Highly selective ylide-initiated michael addition/cyclization reaction for synthesis of cyclohexadiene epoxide and vinylcyclopropane derivatives

Article abstract of DOI:10.1021/jo100306z

On the basis of the reactions of camphor-derived sulfur ylide with α,β-unsaturated ketone, highly efficient and selective synthesis of optically active cyclohexadiene epoxides and vinylcyclopropanes with excellent diastereoselectivities, moderate to high

Full text of DOI:10.1021/jo100306z

pubs.acs.org/joc
attracted much attention recently1 because such research
Highly Selective Ylide-Initiated Michael Addition/
Cyclization Reaction for Synthesis of Cyclohexadiene
Epoxide and Vinylcyclopropane Derivatives
not only maximizes the diverse utility of reactants but also
benefits the understanding of reaction mechanism. During
our previous research on this subject,2 we documented that
HMPA could switch the stereochemistry of the cyclopro-
panation reaction between telluronium allylides with R,β-
unsaturated esters and amides, providing a facile synthesis
of two geometrical isomers of vinylcyclopropane derivati-
ves.2b,c We also observed solvent-reversed enantioselect-
ivity in the Friedel-Crafts reaction of indole with arylidene
malonates catalyzed by trisoxazoline (TOX)-derived copper
complex2f and temperature-controlled diastereoselection in the
1,3-dipolar cycloaddition of nitrones with arylidene malonates.2d
In addition, we reported that 2H-chromenes and 4H-chro-
menes could be synthesized controllably from the same starting
material just by the choice of base via tetrahydrothiophene-
catalyzed ylide annulation reaction.2g
Ben-Hu Zhu,† Rui Zhou,† Jun-Cheng Zheng,‡
Xian-Ming Deng,‡ Xiu-Li Sun,‡ Qi Shen,*,† and
Yong Tang*,‡
†Key Laboratory of Organic Synthesis, Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Suzhou University, Suzhou 215123, P. R. China, and
‡Department State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry 345
Lingling Lu, Shanghai 200032, P. R. China
tangy@mail.sioc.ac.cn
Received February 21, 2010
Optically active cyclohexadiene epoxide and vinylcyclo-
propane derivatives are important subunits in a number of
biologically active compounds3 and also valuable synthetic
intermediates.4 Very recently, we developed a tandem reac-
tion of crotonate-derived sulfur ylide with R,β-unsaturated
ketone for the rapid construction of functionalized cyclo-
hexadiene epoxide derivatives.5 Further study revealed the
reaction profile between sulfonium salt 1 with R,β-unsatu-
rated ketone 2 could be switched to give rise to enantioen-
riched vinylcyclopropane.6 As part of our research in ylide
chemistry7 and tunable reaction, we wish to describe the
details about the aforementioned process.
On the basis of the reactions of camphor-derived sulfur
ylide with R,β-unsaturated ketone, highly efficient and
selective synthesis of optically active cyclohexadiene ep-
oxides and vinylcyclopropanes with excellent diastereo-
selectivities, moderate to high enantioselectivities, and
yields has been achieved.
(3) For recent reviews, see: (a) Henrick, C. A. Pyrethroids in Agrochemicals
from Natural Products; Godfrey, C. R. A., Ed.; Marcel Dekker: New York, 1995;
pp 147-213; (b) Krohn, K. Natural Products Derived from Naphthalenoid
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Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 525. (d) Nara, F.; Tanaka,
M.; Masuda-Inoue, S.; Yamasato, Y.; Doi-Yoshioka, H.; Suzuki-Konagai, K.;
Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531. (e) Sala€un, J. Top. Curr.
Chem. 2000, 207, 1. (f) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251.
(g) Pietruszka J. Chem. Rev. 2003, 103, 1051. (h) Wessjohann, L. A.; Brandt, W.
Chem. Rev. 2003, 103, 1625. (i) Marco-Contelles, J.; Molina, M. T.; Anjum, S.
Chem. Rev. 2004, 104, 2857.
