Asymmetric Organocatalysis (From Biomimetic Concepts to Applications in Asymmetric Synthesis) || Cycloaddition Reactions

8

Cycloaddition Reactions

8.1

[4B2]-Cycloadditions – Diels–Alder Reactions

The asymmetric Diels–Alder reaction is one of the most important organic trans-

formations and has proven to be a versatile means of synthesis of a large number

of important chiral building blocks, e.g. intermediates in the total synthesis of nat-

ural products [1, 2]. Much work by many groups has emphasized that chiral metal

complexes have a high potential for efficient asymmetric synthesis of ‘‘carbon skel-

etons’’ via a Diels–Alder reaction. The high state of the art of the asymmetric

metal-catalyzed Diels–Alder reaction has also been shown by a recent excellent re-

view [1]. For a long time it was not known that organocatalysts could be used to

catalyze the Diels–Alder reaction and base-catalyzed Diels–Alder reactions, in par-

ticular, were regarded as ‘‘unusual’’ [3].

8.1.1

Diels–Alder Reactions Using Alkaloids as Organocatalysts

Kagan et al. reported the first organocatalytic asymmetric Diels–Alder reaction

in 1989 [4]. Alkaloid bases, prolinol, and N-methylephedrine were investigated

as organocatalysts. In the presence of 1–10 mol% of these chiral organocatalysts

anthrone, 1, reacts as a ‘‘masked diene’’ with N-methylated maleimide, 2, forming

Diels–Alder adducts 4 in high yields and with enantioselectivity up to 61% ee.

Whereas yields are high – between 84 and 100% for all the organocatalysts tested

– enantioselectivity varied substantially, depending on the type of catalyst. The best

result was obtained with 10 mol% quinidine, 3, in chloroform at �50 �C; the de-

sired product 4 was obtained in 97% yield and with 61% ee (Scheme 8.1) [4].

Higher reaction temperatures led to reduced enantioselectivity. For example, enan-

tioselectivity dropped from 61% ee to 35% ee when the reaction was performed at

room temperature. During their study Kagan et al. also observed that the ‘‘free’’

hydroxyl group in the alkaloid organocatalyst was essential if high enantioselectiv-

ity was to be achieved.

A detailed study of the effect of several reaction conditions was also conducted by

the Kagan group [3]. The nature of the solvent had a substantial effect on enantio-

selectivity. Compared with chloroform, much lower ee values were obtained with

Asymmetric Organocatalysis. Albrecht Berkessel and Harald GrogerCopyright 8 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30517-3

256

THF, ethyl acetate, and methanol. In contrast, use of other chlorinated solvents,

e.g. CCl4, and cyclohexane resulted in higher enantioselectivity, comparable with

that for chloroform. The range of dienophile substrates was also studied. Replacing

N-methylmaleimide by N-phenylmaleimide, in the presence of quinidine as a cat-

alyst, also led to a good yield, although enantioselectivity was lower (20% ee com-

pared with 61% ee). Much slower reaction rates were observed when methyl acry-

late and methyl fumarate were used and enantioselectivity was low (0% ee for

methyl acrylate and 30% ee for methyl fumarate). With methyl maleate as a dien-

ophile no reaction was observed. Mechanistic studies were also conducted by Ka-

gan et al.; results were in accordance with a concerted [4þ2]-cycloaddition process.

Extension of this method to the use of other diene components was demon-

strated by Okamura et al. using 3-hydroxy-2-pyrone, 5, as diene [5, 6]. When N-

methylmaleimide, 2, was used as dienophile initial screening of different types of

amino alcohol as catalysts revealed that endo adducts were always formed as the

major diastereomer [5]. Once again, cinchona alkaloids, particularly cinchonine

and cinchonidine, were found to be the most promising catalysts. Under opti-

mized reaction conditions this asymmetric Diels–Alder reaction afforded the endo

adduct 8 in 98% yield and with 77% ee when chinchonidine was used as catalyst

(Scheme 8.2) [5]. The diastereomeric ratio was d.r. (endo/exo) ¼ 11:1. For this

reaction, however, one equivalent of the catalyst was needed. Reducing the amount

