Enantioselective synthesis of vinylcyclopropanes and vinylepoxides mediated by camphor-derived sulfur ylides: Rationale of enantioselectivity, scope, and limitation

Article abstract of DOI:10.1021/ja056751o

By a sidearm approach, camphor-derived sulfur ylides 1 were designed and synthesized for the cyclopropanation of electron-deficient alkenes and epoxidation of aldehydes. Under the optimal conditions, the exo-type sulfonium salts 4a and 4b reacted with β-a

Full text of DOI:10.1021/ja056751o

Published on Web 07/07/2006
Enantioselective Synthesis of Vinylcyclopropanes and
Vinylepoxides Mediated by Camphor-Derived Sulfur Ylides:
Rationale of Enantioselectivity, Scope, and Limitation
Xian-Ming Deng,† Ping Cai,‡ Song Ye,† Xiu-Li Sun,† Wei-Wei Liao,† Kai Li,†
Yong Tang,*,† Yun-Dong Wu,*,§ and Li-Xin Dai†
Contribution from the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China,
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and
Department of Chemistry, The Hong Kong UniVersity of Science & Technology, Clear Water
Bay, Kowloon, Hong Kong, China
Received October 2, 2005; E-mail: tangy@mail.sioc.ac.cn; chydwu@ust.hk
Abstract: By a sidearm approach, camphor-derived sulfur ylides 1 were designed and synthesized for the
cyclopropanation of electron-deficient alkenes and epoxidation of aldehydes. Under the optimal conditions,
the exo-type sulfonium salts 4a and 4b reacted with â-aryl-R,â-unsaturated esters, amides, ketones, and
nitriles to give 1,3-disubstituted-2-vinylcyclopropanes with high diastereoselectivities and enantioselectivities.
When the endo-type sulfonium salts 5a and 5b were used, the diastereoselectivities were not changed,
whereas the absolute configurations of the products became the opposite to those of the reactions of 4a
and 4b. An ylide cyclopropanation of chalcone derivatives with phenylvinyl bromide in the presence of
catalytic amount of chiral sulfonium salts 4b and 5b has been developed. The sidearmed hydroxyl group
was found to play a key role in the control of enantioselectivity and diastereoselectivity. The origins of the
high diastereoselectivity and enantioselectivity were also studied by density functional theory calculations,
which reveal the importance of the hydrogen-bonding between the sidearmed hydroxyl group and the
substrate in determining the diastereoselectivity and enantioselectivity. The ylides 1 were also successfully
applied for the epoxidation of aromatic aldehydes.
Introduction
remains challenging due to the difficulty in controlling regi-
oselectivity, diastereoselectivity (cis/trans) and enantioselectivity.
Vinylcyclopropane derivatives have received considerable
attention because of their frequent occurrence in biologically
active compounds,1 as well as their utility as valuable synthetic
intermediates.2 Although many synthetic methods for cyclo-
propanes3 such as the Simmons-Smith reaction and transition
metal-catalyzed cyclopropanation of electron-rich alkenes with
R-diazocarbonyl compounds have been developed, the prepara-
tion of multisubstituted vinylcyclopropanes with high selectivity
Of the methods for the synthesis of vinylcyclopropanes,4 only
a few successful direct asymmetric synthesis has been reported
except those related to disubstituted or 1,1,2-trisubstituted ones,5
involving the use of symmetric dienes5a-c or â-phenylvinyldiazo-
ester.5e-g For the preparation of other trisubstituted vinylcyclo-
propanes, Hanessian et al.6 reported a cycloaddition reaction
of chiral chloroallylphosphonic amide to afford 1,2,3-trisubsti-
tuted cyclopropanes with excellent diastereoselectivity. Suzuki7a
and Taylor7b,7c found that these kinds of compounds could be
prepared from optically pure homoallylic alcohols. Aggarwal
† State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences.
‡ Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences.
§ Department of Chemistry, The Hong Kong University of Science &
Technology.
(3) For selected recent reviews, see: (a) Lebel, H.; Marcoux, J.-F.; Charette,
A. B. Chem. ReV. 2003, 103, 977. (b) Maas, G. Chem. Soc. ReV. 2004, 33,
183. (c) Mu¨ller, P. Acc. Chem. Res. 2004, 37, 243. (d) Davies, H. M. L.;
Antoulinakis, E. Org. React. 2001, 57, 1. (e) Fedoryn˜ski, M. Chem. ReV.
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Castro, A. M. Org. Lett. 2004, 6, 4945. (n). Lacassae, M.-C.; Poulard, C.;
Charette, A. B. J. Am. Chem. Soc. 2005, 127, 12440. (o) Kim, H. Y.; Lurain,
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9
9730
J. AM. CHEM. SOC. 2006, 128, 9730-9740
10.1021/ja056751o CCC: $33.50 © 2006 American Chemical Society

Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides
A R T I C L E S
Chart 1
Scheme 1
et al.8 also reported the reaction of a chiral silylated allylic sulfur
ylide with R-aminoacrylate to afford the desired vinylcyclo-
propane with 71% de and 75% ee.
