assymetric claisen rearrangment

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Current Organic Synthesis, 2015, 12, 000-000

1570-1794/15 $58.00+.00 2015 Bentham Science Publishers

Recent Advances in the Asymmetric Claisen Rearrangement Promoted by ChiralOrganometallic Lewis Acids or Organic Brnsted-Lowry Acids

Tiago Costa Alves Fontoura Rodriguesa, Wender Alves Silva*

aand Angelo Henrique Lira Machado

*a

aInstitute 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.

Keywords: [3,3] sigmatropic, organocatalysis, chiral Lewis acids, claisen rearrange-ment, asymmetric rearrangement; catalysis.

1. INTRODUCTION

In 1912, Ludwig Claisen reported the first examples of thethermic 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 theproducts [2].

O OH

OMe OMe

230-255 oC

1 2

3 4

O

EtO2C

NH4Cl

O

EtO2C

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

The conversion of the substrate to the product involves the mi-gration of a bond, previously connecting 1` and 1, to atoms 3 and3` and also the change in the position of the double bonds, featuringa [3,3] sigmatropic rearrangement.

Although L. Claisen has described the mechanism of this reac-tion in 1925 as a cyclic process involving simultaneous formationand 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, givingfurther support to this proposal [4].

The rationale for the Claisen rearrangement was first introducedby Woodward and Hoffmann rules of orbital conservation [5].More recently, a model based on Frontier Orbital Theory describedit as a thermally allowed [3,3] rearrangement that occurs in two

*Address correspondence to this author at the University of Brasilia, Institute of Chem-istry P.O box 4408, Brasilia, Brazil; Tel: ++55-61-3107-3858; Fax: ---------------------;

E-mails: [email protected] and [email protected]

X

X

1' 3'2'

12

33'

2'

1'

12

3

3'2'

1'

12

3

X

LUMO

HOMO

X

3'

2'1'

12

3

X

unfavorable secondary orbital

interactions

chair like transition

state

boat like transition state

Scheme 2. Proposed transition state to Claisen rearrangement.

possible aromatic transition states. The chair like state is more sta

ble than the boat state like due to unfavorable secondary orbitainteractions of the last one (Scheme 2).

The position and the chemical nature of the substituent attachedto the carbon framework of the starting ether can change the rate othe Claisen rearrangement [6]. The introduction of a substituent onC2 can also enhance, the chemical stability of the allylvinyletherand avoid hydrolyses of the vinyl moiety. These modified Claisenreactions receive special attention and have been recognized aspecial classes of this rearrangement (Scheme 3).

The use of Lewis and Brnsted-Lowry acids as catalysts waalso 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 o

the rearrangement.

In his first report, Claisen pointed out the catalytic role oNH4Cl, as Brnsted acid, on that rearrangement reaction [1]. Onlyin 1941, the first use of a Lewis acid as catalyst in this type of reac

tion could be found [8]. In an attempt to prepare eugenol (6) fromthe 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 helpto select one of the diastereomeric transition states by blocking one

Wender Alves Silva A. H. Lira Machado


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4 Current Organic Synthesis, 2015, Vol. 12, No. ? Rodrigues et a

the Eproduct as the major one. When using the catalyst 14 in anintermediate steric demand compared to 12 and 13, there was a

decrease in selectivity, but with a clear preference for Eproduct.This Yamamotos work was the basis for his development of thefirst catalytic asymmetric Claisen rearrangement presented inScheme 5[9].

1.1.1. Palladium

The first report of a palladium catalyzed asymmetric Claisenrearrangement was done by Mikami and coworker in 2004 [12].Binaphtyl based palladium complexes were evaluated and 18pro-vided the best results. The rearrangement product was obtained ingood yield and modest diastereo and enantiomeric ratio (Scheme 8).

Kozlowski and coworkers recently screened nine chiralphosphine based ligands in a palladium cataly tic system to performthe Eschenmoser-Claisen rearrangement in allyloxy-indoles 19 toafford enantio enriched oxindoles 20 bearing a quaternary stereo-center (Scheme 9) [13]. The phosphinoxazoline based palladiumcomplex 21 showed the best yields and enatioselectivities for awide range of substrates.

They also studied the relationship between the enantioselectiv-ity of the palladium catalyzed allyloxy-indoles Eschenmoser-Claisen rearrangement and the steric requirements of the substituenton the substrate (Scheme 10). The former study presented the cata-lytic system based on BINAP 22as a modest one [13a]. However,

better enantioselectivity on the transformation could be observed asa consequence of the increase in the volume of the ester moiety. In

contrast, when this transformation was conducted with catalytisystem based on phosphinoxazoline 21, the increase on the stericrequirements of the ester caused a decrease in enantioselectivity.