of catalyst to 10 mol% still gave the desired product 8 in high yield (100%) but with

somewhat lower enantioselectivity (66% ee) and diastereoselectivity (d.r. (endo/

exo) ¼ 6.9:1) [5]. The opposite enantiomer was formed in 95% yield, and with

71% ee and a diastereomeric ratio of d.r. (endo/exo) ¼ 7.1:1 in the presence of cin-

chonine as organocatalyst.

This asymmetric Diels–Alder reaction in the presence of cinchonidine (1

equiv.) also proceeds efficiently with N-benzylmaleimide, 6, as dienophile, afford-

ing the product 9 in 99% yield, and with 54% ee (Scheme 8.2) [6]. The reaction is

1 4

3 (10 mol %),

-50 °C,CHCl3

97% yield61% ee

OOH

N

O

ON

O

O

CH3

CH3

+

2

N

N

OH

OCH3

Scheme 8.1

8.1 [4þ2]-Cycloadditions – Diels–Alder Reactions 257

highly diastereoselective – formation of the exo diastereomer was not observed. In

this conversion the use of quinine (1 equiv.) as catalyst led to improved enantiose-

lectivity of 63% ee, and a still a high yield of 99%. If a smaller amount of catalyst

was used slow addition of the diene was found to be beneficial. Thus, a yield of

95%, and nearly comparable enantioselectivity of 59% ee was achieved when the

amount of catalyst was 30 mol%. The product 9, a key intermediate in the synthe-

sis of an SP antagonist, can be readily obtained as the enantiomerically pure com-

pound by simple recrystallization.

8.1.2

Diels–Alder and hetero-Diels-Alder Reactions Using a-Amino Acid Derivatives as

Organocatalysts

The first highly enantioselective and general asymmetric organocatalytic Diels–

Alder reaction was developed very recently by the MacMillan group, who used

HCl salts of a-amino acid-derived imidazolidinones (of type 13) as catalysts [7, 8].

The catalytic activity of these chiral amino acid derivatives, e.g. 13, which was iden-

tified as the optimum catalyst, is based on their capacity to reversibly form imi-

nium ions with the a,b-unsaturated aldehydes, 10. Other a-amino acid derivatives

have also been investigated as catalysts, but led to lower yields and enantioselectiv-

ity. The organocatalytic Diels–Alder reaction in the presence of 13 proceeds with

high diastereoselectivity (exo/endo ratio up to 35:1) and with up to 96% ee

(Scheme 8.3) when using non-cyclic dienes of type 12 [7]. Use of cyclopentadiene

11 led to good to high yields of 75–99% and diastereoselectivity in the range

d.r. ¼ 1:1 to 3:1; this enabled isolation of both endo and exo adducts, 14 and 15.

Interestingly, enantioselectivity was high (ee values up to 93%) for both adducts.

5 8 (R=CH3):

7 (100 mol %),

-78 to -20 °C,CH2Cl2

98% yielddr(endo /exo)=11:177% ee

O

O

OH

O

OHN

O

O

R+

O

NO

O

R

9 (R=CH2Ph): 99% yieldonly endo-diasteromer54% ee

N

N

OH

2 (R=CH3)6 (R=CH2Ph)

Scheme 8.2

258 8 Cycloaddition Reactions

It is worthy of note that a broad range of dienophiles and dienes can be used

without loss of yield or enantioselectivity. Thus, dienophile components of type 10

bearing aromatic and alkyl substituents are tolerated. This organocatalytic Diels–

Alder reaction is, furthermore, general with regard to diene structure, as has been

demonstrated by the use of cyclopentadiene, 11, and non-cyclic dienes of type 12

(Scheme 8.3). Although yield and enantioselectivity were almost always high, dia-

stereoselectivity varied from d.r. ¼ 1:1 to 35:1. This efficient organocatalytic Diels–

Alder reaction was performed under an aerobic atmosphere and in the presence of

‘‘non-dried’’ solvents.