Ylides proved to be efficient reagents not only for construct-
ing carbon-carbon double bonds but also for preparing small
ring compounds such as epoxides,9 aziridines,9b,9c,10 and
cyclopropanes.9b,9c,11 In a previous study on ylide chemistry,12
we found that lithium ion could switch the diastereoselectivity
of cyclopropanation reaction of telluronium allylides with R,â-
unsaturated esters or amides. The mechanism for this tuning
has been rationalized as the formation of a chelating six-
membered ring transition state (A in Chart 1) by coordination
of lithium ion with carbonyl oxygen and ylidic carbanion
simultaneously.13 On the basis of this mechanistic insight, we
designed chiral ylides 1 with a hydroxyl group at the â-position
of the sulfur atom by a sidearm approach.14 It is envisaged that
ylides of type 1 might form a rigid six-membered ring in the
presence of metal ion as shown in Chart 1 (B in Chart 1) and
thus the chirality of ylidic carbon is fixed, beneficial to the
diastereoselectivity and enantioselectivity. On the basis of this
strategy, we recently developed a highly enantioselective
cyclopropanation reaction and reported that ylide 1a, generated
from the corresponding salt 4a and t-BuOK (3.0 equiv) in situ,
could react in a stoichiometric manner with a variety of R,â-
unsaturated carbonyl compounds in one pot to afford 1,3-
disubstituted-2-silylvinylcyclopropanes 10 in high enantiomeric
excess (ee) and in good to high yields.15 The substrates,
however, were limited to â-aryl-R,â-unsaturated esters, amides,
ketones, and nitriles. For methyl crotonate, only 20% yield was
obtained due to the rearrangement of the sulfur ylide, although
the enantioselectivity was high. Very recently, we found that
both exo-type sulfur salt 4b and endo-type sulfur salt 5b also
worked well in the cyclopropanation of both â-aryl- and â-alkyl-
R,â-unsaturated carbonyl compounds and nitriles. Compared
with the exo ones, remarkably, the endo ones gave the opposite
enantioselectivity. Thus, the new development provides an easy
access to both enantiomers of trisubstituted cyclopropanes. We
also extended this reaction successfully to the epoxidation of
aromatic aldehydes and catalytic asymmetric ylide cyclopro-
panation. In this paper, we wish to report the details of these
reactions and their applications in organic synthesis, as well as
the theoretical studies toward understanding the origins of the
diastereo- and enantioselectivities of these reactions.
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Results and Discussion
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Synthesis of Sulfonium Salts. Chiral sulfides 2 and 3 were
easily prepared from D-(+)-camphor in two steps by a known
procedure.16 The reactions of 2 and 3 with allylic bromides in
acetone result in sulfonium salts 4 and 5, respectively, in good
yields (Scheme 1).
Enantioselective Synthesis of Silylvinylcyclopropanes.
Initially, we tried the stepwise reaction of sulfonium salt 4a
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Chem. Soc. 2002, 124, 9030. (b) Ye, M.-C.; Zhou, J.; Huang, Z.-Z. Tang,
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2002, 124, 2432.
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J. Org. Chem. 2000, 65, 6257.
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9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9731

A R T I C L E S
Scheme 2
Deng et al.
than -78 °C decreased the yield probably due to the rearrange-
ment (entries 2-3, Table 1). Choice of solvents proved crucial
for this reaction (entries 4-7, Table 1). In ethylene glycol
dimethyl ether (DME), the yield of cyclopropanation was
slightly decreased (entry 4, Table 1). In dichloromethane (DCM),
only 22% (entry 5, Table 1) yield was obtained. When the
solvent was switched to ether or hexane (entries 6, 7, Table 1),
only a trace amount of the desired cyclopropane was observed
due to the insolubility of both t-BuOK and sulfonium salt in
these solvents. Increasing the amount of t-BuOK also increased
the yield of the cyclopropane (entries 1, 8-9, Table 1). When
1.3 equiv of t-BuOK were used, the reaction was sluggish and
only 25% yield was obtained. However, when 3.6 equiv of the
base were added, the reaction rate increased and the yield was
also improved to 85%. A significant effect of the base on yield
was observed (entries 10-17, Table 1). Strong bases such as
NaHMDS and KHMDS lowered the yield. Weak bases such as
KOH, NaOMe, and t-BuOK /LiBr did not work in this reaction.
Interestingly, in all of the reaction conditions screened, the
enantioselectivities were higher than 90% and the diastereose-
lectivities were excellent with only one diastereomer 10a
isolated.
