current reaction. The results
are summarized in Table 2. The enantioselective intramolecular oxo-
Michael reaction was found to be general with a wide range of
substrates. The alkyl group at the 4-position of the cyclohexadienone
has great influence on the enantioselectivity and reactivity (entries
1-3). Both the enantioselectivity and reactivity decreased when a more
sterically hindered group was introduced (Me, 94% ee; Et, 78% ee;
iPr, 61% ee). Notably, neat substrates 2a-c underwent the cyclization
slowly, and carrying out the reaction immediately after the purification
of these substrates was important for obtaining the best enantioselec-
tivity. Delightfully, different aromatic groups at the 4-position were
all well-tolerated. The intramolecular cyclization of cyclohexadienone
derivatives 2d-l, containing either electron-donating or electron-
withdrawing groups on the phenyl ring, all led to their desired products
in 81-93% yield and 88-95% ee (entries 4-12). Notably, many of
the products are crystalline compounds, and optically pure products
(>99% ee) could be obtained after one simple recrystallization (entries
1, 4-8, 10, and 11). To determine the absolute configuration of the
products, crystals of enantiopure 4g were obtained, and single-crystal
X-ray analysis revealed the configuration to be (4aS, 8aS) (see the
Supporting Information).
The intramolecular oxo-Michael adduct can be readily transformed.
As shown in Scheme 1, hydrogenation of enantiopure 4d afforded
ketone 5 in 85% yield, and selective reduction of the ketone moiety
in 4d led to cyclohexene 6 in 58% yield over three steps. In both cases,
the products were obtained without loss of optical purity.
9
4056 J. AM. CHEM. SOC. 2010, 132, 4056–4057
10.1021/ja100207s  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Intramolecular Oxo-Michael Reaction
The catalytic working model shown below was proposed for
desymmetrization process. The chiral phosphoric acid acts as a
bifunctional catalyst in which the acidic proton and the PdO moiety
of the catalyst form hydrogen bonds with the carbonyl group and
the hydroxyl group, respectively.
c d
,
entrya
2, R
time (h)
4, yield (%)b d
ee (%)
,
1
2
3
4
5
6
7
8
2a, [Me
2b, [Et
2c, [iPr
2d, [Ph
2e, [4-FC6H4
2f, [4-ClC6H4
2g, [4-BrC6H4
2h, [4-MeC6H4
2i, [3-MeC6H4
2j, [2-MeC6H4
2k, [3,5-Me2C6H3
2l, [3,5-(CF3)2C6H3
3
5
24
10
8
4a, [91 [62]
4b, [91
4c, [71
94 [99]
78
61
4d, [92 [68]
4e, [91 [78]
4f, [90 [68]
4g, [84 [64]
4h, [91 [72]
4i, [91 [75]
4j, [92 [57]
4k, [81 [60]
4l, [93
91 [99]
90 [99]
91 [99]
90 [99]
92 [99]
91 [96]
95 [99]
90 [99]
88
8
In summary, we have developed chiral phosphoric acid-catalyzed
desymmetrization of cyclohexadienones via oxo-Michael reaction,
affording enantioenriched 1,4-dioxane derivatives in excellent yield.
With this newly established methodology, enantioselective synthesis
of cleroindicins could be realized in a highly efficient and concise
manner.
10
10
10
20
8
9
10
11
12
10
a Reaction conditions: 3h (10 mol %) in CH2Cl2 at room temperature.
b Isolated yields. c Determined by chiral HPLC analysis. d Values after
one recrystallization are given in brackets.
Acknowledgment. We thank the NSFC (20732006, 20821002,
20923005) and MOST (973 Program 2010CB833300) for financial
support and CNIBR for a postdoctoral fellowship to Q.G.
Scheme 1. Derivatization of the Oxo-Michael Adduct
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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