Diastereoselective synthesis of vinylcyclopropanes from dienes and sulfur ylides

Article abstract of DOI:10.1055/s-2008-1032080

The reaction of aryl- and vinyl-stabilized sulfonium ylides with electron-poor dienes has been investigated. Clean cyclopropanation to 2-aryl- and 2-vinyl-substituted vinylcyclopropanes, with high regio- and stereocontrol, was observed. This new diastereo

Full text of DOI:10.1055/s-2008-1032080

LETTER
517
Diastereoselective Synthesis of Vinylcyclopropanes from Dienes and Sulfur
Ylides
D
iastereoselectiv
a
e
Synthesis
p
of Vinylcyc
h
lopropanes aël Robiette,* Jacqueline Marchand-Brynaert
Université Catholique de Louvain, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Fax +32(10)474168; E-mail: raphael.robiette@uclouvain.be
Received 16 November 2007
Several strategies have been developed for the synthesis
of cyclopropanes.1,3 Among these, the sulfur ylide medi-
ated cyclopropanation has emerged as a powerful method:
addition of substituted sulfonium ylides to acrylate deriv-
Abstract: The reaction of aryl- and vinyl-stabilized sulfonium
ylides with electron-poor dienes has been investigated. Clean cyclo-
propanation to 2-aryl- and 2-vinyl-substituted vinylcyclopropanes,
with high regio- and stereocontrol, was observed. This new diaste-
reoselective strategy was applied to formal synthesis of lamoxirene atives leads to cyclopropanes in good yields and generally
high diastereoselectivity.8,9 Recently, Aggarwal, Dai, and
and dictyopterene B.
others have also developed an efficient asymmetric ver-
sion of this methodology using chiral sulfonium salts.10
This prompted us to consider the possibility of applying
this methodology to diene esters for the synthesis of sub-
stituted vinylcyclopropanes. However, the presence of
two electrophilic double bonds in the diene raised the is-
sue of regioselectivity11 as well as the possibility of dou-
ble addition.
Key words: vinylcyclopropane, diene, stereoselective synthesis,
sulfur, ylides
Vinylcyclopropanes are important compounds which
serve as versatile intermediates in the synthesis of many
biologically active compounds (Figure 1).1 This structural
motif is also present in numerous natural products.2 As a
result, several strategies have been devised for the synthe-
sis of such structures.3 The vast majority of these ap-
proaches is, however, restricted to the preparation of 2-
vinylcyclopropane (di)carboxylic esters,4,5 with the syn-
thesis of aryl- and vinyl-substituted vinylcyclopropanes
remaining a challenge. Indeed, despite the great interest to
the latter compounds, their preparation involves generally
indirect multistep syntheses.6,7 We report herein our re-
sults on the development of a diastereoselective one-step
strategy to aryl- and vinyl-substituted vinylcyclopropanes
from dienes and sulfur ylides, and the application of this
methodology to the formal synthesis of some natural
products.
Thus, we first assessed the feasibility of our strategy by
investigating the reaction of diene 1 with the ylide formed
by deprotonation of sulfonium salt 2a.12 After optimiza-
tion of base, solvent, and order of addition, we were
pleased to find that addition of LiHMDS to a solution of
the diene and the salt 2a, in CH2Cl2 at –78 °C, leads clean-
ly to vinylcyclopropane 3a in excellent yield (Scheme 1).
Diastereoselectivity was determined by 1H NMR and GC
of the crude mixture. The trans diastereomer of 3a was
obtained with a good diastereoselectivity (93:7). No prod-
uct arising from a second addition (5a) could be detected
1
in H NMR whereas the undesired regioisomer 4a was
present in 12% yield in the crude mixture. Regioselectiv-
O
1–2
N
H
N
CO2H
αvβ3 inhibitors
(–)-dictyopterene B
O
HN
O
N
O
H
OH
N
OH
O
FR-900848
Figure 1 Biologically active cyclopropanes
SYNLETT 2008, No. 4, pp 0517–0520
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032080; Art ID: D37907ST
© Georg Thieme Verlag Stuttgart · New York

