Beruflich Dokumente
Kultur Dokumente
ae
Current Organic Synthesis, 2015, 12, 000-000
Abstract: The Claisen rearrangement, an important CC bond forming reaction, has been used
enormously for many decades in the synthesis of important class of compounds. This review
covers developments in this rearrangement since 2008, discusses important aspects about the
asymmetric Claisen rearrangement catalyzed by chiral organometallic Lewis acids or organic
Brnsted-Lowry acids.
Wender Alves Silva
Keywords: [3,3] sigmatropic, organocatalysis, chiral Lewis acids, claisen rearrangement, asymmetric rearrangement; catalysis.
chair like transition
state
1. INTRODUCTION
In 1912, Ludwig Claisen reported the first examples of the
thermic rearrangement of allylvinylethers and allylphenylether
(Scheme 1) [1]. This transformation, called Claisen rearrangement,
was quickly recognized as a powerful synthetic tool to install new
C-C bonds with high control on the relative stereochemistry of the
products [2].
OMe
1'
X
2'
1
2
3'
1' X
2
3
1'
3'
2'
X 2'
230-255
1'
X
3'
X
HOMO
3
2'
3'
LUMO
3
OH
oC
OMe
O
A. H. Lira Machado
NH4Cl
EtO2C
possible aromatic transition states. The chair like state is more stable than the boat state like due to unfavorable secondary orbital
interactions of the last one (Scheme 2).
EtO2C
3
The conversion of the substrate to the product involves the migration of a bond, previously connecting 1` and 1, to atoms 3 and
3` and also the change in the position of the double bonds, featuring
a [3,3] sigmatropic rearrangement.
Although L. Claisen has described the mechanism of this reaction in 1925 as a cyclic process involving simultaneous formation
and bond breaking followed by re-positioning of the double bonds,
only in 1950 a detailed understanding of this process was achieved
[3]. Recently, Iwakura and coworkers detected the formation of this
aromatic transition state through vibrational spectroscopy, giving
further support to this proposal [4].
The rationale for the Claisen rearrangement was first introduced
by Woodward and Hoffmann rules of orbital conservation [5].
More recently, a model based on Frontier Orbital Theory described
it as a thermally allowed [3,3] rearrangement that occurs in two
*Address correspondence to this author at the University of Brasilia, Institute of Chemistry P.O box 4408, Brasilia, Brazil; Tel: ++55-61-3107-3858; Fax: ---------------------;
E-mails: nagelo@unb.br and wender@unb.br
1570-1794/15 $58.00+.00
OH
Rodrigues et al.
O
-CO2
NMe2
NMe2
NMe2
MeC(OMe)2
OH
Carrol-Claisen
Eschenmoser-Claisen
OMe
OMe
MeC(OMe)3
OH
OH
OTMS
LDA
O
H3O+
CO2R
CO2R
O
OH
Cl
Reformatsky-Claisen
O
C O
SEt
Gosteli-Claisen
OZnBr
O
Br
Cl
Ireland-Claisen
then
Me3SiCl
Johnson-Claisen
SEt
Cl
EtS
Ketene-Claisen
Cl
PhO2S
PhO2S
PhO2S
KH
O
HMPA
Denmark-Claisen ("carbanion
accelerated")
50oC
of the prochiral faces of the double bonds and provide enantio enriched mixtures of the rearrangement product. Yamamoto and coworkers were the first to explore this feature using stoichiometric
chiral organoaluminum compounds to promote an asymmetric
Claisen rearrangement (Scheme 5) [9].
OH
MeO
The first report of a non-aromatic Claisen rearrangement catalyzed by a metallic Lewis acid was done in 1981. The conversion of
vinyl ether 10 to the aldehyde 11 was promoted by Et2AlSPh or
Et2AlCl/PPh3 (Scheme 6) [10]. Besides the lowering on the reaction temperature, the use of these Lewis acids promoted the decrease in E/Z selectivity, indicating the influence of the catalyst on
the preference between the possible boat and chair transition states
due to the steric hindrance between the Lewis acid coordinated to
the oxygen atom and the alkyl substituent at C1.
MeO
i. BF3.2 AcOH
70-80oC; 10min
5
ii. H3O+
O
n-Bu
Ph
ClCH2CH2Cl
n-Bu
10
11
-20oC, 3-8 h
SiMe3
180oC
yield not reported
E/Z > 95/5
Et2AlSPh 25oC
84% yield
E/Z = 39/61
8
Scheme 6. The first report of a non-aromatic Claisen rearrangement catalyzed by organometallic Lewis acid.
SitBuPh2
O
Al Me (R)-9
O
SitBuPh2
Scheme 5. First report of an asymmetric Claisen rearrangement mediated by
a chiral lewis acid.
