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Current Organic Synthesis, 2015, 12, 000-000

Recent Advances in the Asymmetric Claisen Rearrangement Promoted by Chiral

Organometallic Lewis Acids or Organic Brnsted-Lowry Acids
Tiago Costa Alves Fontoura Rodriguesa, Wender Alves Silva*a and Angelo Henrique Lira Machado*a
a

Institute of Chemistry, University of Brasilia, Brasilia, Brazil

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'

unfavorable secondary orbital

interactions

3'

boat like transition state

LUMO
3

OH

oC

OMe
O

A. H. Lira Machado

Scheme 2. Proposed transition state to Claisen rearrangement.

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

Scheme 1. Former results reported by L. Claisen in 1912.

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

The position and the chemical nature of the substituent attached

to the carbon framework of the starting ether can change the rate of
the Claisen rearrangement [6]. The introduction of a substituent on
C2 can also enhance, the chemical stability of the allylvinylethers
and avoid hydrolyses of the vinyl moiety. These modified Claisen
reactions receive special attention and have been recognized as
special classes of this rearrangement (Scheme 3).
The use of Lewis and Brnsted-Lowry acids as catalysts was
also applied as a strategy to increase the rate of the Claisen rearrangement [7]. The oxygen atom can act as Lewis base and its coordination with Lewis acids or hydrogen bond with BrnstedLowry acids can stabilize the transition state, increasing the rate of
the rearrangement.
In his first report, Claisen pointed out the catalytic role of
NH4Cl, as Brnsted acid, on that rearrangement reaction [1]. Only
in 1941, the first use of a Lewis acid as catalyst in this type of reaction could be found [8]. In an attempt to prepare eugenol (6) from
the allyl ether 5, the authors used BF3.2AcOH and achieved 38%
yield of the desired product from a tandem Claisen\Cope rearrangement (Scheme 4).
Based on these features, the use of chiral acids could also help
to select one of the diastereomeric transition states by blocking one
2015 Bentham Science Publishers

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

Scheme 3. Modified Claisen rearrangements.

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].

Since this Yamamoto communication, a wide range of chiral

catalysts have been reported for this transformation [7]. To the best
of our knowledge, the last review only focused on every aspect of
this rearrangement date from 2003 [7e]. The present review covers
the chemical literature on this area from 2008 until the end of 2014.

Recent Advances in the Asymmetric Claisen Rearrangement

Current Organic Synthesis, 2015, Vol. 12, No. ?

1.1. Organometallic Lewis Acids

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+

Scheme 4. First Lewis acid catalyzed Claisen rearrangement.

The examples presented here are organized as organometallic

Lewis acids or organic Brnsted-Lowry acids to help in the comparison of the results.
Ph

O
n-Bu

Ph

ClCH2CH2Cl
n-Bu

10

11

(R)-9 (1.1 to 2 eq.)

SiMe3

-20oC, 3-8 h

SiMe3

yield 99%, 88% ee

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

One of the most important works on the use of Lewis acids as

catalyst on Claisen rearrangements was reported by Yamamoto and
coworkers [11]. They used the complexes 12, 13 and 14 for obtaining ,
-unsaturated aldehydes (Scheme 7). The observed selectivity
on the product geometry has complete dependence on steric hindrance imposed by aluminum ligands. The use of the catalyst 13 led
to the formation of the Z product in excellent E/Z ratio, in agreement with published results for thermally promoted rearrangement.
When using more bulky ligands for aluminum, as seen in 12, the
Z/E selectivity was completely reversed, leading to the formation of

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

should be tBu like

in the other ring

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

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

Scheme 8. First palladium catalyzed asymmetric Claisen rearrangement.

Me

Me

RO2C
RO2C

21 (5 mol%)
O
N
H
19

20 min, CH2Cl2, 0oC

89% yield
91% ee

O
N
H
20

R = Me
2 SbF6
O
Ph2P

N
Pd2
21

tBu

should be closed to 2 of the Pd

Scheme 9. tBuPHOX palladium catalyst for asymmetric Eschenmoser-Claisen rearrangement.

the E product as the major one. When using the catalyst 14 in an

intermediate steric demand compared to 12 and 13, there was a
decrease in selectivity, but with a clear preference for E product.
This Yamamotos work was the basis for his development of the
first catalytic asymmetric Claisen rearrangement presented in
Scheme 5 [9].
1.1.1. Palladium
The first report of a palladium catalyzed asymmetric Claisen
rearrangement was done by Mikami and coworker in 2004 [12].
Binaphtyl based palladium complexes were evaluated and 18 provided the best results. The rearrangement product was obtained in
good yield and modest diastereo and enantiomeric ratio (Scheme 8).
Kozlowski and coworkers recently screened nine chiral
phosphine based ligands in a palladium catalytic system to perform
the Eschenmoser-Claisen rearrangement in allyloxy-indoles 19 to
afford enantio enriched oxindoles 20 bearing a quaternary stereocenter (Scheme 9) [13]. The phosphinoxazoline based palladium
complex 21 showed the best yields and enatioselectivities for a
wide range of substrates.
They also studied the relationship between the enantioselectivity of the palladium catalyzed allyloxy-indoles EschenmoserClaisen rearrangement and the steric requirements of the substituent
on the substrate (Scheme 10). The former study presented the catalytic system based on BINAP 22 as a modest one [13a]. However,