Encouraged by the observed excellent diastereoselectivity and
high enantioselectivity, we evaluated a variety of R,â-unsatur-
ated carbonyl compounds as substrates to study the generality
of this reaction. As shown in Table 2, R,â-unsaturated esters,
amides, ketones, and nitriles all worked well to give desired
products in good yields with excellent enantioselectivities. For
â-aryl-R,â-unsaturated esters and amides (entries 1-7, Table
2), the diastereoselectivities of this reaction were outstanding
and only the anti diastereoisomer 10 was isolated for each
reaction. When R,â-unsaturated ketones (entries 8, 9, Table 2)
were employed, the desired cyclopropane products were ob-
tained with high diastereoselectivities and enantioselectivities
in moderate to good yields and no epoxides were detected. It is
known that simple sulfonium allylides are hard to react with
R,â-unsaturated nitriles (Scheme 5). In the present case,
however, the ylide derived from 4a reacted with R,â-unsaturated
nitriles well to give excellent diasteroselectivities and enanti-
oselectivities (entries 10-12, Table 2). Methyl acrylate gave a
high yield with excellent ee and diastereoselectivity but methyl
crotonate afforded cyclopropane only in 20% yield, although
the diastereoselectivity (86/14) and enantioselectivity (92% ee)
were good (entries 13, 14, Table 2). Methyl cis-cinnamate was
inactive in this reaction and only gave a trace amount of the
desired product (entry 15, Table 2).
Table 1. Effects of Reaction Conditions on the Cyclopropanation
of Sulfonium Salt 4a with Methyl Cinnamate 9aa
yield
(%)b
ee
entry
solvent
base
4a/9a/base
T(
×
c1a˜C)
(%)c
1
2
3
4
5
THF
THF
THF
DME
DCM
ether
KOBut
1/1.2/2.4
1/1.2/2.4
1/1.2/2.4
1/1.2/2.4
1/1.2/2.4
1/1.2/2.4
1/1.2/2.4
1/1.2/1.3
1/1.2/3.6
1/1.2/2.4
1/1.2/2.4
1/1.2/3.6
1/1.2/3.6
1/1.2/3.6
-78
-40
0
82d
23
12
74
22
trace
trace
25d
85d
62
43
0
trace
0
75
96
92
91
96
95
/
KOBut
KOBut
KOBut
KOBut
KOBut
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
6
7
hexane KOBut
/
8
9
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
KOBut
96
97
95
93
/
/
/
95
/
96
KOBut
10
11
12
13
14
15
16
17
NaHMDS
KHMDS
KOH
KOBut/LiBr
NaOMe
KOBut/HMPA 1/1.2/3.6
KOBut/ZnCl2
KOBut/HMPA 1/1.2/3.6
1/1.2/3.6
trace
35
a Unless otherwise noted, the reaction time was 4 h. bIsolated yield and
only 10a was observed. Determined by chiral HPLC. The reaction time
was 2 h.
c
d
with methyl cinnamate. Deprotonation of compounds 4a by
lithium diisopropylamide (LDA) or n-butyllithium, followed by
treatment with methyl cinnamate, unfortunately, only gave trace
amount of the desired product. In this case, sulfide 8a was
isolated as the major product, indicating that the [2,3]-sigma-
tropic rearrangement17 of ylide 7a dominated (Schemes 2 and
3).
We reasoned that a weaker base than LDA would reduce the
formation of sulfur ylide 7a and should be beneficial to the
cyclopropanation. Thus, when t-BuOK was used instead of
LDA, we were pleased to find that vinylcyclopropane 10a was
achieved with 96% ee in 71% yield. Considering that the
rearrangement of compound 7a is an intramolecular reaction,
to further improve the yield, we also tried a one-pot reaction
by mixing salt 4a and t-BuOK with methyl cinnamate at -78
°C and stirring for several hours. In this case, the yield was
increased to 82% and the enantioselectivity remained the same
(96% ee) (entry 1, Table 1).
Enantioselectivity-Controllable Synthesis of Phenylvinyl-
cyclopropanes. The camphor-derived exo-sulfonium ylide
proved to be an excellent reagent for the cyclopropanation of
methyl cinnamate. The camphor-derived endo-isomer 5a (eq
1) could also react with methyl cinnamate to afford the
corresponding cyclopropanation product with moderate but
opposite enantioselectivity. Although the yield and the enanti-
Further studies showed that the yield and enantioselectivity
of the cyclopropanation were significantly influenced by the
reaction conditions. As shown in Table 1, higher temperature
(17) (a) Block, E. In The Chemistry of the Sulphonium Group; Stirling, C. J.
M., Patai, S. Eds.; Wiley: New York, 1981; p 673. (b) Marko´, I. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, UK, 1991; Vol. 3, p 913.
oselectivity are not good, it suggested that both enantiomers
might be prepared selectively using the natural camphor as the
9
9732 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides
A R T I C L E S
Table 2. Asymmetric Cyclopropanation of Sulfonium Salts 4a and 5a with Michael Acceptorsa
a All reactions were carried out in 2-4 h. b Isolated yield and sulfide 2 was recovered in 50-70% yield. c Determined by 1H NMR. d Determined by
chiral HPLC. e Ee for 10. f 4 equiv. of 9m or 9n were used. g The major products were sulfides 8a and 8a′ (Scheme 2). h Not determined. i The enantiomer
of 10 was obtained.