Palladium, nickel and zinc bisoxazoline catalytic systems werealso tested to afford this Eschenmoser-Claisen rearrangemen

(Scheme 11) [9]. Despite the complete conversion of the substrateto the oxindoles 20and 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 coppecomplex 24 as chiral catalyst to Gosteli-Claisen rearrangement in2001, (Scheme 12) [14]. This catalytic system used substoichiometric amounts of this preformed complex to produce the rearrangement products in excellent yields and enantioselectivity. Since thireport, this catalytic system has been the most efficient one and habeen used in the total synthesis of natural products and other organic substances.

In 2009, Hiersemann and coworkers reported a stereo divergenenantioselective approach to the C5C8 Segment of berkelic acidbased on asymmetric Gosteli-Claisen rearrangement promoted bybisoxazoline copper complex [15]. The diene (Z, Z)-25 was con

O

E/Z= 83/17

15

Pd(OAc)2(5 mol%)

18(5 mol%)

MeCN, 24 h, 60oC

O

16

O

17

+

54 % yield

16/17= 82/18e.r. 81/53 for 16

NHTf

NHTf

18

Scheme 8. First palladium catalyzed asymmetric Claisen rearrangement.

NH

O

Me

NH

O

RO2C

Me

20 min, CH2Cl2, 0oC

89% yield

91% ee

21 (5 mol%)

RO2C

1920

R = Me

N

O

tBu

Ph2P

21

Pd2

SbF62

Scheme 9.t

BuPHOX palladium catalyst for asymmetric Eschenmoser-Claisen rearrangement.

should be closed to 2 of the Pd


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Recent Advances in the Asymmetric Claisen Rearrangement Current Organic Synthesis, 2015, Vol. 12, No. ?

verted to the -ketoester 26in excellent yield, diastereisomeric ratioand enantioselectivity (Scheme 12). After few steps, 26 could be

converted to ketone 27, an advanced intermediate in the total syn-thesis 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 30was ob-tained from diene (Z, Z)-29in excellent yield, diastereisomeric ratioand enantioselectivity (Scheme 13). Intermediate 30 was converted

to the carboxylic acid 31, an advanced intermediate in the totalsynthesis of (-)-lytophilippine A (32).

Hiersemann and coworkers reported in 2012 a {1,6}transannular catalytic asymmetric Gosteli-Claisen rearrangemen

mediated by a similar bisoxazoline copper catalytic system wherecoordinated water molecules were substituted by phenol (Scheme14) [17]. This modification increased the results to the same leve

previously observed for acyclic asymmetric Gosteli-Claisen rearrangement. The geometry of the double bonds and the size of themacrocycle were show to be important to the yield and the di-

astereoisomeric ratio.

In 2013, Hiersemanns group reported the total synthesis of (-)

ecklonialactone B (39) by two synthetic routes based on catalyticasymmetric Gosteli-Claisen rearrangement mediated by the pre-

NH

O

Me

NH

O

RO2C

Me

50-80 min, CH2Cl2, 0oC

100% conv.

85% ee when R = tBu

against

48% ee when R = Me

22 (20 mol%)

RO2C

19 20

PPh2

PPh2

Pd2

22

SbF62

5-30 min, CH2Cl2, 0oC

100% conv.

58% ee when R = tBu

against

89% ee when R = Me

21 (20 mol%)

Scheme 10. The relation between steric requirements on ester moiety and the enantioselectivity of the Eschenmoser-Claisen rearrangement with 21and 22.

NH

O

Me

N

H

O

RO2C

Me

1h, CH2Cl2, r.t.

100% conv.

73% ee M = Pd (R)47% ee M = Ni (R)

24% ee M = Zn (S)

23 (100 mol%)

RO2C

19 20

23

R = Me

N

M2

N

Me Me

O O

SbF62

*

Scheme 11. Palladium, nickel and zinc bisoxazoline as stoichiometric system for the Eschenmoser-Claisen rearrangement to afford oxindoles.


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(iPr)3SiO

CO2Me

O

O

CO2Me(iPr)3SiO

24

N

Cu2

N

Me Me

O O

tBuBut

SbF62

(S,S)-24(8 mol%)

CH2Cl2, CF3CH2OH

r.t., 1 day

(iPr)3SiO

O

56

78

9

O

OOO O

HO2C OH

5

7

96

8

()-berkelic acid (28)

2526

27H2O OH2

96% yield

dr > 95:5

ee > 90%

Scheme 12. Enantioselective synthesis of the C5C8 segment of berkelic acid (28) based on asymmetric Gosteli-Claisen rearrangement promoted by bisoxazoline copper complex 24.

CO2Me

O

O

CO2Me

(S,S)-24(5 mol%)

CH2Cl2, r.t., 1 day

293093% yield

dr > 95:5

99% ee

PMBO

OTBS

CO2H

1

7

O

OH

HO

OH

O

OH

O

OH

OH OH

Cl

OH

O

(-)-lytophilippine A (32)

1

7

18

31

Scheme 13. Enantioselective synthesis of the C1C18 segment of (-)-lytophilippine A (32) based on asymmetric Gosteli-Claisen rearrangement promoted bychiral complex 24.

should be tBu like

the other in the

same structure

correct


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Recent Advances in the Asymmetric Claisen Rearrangement Current Organic Synthesis, 2015, Vol. 12, No. ?