The control of reaction pathways for selective synthesis of
different products from the same starting materials has
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Wender, P. A. J. Am. Chem. Soc. 2005, 127, 6530.
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see: (c) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.; Tang, Y. Angew. Chem., Int. Ed.
2007, 46, 5951. (d) Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang,
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3454 J. Org. Chem. 2010, 75, 3454–3457
Published on Web 04/13/2010
DOI: 10.1021/jo100306z
r
2010 American Chemical Society

Zhu et al.
JOCNote
TABLE 1. Effects of Reaction Conditions on the Tandem Michael
Addition/Ylide Epoxidation Reactiona
TABLE 2. Stereoselective Synthesis of Cyclohexadiene Epoxides via
Camphor-Derived Sulfur Ylidea
3a
3
temp
(°C) 3a/4ab
yieldc
(%)
eed
(%)
yieldc
(%)
eed
(%)
entry solvent
base/additive
MeCN Cs2CO3
MeCN K2CO3
entry
R1
R2
Ph (2a)
Ph (2b)
Ph (2c)
Ph (2d)
Ph (2e)
Ph (2f)
3/4b
1e
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
rt
0
100/0 20
88
57
57
62
1
2
3
4
5
6
7
8
9
Ph
9.2/1
13.0/1
7.9/1
18.8/1
12.7/1
5.0/1
9.5/1
8.2/1
6.5/1
5.0/1
3.8/1
22.5/1
83
91
87
75
76
65
57
82
52
80
72
45
80
85
87
88
79
74
78
67
85
82
71
54
12.0/1 60
4.7/1 47
9.8/1 49
disordered
4.9/1 54
3.4/1 54
2.9/1 55
6.5/1 52
4.3/1 26
1.3/1 52
5.2/1 67
5.4/1 65
9.2/1 83
7.8/1 78
5.0/1 65
p-Cl-C6H4
p-Br-C6H4
p-NO2-C6H4
p-Me-C6H4
p-MeO-C6H4
3
4
5
MeCN CsOH H2O
3
MeCN Cs2CO3
MeCN t-BuOK
6
7
DCE
THF
Cs2CO3
Cs2CO3
63
57
54
51
61
67
83
75
80
79
77
(E)-PhCHdCH Ph(2g)
8
9
10
11
AcOEt Cs2CO3
DMF Cs2CO3
DM SO Cs2CO3
Me
H
Ph
Ph
Ph
Ph(2h)
p-Br-C6H4 (2i)
p-Me-C6H4(2j)
p-Cl-C6H4 (2k)
CO2Me (2l)
10
11
12
BTF
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3/H2O
Cs2CO3/H2O
Cs2CO3/ n-Pr4NI
12 f BTF
13 f BTF
14 f,g BTF
15 f,g BTF
16 f,h BTF
a2 (0.2 mmol) and 1 (113.8 mg, 0.3 mmol, dr >25/1) were mixed in
BTF (3.0 mL) at 0 °C, 15 min, Cs2CO3 (130.4 mg, 0.4 mmol) was added,
c
then 10 μL H2O was added. bDetermined by isolated yield. Isolated
yield. dDetermined by chiral HPLC.
a2a (1.0 equiv, c = 0.07 M) and 1 (1.5 equiv, dr =5/1) were mixed in
solvent, and then base (2.0 equiv) was added. bDetermined by isolated
yield. cIsolated yield. dDetermined by chiral HPLC. eKetone was added
after sulfonium salt 1 and Cs2gCO3 were mixed in CH3CN for 1 h. dr
(at sulfur atom) of 1 > 25/1. 10 μL of H2O was added 2.0 equiv of
n-Pr4NI was added.
would possibly benefit the formation of sulfur ylide by
improving the solubility of Cs2CO3 and/or sulfonium salt
1, have also been tested in order to further improve those
results (entries 14-16). To our delight, the addition of H2O
could give 3a in 83% yield and better ratio of 3a/4a, albeit
at cost of slightly decreased ee of 3a (entries 12 vs 14). In
all cases, no other diastereoisomer of the cyclohexadiene
epoxide 3a was observed.
