Catalytic asymmetric cyclopropanation of electron deficient alkenes mediated by chiral sulfides

Article abstract of DOI:10.1039/a704214k

Catalytic asymmetric cylopropanation of enones has been achieved using diazo compounds, catalytic quantities of a metal catalyst and a camphor-derived thioacetal; this sulfide shows exceptionally high levels of enantioselectivity.

Full text of DOI:10.1039/a704214k

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Catalytic asymmetric cyclopropanation of electron deficient alkenes mediated
by chiral sulfides
Varinder K. Aggarwal,*a Helen W. Smith,a Ray V. H. Jonesb and Robin Fieldhouseb
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, UK S3 7HF
b Zeneca Process Technology Dept., Earls Road, Grangemouth, Stirlingshire, UK
Catalytic asymmetric cylopropanation of enones has been
achieved using diazo compounds, catalytic quantities of a
metal catalyst and a camphor-derived thioacetal; this sulfide
shows exceptionally high levels of enantioselectivity.
let–Hauser product was observed.‡ Under standard reaction
conditions an excess of the sulfonium salt22 or the ylide is
typically used to cyclopropanate alkenes, perhaps for this
reason.
To reduce the extent of this rearrangement the six membered
analogue, pentamethylene sulfide, was employed and, gratify-
ingly, high yields of cyclopropanes were obtained (entries 3–6).
Even using catalytic amounts of sulfide, cyclopropanes were
formed in moderate to good yields (entries 7–10). The least
reactive enone (entry 10) gave reduced yields as the rearrange-
ment of the ylide was once again a significant competing side
reaction.
We next explored asymmetric cyclopropanation (Table 2)
and chose oxathiane 1 as this sulfide had previously given high
enantioselectivity in epoxidation of carbonyl compounds14 and
aziridination of imines.16 Furthermore, sulfide 1 is readily
available, in either enantiomeric form, from camphorsulfonyl
chloride in two steps.14 We applied this sulfide to the 4-phenyl
substituted enones (as this would give rise to a maximum of two
diastereoisomers) and we were delighted to find that exception-
ally high levels of enantioselectivity were obtained with both
stoichiometric and catalytic amounts of sulfide.§ However,
reduced yields were obtained when using catalytic compared to
stoichiometric amounts of sulfide. This was also observed in the
related epoxidation process14,15 but the differences in yield are
greater in cyclopropanation, presumably because of the lower
reactivity of enones compared to aldehydes. The constant
enantiomeric excess (no reduction observed) in reactions using
catalytic quantities of sulfides indicates that no direct cyclopro-
panation occurs and that the sulfide reacts with the metal
carbenoid (to give a sulfur ylide) at a significantly faster rate
than the alkene (to give direct cyclopropanation). The major
isomer of the cyclopropane is tentatively assigned as the R,R
Cyclopropanes are common functional groups in biologically
active molecules, the most notable examples being the pyr-
