Stereoselective synthesis of epoxides by reaction of donor/acceptor-substituted carbenoids with α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/S0040-4039(01)01415-0

The reaction of donor/acceptor-substituted carbenoids with α,β-unsaturated aldehydes results in the highly diastereoselective synthesis of epoxides.

Full text of DOI:10.1016/S0040-4039(01)01415-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6803–6805
Stereoselective synthesis of epoxides by reaction of
donor/acceptor-substituted carbenoids with a,b-unsaturated
aldehydes
Huw M. L. Davies* and Jason DeMeese
Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY 14260-3000, USA
Received 30 March 2001; accepted 27 July 2001
Abstract—The reaction of donor/acceptor-substituted carbenoids with a,b-unsaturated aldehydes results in the highly diastereo-
selective synthesis of epoxides. © 2001 Published by Elsevier Science Ltd.
The metal-catalyzed decomposition of diazocarbonyl
compounds is a very useful transformation in organic
synthesis.1 Traditionally, unsubstituted diazoacetates
have been most commonly used, but in recent years it
has become recognized that the diazoacetate structure
has a profound effect on the reaction outcome.1 Most
notably, diazoacetates functionalized with a potentially
electron donating group that would stabilize the result-
ing metal-carbenoid, such as vinyl,2 aryl,3 heteroaryl4 or
alkynyl,5 exhibit very different reactivity compared to
the unsubstituted diazoacetates. Metal-catalyzed inter-
molecular cyclopropanations with these donor/accep-
tor-substituted carbenoids are routinely highly
diastereoselective and chemoselective.6 These car-
benoids are less prone to dimerization than simple
diazoacetates. Aryldiazoacetates, in particular, are
excellent reagents for catalytic asymmetric intermolecu-
lar CꢀH insertions.7 Prompted by a recent report8 that
the epoxidation chemistry of methyl phenyldiazoacetate
and methyl styryldiazoacetate is different from that of
simple diazoacetates, we describe herein our extensive
studies on the reaction of aryl-, heteroaryl- and vinyldi-
azoacetates with a,b-unsaturated aldehydes. These
studies confirm that the reaction of donor/acceptor-
substituted carbenoids with a,b-unsaturated aldehydes
is a very general and stereoselective method for the
synthesis of trisubstituted epoxides (Eq. (1)).
The metal-catalyzed decomposition of ethyl diazoac-
etate in the presence of aldehydes does not effectively
form epoxides.9 Instead, dioxolanes are formed,
whereby, the intermediate ylide undergoes a 1,3-diploar
cycloaddition with a second equivalent of aldehyde. As
recently reported,8 we have also found that the rhod-
ium(II) acetate catalyzed decomposition of methyl
phenyldiazoacetate in the presence of benzaldehyde
results in the highly diastereoselective formation of the
epoxide 1 (Eq. (2)). A particularly attractive feature of
this reaction is that the epoxide that is formed is the
opposite diastereomer to that which is formed in the
traditional Darzen’s condensation.10
4.15 ppm
N2
O
Rh2(OAc)4
H
CO2Me
benzaldehyde
76% yield
CO2Me
1
3.54 ppm
(2)
The reaction is applicable to a range of a,b-unsaturated
aldehydes as summarized in Table 1. Benzaldehydes,
various heteroaromatic aldehydes and other a,b-unsat-
urated aldehydes are appropriate substrates (entries
1–11), and in all cases, a single diastereomer of the
epoxide is formed.11 The stereoselective epoxidation can
be extended to many of the other donor/acceptor sub-
stituted carbenoids that we have developed. Electron
rich or electron deficient functionality can be accommo-
dated on the phenyldiazoacetate without any detrimen-
tal effect (entries 12–14). Also, heteroaryldiazoacetates
may be utilized as illustrated in the reaction of the
thiophene and indole derivatives (entries 15 and 16). In
all instances, the reactions are highly diastereoselective
(>94% de). An effective reaction is also possible with
N2
O
H
Rh2(OAc)4
+
H
R1
CO2Me
O
R1
R2
CO2Me
R2
(1)
* Corresponding author. E-mail: hdavies@acsu.buffalo.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01415-0