f
h
Initially, we used chalcone as a substrate instead of (E)-
3-(4-bromophenyl)-1-phenylprop-2-en-1-one to extend the
scope of our previously reported reaction.5 Unfortunately,
under the same stepwise reaction conditions (adding 2a 1 h
after mixing 1 with Cs2CO3),5 only 20% yield was obtained
after purification by preparative HPLC, although an excel-
lent ratio of 3a/4a and a good ee of 3a could be delivered
(entry 1). Further efforts to improve the yield failed.8 Then,
we tested a one-pot reaction. As summarized in Table 1, the
solvent, base, temperature, additive, and diastereomeric
purity of sulfonium salt 1 all strongly influenced the ratio
of 3a to 4a and ee of product 3a. When the reaction was run in
MeCN with K2CO3 as a base, 3a could be isolated in 60%
yield and 57% ee with 12/1 ratio of 3a/4a (entry 2). A slightly
better ee was obtained when Cs2CO3 was used as a base
(entries 2 vs 4). However, in the case of strong base t-BuOK,
we observed a disordered system (entry 5). Of all solvents
screened, trifluoromethylbenzene (BTF) was found to be the
best in terms of the ee of compound 3a (entry 11).
We then decided to investigate the scope and limitation of
the enantioselective tandem ylide-initiated Michael addi-
tion/epoxidation process by employing a variety of R,β-
unsaturated ketones bearing different R1 and R2 substitu-
ents. As shown in Table 2, aryl- and alkyl-substituted as
well as unsubstituted R,β-unsaturated ketones all proved to
be suitable substrates to afford cyclohexadiene epoxide
derivatives over the competing cyclopropanes; however, a
significant substituent effect was identified. Introducing
an electron-withdrawing group on the aryl substituent at
the R1 position led to increased ee (entries 1-4), which was
opposite to the effect of the electron-donating group
(entries 5 and 6). A vinyl-type group was also tolerable,
although the yield decreased to 57% (entry 7). β-Methyl
R,β-unsaturated ketone 2h furnished the desired product
in 82% yield and 67% ee (entry 8). Switching R2 to an
electron-deficient group deteriorated both the yield and ee
(entries 1 vs 11 and 12). Substrate 2j, containing a p-methyl-
phenyl group at the R2 position, participated in this tandem
reaction and afforded 3j as a major product in 80% yield with
82% ee (entry 10). To our surprise, the ee of the cyclohexa-
diene epoxide formed from 2i could be up to 85% (entry 9).
Noticeably, cyclohexadiene epoxide derivatives all were
formed as a single diastereoisomer as depicted in Table 2.
During the study of this tandem intermolecular ylide-
initiated Michael addition/epoxidation reaction, it was
noticed that the distribution between 3 and 4 was vari-
able (Table 1), which prompted us to consider the
possibility that optically active vinylcyclopropanes are
Further study demonstrated the dr of sulfonium salt 1 had
profound effect on the ratio of 3a/4a and ee of 3a.7e,9 For
example, salt 1 with dr 5/1 resulted in compound 3a with only
67% ee and a 1.3/1 ratio of 3a/4a (entry 11). When a nearly
diastereomeric pure salt 1 (dr >25/1) was employed, 83% ee
of 3a could be achieved, and the ratio of 3a/4a was raised to
5.2/1 (entry 12). Additives like H2O and n-Pr4NI, which
(8) We also tried other different combinations of base and solvent using
this addition sequence, but all gave complex systems and a low yield was
obtained.
(9) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.;
Hynd, G.; Ohara, D.; Picoul, W.; Robiette, R.; Smith, C.; Vasse, J.-L.; Winn,
C. L. J. Am. Chem. Soc. 2006, 128, 2105.
J. Org. Chem. Vol. 75, No. 10, 2010 3455

Zhu et al.