ethroids which are a highly potent class of insecticides.1 Much
effort has therefore been expended in the synthesis of
cyclopropanes in racemic and more recently, in asymmetric
form.2,3 High enantioselectivity has been achieved in the
Simmons–Smith4,5 cyclopropanation of allylic alcohols using
chiral promoters.6,7 High enantioselectivity has also been
achieved in metal catalysed reactions of diazocarbonyl com-
pounds with alkenes. The chirality may be linked to the metal in
the form of a chiral ligand (e.g. bis-oxazolines8) or linked to
both the metal and the diazo compound to enhance the
enantioselectivity.9,10 However, in all the above cases, the metal
carbenoid only reacts efficiently with electron rich alkenes11
and so methods are required for the cyclopropanation of
electron deficient alkenes. Towards this end enantiomerically
pure aminosulfoxonium ylides have been successfully em-
ployed in asymmetric cyclopropanation of electron deficient
alkenes.12,13 However, such reagents have to be employed in
stoichiometric amounts, and cannot be recycled. Sulfur ylides
are also known to react with electron deficient alkenes to furnish
cyclopropanes, but there are no asymmetric examples and so we
embarked on such a study. In addition, we sought to utilise our
recently reported catalytic process for asymmetric epoxida-
tion14,15 and aziridination16 so that catalytic quantities of
sulfides could ultimately be employed (Scheme 1). Here we
report our success in achieving these goals.
Reactions were carried out on enones with phenyldiazo-
methane (Table 1) and we initially used tetrahydrothiophene, in
stoichiometric amounts, as a representive sulfide under the
conditions previously employed for the epoxidation reaction.15
However, only low yields of cyclopropanes were obtained
(entries 1 and 2). We were surprised at the low yields obtained,
as high yields were obtained in the related epoxidation and
aziridination reactions. We suspected that the lower reactivity
of enones compared to aldehydes† and imines could have been
responsible for the lower yields observed, as the ylide will have
a longer lifetime in reactions with enones. This in turn would
mean that the ylide might have time to undergo competitive
rearrangement reactions, such as the Stevens17,18 or the
Sommelet–Hauser rearrangement,17,18 and indeed the Somme-
Table 1 Cyclopropanation of enones using simple sulfides
(
)
n
O
Ph
O
Rh2(OAc)4
+ PhCHN2
+
R1
R2
PhMe
room temp.
R1
R2
S
Enone
Entry R1
Sulfide
Yield
Equiv. (%)b
Isomeric
ratioc
R2
t/ha
n
1
2
3
4
5
6
7
8
9
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
3
3
3
1
1
2
2
2
2
2
2
2
2
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.2
0.2
0.2
40
41
92
80
65
55
70
82
50
30
1:1
1:1
4:1
4:1
1:1:1
1:1:1
4:1
4:1
1:1:1
1:1:1
+
–
R2S
Ph
3
O
Rh2(OAc)4
Ph
Me
Me
Ph
Ph
Me
Me
12
12
12
12
12
12
PhCHN2
R1
R2
Ph
O
10
N2
R1
R2
Rh CHPh
R2S
a Addition of PhCHN2 using syringe pump. b Yield of cis and trans isomers.
c Ratios determined by NMR spectroscopy.
Scheme 1 Catalytic process for cyclopropanation
Chem. Commun., 1997
1785