Scheme 3
Scheme 4
chiral source. The key is to inhibit the [2, 3]-σ-rearrangement
reaction of the ylide 7. To reduce the formation of ylide 7, we
used an electron-withdrawing group instead of trimethylsilyl
group to increase the acidity of the allylic hydrogen of sulfonium
salts 4 (Scheme 2). As expected, phenyl-substituted sulfonium
salt 4b, which was readily available from the corresponding
exo-sulfide 2 and phenylallylic bromide as a 9/1 mixture of
diastereoisomers, could be used directly to react with methyl
cinnamate in the presence of t-BuOK to afford vinylcyclopro-
pane 12a with high diastereoselectivity (>99/1) and excellent
enantioselectivity (99% ee) in 77% yield (entry 1, Table 3).
Encouraged by these results, we studied the generality of this
reaction and evaluated a variety of R,â-unsaturated carbonyl
compounds with different structures. As shown in Table 3,
â-aryl and â-alkyl-R,â-unsaturated esters, ketones, amides, and
nitriles were good substrates for this reaction. For â-aryl-R,â-
unsaturated substrates, both diastereoselectivities and enanti-
oselectivities were good to excellent (entries 1-6, Table 3).
For â-alkyl-R,â-unsaturated substrates, compared with our
previous work using sulfonium salt 4a, the yields were improved
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9733

A R T I C L E S
Scheme 5
Deng et al.
without epoxide observed. The R-benzyl acrylate also gave the
desired 1,1,2-trisubstituted cyclopropane with good diastereo-
selectivity (91/9) and enantioselectivity (88% ee) and in 83%
yield (entry 13, Table 3). Thus, 1,2-disubstituted or 1,2,3-
trisubstituted or 1,1,2-trisubstituted cyclopropanes could be
synthesized with high to excellent enantioselectivities.
The reaction of silylated endo-sulfonium salt 5a with methyl
cinnamate afforded the desired cyclopropane in low yield with
moderate enantioselectivities. However, phenyl-substituted endo-
sulfonium salt 5b furnished vinylcyclopropane 13 in 86% yield
with high diastereoselectivity (>99/1) and excellent but opposite
enantioselectivity (98% ee), compared with that using exo-
sulfonium salt 4b. As shown in Table 3, a variety of electron
deficient alkenes with different structures worked well in this
reaction, affording vinylcyclopropanes with high to excellent
enantioselectivities (up to 99% ee). Thus, either one of the two
enantiomers could be obtained at will just by the choice of exo-
or endo- sulfonium salts, both derived from cheap D-camphor.
To the best of our knowledge, these were the best results of
enantioselective synthesis of both enantiomers of vinylcyclo-
propanes via chiral sulfonium ylides.
greatly (entries 10-11, Table 3) and the enantioselectivities were
increased slightly. Acrylate, acrylamide, and acrylonitrile18 gave
high to excellent diastereo- and enantioselectivities (entries 7-9,
Table 3). Methyl crotonate afforded the cyclopropane with high
enantioselectivities of 97% ee (12j′) and 95% ee (12j) in 98%
yield (entry 10, Table 3), but their diastereoselectivities
decreased. â-Alkyl-R,â-unsaturated ketone also worked well
with high enantioselectivity 99% ee and in 88% yield (entry
12, Table 3) to give cis-diastereomer 12′ as the major product,
Table 3. Highly Enantioselective Synthesis of Both Enantiomers of Phenylvinylcyclopropane
a Isolated yield and the reactions were carried out for 2-4 h. b Determined by 1H NMR. c Determined by chiral HPLC. d 5 equiv. of R,â-unsaturated
compounds were used. e The enantioselectivity of the cis product 12′ and 13′.
9
9734 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides
A R T I C L E S
Table 4. Effects of Reaction Conditions on Catalytic Ylide Cyclopropanation
conver-
siona
(%)
base/
T
ee
(%)c
b
entry
solvent
additive
(
°
C)
16a/16a
′
1d
2e
3f
ButOH
ButOH
ButOH
THF
CH3CN
acetone
DME
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
t-BuOK
NaOH
KOH
K2CO3/18-
crown-6
Cs2CO3
30
30
30
30
30
30
30
30
30
30
30
30
77g,h
86g,h
79g,h
20i
77/23
80/20
75/25
55/45
50/50
50/50
50/50
82/18
60/40
50/50
50/50
85/15
72
74
73
52
51
54
51
75
80
65
73
81
4f
5f
56i
6f
40i
7f
45i
8f
ButOH
ButOH
ButOH
ButOH
ButOH/
CH3CNj
ButOH/
CH3CNj
ButOH/
CH3CNj
ButOH/
CH3CNj,k
65i
9f
75i,l
86i,l
70i,l
71i,l
10f
11f
12f
13f
14f
15f
0
0
0
92g,i
60g,i
86g,i
86/14
86/14
86/14
82
81
81
Cs2CO3/KIm
Cs2CO3
1
a On the basis of the recovered 14a. b Determined by H NMR. c Determined by Chiral HPLC. d Phenyl allylic bromide was added in one pot. e Added
by syringe pump in 6 h. f Added in 3 h. g Isolated yield and 100% conversion. h 24 h. i 36 h. j The ratio of ButOH/CH3CN (v/v, 2.5/1). k Trace amount of
H2O was added. l Disordered reactions and low yields for cyclopropanes. m 0.2 equiv. of KI was added.
