Asymmetric tandem Michael addition-ylide olefination reaction for the synthesis of optically active cyclohexa-1,3-diene derivatives

Article abstract of DOI:10.1039/b900048h

The reaction of a crotonate-derived chiral phosphonium salt with α,β-unsaturated carbonyl compounds in the presence of Cs ₂CO₃ affords optically active cyclohexa-1,3-diene derivatives with up to 90% ee in good yields. The Royal Socie

Full text of DOI:10.1039/b900048h

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Asymmetric tandem Michael addition–ylide olefination reaction
for the synthesis of optically active cyclohexa-1,3-diene derivativesw
Long-Wu Ye,a Shou-Bing Wang,b Qing-Gang Wang,a Xiu-Li Sun,a Yong Tang*a
and Yong-Gui Zhou*b
Received (in Cambridge, UK) 5th January 2009, Accepted 24th March 2009
First published as an Advance Article on the web 15th April 2009
DOI: 10.1039/b900048h
The reaction of a crotonate-derived chiral phosphonium salt with
a,b-unsaturated carbonyl compounds in the presence of Cs2CO3
affords optically active cyclohexa-1,3-diene derivatives with up
to 90% ee in good yields.
Cyclohexa-1,3-dienes and their derivatives are frequently used
as versatile intermediates in the synthesis of natural products1
and biologically active compounds.2 The ylide-initiated
Michael addition–olefination reaction has been established
as a promising method for the preparation of such highly
functionalized compounds due to its unambiguous positioning
and good stereoselectivity.2e,3 To date, however, its asymmetric
version using a chiral phosphonium ylide has not yet been
developed. The reason, most likely, is that the chiral inductive
center is far from the reaction site (Scheme 1), which usually
leads to low enantioselectivity.4 As part of our on-going
Scheme 2 Chiral phosphines screened.
research project on ylide reactions and their applications in
recently, we found that a 2,20-bis(diphenylphosphino)-1,10-
biphenyl (BIPHEP)-derived phosphorus ylide reacted with
a,b-unsaturated ketones to give the desired cyclohexa-1,3-
dienes with good to high ees in good yields. To the best
of our knowledge, this represents the first example of
the asymmetric tandem ylide Michael addition–olefination
reaction. In this communication, we wish to report the
preliminary results.
organic synthesis,5 we reported a tandem reaction of allylic
sulfur ylides with a,b-unsaturated ketones for the preparation
of functionalized multisubstituted cyclohexadiene epoxides.6
On the basis of this reaction, we developed a tandem
Michael addition–ylide olefination for the creation of highly
functionalized cyclohexadiene.7 It is envisioned that the
aforementioned reaction will afford optically active cyclohexa-
1,3-dienes by employing a chiral phosphorus ylide. Very
Initially, we tested (S)-BINAP 1a-derived phosphonium salt
2a in the presence of Cs2CO3 using chalcone 3a as a model
substrate.8a–8e As shown in Table 1, salt 2a could afford
optically active annulation product 4a with 36% ee at room
temperature (entry 1, Table 1). This result encouraged us to
explore other chiral phosphine-derived salts (Scheme 2). It
was found that phosphonium salts derived from chiral
MeO-BIPHEP8f,8g could give better ees than 2a (entries 2–8,
Table 1). For example, (R)-2-MeO-MeOBIPHEP-derived
phosphonium salt 1d could furnish 83% ee in 62% yield
(entry 4, Table 1). The enantiomeric excess was slightly
decreased when using KOBut instead of Cs2CO3 as a base
(entries 4–5, Table 1). The reaction temperature proved also to
influence the enantioselection. Elevating the temperature from
room temperature to 50 1C resulted in an obvious decrease of
the ee when (R)-2-MeO-MeOBIPHEP 1d was used (entry 4 vs. 8,
Table 1). Solvent effects were also examined. In CH3CN and
toluene, both the yield and enantiomeric excess decreased
(entries 6–7, Table 1).
Scheme 1 Tandem Michael addition–ylide olefination reaction.
a State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China.
E-mail: tangy@mail.sioc.ac.cn
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
457 Zhongshan Road, Dalian 116023, China.
E-mail: ygzhou@dicp.ac.cn
Under the optimal conditions, the generality of this tandem
ylide annulation reaction was investigated by studying a
variety of a,b-unsaturated carbonyl compounds. As shown
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b900048h
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Table 1 Effects of reaction conditions on the tandem Michael
addition–ylide olefination reactiona
Fig. 1 Stereochemical model.
Entry