CHO
R
Z/E
~1:9
13
CHO
R
12
-20oC
CH2Cl2,
15min
CH2Cl2, -78oC
15-30min
CHO
R
14
CH2Cl2, -78oC
15-30min
Z/E
3:97
Z/E
93:7
CHO
R
Z/E
29:71
correct
tBu
O
tBu
Et2AlCl/PPh3 25oC
81% yield
E/Z = 43/57
But
Al
Ph
O
Me But
12
Ph
Ph
Al
Me
tBu
O
Ph
13
Scheme 7. Yamamotos aluminum based Lewis acids as catalysts on the Claisen rearrangement.
tBu
14
Al
Me
Me
Rodrigues et al.
Pd(OAc)2 (5 mol%)
18 (5 mol%)
+
MeCN, 24 h, 60oC
15
16
54 % yield
16/17 = 82/18
e.r. 81/53 for 16
E/Z = 83/17
17
NHTf
18
NHTf
Me
Me
RO2C
RO2C
21 (5 mol%)
O
N
H
19
O
N
H
20
R = Me
2 SbF6
O
Ph2P
N
Pd2
21
tBu
21 (20 mol%)
5-30 min, CH2Cl2, 0oC
100% conv.
58% ee when R = tBu
against
89% ee when R = Me
Me
RO2C
Me
RO2C
N
H
N
H
19
20
22 (20 mol%)
50-80 min, CH2Cl2, 0oC
100% conv.
85% ee when R = tBu
against
48% ee when R = Me
2 SbF6
PPh2
Pd2
PPh2
22
Scheme 10. The relation between steric requirements on ester moiety and the enantioselectivity of the Eschenmoser-Claisen rearrangement with 21 and 22.
Me
Me
RO2C
RO2C
23 (100 mol%)
O
N
H
19
O
N
H
20
R = Me
Me
Me
O
N
23
N
M2
2 SbF6
Scheme 11. Palladium, nickel and zinc bisoxazoline as stoichiometric system for the Eschenmoser-Claisen rearrangement to afford oxindoles.
Hiersemann and coworkers reported in 2012 a {1,6}transannular catalytic asymmetric Gosteli-Claisen rearrangement
mediated by a similar bisoxazoline copper catalytic system where
coordinated water molecules were substituted by phenol (Scheme
14) [17]. This modification increased the results to the same level
previously observed for acyclic asymmetric Gosteli-Claisen rearrangement. The geometry of the double bonds and the size of the
macrocycle were show to be important to the yield and the diastereoisomeric ratio.
In 2013, Hiersemanns group reported the total synthesis of (-)ecklonialactone B (39) by two synthetic routes based on catalytic
asymmetric Gosteli-Claisen rearrangement mediated by the pre-
Rodrigues et al.
(iPr)3SiO
(S,S)-24 (8 mol%)
CO2Me
CH2Cl2, CF3CH2OH
CO2Me
(iPr)3SiO
r.t., 1 day
96% yield
dr > 95:5
ee > 90%
25
26
O
Me
Me
O
N
2 SbF6
But
H2O
(iPr)3SiO
N
Cu2
OH2
27
tBu
24
correct
O
HO2C
O
O
6
OH
Scheme 12. Enantioselective synthesis of the C5C8 segment of berkelic acid (28) based on asymmetric Gosteli-Claisen rearrangement promoted by bisoxazoline copper complex 24.
(S,S)-24 (5 mol%)
CO2Me
CO2Me
93% yield
dr > 95:5
99% ee
29
30
7
1
CO2H
PMBO
OTBS
31
OH
HO
OH
OH
OH
18
OH
7
1
OH
Cl
O
O
(-)-lytophilippine A (32)
OH
Scheme 13. Enantioselective synthesis of the C1C18 segment of (-)-lytophilippine A (32) based on asymmetric Gosteli-Claisen rearrangement promoted by
chiral complex 24.
OMe
O
(S,S)-35 (5 mol%)
OMe
ClCH2CH2Cl, r.t., 26 h
86% yield
dr > 83:17
ee > 98%
33
Me
Me
34
2 SbF6
O
N
N
Cu2
L
L
But
35
tBu
correct
L=PhOH
Scheme 14. {1,6}-transannular catalytic asymmetric Gosteli-Claisen rearrangement promoted by chiral copper complex 35.
CO2Me
(S,S)-35 (0,1 mol%)
O
BnO
CO2Me
(CH2Cl)2, r.t., 16 h
91% yield
dr > 95:5
ee > 99%
36
CO2i-Pr
BnO
37
O
OH
OH
O
42
OBn
38
O
()-ecklonialactone B (39)
CO2i-Pr
(S,S)-35 (0,1 mol%)
CO2i-Pr
(CH2Cl)2, r.t., 16 h
O
97% yield
ee = 97%
41
Me
Me
40
2 SbF6
O
N
Cu2
L
L
But
35
tBu
correct
L=CF3CH2OH
Scheme 15. Enantioselective synthesis of the cyclopentane segment of (-)-ecklonialactone B (39) based on asymmetric Gosteli-Claisen rearrangement promoted by chiral complex 35.
Rodrigues et al.