518
R. Robiette, J. Marchand-Brynaert
LETTER
Ph
CO2Me
BF4
LiHMDS
Ph
+
S
+
CH2Cl2, –78 °C,
1 h
Ph
CO2Me
CO2Me
1
2a
3a
4a
12%
yield = 86%
trans/cis = 93:7
Ph
S
CO2Me
Ph
5a
Ph
not detected
Scheme 1
O
CO2Me
Br
LiHMDS
ref. 16
+
S
CH2Cl2
–78 °C, 1 h
CO2Me
1
6
7
lamoxirene
yield = 60%
regioselectivity = 71:29
trans/cis = 94:6
1. DIBAL-H
2. PCC
ref. 18
dictyopterene B
CHO
yield = 83%
8
Scheme 2 Application to formal synthesis of natural products
ity could be improved (>98:2) by the use of KHMDS as a presence of this new functional group (phosphonate) in-
base but a low decrease of diastereoselectivity was then creases the possibilities for further transformations.
observed (dr = 88:12).
Finally, the general utility of this new process was further
These conditions were then applied to a variety of aryl- demonstrated by extending its scope to the synthesis of di-
stabilized ylides. The corresponding trans-aryl-vinylcy- vinylcyclopropane 7, which represents a formal synthesis
clopropanes were obtained in good to excellent yields of lamoxirene. The synthesis of this natural compound
(Table 1, entries 1–9). Electronic properties of the aryl which has an important role in the reproductive cycle of
group (electron-rich or electron-poor) have very little ef- marine brown algae15 has been described by Boland.16 In
fect on regio- and diastereoselectivities. Steric hindrance, this synthesis, intermediate 7 was obtained by a three-step
on the other hand, appeared to have a significant influ- procedure.17 Application of our strategy to allylic sulfo-
ence. Indeed, sterically hindered ortho-substituted ylides nium salt 6 enables the expedient preparation of divinyl-
showed an increased regioselectivity (entries 8 and 9).
cyclopropane 7 with a moderate yield and a good
diastereoselectivity (Scheme 2). Further, transformation
of this ester into the corresponding aldehyde constitutes a
new diastereoselective access to 8 which is a known inter-
mediate in the synthesis of the gamete attractant dicty-
opterene B.18
Phosphonic groups are often used as bioisosteric replace-
ments of carboxylic functions,13 we also tried the reaction
with 1-(diethylphosphono)butadiene14 (Table 1, entry10).
Reaction of this latter with 2a gave the corresponding sub-
stituted vinylcyclopropane with a good yield and an excel-
1
lent regioselectivity (no regioisomer was detected in H In summary, we have developed a practical and general
NMR). The observed high regioselectivity can most prob- synthesis of substituted vinylcyclopropanes from sulfo-
ably be accounted for by the bulkiness of the phosphonate nium ylides and electron-poor dienes. We have demon-
groups disfavoring 1,4-addition. Diastereoselectivities, on strated that this reaction proceeds with a good
the contrary, are slightly lower than with diene 1. The regiocontrol and is highly trans diastereoselective. The re-
action is applicable to a range of substrates with a variety
Synlett 2008, No. 4, 517–520 © Thieme Stuttgart · New York