P*R3
Solvent
Base
Yield (%)b
ee (%)c
carried out using an (S)-2-MeO-MeOBIPHEP 1d-derived
phosphonium salt instead of an (R)-2-MeO-MeOBIPHEP-
1d-derived phosphonium salt to give the opposite enantio-
selectivity with 84% ee (entries 1 and 2, Table 2). Thus, both
enantiomers could be obtained easily just by the choice of the
phosphonium salt. In addition, increasing the amount of
phosphonium salt from 1.1 equivalents to 1.5 equivalents
improved the yield obviously with well-maintained enantio-
selectivities (entries 4 and 6, Table 2). (E)-But-2-enal worked
well to give the desired product in 67% yield with 25% ee
(entry 8). Only a trace amount of the products was observed
when both the enone with b-substituent and (E)-dec-3-en-
2-one were employed (entries 9 and 11). Using chalcone as a
substrate, cinnamyl phosphonium salt afforded good yield and
30% ee (entry 10).
1
2
3
4
5
6
7
8d
1a
1b
1c
(R)-1d
(R)-1d
(R)-1d
(R)-1d
(R)-1d
THF
THF
THF
THF
THF
CH3CN
Toluene
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
ButOK
Cs2CO3
Cs2CO3
Cs2CO3
52
45
58
62
61
58
38
56
36
56
63
83
81
46
44
71
a
Reagents and conditions: base (0.23 mmol), 2 (0.17 mmol) in solvent
(1.5 mL), room temperature, 45 min, then 3a (32 mg, 0.15 mmol) in
solvent (1.5 mL) was added and stirred for another 48 h at room
b
c
d
temperature. Isolated yield. Determined by chiral HPLC. At 50 1C.
in Table 2, various a,b-unsaturated arylketones are good
substrates for this reaction to give the desired products with
high enantioselectivities in good yields. Both methoxy and
bromo groups on the aryl ring of chalcones proved to be
well-tolerated and influenced the enantioselectivities slightly
(entries 1–6, Table 2). The ester group of phosphonium salt 2d
had little effect on the enantioselectivity. For instance, the
tert-butyl ester gave a slightly lower ee than the methyl ester
(entry 1 vs. 3, Table 2). 1-Phenyl-but-2-en-1-one 3e gave the
desired cyclohexadienes with 78% ee in 53% yield (entry 7,
Table 2). As expected, the same tandem cyclization was
In order to determine the absolute configuration, we developed
a single crystal of enantiopure product9 4f. By X-ray
analysis, however, the unit cell is symmetric and the absolute
configuration cannot be assigned by this way. Fortunately,
optically active product 4f is a known compound10 and by
comparing the rotation, it is assigned as ‘S’ configuration. On
the basis of this result, a stereochemical model shown in Fig. 1
was developed to explain the stereoselection. The ylide
attacked the enone from the re-face due to the steric hindrance.
The current reaction is very useful in organic synthesis.2a,10,11
For example, reduction of 4a with DIBAL-H, followed
by Dess–Martin oxidation, provided biologically active
compound 5 in a total 83% yield with 82% ee (Scheme 3).1a
In these transformations, the ee was well maintained.
In conclusion, we have developed an efficient method for the
preparation of optically active cyclohexa-1,3-dienes using a
BIPHEP-derived phosphonium salt. This provides the first
example of the asymmetric tandem ylide Michael addition–
olefination reaction. The easily available phosphonium
salts, in particular the recovery5d and the reuse of chiral
phosphines, make the present method potentially useful.
Further investigations into the synthetic applications of the
current tandem asymmetric reaction are in progress in our
laboratory.
Table 2 Assembly of optically active cyclohexa-1,3-diene derivatives
via chiral phosphonium ylidea
Entry
R
R1/R2/R3
Yield (%)b ee (%)c
1
2d
3
4
5
CO2Me Ph/H/Ph (3a)
CO2Me Ph/H/Ph (3a)
CO2 Bu Ph/H/Ph (3a)
62
64
83
84
79
80
90
80
78
25
—
30
—
t
55
73 (85)e
65
CO2Me p-BrC6H4/H/Ph (3b)
CO2Me p-OMeC6H4/H/Ph (3c)
CO2Me o-BrC6H4/H/Ph (3d)
CO2Me Me/H/Ph (3e)
6
60 (73)e
53
67
We are grateful for the financial support from the Natural
Sciences Foundation of China (Grant No. 20821002 and
7
8f
9
CO2Me Me/H/H (3f)
CO2Me p-MeC6H4/CH3CO/CH3 (3g) Trace
79
Trace
10
11
Ph Ph/H/Ph (3a)
CO2Me C6H13/H/CH3 (3h)
a
Reagents and conditions: Cs2CO3 (74 mg, 0.23 mmol), 2 (0.17 mmol)
in THF (1.5 mL), room temperature, 45 min, then 3 (0.15 mmol) in
THF (1.5 mL) was added and stirred for further 48–72 h at room
b
c
d
temperature. Isolated yield. Determined by chiral HPLC. Using
e
(S)-1d-derived phosphonium salts. 1.5 equiv. of 2, 1.8 equiv. of
f
Cs2CO3. At 0 1C.
Scheme 3 Synthesis of biologically active compound 5.
Chem. Commun., 2009, 3092–3094 | 3093
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3094 | Chem. Commun., 2009, 3092–3094