Desymmetrization of cyclohexadienones via asymmetric michael reaction catalyzed by cinchonine-derived urea

Article abstract of DOI:10.1021/ol202073p

Desymmetrization of cyclohexadienones bearing a bisphenylsulfonyl methylene group via asymmetric Michael reaction catalyzed by cinchoninederived urea was realized to afford a series of highly enantioenriched polycyclic cyclohexenones in high yields and ee

Full text of DOI:10.1021/ol202073p

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5192–5195
Desymmetrization of Cyclohexadienones
via Asymmetric Michael Reaction
Catalyzed by Cinchonine-Derived Urea
Qing Gu 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
slyou@sioc.ac.cn
Received July 31, 2011
ABSTRACT
Desymmetrization of cyclohexadienones bearing a bisphenylsulfonyl methylene group via asymmetric Michael reaction catalyzed by cinchonine-
derived urea was realized to afford a series of highly enantioenriched polycyclic cyclohexenones in high yields and ee’s.
Functionalized chiral cyclohexenones1 are versatile
building blocks that have been widely utilized in the total
synthesis of natural products and found in numerous
compounds that display significant biological activities.2
For instance, the abietane type diterpenoid 1 is a novel and
highly potent inhibitor of nitric oxide (NO) production in
mouse macrophages2d (Figure 1). It has also been shown to
be orally active in a preliminary in vivo inflammation
model. Compound 2 acts as a pathway-selective or “dis-
sociated” agonist of the glucocorticoid receptor (GR).2e
Various methodologies have been developed toward the
construction of enantioenriched cyclohexenone deriva-
tives. These include the kinetic resolution of racemic sub-
stituted cyclohexenones by catalytic asymmetric reactions,3
organocatalytic cascade reactions4 and various multistep
syntheses.5 Despite extensive efforts, most of these methods
only provide access to simple substituted cyclohexenones.
The development of highly efficient synthesis of chiral
polycyclic cyclohexenones is still in great demand.
(1) (a) Hareau, G. P-J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am.
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Oxidative dearomatization ofarenes offers a facile intro-
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r
10.1021/ol202073p
Published on Web 09/14/2011
2011 American Chemical Society

materials; (2) more than two stereogenic centers are
formed in one step; and (3) chiral quaternary carbon center
is installed with high enantioselectivity.
Recently, efforts from our group demonstrated that the
desymmetrization of cyclohexadienone via a chiral phos-
phoric acid-catalyzed oxo-Michael reaction11 and cincho-
nine-derived thiourea-catalyzed aza-Michael reaction12
could be realized to provide a series of highly enantio-
enriched heterocycle-fused cyclohexenone derivatives. We
envisioned that carbocycle-fused cyclohexenones could also
be obtained utilizing such a dearomatization/desymmetriza-
tion process in a highly efficient manner through a Michael
addition reaction of active methylene side chain. As part of
our ongoing program on asymmetric dearomatization reac-
tion,13 we recently found that the bisphenylsulfonyl methylene
group bearing cyclohexadieones could be synthesized easily
via the dearomatization reaction and undergo the asym-
metric Michael reaction smoothly. Herein we report
such a desymmetrization reaction of cyclohexadieones
bearing an active methylene group via a cinchonine-
derived urea-catalyzed asymmetric Michael reaction.
We began our studies by synthesizing the cyclohexadie-
none substrate bearing an active methylene group. The
bisphenylsulfonyl methyl group was chosen given its highly
enhanced acidity of the methylene proton and the facile
removal ability of the phenylsulfonyl group.14 Therefore,
substrate 4awas obtained from phenol 3avia a PhI(OAc)2-
mediated oxidative dearomatization process. We then tested
the intramolecular Michael reaction of 4a with bifunc-
tional (thio)ureas 6 as the catalysts.15,16 With 10 mol %
of (thio)ureas (6aÀh) in CH2Cl2 at room temperature,
Figure 1. Representative compounds containing chiral cyclo-
hexenones.
aromatics.6 On the other hand, desymmetrization reaction
is a very powerful methods for enantioselective synthesis of
chiral molecules.7 The combination of desymmetrization
reaction with the dearomatization process provides a facile
construction of optically active cyclic and polycyclic com-
pounds from readily available starting materials. This
strategy has been demonstrated successfully in asymmetric
desymmetrization of cyclohexadienones providing effi-
cient carbonÀcarbon bond formation methods.8À10 For
instance, Feringa et al. realized the desymmetrization of
cyclohexadienone via intramolecular Heck reaction with
excellent enantioselectivity using TADDOL-derived phos-
phoramidite ligands.8 For cyclohexadieones bearing an
aldehyde side chain, Rovis et al. elegantly developed an
highly enantioselective intramolecular-type Stetter reac-
tion with a nucleophilic carbene catalyst generatedfrom an
aminoindanol-derived triazolium salt.9 Hayashi et al. and
Gaunt et al. respectively utilized diarylprolinol silyl ether
as the catalyst to achieve the intramolecular Michael
reaction of cyclohexadieones bearing aldehyde side chain
providing highly functionalized enantioenriched polycyclic
molecules.10 In general, the strategy combining oxidative
dearomatization of phenol derivatives and subsequent
desymmetrization reaction has the following advantages:
(1) cheap aromatic compounds are used as starting
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Org. Lett., Vol. 13, No. 19, 2011
5193