better enantioselectivity on the transformation could be observed as

a consequence of the increase in the volume of the ester moiety. In
contrast, when this transformation was conducted with catalytic
system based on phosphinoxazoline 21, the increase on the steric
requirements of the ester caused a decrease in enantioselectivity.
Palladium, nickel and zinc bisoxazoline catalytic systems were
also tested to afford this Eschenmoser-Claisen rearrangement
(Scheme 11) [9]. Despite the complete conversion of the substrate
to the oxindoles 20 and moderate to good observed enantioselectivity, stoichiometric amounts of the bisoxazoline 23 were needed to
afford the reaction.
1.1.2. Copper
Hiersemann and coworkers first reported bisoxazoline copper
complex 24 as chiral catalyst to Gosteli-Claisen rearrangement in
2001, (Scheme 12) [14]. This catalytic system used substoichiometric amounts of this preformed complex to produce the rearrangement products in excellent yields and enantioselectivity. Since this
report, this catalytic system has been the most efficient one and has
been used in the total synthesis of natural products and other organic substances.
In 2009, Hiersemann and coworkers reported a stereo divergent
enantioselective approach to the C5C8 Segment of berkelic acid
based on asymmetric Gosteli-Claisen rearrangement promoted by
bisoxazoline copper complex [15]. The diene (Z, Z)-25 was con-

Recent Advances in the Asymmetric Claisen Rearrangement

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

1h, CH2Cl2, r.t.

100% conv.
73% ee M = Pd (R)
47% ee M = Ni (R)
24% ee M = Zn (S)

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.

verted to the
-ketoester 26 in excellent yield, diastereisomeric ratio

and enantioselectivity (Scheme 12). After few steps, 26 could be
converted to ketone 27, an advanced intermediate in the total synthesis of (-)-berkelic acid (28).
During the next year, the same research group published the
synthesis of a C1-C18 building block of (-)-lytophiline A (32)
based on asymmetric Gosteli-Claisen rearrangement promoted by
bisoxazoline copper complex 24 [16]. The
-ketoester 30 was obtained from diene (Z, Z)-29 in excellent yield, diastereisomeric ratio
and enantioselectivity (Scheme 13). Intermediate 30 was converted
to the carboxylic acid 31, an advanced intermediate in the total
synthesis of (-)-lytophilippine A (32).

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-

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

should be tBu like

the other in the
same structure

2 SbF6

But
H2O

(iPr)3SiO

N
Cu2
OH2

27

tBu

24

correct
O

HO2C
O

O
6

OH

()-berkelic acid (28)

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

CH2Cl2, r.t., 1 day

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.

Recent Advances in the Asymmetric Claisen Rearrangement

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

should be tBu like

the other in the
same structure

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

should be tBu like

the other in the
same structure

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.

formed bisoxazoline copper complex 35 (Scheme 15) [18]. Both

rearrangement products, 37 and 41, were obtained in high chemical
yield and enantiomeric excess. Product 37 also showed excellent
diastereomeric ratio favoring the anti isomer. Those ketoesters were
readily converted to cyclopentene intermediates to accomplish the
total synthesis of 39.

In 2012, Yamamoto and coworkers reported the asymmetric

synthesis of
-ketophosphonates by the action of a catalytic system
prepared by Cu(OTf)2 and the bisoxazoline (R, R)-45 (Scheme 16)
[19]. The rearrangement products were obtained in excellent yields
and enantioselectivities. The phosphonate group is a versatile or-

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

should be tBu like

the other in the
same structure

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

CH2Cl2, r.t., 35 min

100 % conv.
81% ee

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

5 mol% B(OPh)3, 4 MS,

20 mol% CH3CN, THF, 23oC

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.

25 mol %, increased the reaction time to 2.5 h and decreased the

conversion (78 %) and the enantioselectivity (76% ee).

Kozlowski and coworkers, during the investigation of catalytic

systems to perform the Eschenmoser-Claisen rearrangement in
allyloxy-indoles 19 also used stoichiometric amounts of the copper
bisoxazoline complex 46 (Scheme 17) [13c]. Despite the complete
conversion of 19 to 20, moderate to good enantioselectivity was
reported. Attempts to use substoichiometric amounts of the catalyst,

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

Recent Advances in the Asymmetric Claisen Rearrangement

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

Scheme 19. Hydrated Claisen transition state.