(EtO)2P
Cu(OTf)2 (5 mol%)
(EtO)2P
(R,R)-45 (6 mol%)
CH2Cl2, n-hexane
r.t., 2 h
Ph
43
Ph
44
90% yield
ee > 97%
Me
Me
O
N
But
correct
tBu
(R,R)-45
Scheme 16. Catalytic asymmetric Phoshponate-Gosteli-Claisen rearrangement of enolphosphonates by chiral catalytic system copper/(R, R)-38.
Me
Me
RO2C
RO2C
46 (100 mol%)
O
N
H
19
Me
R = Me
O
N
H
20
Me
46
O
N
N
Cu2
2 SbF6
Scheme 17. Copper bisoxazoline complex 46 as a catalytic system for the Eschenmoser-Claisen rearrangement to afford oxindoles.
Et
52 (5 mol%)
CpRu(CH3CN)3PF6 (5 mol% )
Ph
Et
O
Ru
Ru
Ph
Ph
48
49
[3,3]
47
Et
[1,3]
HO
O
N
Et
Et
N
H
O
+
Ph
NMe2
50
52
Ph
51
anti/syn 6.3:1
anti > 99% ee
50/51 3.6:1
yield (50+51) 89%
Scheme 18. Chiral ruthenium based catalytic system for asymmetric Claisen rearrangement.
ganic moiety and can be easily converted into a wide range of functional groups.
1.1.3. Ruthenium
Nelson and coworkers carried out a Claisen like rearrangement
of allyl 1,6-disubstituted vinyl ethers using the chiral ligand 43 and
ruthenium complex as a catalyst to obtain the enantio enriched
compound 41 (Scheme 18) [20]. The presence of the [1,3] rearrangement product 42 suggested a competitive non-concerted
mechanism, where a -allyl ruthenium enolate worked as an intermediate. This observation seemed to be dependent on the substrate
used and the geometry of the double bond.
1.2. Brnsted-Lowry Acid Organocatalysts
H
O
H
+
+
O
H
53
OBn
3
1
H2N
48 h, 40 oC
NH
NH
+
OBn
+
Ph
57
58
CF3
BArF
OBn
O
4
59
CF3
75 % yield
MeO
30 C, 8 days
N
H
61
Et
Et
O
19
O
MeO
RO2C
N
H
Ph
60 ( 20 mol%)
Me
RO2C
N
H
1'
N
H
Ph
3'
2'
BArF
NH2
Ph
nPr
nPr
88% yield
dr > 20:1
82 % ee
62
20
R = Me
N
H
Ph
100 % conv.
16% ee (R)
Ph
Ph
HN
2 BArF
Ph
54
H
N
H
N
NH
56
O
NHSO2CF3
80 % conv.
1% ee (S)
Ph
F3C
N
H
63
Ph
NHSO2CF3
55
BArF
NH2
tBu
N
H
N
H
Ph
80 % conv.
6% ee (R)
The authors observed low ee values when more sterically hindrance was placed at exerted C1, when compared with ethyl group.
Disubstituted substrates rearranged to form anti product in high
enantio and diastereoselectivity. One example of the formation of a
product bearing quaternary stereogenic center was also reported in
good yield, enantio and diastereoselectivity.
Jacobsen and coworkers complemented the investigation on the
scope of the C2-symmetric guanidinium barfate 63 on the enantioselective Claisen rearrangements [24]. O-allyl -ketoester 64 provided the formation of quaternary stereogenic center with higher
enantio and diastereoselectivity (Scheme 23). The complete study
10
Rodrigues et al.
O
OMe
O
63 (20 mol%), hexanes
Me
EtO
OMe
30 0C, 72 h
81% yield
dr 7:1
81 % ee
EtO
64
65
Me
I
O
Me
1. HCl, THF
O
iPr
HO
2. I2 , KI, KHCO3
THF, H2O
OMe
O
59% yield
hyperforin (67)
66
Scheme 23. Asymmetric Gosteli-Claisen rearrangement of substituted O-ally -ketoesters toward the total synthesis of hyperforin (67).
O
O
MeO
Et
MeO
30 0C, 8 days
63
BArF
NH2
Me2N
N
N
H
N
H
nPr
90% yield
dr > 20:1
88 % ee
nPr
61
Et
NMe2
N
68
Scheme 24. Improved C2-symmetric guanidinium barfate 55 as organocatalyst on Gosteli-Claisen rearrangement.
The structure of this class of organocatalyst was further improved to 68 by computational and experimental studies (Scheme
24) [25].
CONCLUSION
Since its discovery, a lot of attention have been devoted toward
the understanding and application of the [3,3]-sigmatropic Claisen
rearrangement. Despite these efforts, important questions still have
to be answered, especially those concerning its enantioselective
versions catalyzed by organometallic Lewis acids and Brnsted
protocols was only evaluated to more simple substrates and new steric
and electronic effects certain operate in the allyloxy-indoles substrates.
[8]
[9]
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
[10]
ACKNOWLEDGEMENTS
[11]
We are grateful to for CAPES, CNPq, FINEP-MCT, and DPPUnB for financial support.
[12]
[13]
REFERENCES
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11