(S,S)-35(5 mol%)

ClCH2CH2Cl, r.t., 26 h

33 34

86% yield

dr > 83:17

ee > 98%

O

OMeO

O

OMeO

35

N

Cu2

N

Me Me

O O

tBuBut

SbF62

L L

L=PhOH

Scheme 14. {1,6}-transannular catalytic asymmetric Gosteli-Claisen rearrangement promoted by chiral copper complex 35.

CO2Me

BnOO

35

N

Cu2

N

Me Me

O O

tBuBut

SbF62

(S,S)-35(0,1 mol%)

(CH2Cl)2, r.t., 16 h

()-ecklonialactone B (39)

36

37

38

L L

91% yield

dr > 95:5

ee > 99%

L=CF3CH2OH

OBn

OHO

O

O42

OH

CO2i-Pr

CO2i-Pr

O

41

(S,S)-35(0,1 mol%)

(CH2Cl)2, r.t., 16 h

97% yield

ee = 97% 40

O

CO2i-Pr

O

CO2Me

BnO

Scheme 15. Enantioselective synthesis of the cyclopentane segment of (-)-ecklonialactone B (39) based on asymmetric Gosteli-Claisen rearrangement pro

moted by chiral complex 35.

formed bisoxazoline copper complex 35 (Scheme 15) [18]. Bothrearrangement products, 37 and 41, were obtained in high chemicalyield and enantiomeric excess. Product 37 also showed excellentdiastereomeric ratio favoring the antiisomer. Those ketoesters werereadily converted to cyclopentene intermediates to accomplish thetotal synthesis of 39.

In 2012, Yamamoto and coworkers reported the asymmetri

synthesis of -ketophosphonates by the action of a catalytic system

prepared by Cu(OTf)2and the bisoxazoline (R,R)-45 (Scheme 16

[19]. The rearrangement products were obtained in excellent yield

and enantioselectivities. The phosphonate group is a versatile or

should be tBu like

the other in the

same structure

correct

should be tBu like

the other in thesame structure

correct


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explored a wide range of substrates with different ring sizes, thepresence of heteroatoms and unsaturated fused aromatic rings. Therearrangement afforded the product in high yields and enantiomeric

excess in the range of 79 % to 87%. Product 65 was readily con-

verted to diiodine 66, a possible advanced intermediate in the syn-thesis of the complex natural product hyperforin (67).

The structure of this class of organocatalyst was further im-proved to 68 by computational and experimental studies (Scheme

24) [25].

CONCLUSION

Since its discovery, a lot of attention have been devoted towardthe understanding and application of the [3,3]-sigmatropic Claisenrearrangement. Despite these efforts, important questions still haveto be answered, especially those concerning its enantioselectiveversions catalyzed by organometallic Lewis acids and Brnsted

acid organocatalysts. The last one has proved to be a promisingsimpler experimental alternative when compared to the use of chirametal complexes as catalysts in enantioselective Claisen rearrange

ment. However, the reaction times and the catalyst load should be

decreased to the same range of the reported organometallic catalysts.

Another challenge to both strategies is the increase of the substrate

scope. One example of this is the Eschenmoser-Claisen rearrange

ment to afford oxindoles which was extensively studied by Ko

zlowskis group [13]. The palladium based catalytic systems de

scribed in Scheme 9 proved to be the best one when compared to

other palladium, nickel, zinc, copper based organometallic catalyti

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 pro-

mote asymmetric Claisen rearrangement. However, the scope of these

O

OMe

O

EtO

63(20 mol%), hexanes

30 0C, 72 h

81% yield

dr 7:181 % ee

O

OMe

O

EtO Me

O

I

I

O

OMe

O

Me

1. HCl, THF

2. I2, KI, KHCO3

THF, H2O

59% yield

O

HO

iPr

O

Me

O

hyperforin (67)

64 65

66

Scheme 23.Asymmetric Gosteli-Claisen rearrangement of substituted O-ally-ketoesters toward the total synthesis of hyperforin (67).

MeO Et

O

O

nPr

68(20 mol%), hexanes

30 0C, 8 days

MeO

O

O

Et

NH

NH

NH2BArF

N N

61 63

nPr

68

90% yield

dr > 20:1

88 % ee

Me2N NMe2

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


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protocols was only evaluated to more simple substrates and new stericand electronic effects certain operate in the allyloxy-indoles sub-strates.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict ofinterest.

ACKNOWLEDGEMENTS

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

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Received: April 01, 2015 Revised: June 16, 2015 Accepted: June 16, 201

assymetric claisen rearrangment

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