JOCNote
TABLE 3. Effects of Reaction Conditions on the Cyclopropanation of
Sulfonium Salt 1 with Chalconea
TABLE 4. Asymmetric Cyclopropanation of Sulfonium Salts 1 with
Michael Acceptora
yieldc eed
4a
entry
R1
R2
Ph (2a)
Ph(2b)
Ph (2c)
Ph (2e)
Ph (2f)
p-Me-C6H4(2j)
p-Cl-C6H4 (2k) >25/1
Ph(2m) 90/10
4/4b
(%)
(%)
temp
(°C) 4a/4a0 (%)
yieldc
eed
(%)
b
1
2
3
4
5
6
7
8
Ph
>99/1
>99/1
>25/1
>99/1
>99/1
>25/1
77
57
61
87
78
75
56
61
99
99
99
99
99
99
99
97
entry solvent
base/additive
t-BuOK
p-Cl-C6H4
p-Br-C6H4
p-Me-C6H4
p-MeO-C6H4
Ph
1
DME
-50
-78
-78
-78
-40
-40
-78
-78
-78
-78
-78
-78
-78
25/1 61
25/1 24
25/1 28
0
trace
trace
25/1 66
98
98
97
2
3
4
EtOAc t-BuOK
CH2Cl2 t-BuOK
EtOH t-BuOK
5
6
DMF t-BuOK
MeCN t-BuOK
Ph
2-furyl
7
THF
THF
THF
THF
THF
THF
THF
THF
t-BuOK
t-BuOK
t-BuOK
LiHMDS
NaHMDS
KHMDS
t-BuONa
t-BuOK
97
98
96
a2 (0.3 mmol, c = 0.05 M) and 1 (137.0 mg, 0.36 mmol, dr >10/1)
were mixed in THF (6.0 mL) for 15 min, then t-BuOK (81.0 mg,
0.72 mmol) was added in three portions. bDetermined by 1H NMR.
cIsolated yield. dDetermined by chiral HPLC.
8e
9f
10
11
12
13
14g
10/1 24
5.0/1 50
trace
25/1 25
3.5/1 44
11/1 76
96
98
99
99
99
99
-78 >99/1 65
-78 >99/1 77
-78 >99/1 61
15g,h THF
16g,i THF
17g, j THF
t-BuOK
t-BuOK/HMPA
t-BuOK/18-crown-6 -78
trace
a2a (62.4 mg, 0.3 mmol c = 0.05 M) and 1 (137.0 mg, 0.36 mmol,
dr =5/1) were mixed in solvent, 15 min, then base (0.72 mmol) was
added in one portion. bDetermined by 1H NMR. cIsolated yield.
e
f
dDetermined by chiral HPLC. Base (0.36 mmol). Base (1.08 mmol).
gdr (at sulfur atom) of 1 is 10/1. hBase was added by trisection. it-BuOK/
HMPA = 1/3. jt-BuOK/18-crown-6 = 1/3.
formed predominantly.10 Fortunately, we found that
cyclopropane 4a was obtained in 66% yield and 97% ee in the
presence of strong base t-BuOK using THF as solvent, and the
corresponding cyclohexadiene epoxide 3a was not observed
(entry 7, Table 3). As shown in Table 3, after detailed investiga-
tion on the effects of reaction conditions, the best result was
achieved when t-BuOK (2.4 equiv) was added in three portions
to the mixture of chalcone 2a (1.0 equiv) and sulfonium salt 1(1.2
equiv, dr = 10/1) at -78 °C in THF. In this case, the reaction
could deliver cyclopropane 4a in 77% yield with excellent
diastereo- and enantioselectivities (entry 15).
With the optimal conditions for the selective synthesis of
optically active cyclopropane derivatives in hand, we set out to
examine the effects of substituents at the R1 and R2 positions on
R,β-unsaturated ketones. As exhibited in Table 4, cyclohexa-
diene epoxide derivatives were not observed in all cases exam-
ined. Variation of the electronic property of aryl substituents at
the R1 and R2 positions did not influence the diastereo- and
enantioselectivities too much. In this case, both excellent dr
(>25/1) and ee (99%) were consistently obtained (entries 1-7).