Catalytic Asymmetric Cyclopropanation. The stoichiomet-
ric reaction of camphor-derived sulfonium salts provides a good
method for highly enantioselective synthesis of both enantiomers
of phenylvinylcyclopropanes. For a more practical application,
we tried to develop a catalytic asymmetric ylide cyclopropa-
nation. Fortunately, we found that chalcone could react with
phenylallylic bromide to afford cyclopropane with 72% ee and
moderate diastereoselectivity in the presence of 20% mol
sulfonium salt 4b in ButOH at 30 °C.
enantiomer of 16a could be obtained using 5b as the catalyst,
similar to the results in the case of stoichiometric amount of
sulfonium salts employed (entry 11, Table 5). A catalytic cycle
is proposed as shown in Scheme 4. First, the sulfide 2 reacts
with bromide 15 to afford the salt 4b, which is deprotonated
by Cs2CO3 to generate ylide 1b. Then, the ylide reacts with
unsaturated alkenes readily to give the cyclopropanes and
regenerate the sulfide 2 to complete the catalytic cycle. Attempts
to extend this catalytic reaction to ester 11a and amide 11d
failed.
To further improve the yield and stereoselectivity, we
investigated the effects of the reaction conditions on the
cyclopropanation, including solvents, temperature, bases as well
as addition sequence of the reactants. Finally, the best result
was achieved when a mixture of chalcone 14a (1.0 equiv),
phenyl allylic bromide 15 (1.5 equiv) and sulfonium salt exo-
4b (0.2 equiv) was stirred at 0 °C for 36 h in the mixed solvent
of tert-butyl alcohol and acetonitrile. In this case, the cyclo-
propanation product was obtained with a moderate diastereo-
selectivity (86/14) and a good enantioselectivity (82% ee) in
high yield (92%) (entry 13, Table 4). To investigate the
generality of this catalytic reaction, a variety of R,â-unsaturated
carbonyl compounds were investigated (Table 5). While the
silylated sulfonium salts 4a and 5a were inert, both exo-
sulfonium salt 4b and endo-sulfonium salt 5b were found to
catalyze the cyclopropanation of R,â-unsaturated ketones with
bromide 15 well, affording the desired cyclopropanes in good
to high yields and with good to high enantioselectivities (Table
5). Using chiral sulfide 2 as the catalyst, similar results were
achieved (entries 2 and 5, Table 5).19 It is worth noting that the
Mechanism. The camphor-derived â-hydroxyl-sulfonium
ylide proves to be efficient for the cyclopropanation of electron-
deficient alkenes. For example, the reaction of salt 4a with R,â-
unsaturated nitrile affords the desired cyclopropane in 66% yield
with 96% ee. But the corresponding dimethyl sulfonium salt
17 as well as tetrahydrothiophene-derived sulfonium salt 18 only
gave a trace amount of cyclopropane (Scheme 5).
We rationalized that the hydroxyl group in salt 4a might play
a crucial role in this reaction. An attempt to remove the hydroxyl
group of the compound 4a failed.20 Thus, we tried to protect
the free hydroxyl group of 4a with methyl and prepared the
sulfonium salt 19 for study (Scheme 6). It was found that no
desired cyclopropane was observed when salt 19 was used
instead of 4a and only rearrangement products 20 were isolated
(Scheme 6). These demonstrate that the free sidearmed hydroxyl
group strongly influenced the reaction behavior of the ylides in
the cyclopropanation reactions.
To understand the difference between salts 4a and 19, we
obtained their crystals. As shown in Figure 1, from the X-ray
(19) It is always more convenient to add sulfide rather than to have to make
sulfonium salt.
(20) For details please see Supporting Information.
(18) Polymerization was observed in this reaction, similar to the cyclopropanation
of acrylonitrile using ammonium ylide, see ref 11c.
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9735

A R T I C L E S
Deng et al.
Table 5. Catalytic Asymmetric Cyclopropanation by Chiral Sulfonium Saltsa
a Sulfonium salt exo-4b (0.2 equiv), R,â-unsaturated ketone 14 (1.0 equiv.), phenyl allylic bromide 15 (1.5 equiv.), Cs2CO3 (2.0 equiv.), ButOH/CH3CN
(v/v, 2.5/1.0), 0 °C. b Isolated total yield for cis- and trans-isomers. c Determined by 1H NMR. d Ee for 16 and determined by chiral HPLC. e Chiral sulfide
2 was used as a catalyst. f Conversion. g 5b was used and the enantiomer of 16a was isolated.
Figure 1. X-ray crystal structures of sulfonium salts 4a and 19.
Scheme 6
carbon, due to both effects of hydroxyl-directing and the steric
hindrance of the S-methyl group. It appears that transition state
A is favored over B and thus cyclopropanes 10 are obtained as
the major products, which is consistent with the experimental
results.