LETTER
Diastereoselective Synthesis of Vinylcyclopropanes
519
166.1 (CO2Me). GC (MN OPTIMAS-5; 150 °C for 10 min and then
290 °C, 7 °C/min): 22.3 min. MS (APCI): m/z = 233 [M + 1]+, 201
[M + 1 – MeOH]+, 173 [M + 1 – HCO2Me]+.
Table 1 Synthesis of Vinylcyclopropanes
R
BF4
LiHMDS
Minor (cis) isomer: 1H NMR (500 MHz, CDCl3): d = 1.32 (m, 1 H,
HCH), 1.36 (m, 1 H, HCH), 1.65 (m, 1 H, HCCH2=CH2), 2.43 (m,
1 H, HCAr), 3.67 (s, 3 H, OCH3), 3.73 (5.83 (s, 3 H, OCH3), 5.84
(d, 1 H, J = 15.4 Hz, CHCO2Me), 6.16 (dd, 1 H, J = 15.4, 10.5 Hz,
Ar
S
+
Ar
CH2Cl2, –78 °C
R
1
2
3
Entry
R
Ar
Yield Regiose- trans/cisb
CH=CHCO2Me), 6.75 (m, 2 H, ArH), 7.06 (d, 2 H, J = 8.6 Hz). 13
C
(%)a
lectivityb
88:12
88:12
91:9
NMR (125 MHz, CDCl3): d = 12.8 (CH2), 16.4 (CHAr), 23.8
(CHCH2=CH2), 50.2 (OCH3), 54.2 (OCH3), 112.8 (CHCOMe),
118.4 (CHCO2Me), 129.0 (CHC-cyclopropyl), 129.4 (C-cyclopro-
pyl), 149.6 (CH-cyclopropyl), 158.1 (COMe), 165.7 (CO2Me). GC
(MN OPTIMAS-5; 150 °C for 10 min and then 290 °C, 7 °C/min):
20.7 min.
1
2
3
4
5
6
7
8
9
10
CO2Me
Ph
98
93:7
4-MeOC6H4
94
85:15
89:11
94:6
4-CO2MeC6H4 77
4-MeC6H4
4-FC6H4
98
99
99
99
99
88
70c
88:12
86:14
89:11
87:13
97:3
Characterization of 4 with Ar = 4-MeOC6H4 and R = CO2Me
1H NMR (500 MHz; CDCl3): d = 2.15 (dd, 1 H, J = 5.4, 4.8 Hz,
HCAr), 2.43 (ddd, 1 H, J = 9.6, 8.7, 4.8 Hz, HCH=CH2), 2.90 (dd,
1 H, J = 9.6, 5.4 Hz, HCCO2Me), 3.76 (s, 3 H, OCH3), 3.81 (s, 3 H,
OCH3), 5.01 (dd, 1 H, J = 9.9, 2.1 Hz, cis-HCH=CH), 5.17 (ddd, 1
H, J = 17.1, 9.9, 8.7 Hz, CH=CH2), 5.26 (dd, 1 H, J = 17.1, 2.1 Hz,
trans-HCH=CH), 6.85 (d, 2 H, J = 8.7 Hz, Ar), 7.13 (d, 1 H, J = 8.7
Hz, Ar). GC (MN OPTIMAS-5; 150 °C for 10 min and then 290 °C,
7 °C/min): 18.3 min.
90:10
95:5
2-ClC6H4
2-MeOC6H4
3-MeC6H4
3-FC6H4
93:7
94:6
96:4
92:8
PO(OEt)2 Ph
>95:5
72:28
Acknowledgment
a Global yield.
The authors thank the Fonds de la Recherche Scientifique - FNRS
(F.R.S.-FNRS) for financial support, Dr. David Chapon for assi-
stance with NMR spectroscopy, and J.-C. Monbaliu for a generous
gift of 1-(diethylphosphono)butadiene. R.R. is indebted to Prof. V.
K. Aggarwal for fruitful discussions and his support. R.R. is a Char-
gé de Recherches F.R.S.-FNRS and J.M.-B. is a senior research as-
sociate of the F.R.S.-FNRS.
b Ratio was determined by 1H NMR and/or GC analysis, and relative
stereochemistry was determined by 1H NMR (500 MHz).
c Reaction carried out at –5 °C.
of functional groups. The efficiency of this method has
been demonstrated by the short synthesis of key interme-
diates in the synthesis of lamoxirene and dictyopterene B.
We are currently exploring the use of chiral sulfonium
salts to develop an asymmetric version of this strategy.
References and Notes
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Typical Procedure for the Cyclopropanation Reaction
LiHMDS (2.2 mmol; 1 M solution in THF) was added dropwise, at
–78 °C, to a solution of sulfonium salt (2 mmol) and diene (2.2
mmol) in CH2Cl2 (7 mL) The reaction mixture was stirred at this
temperature for 1–6 h. The cold bath was then removed, allowing
the solution to warm to r.t. The reaction was quenched with HCl (1
N). The organic extract was concentrated under reduced pressure
and redissolved in Et2O. This solution was washed with HCl (1 N),
H2O, and brine before being dried over MgSO4 and concentrated
under vacuum to yield the desired substituted cyclopropane. The
cis- and trans-isomers can be separated by column chromatography
on silica gel.
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Characterization of 3 with Ar = 4-MeOC6H4 and R = CO2Me
Major (trans) isomer: 1H NMR (500 MHz, CDCl3): d = 1.19 (ddd,
1 H, J = 9.0, 5.3, 5.2 Hz, HCH), 1.32 (ddd, 1 H, J = 8.4, 6.2, 5.3 Hz,
HCH), 1.67 (m, 1 H, HCCH2=CH2), 2.07 (ddd, 1 H, J = 9.0, 6.2, 4.2
Hz, HCAr), 3.65 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 5.82 (d, 1 H,
J = 15.4 Hz, CHCO2Me), 6.52 (dd, 1 H, J = 15.4, 9.9 Hz,
CH=CHCO2Me), 6.75 (d, 2 H, J = 8.7 Hz, ArH), 6.94 (d, 2 H,
J = 8.7 Hz, ArH). 13C NMR (125 MHz, CDCl3): d = 16.4 (CH2),
25.3 (CHAr), 25.4 (CHCH2=CH2), 50.4 (OCH3), 54.3 (OCH3),
112.8 (CHCOMe), 117.1 (CHCO2Me), 126.0 (CHC-cyclopropyl),
128.4 (C-cyclopropyl), 151.2 (CH-cyclopropyl), 157.2 (COMe),
Synlett 2008, No. 4, 517–520 © Thieme Stuttgart · New York

520
R. Robiette, J. Marchand-Brynaert
LETTER
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