Based on this previous information, Kozlowski and coworkers

reported in 2008 the first attempts to use the chiral compounds 54,
55 and 56 as catalysts on asymmetric Claisen rearrangement
(Scheme 20) [13a][13c]. Unexpressive asymmetric induction was
observed for this reaction in spite of conversions higher than 80 %.
Me
54 or 55 or 56
(100 mol%)

OBn
3
1

H2N

48 h, 40 oC





NH
NH

+

OBn

+

Ph

57

58
CF3

BArF

OBn

O
4

59

CF3

75 % yield

Based on the previous work published by Currans group about

enhancement in the reaction rate of the Claisen rearrangement by
the use of a diaryl urea [22], Jacobsen and coworkers used the N,N
diphenylguanidinium barfate 60. They found rate enhancements in
the rearrangement of a variety of substituted allylvinylethers like 57
(Scheme 21) [23]. Substrates bearing electron-donating substituents
at the positions 1 and 3 or electron-withdrawing groups at the position 2 all underwent rearrangement with significant rate of acceleration in the presence of catalytic levels of 60.
In this work, the authors also reported the C2-symmetric guanidinium barfate 63 derived from trans-1-pyrrolo-2-aminocyclohexane. It was effective to perform the asymmetric Claisen rearrangement on substrates like 61 with excellent yield and enantioselectivity (Scheme 22) [23].
O

MeO
30 C, 8 days

N
H

61

Et

63 (20 mol%), hexanes

Et
O

19

O
MeO

RO2C

CH2Cl2, r.t., 35 min

N
H

Ph

60 ( 20 mol%)

Me

RO2C

N
H

Scheme 21. General Claisen Rearrangement catalyzed by Guanidinium salt

60.

1'

N
H

Ph

3'

2'

The first report of the use of a Brnsted-Lowry acid on Claisen

rearrangements coincides with its discovery in 1912 [1]. Jorgensen
and coworkers published one of the most important former works in
this area [21]. Using quantum mechanical calculations, they developed a transition state model where two water molecules were connected by hydrogen bond to the oxygen atom of the allyl vinyl ether
(Scheme 19). This interaction stabilized this transition structure and
increased the rate of the Claisen rearrangement. Based on this information, many groups around the world have studied the acceleration of the Claisen rearrangement by hydrogen bonds between
organic Brnsted-Lowry acids and the allyl vinyl ether/phenyl vinyl
ether [7c][7d] [22].

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

Scheme 22. C2-symmetric guanidinium barfate 63 as organocatalyst on

Gosteli-Claisen rearrangement.
CF3

F3C

N
H

63

Ph

NHSO2CF3

55

BArF

NH2

tBu

N
H

N
H

Ph

80 % conv.
6% ee (R)

Scheme 20. First examples of chiral organocatalysts on EschenmoserClaisen rearrangement.

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

Current Organic Synthesis, 2015, Vol. 12, No. ?

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

68 (20 mol%), hexanes

NMe2
N

68
Scheme 24. Improved C2-symmetric guanidinium barfate 55 as organocatalyst on Gosteli-Claisen rearrangement.

explored a wide range of substrates with different ring sizes, the

presence of heteroatoms and unsaturated fused aromatic rings. The
rearrangement afforded the product in high yields and enantiomeric
excess in the range of 79 % to 87%. Product 65 was readily converted to diiodine 66, a possible advanced intermediate in the synthesis of the complex natural product hyperforin (67).

acid organocatalysts. The last one has proved to be a promising,

simpler experimental alternative when compared to the use of chiral
metal complexes as catalysts in enantioselective Claisen rearrangement. However, the reaction times and the catalyst load should be
decreased to the same range of the reported organometallic catalysts.

The structure of this class of organocatalyst was further improved to 68 by computational and experimental studies (Scheme
24) [25].

Another challenge to both strategies is the increase of the substrate

scope. One example of this is the Eschenmoser-Claisen rearrangement to afford oxindoles which was extensively studied by Kozlowskis group [13]. The palladium based catalytic systems described in Scheme 9 proved to be the best one when compared to
other palladium, nickel, zinc, copper based organometallic catalytic
systems (Schemes 10, 11 and 17) and the bisdihydroimidazolium,
bissulfonamide, and urea based organocatalysts (Scheme 23).
Among these, we can find well established catalytic systems to promote asymmetric Claisen rearrangement. However, the scope of these

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

Recent Advances in the Asymmetric Claisen Rearrangement

Current Organic Synthesis, 2015, Vol. 12, No. ?

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.

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ACKNOWLEDGEMENTS

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We are grateful to for CAPES, CNPq, FINEP-MCT, and DPPUnB for financial support.

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Accepted: June 16, 2015