However, introducing an electron-withdrawing group on the
phenyl substituent at either the R1 or R2 position diminished
FIGURE 1. Proposed mechanism for controllable synthesis of
cyclohexadiene epoxides and vinylcyclopropanes.
(10) For reviews, see: (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem.
Rev. 1997, 97, 2341. (b) Dai, L.-X.; Hou, X.-L.; Zhou, Y.-G. Pure Appl.
Chem. 1999, 71, 369. (c) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette,
A. B. Chem. Rev. 2003, 103, 977. (d) McGarrigle, E. M.; Myers, E. L.; Illa, O.;
Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007, 107, 5841. For
recent examples, see: (e) Hanessian, S.; Andreotti, D.; Gomtsyan, A. J. Am.
the yield of cyclopropane (entries 1 vs 2, 3, and 7), probably
because the ring-closing reaction of intermediates formed by
Michael addition between ylide and unsaturated ketones is
slowed in these cases. In addition, the heteroaromatic group
2-furyl could be tolerated, affording the corresponding cyclo-
propane in 67% yield with 97% ee and good diastereoselec-
tivity (entry 8).
ꢀ
Chem. Soc. 1995, 117, 10393. (f) Solladie-Cavallo, A.; Diep-Vohuule, A.;
Isarno, T. Angew. Chem., Int. Ed. 1998, 37, 1689. (g) Ye, S.; Huang, Z.-Z.;
Xia, C.-A.; Tang, Y.; Dai, L.-X. J. Am. Chem. Soc. 2002, 124, 2432. (h) Deng,
X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.;
Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730.
3456 J. Org. Chem. Vol. 75, No. 10, 2010

Zhu et al.
JOCNote
SCHEME 1. Determination of Absolute Configuration of
Cyclopropane 4a
(113.8 mg, 0.3 mmol) and ketone 2c (57.4 mg, 0.2 mmol) in
trifluoromethylbenzene (3 mL) was added Cs2CO3 (130.4 mg,
0.4 mmol) in one portion at 0 °C, followed by 10 μL of H2O. The
resulting mixture was stirred at 0 °C until the reaction was
complete (monitored by TLC). The reaction mixture was passed
through a short pad of silica gel and eluted with ethyl acetate.
The filtrate was concentrated, and the residue was purified by
flash column chromatography (petroleum ether/EtOAc = 50:1)
to afford cyclohexadiene epoxide 3c: white solid; yield 87%;
3c/4c = 7.9/1; [R]20 = -172.5 (c = 1.00, CHCl3), 87% ee
D
i
(determined by HPLC, Chiralcel AD, 10/90 PrOH/hexanes,
The relative configuration of cyclohexadiene epoxide and
cyclopropane derivates were determined by 1H NMR spectra.
The absolute structures of cyclohexadiene epoxide 3c and
cyclopropane 4a were further elucidated by X-ray analysis11
and chemical transformation (Scheme 1)10h as (1S,4S,6S)-3c
and (1S,2S,3R)-4a, respectively.
0.8 mL/min, 238 nm, tR (minor) = 18.95 min, tR (major) =
23.28 min); H NMR (300 MHz, CDCl3/TMS) 7.45 (d, J =
2.7 Hz, 2H), 7.42-7.24 (m, 5H), 7.15-7.07 (m, 1H), 7.04 (d, J =
2.4 Hz, 2H), 3.90 (ddd, J = 9.6, 7.2, 2.4 Hz, 1H), 3.52 (s, 3H), 3.40
(d, J = 3.9 Hz, 1H), 2.68 (dd, J = 15.0, 7.5 Hz, 1H), 2.42 (dd, J =
14.7, 9.9 Hz, 1H).
1
General Procedure for Asymmetric Cyclopropanation Reac-
tion between Sulfonium Salt 1 and R,β-Unsaturated Ketone 2c.