Theoretical Studies on Mechanism. Although a crude
transition state model has been proposed (Scheme 7) to explain
the high diastereo- and enantio-selectivities of the reaction of
hydroxyl-assisted sulfur ylide with R,â-unsaturated substrates,
the detailed reaction mechanism is waiting to be disclosed.
structure analysis of the salts, the distance between the sulfur
and oxygen is only 2.78 Å, and the distortion angle O-C1-
C2-S is 0° in salt 4a; similarly, in salt 19, they are 2.74 Å21
and 4.2° respectively, indicating that both salts have similar
Therefore, density functional theory has been employed for the
structures with bonding interactions between sulfur and oxygen
study of the mechanism and stereochemistry of the aforemen-
atoms. Therefore, the free hydroxyl group must play a crucial
tioned cyclopropanation reactions. First, the reactions of exo-
role in determining both the reactivity and stereoselectivity.
sulfur ylide 1a with methyl acrylate 9m and endo-sulfur ylide
with methyl cinnamate 9a were chosen as models (Scheme 8).
On the basis of these results, together with the absolute
configuration of the product, stereochemical models were
developed to explain the stereochemistry as shown in Scheme
7. When exo-salt 4a was used, 4a was deprotonated by tBuOK
to afford the ylide, which attacked R,â-unsaturated carbonyl
compounds to afford the desired cyclopropanes. The electron-
deficient alkenes could only approach the Re face of the ylidic
Computational Methodology
All calculations were performed with the Gaussian 03 program.22
Geometries were fully optimized with the density functional theory of
B3LYP method.23,24 For the part of exo-ylide calculation, the 6-31+G*
(22) Gaussian 03, ReVision B.03, Frisch, M. J. et al. Gaussian, Inc., Pittsburgh,
PA. 2003.
(21) The van der Waals sum of S-O is about 3.25 Å.
9
9736 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides
A R T I C L E S
Scheme 7
Scheme 8
basis set was used for carbon, hydrogen, and oxygen atoms and
LANL2DZ basis set25 with effective core potential (ECP) for silicon
and sulfur atoms; while for the part of endo-ylide calculation, the
standard 6-31G* basis set26 was used for carbon, hydrogen, and oxygen
atoms and ECP (LANL2DZ) basis set25 for silicon and sulfur atoms.
Harmonic vibration frequency calculations were carried out for all the
stationary points to confirm each structure being either a minimum
(no imaginary frequency) or a transition structure (one imaginary
frequency). Solvent effect has been considered by using the IEFPCM27
(UAHF atomic radii) model in THF (ꢀ ) 7.58) based on the gas-phase
structures. The relative Gibbs free energies given in this paper are at
298 K.
Computation Results and Discussion
We proposed that the reaction might go through a hydrogen
bond model, as shown in Figure 2. Since the ylide has two
conformations, with the vinyl group either syn (e.g., in TS 21
and TS 24) or anti (e.g., in TS 22 and TS 23) to the sulfur
lone-pair. Therefore, four transition structures are possible with
the hydrogen bond model for each ylide as shown in Figure 2.
Such hydrogen bond model should be favorable for reducing
the activation energy. We also calculated several transition
structures without a hydrogen bond and indeed they have higher
activation energies, and they are not discussed here.
Figure 2. Analysis of hydrogen-bonded transition structure models for the
reactions of exo-ylide 1a with methyl acrylate 9m and endo-ylide with
methyl cinnamate 9a.
The stereoviews of the four calculated transition structures
for the reaction of exo-ylide 1a are shown in Figure 3. In the
10-membered-ring transition structures, the H-O-C-C-S-C
moiety is in a boatlike conformation. The methyl acrylate moiety
is in an S-cis conformation, with the CdC-CdO dihedral angle
varying from -6° to 3°. The OH- - -OdC hydrogen bonds are
formed in the carbonyl planes. These hydrogen bonds are quite
strong, judging from the short H- - -O distances of 1.691-1.772
Å and the nearly linear O-H- - -O angles. Three of the transition
structures, TS 21, TS 23, and TS 24, are considerably eclipsed
about the forming C- - -C bond, whereas TS 22 is more close
to a staggered conformation. Calculations indicate that in TS
21 and TS 23, the methyl acrylate approaches the ylide from
the front side, so that it has no steric interaction with H8 and
(23) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.;
Parr, R. Phys. ReV. B 1988, 37, 785.
(24) For reviews of density-functional methods, see: (a) Parr, R. G.; Yang, W.
Density Functional Theory of Atoms and Molecules; Oxford University
Press: New York, 1989. (b) Ziegler, T. Chem. ReV. 1991, 91, 651. (c)
Density Functional Methods in Chemistry; Labanowski, J., Andzelm, J.,
Eds.; Springer: Berlin, 1991.
(25) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (b) Wadt, W.
R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
(26) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257. (b) Petersson, G. A.; Al-Laham, M. A. J. Chem. Phys. 1991, 94,
6081.
(27) (a) Cances, M. T.; Mennucci, V.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032. (b) Cossi, M.; Barone, V.; Tomasi, J. Phys. Lett. 1998, 286, 253.