Table 1. Screening of the Catalystsa
Table 2. Screening of Solventsa
entry
solvent
time (h)
yield (%)b
ee (%)c
1
CH2Cl2
CHCl3
CCl4
72
48
72
48
48
48
72
72
40
30
88
97
86
87
2
3
58
84
4
Toluene
Benzene
DCE
98
85
entry
catalyst (Ar, X)
time (h)
yield (%)b
ee (%)c
5
98
91
6
97
90
1
2
6a(3,5-(CF3)2C6H3, S)
6b (C6H5, S)
72
72
72
72
72
72
72
72
72
72
90
12
18
42
88
82
93
92
88
87
84
33
7
Ether
THF
trace
trace
95
n.d.
n.d.
79
8
3
6c (4-FC6H4, S)
6d (4-CF3C6H4, S)
6e (3,5-(CF3)2C6H3, O)
6f (3,5-(CF3)2C6H3, S)
6g (X = S)
58
9 d
10 e
DCE
4
78
DCE
96
90
5
86
a Reaction conditions: 10 mol % of 6e, 0.1 mol/L 4a in solvent at
room temperature. b Isolated yields. c Determined by HPLC analysis
(Chiralpak AD-H). d 4 A MS was added. e 20 mol % of 6e.
6
À51
81
7
8
6h (X = O)
84
9
cinchonine
35
10
quinine
À12
(68%) but with excellent ee (93%) after 14 days under
the above reaction conditions. After further optimizing
the reaction conditions including catalyst loading and
substrate concentration, the Michael adduct 5g was
a Reaction conditions: 10 mol % of catalyst, 0.1 mol/L 4a in CH2Cl2
at room temperature. b Isolated yields. c Determined by HPLC analysis
(Chiralpak AD-H).
(16) Selected examples: (a) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481. (b) McCooey, S. H.; Connon, S. J. Angew. Chem.,
Int. Ed. 2005, 44, 6367. (c) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.;
Ding, L.-S.; Wu, Y. Synlett 2005, 603. (d) Vakulya, B.; Varga, S.;
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (e) Tillman, A. L.; Ye,
J.; Dixon, D. J. Chem. Commun. 2006, 1191. (f) Song, J.; Wang, Y.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (g) Wang, J.; Li, H.; Zu, L.;
Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128,
12652. (h) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am.
Chem. Soc. 2007, 129, 1036. (i) Hynes, P. S.; Stranges, D.; Stupple, P. A.;
Guarna, A.; Dixon, D. J. Org. Lett. 2007, 9, 2107. (j) Wang, J.; Zu, L.; Li,
H.; Xie, H.; Wang, W. Synthesis 2007, 2576. (k) Wang, B.; Wu, F.;
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Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C.
gratifyingly, all reactions proceeded smoothly to give the
desired product 5a with yields ranging from 12 to 93% and
ee values ranging from 33 to 86% (Table 1, entries 1À8).
Urea 6e17 derived from cinchonine bearing a 3,5-(CF3)2-
C6H3 group proved to be the most efficient catalyst, afford-
ing 5a in 88% yield and 86% ee. Notably, Takemoto
catalysts18 also gave the product 5a in excellent yields
and good ee’s (Table 1, entries 7, 8). Both cinchonine
and quinine alone afforded product in good yields but
low ee’s (88% yield, 35% ee and 87% yield, À12% ee,
Table 1, entries 9, 10). These results indicate the im-
portance of the double-hydrogen bonding mode of the
thio(urea) catalysts.
With 10 mol % of urea 6e as the catalyst, various
solvents were investigated. The results are summarized in
Table 2. Various solvents such as CHCl3, CCl4, toluene,
and DCE led to the formation of 5a in good yields and
enantioselectivity (58À98% yields and 84À91% ee’s,
Table 2, entries 1À6). However, reaction in THF or ether
gave only trace amount of product 5a (entries 7, 8). The
addition of 4 A MS or increasing the catalyst loading to 20
mol % did not give better results (entries 9, 10).
Under the above optimized reaction conditions (10 mol %
of 6e, DCE, rt), different substrates were carried out to test
the generality of the current methodology. As summar-
ized in Table 3, regardless of the substituent R1 in the
4-position of cyclohexadienones, all the asymmetric
Michael reaction proceeded smoothly to afford pro-
ducts with good enantioselectivities (85À90% ee’s,
Table 3, entries 1À6). For substrate 4g, the desired
product was obtained in a slightly decreased yield
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J. Org. Chem. 2008, 73, 6409. (r) Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang,
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Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 2009, 131, 16016.
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5194
Org. Lett., Vol. 13, No. 19, 2011