6804
H. M. L. Da6ies, J. DeMeese / Tetrahedron Letters 42 (2001) 6803–6805
Table 1. Reaction of aryl- and heteroaryldiazoacetates with aldehydes
N2
O
H
Rh2(OAc)4
R1
CO2Me
+
H
O
R1
R2
CO2Me
R2
Entry
R1
R2
Ph
Yield %a (lit. yield %)b
1
2
3
Ph
Ph
Ph
76 (65)
85 (81)
74
p-(OMe)Ph
p-ClPh
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-(NO2)Ph
3,4-diClPh
2-(N-BOC-pyrrolyl)
2-Furanyl
3-Furanyl
2-Thienyl
(E)-MeCHꢁCH
(E)-PhCHꢁCH
Ph
Ph
Ph
Ph
Ph
60 (80)
71
49
82
60
92
98c
71 (86)
89
78
49
55
p-BrPh
p-(OMe)Ph
p-(NO2)Ph
3-(N-BOC-indolyl)
3-Thienyl
68
a Reaction conditions: hexane/CH2Cl2, 30:1, rt, 1 h addition of diazo compound.
b Ref. 8; reaction conditions: CH2Cl2, reflux.
c Reaction conditions: CH2Cl2, rt, 1 h addition of diazo compound.
cyclohexenone, but in this case the epoxide 2 is formed
mixture formed from the rhodium-catalyzed reaction
likely arise due to competing cyclization of the ylide
intermediate between epoxide formation and a 6p-elec-
trocyclization to give the dihydrofuran.14,15 Illustrative
examples of the scope of these reactions are shown in
Table 2.
as a 6.8:1 mixture of diastereomers (Eq. (3)).
N2
O
Rh2(OAc)4
Ph
CO2Me
+
O
Ph
CO2Me
72% yield
6.8 : 1 dr
2
(3)
In conclusion, these studies further demonstrate that
donor/acceptor substituted carbenoids display very dif-
ferent reactivity to the traditional carbenoids derived
from unsubstituted diazoacetates. The reaction of aryl-
diazoacetates and heteroaryldiazoacetates with a,b-
unsaturated aldehydes is confirmed to be a general and
highly diastereoselective method for the synthesis of
epoxides. A similar reaction is possible with vinyldia-
zoacetates, although in this case the formation of dihy-
drofurans as side-products is observed.
No asymmetric induction in these reactions was
observed when they were catalyzed by a chiral rhodium
amide catalyst.8 We found a similar lack of asymmetric
induction using Rh2(S-DOSP)4 as catalyst, which has
generally been found to be an excellent chiral catalyst
of aryldiazoacetate transformations.12 These observa-
tions are indicative that ylide intermediates are initially
formed and the metal catalyst is no longer connected to
the ylide at the stage of the cyclization event.
Methyl styryldiazoacetate also was reported8 to form
epoxides in the rhodium-catalyzed reaction with ben-
zaldehyde and cinnamaldehyde. In our hands this reac-
tion is more complex than was previously described.8
We found that the cis-dihydrofuran 4a13 is formed in
addition to the epoxide 3a (Eq. (4)). The thermal
rearrangement of vinylepoxides to cis-dihydrofurans is
an established reaction14,15 but under rhodium-cata-
lyzed reaction conditions, the epoxide 3 is stable. The
Acknowledgements
This work was supported by a grant from the National
Science Foundation (CHE 0092490). Preliminary stud-
ies by Evan Antoulinakis are also gratefully acknowl-
edged.
Ph
O
N2
CO2Me
H
Ph
Ph
O
Rh2(OAc)4
+
+
H
Ph
O
Ph
CO2Me
(4)
CO2Me
Ph
55% yield
20% yield
3a
4a

H. M. L. Da6ies, J. DeMeese / Tetrahedron Letters 42 (2001) 6803–6805
Table 2. Reaction of vinyldiazoacetates with aldehydes
6805
Entry
R1
R2
R3
3:4 Ratio
3, Yield %a (lit.b yield %)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Et
Ph
2.5
2.0
1.8
4.6
3.6
1.6
2.3
4.6
55 (50)
60
44
36
65 (75)
60
p-(OMe)Ph
3,4-diClPh
(E)-MeCHꢁCH
(E)-PhCHꢁCH
Ph
(E)-MeCHꢁCH
(E)-PhCHꢁCH
Ph
CO2Et
CO2Et
CO2Et
Et
Et
58
76
a Reaction conditions: hexane/CH2Cl2, 30:1, rt, 12 h addition of diazo compound.
b Ref. 8; reaction conditions: CH2Cl2, reflux.
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