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9737

A R T I C L E S
Deng et al.
Figure 3. Stereoviews of the addition transition structures for the reaction of exo-sulfur ylide 1a with methyl acrylate. Most of the H atoms in these
structures are omitted for clarity. Bond distances are in angstrom. The calculated relative free energies in the gas phase and in THF solution (in parentheses)
with respect to TS 21 are in kcal/mol.
Table 6. Stereo-Selective Reactions of Exo-Sulfur Ylide with
H9 of the norbornyl moiety. On the other hand, in TS 22 and
Methyl Acrylate and Endo-Sulfur Ylide with Methyl Cinnamate28
TS 24, to maintain a good hydrogen-bonding, the methyl
c
d
∆
Ha
∆
Sb
∆Ggas
∆Gsol
acrylate and the ylide have to rotate by about 90°. As a result,
the acrylate suffers from steric interactions with the H8 and H9,
as indicated by short H6- - -H8 and H6- - -H9 distances (Figure
3). Therefore, they are found to be less stable than TS 21 and
TS 23, respectively. In addition, solvent also has an effect on
the stability of the transition structures. Although calculated
solvent effect should be treated with care, the calculation results
can be qualitatively understood. TS 21, which has the largest
surface, benefits the most from the solvent effect. On the other
hand, TS 23 has the least surface area and benefits least from
solvation. We failed to locate an intermediate for the reaction.
In contrast to epoxidation and aziridination where sulfur ylide
reactions with the appropriate electrophiles occur via betaine
intermediates,29 these addition transition structures lead directly
to the formation of cyclopropane product and ring closure must
occur without barrier. So the stereochemistry of the reaction is
determined by the relative stabilities of these transition struc-
tures. As shown in Figure 3 and Table 6, the calculated results
are qualitatively similar in the gas phase and in solution. That
is, TS 21 is most stable and its stability over the other transition
structures is increased in solution. The calculations indicate a
high selectivity for the anti product over syn product and a high
(kcal/
mol)
(cal/
(kcal/
mol)
(kcal/
mol)
entry
TS
mol-K)
PRe
syn:anti
ee (%)
exo-
ylide 22
21
0.0
0.56
0.0
0.0
0.0
10m1 1/99
93
0.38 0.45 1.28 10m2 (calcd)f (calcd)f
23 -0.12 -1.80 0.41 2.27 10m3 <1/99
24 -0.06 -3.79 1.07 2.02 10m4 (excpt) (expt)
95
endo- 25 -0.06 -1.44 0.37 0.93 10a1 2:98 83
ylide 26 0.0 0.0 0.0 0.0
10a2 (calcd)f (calcd)f
27 -0.67 -6.23 1.19 2.03 10a3 <1/99
28 -0.61 -4.51 0.74 1.46 10a4 (expt)
74
(expt)
a Relative enthalpy in gas phase. b Relative entropy in gas phase.
c Relative Gibbs free energy in gas phase. d Relative Gibbs free energy in
solution (THF). e The corresponding cyclopropane products of each transi-
tion state (Scheme 9). f Calculated based on the relative Gibbs free energies
in solution.
enantioselectivity, both agree with the experimental observations
well.
Figure 4 shows the stereoviews of the four addition transition
structures for the reaction of endo-ylide. These transition
structures have similar geometrical features with the transition
structures for the reaction of the exo-ylide. That is, the H-O-
C-C-S-C moiety is in boatlike conformation and the CdC-
CdO is in an S-cis conformation. The forming C- - -C bond is
in a staggered conformation in TS 25 (-77°) and TS 26 (83°)
and it is more close to an eclipsed conformation in TS 27 (16°)
and TS 28 (-16°).
(28) Calculations have also been carried out for the reaction of endo-sulfur ylide
with methyl acrylate. The results, which are given in the Supporting
Information (Table S2 on page S37-38), reproduce the experimental
observation very well (Table 2, entry 20).
(29) Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002,
124, 5747.
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9738 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides
A R T I C L E S
Figure 4. Stereoviews of the addition transition structures for the reaction of endo-sulfur ylide with methyl cinnamate. Most of the H atoms in these
structures are omitted for clarity. Bond distances are in Å. Dihedral angles are in degrees. The calculated relative free energies in gas phase and in THF
solution (in parentheses) with respect to TS 26 are in kcal/mol.
Scheme 9
Because of the constraint of the 10-membered-ring hydrogen-
bonding, the methyl cinnamate in TS 26 and TS 28 can
approach the ylide from the front side without geometrical
distortion, but a rotation of the methyl cinnamate and the ylide
is needed in TS 25 and TS 27. Thus, the cinnamate moiety in
TS 26 and TS 28 does not have steric interaction with the H8
and H9 of the norbornyl group but TS 25 and TS 27 suffer
steric interactions, as indicated by the calculated H6- - -H8 and
H6- - -H9 distances shown in Figure 4. As a result, TS 26 and
TS 28 are more stable than TS 25 and TS 27, respectively.
carbonyl compounds with sulfonium salt 4a encouraged us to
extend 4a to the epoxidation of aldehydes (Scheme 9).