cases, the products were obtained without loss of the en-
antiomeric purity. The one-pot dearomatization/desymme-
trization process was also explored for the synthesis of 5a.
As shown in Scheme 2, after the dearomatization reaction
(PhI(OAc)2 in MeOH), the solvent was removed and then
the residue was treated with 10 mol % 6e in DCE. The
product 5a was obtained in a 33% overall yield and 85% ee.
Table 3. Asymmetric Intramolecular Michael Reactiona
Scheme 1. Transformation of the Michael Adduct
a Condition A: 10 mol % of 6e, 0.1 mol/L 4aÀf in DCE, rt; condition
B: 20 mol % of 6e, 0.3 mol/L 4gÀj in DCE, rt. b Isolated yields.
c Determined by HPLC analysis (Chiralpak AD-H).
obtained in 95% yield and 91% ee in 72 h when the
reaction was carried with 20 mol % of 6e in DCE
(0.3 mol/L). These reaction conditions could tolerate
various substrates 4 bearing different aromatic groups
at 4-position (82À96% yields, 84À91% ee’s, entries
7À10). To determine the absolute configuration of the
product, the crystal structure of enantiopure 5g was
obtained, and a single crystal X-ray analysis deter-
mined its configuration as (4aS,10aS).19
Several transformations of the multifunctionalized pro-
ducts obtained here have been demonstrated. Product 5d
bearing a hydroxyl group could undergo oxo-Michael
addition in the presence of catalytic amount of p-TsOH
affording a spiro-tricyclic compound 7 (eq 1). Interest-
ingly, it could also be obtained in a one-pot process
including the Michael and oxo-Michael reaction in 93%
yield and 86% ee (eq 2). As shown in Scheme 1, hydrogena-
tion of 5g afforded ketone 8 in 94% yield. Subjecting ketone
8 to activated magnesium in methanol for the reductive
removal of the phenylsulfonyl groups, followed by Jones
oxidation led to ketone 10 in 28% yield over two steps. In all
Scheme 2. One-pot Dearomatization/Desymmetrization Process
In summary, we have developed a cinchonine-derived
urea-catalyzed desymmetrization of cyclohexadienones
bearing active methylene groups via an asymmetric
Michael reaction, affording highly enantioenriched cyclo-
hexenone derivatives in good to excellent yields and ee’s.
The products obtained here could be subjected to versatile
transformations.
(17) Selected examples catalyzed by cinchona-derived urea: (a)
Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841. (b)
Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2089.
(c) Allu, S.; Molleti, N.; Panem, R.; Singh, V. K. Tetrahedron Lett. 2011,
52, 4080. Palacio, C.; Connon, S. J. Org. Lett. 2011, 13, 1298.
(18) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625. (c) Hoashi, Y.; Yabuta, T.; Takemoto, Y.
Tetrahedron Lett. 2004, 45, 9185. (d) Okino, T.; Hoashi, Y.; Furukawa,
T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (e) Hoashi,
Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032.
(19) CCDC 835391 contains the supplementary crystallographic
data for (S)-5g. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
datarequest/cif.
Acknowledgment. We thank MOST (973 Program 2010-
CB833300) and the NSFC (20732006, 21025209, 21002111)
for financial support and CNIBR for a postdoctoral fellow-
ship to Q. Gu.
Supporting Information Available. Experimental proce-
dures and characterization of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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