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Table 2 Cyclopropanation of enones using sulfide 1
dissolved in toluene (0.5 ml) under N2. A solution of phenyldiazomethane
in toluene (1.5 mmol) was added over 12 h via an inverted syringe
pump. The crude mixture was purified by column chromatography to
furnish the cyclopropane as a white solid (60%). The enantiomeric excess
was determined by chiral HPLC on Hichrom column, stationary phase
d-phenylglycine, using PriOH–light petroleum (0.7:99.3) as eluent with a
flow rate of 2 ml min21. The R,R enantiomer eluted at 265 s and the S,S
enantiomer at 282 s.
O
Ph
O
Rh2(OAc)4
+ PhCHN2 +
R1
R2
PhMe
room temp.
R1
R2
O
S
1
Enone
Entry R1
1 H. N. C. Wong, M. Y. Hon, C. W. Tse, Y. C. Yip, J. Tanko and
T. Hudlicky, Chem. Rev., 1989, 89, 165; T. Hudlicky and J. W. Reed,
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, Oxford, 1991, vol. 5, p. 899.
Sulfide Yield Isomeric Ee
[a]2D5
e
R2
t/ha (equiv.) (%)b
ratioc
(%)d
1
2
3
4
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
12 1.0
12 0.2
12 1.0
12 0.2
60
38
55
14
4:1
4:1
4:1
4:1
97f
97f
2136
2136
2 J. Salaun, Chem. Rev., 1989, 89, 1247.
3 V. K. Singh, A. DattaGupta and G. Sekar, Synthesis, 1997, 137.
4 H. E. Simmons and R. D. Smith, J. Am. Chem. Soc., 1958, 80, 5323.
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React., 1973, 20, 1.
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7 A. B. Charette, S. Prescott and C. Brochu, J. Org. Chem., 1995, 60,
1081.
> 98g 2 65
> 98g 2 65
a Addition of PhCHN2 using syringe pump. b Yield of cis and trans isomers.
c Ratio determined by NMR spectroscopy. d Determined using HPLC (see
e
f
footnote §).
Conditions: c = 1, CH2Cl2. Retention times: (R,R)
enantiomer, 4.41 min; (S,S) enantiomer, 4.70 min. g Retention times: (R,R)
enantiomer, 6.10 min; (S,S) enantiomer, 6.68 min.
8 D. A. Evans, K. A. Woerpel, M. M. Hinman and M. M. Faul, J. Am.
Chem. Soc., 1991, 113, 726.
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10 R. E. Lowenthal and S. Masumune, Tetrahedron Lett., 1991, 32,
7373.
11 For an example of metal carbenoid addition to an electron deficient
alkene, see T. Hudlicky and R. P. Short, J. Org. Chem., 1982, 47, 1522.
However, in this example the reaction is intramolecular, which no doubt
facilitates the process. It was also noted in this example that marginally
higher yields were obtained in the presence of sulfides, suggesting the
intermediacy of a sulfur ylide. We thank one of the referees for bringing
this paper to our attention.
isomer by analogy with the epoxidation14 and the aziridina-
tion16 processes. In these latter cases similarly high enantiose-
lectivity was obtained (93–97% ee) for epoxides14 and
aziridines16 and proof of their absolute stereochemistry (R,R)
was obtained.
In conclusion we have developed a process for the catalytic
asymmetric cylopropanation of enones, using a camphor-
derived sulfur ylide which shows exceptionally high levels of
enantioselectivity. We are currently extending the scope of this
reaction.
12 C. R. Johnson and C. W. Schroek, J. Am. Chem. Soc., 1973, 95,
7418.
13 S. G. Pyne, Z. Dong, B. W. Skelton and A. H. White, J. Org. Chem.,
1997, 62, 2337.
14 V. K. Aggarwal, J. G. Ford, A. Thompson, R. V. H. Jones and
M. Standen, J. Am. Chem. Soc., 1996, 118, 7004.
15 V. K. Aggarwal, H. Abdel-Rahman, F. Li, R. V. H. Jones and
M. C. H. Standen, Chem. Eur. J., 1996, 2, 1024.
16 V. K. Aggarwal, A. Thompson, R. V. H. Jones and M. C. H. Standen,
J. Org. Chem., 1996, 61, 8368.
Footnotes and References
* E-mail: v.aggarwal@sheffield.ac.uk
† Competetive experiments between PhCHO, chalcone and substoi-
chiometric amounts of ylide yielded epoxide only, indicating that aldehydes
were much more reactive than enones towards benzylfulfonium ylide.
‡ Sulfide I was formed in 20% yield as a result of ylide equilibration and
Sommelet–Hauser rearrangement from the reaction. Ylide equilibration and
rearrangement has been reported (refs. 19–21).
17 E. Block, The Chemistry of the Sulphonium Group, ed. C. J. M. Stirling
and S. Patai, Wiley, New York, 1981, p. 673.
18 I. E. Marko´, Comprehensive Organic Synthesis, ed. B. M. Trost and I.
Fleming, Pergamon, Oxford, 1991, vol. 3, p. 913.
19 W. Ando, M. Yamada, E. Matsuzaki and T. Migita, J. Org. Chem., 1972,
37, 3791.
S
20 N. A. Nesmayanov and V. A. Kalyavin, Org. Soedin. Sery, 1980, 2, 330
Chem. Abstr., 1981, 94, 192 063.
I
21 M. Yoshimine and M. J. Hatch, J. Am. Chem. Soc., 1967, 89, 5831.
22 M. Hetschko and J. Gossleck, Chem. Ber., 1973, 106, 996.
§ A typical procedure for asymmetric cyclopropanation reaction: Chalcone
(0.5 mmol), oxathiane 1 (0.5 mmol) and Rh2(OAc)4 (1 mol%) were
Received in Liverpool, UK, 16th June 1997; 7/04214K
1786
Chem. Commun., 1997