Under the optimal conditions, as shown in Scheme 9, the
When solvent of THF is included, TS 26 becomes about
0.9, 2.0, and 1.5 kcal/mol more stable than TS 25, TS 27, and
TS 28, respectively. This gives roughly a 2/98 (syn/anti)
diastereoselectivity and an 83% ee enantioselectivity for the anti
product, in quite good agreement with the experimental
observations, as shown in Table 6.
enantioselectivities were excellent although the diastereoselec-
tivities of the reaction of 4a with aromatic aldehydes were only
moderate (ranged from 78/22 to 82/18). For aliphatic aldehydes,
epoxides were not observed.
Product Elaboration. The usefulness of the present work
was exemplified in a short formal synthesis of PCCG-4, a
potential and selective group II mGluRs antagonist.31 Cyclo-
propylaldehyde 31 is regarded as a key intermediate for the
synthesis of PCCG-4 and was reported to be synthesized from
a diazoacetate in five steps.31a It was found that this compound
could be readily prepared in high yield (total yield in two
In summary, the ten-membered-ring hydrogen-bonding model
gave an excellent explanation for the opposite enantioselectivi-
ties of exo- and endo-sulfur ylide cyclopropanation reactions.
Because of the ring constraint, TS 22, TS 24, TS 25, and TS
27 are forced to distort so that they suffer from steric interaction
with the H8 and H9 of the norbornyl group. In addition, solvent
also seems to play an important role in enhancing both
diastereoselectivity and enantioselectivity.
(30) (a) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org.
Chem.1998, 63, 2948. (b) Wang, Z.-X.; Cao, G.-A.; Shi, Y. Chiral Ketone
J. Org. Chem. 1999, 64, 7646.
(31) (a) Marinozzi, M.; Natalini, B.; Costantino, G.; Tijskens, P.; Thomsen, C.;
Pellicciari, R. Bioorg. Med. Chem. Lett. 1996, 6, 2243. (b) Pellicciari, R.;
Marinozzi, M. M.; Natalini, B.; Costantino, G.; Luneia, R.; Giorgi, G.;
Moroni, F.; Thomsen, C. J. Med. Chem. 1996, 39, 2259.
Highly Enantioselective Synthesis of Vinylepoxides. 30 The
high selectivity in the cyclopropanation of R,â-unsaturated
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9739

A R T I C L E S
Scheme 10 a
Deng et al.
a Reaction conditions: (a) O3/Ph3P, 93%; (b) NaClO2 + NaH2PO4, (CH3)2CdCHCH3; (c) NCS + Ph3P/morphine, 80%; (d) (i) NaBH4 + LiCl, THF/EtOH,
(ii) Dess-Martin oxidation, 65%.
steps: 83%) with 98% ee using the present process by ylide
cyclopropanation of amide 11e, followed by oxidation (Scheme
10). One of the advantages is that both enantiomers of 31 could
be prepared with excellent enantioselectivities and in high yields.
Thus, this new process allowed us to access both optically pure
cyclopropylaldehyde 31 easily.
The other two stereoisomers 32 and ent-32 of cyclopropyl-
aldehyde 31 could also be synthesized from the vinylcylopro-
pane 13a and 12a, respectively (Scheme 10). And thus, four
optically active trisubstituted cyclopropylaldehydes could be
prepared easily using D-(+)-Camphor as the chiral source.
of the sidearm free hydroxyl group has been investigated and
proven to be crucial in controlling the enantioselectivity. The
origin of the enantioselectivity and diastereoselectivity in the
current asymmetric cyclopropanation has been studied by both
experiments and density functional theory calculations, revealing
the importance of the hydrogen-bonding between the sidearm
hydroxyl group and the substrate. The readily available ylides
from cheap D-camphor, the controllable enantioselectivity,
together with the easy chemical transformation make the current
method highly potential for practical use in organic synthesis.
Acknowledgment. We are grateful for the financial support
from the Natural Sciences Foundation of China, The Science
and Technology Commission of Shanghai Municipality, and the
Croucher Foundation (Hong Kong) for a studentship.
Conclusion
The newly designed chiral sulfonium ylide 1 by a sidearm
approach has proven to be a highly efficient reagent for
asymmetric cyclopropanation. Using the present method, both
enantiomers of various functionalized vinylcyclopropanes with
high enantioselectivities can be prepared conveniently from the
cheap chiral source D-(+)-Camphor. A catalytic asymmetric
ylide cyclopropanation using chiral sulfonium salts and phenyl
allylic bromide has also been developed. The extension of this
ylide to the epoxidation of aromatic aldehydes provides an easy
access to vinylepoxides in excellent enantioselectivity. The role
Supporting Information Available: Experimental section
containing characterization of key compounds, chiral HPLC data
of 10, 12, 13, 16, 30, 31, and 32 (PDF) and X-ray crystal-
lographic files (CIF), calculated total energies and coordinates
of the transition structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA056751O
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9740 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006