To a stirred solution of sulfonium salt 1 (137.0 mg, 0.36 mmol)
and ketone 2c (86.0 mg, 0.3 mmol) in THF (6 mL) was added
t-BuOK (81.0 mg, 0.72 mmol) by trisection at -78 °C. The
resulting mixture was stirred at -78 °C until the reaction was
complete (monitored by TLC). The reaction mixture was
passed through a short pad of silica gel and eluted with ethyl
acetate. The filtrate was concentrated, and the residue was
purified by flash column chromatography (petroleum ether/
EtOAc = 20:1) to afford vinylcyclopropane 4c: white solid;
yield 61%; 4c/4c0 > 25/1; mp 109-111 °C; [R]20D = -65.8 (c =
0.75, CHCl3), 99% ee (determined by HPLC, Chiralcel AD-H,
10/90 iPrOH/hexanes, 0.8 mL/min, 238 nm, tR (major) = 14.89
min, tR (minor) = 22.46 min); IR (thin film) ν/cm-1 3066, 2945,
1709, 1659, 1450, 1260, 1143, 1022, 753; MS (EI, m/z, rel.
intensity) 384 (Mþ, 0.17), 105(100); 1H NMR (300 MHz,
CDCl3/TMS) 8.04 (d, J = 7.5 Hz, 2H), 7.65-7.45 (m, 5H),
7.16 (d, J = 8.1 Hz, 2H), 6.39 (dd, J = 15.3, 10.5 Hz, 1H), 6.06
(d, J = 15.6 Hz, 1H), 3.68 (s, 3H), 3.38-3.27 (m, 2H), 2.74 (td,
J = 10.2, 4.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) 196.6,
166.2, 144.8, 137.1, 134.3, 133.5, 131.8, 130.6, 128.8, 128.1,
122.7, 121.3, 51.5, 34.6, 33.9, 32.2. Anal. Calcd for C20H17-
BrO3: C, 62.35; H, 4.45. Found: C, 62.49; H, 4.44.
A mechanism is proposed to account for the observed results
of the asymmetric tunable ylide-initiated reaction, although
the detailed mechanistic pathway is not clear. As depicted in
Figure 1, the sulfur ylide has two major contributing reso-
nances 6-A and 6-B, and the latter one undergoes Michael
addition with unsaturated ketone to form intermediate 7. In
the presence of a weak base such as Cs2CO3, the base cannot
remove the proton smoothly on the R-position of ester group
in intermediate 7, and thus, the proton transfers to enolate to
form 8, allowing the intramolecular ylide epoxidation to afford
the product 3as a major product. In the presence of strong base
and under low temperature condition, the intermediate 7
disfavors a proton-transfer process to form ketone 8, and as
a consequence, a normal ylide cyclopropanation between ylide
6-A and unsaturated ketone is preferred to afford enantiomer 4
as a major product.10h
In summary, the camphor-derived sulfonium salt has pro-
ven to be a highly efficient reagent for asymmetric tandem
intermolecular ylide-initiated Michael addition/cyclization
reaction, furnishing either highly functionalized cyclohexa-
diene epoxide or vinylcyclopropane derivatives selectively by
employing appropriate conditions as indicated above. We are
nowworking onthe understandingofthedetailedmechanism,
especially by theoretical chemistry.
Acknowledgment. We are grateful for the financial support
from the National Natural Science Foundation of China (No.
20821002 and 20932008), the Major State Basic Research
Development Program (Grant No. 2006CB806105), The
Chinese Academy of Sciences, and the Science and Techno-
logy Commission of Shanghai Municipality.
Experimental Section
General Procedure for Asymmetric Tandem Michael Addition/
Ylide Epoxidation Reaction between Sulfonium Salt 1 and R,β-
Unsaturated Ketone 2c. To a stirred solution of sulfonium salt 1
Supporting Information Available: Full experimental de-
tails, CIF file for 3c, and chiral HPLC spectra of 3 and 4. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(11) See the Supporting Information. CCDC 764421(3c) contains the
supplementary crystallographic data. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/datarequest/cif.
J. Org. Chem. Vol. 75, No. 10, 2010 3457