This organocatalytic concept based on iminium activation was successfully ex-

tended by MacMillan et al. to the first enantioselective catalytic Diels–Alder reac-

tion with simple ketone dienophiles [8]; previously, low enantiocontrol had usually

been observed for this type of substrate. Whereas the previously developed organo-

catalyst 13 gave less satisfactory results, the analogous amino acid derivative

bearing two stereogenic centers, 18, was found to be highly efficient for this type

of reaction. For example, the Diels–Alder product 19 was obtained in 89% yield,

with 90% ee, and impressive diastereoselectivity of d.r. (endo/exo) ¼ 25:1 (Scheme

8.4, Eq. 1). The reaction proceeded well with a broad range of substituted non-

cyclic and cyclic enones giving the desired products in yields of up to 89%, diastereo-

selectivity up to d.r. (endo/exo) ¼ 25:1, and enantioselectivity of up to 92% ee

[8]. The generality of the Diels–Alder reaction using enones was also shown for

the diene component. When acyclic dienes, e.g. 21, were used as diene component,

instead of cyclopentadiene, excellent diastereoselectivity of up to d.r. (endo/exo) >

90-93% ee

72-90% yielddr(endo/exo ) = 14:1 to 1:35

85-96% ee

+

14 (endo)

16

MeOH-H2O, 23 °C

+

10

R ONH

NO CH3

CH3

CH3

Ph

13

5 mol%

20 mol%23 °C

11

+

12

X

CHOR

84-93% ee15 (exo)

RCHO

75-99% yielddr(endo/exo )=1:1 to 1:3

RCHO

X

endoadduct

•HCl

Scheme 8.3


200 accompanied by high yields and enantioselectivity of up to 98% ee were ob-

tained [8]. A representative example is shown in Scheme 8.4, Eq. (2).

The principle of the reaction mechanism is summarized in Scheme 8.5. A

key step is the reversible formation of the iminium ion I starting from the

imidazolidinone-type organocatalyst and the a,b-unsaturated carbonyl component

[7]. This LUMO-lowering activation of the dienophile via iminium ion formation

is followed by subsequent Diels–Alder cycloaddition with the diene and formation

of the iminium ion II. These steps proceed with high enantiocontrol. Molecular

modeling calculations also have shown that stereocontrolled synthesis of the imi-

nium ion is a prerequisite for achieving high enantioselectivity, because the (E)and (Z) iminium ion isomers are expected to undergo cyclization from opposite

enantiofaces [7].

The preparation of immobilized catalysts related to the imidazolidinone-type or-

ganocatalyst 13 and their application in the asymmetric Diels–Alder reaction was

reported by Pihko and co-workers [9]. The reactivity of the immobilized catalysts

depended on the type of solid support. The silica-supported imidazolidinone 24,

which was prepared starting from N-Fmoc-protected l-phenylalanine, was found

to be a highly active organocatalyst. Several dienes and a,b-unsaturated aldehydes

have been successfully used in the presence of only 3.3 to 20 mol% 24, usually

89% yielddr(endo/exo )=25:1

90% ee

90% yielddr(endo/exo ) >200:1

90% ee

19 (endo )

22

H2O, 0 °C+

17

H3C C2H5

NH

NO CH3

5-Me-furyl

H

Ph

18 (20 mol%)

11

+

21

CH3

CH3

O

H5C2O

(1)

(2)

20

C2H5

OCH3

H2O, 0 °C

NH

NO CH3

5-Me-furyl

H

Ph

18 (20 mol%) O

C2H5H3C

H3C

•HClO4

•HClO4

Scheme 8.4


with good yields (up to 83%) and high enantioselectivity (up to 91% ee). endo/exo

Diastereoselectivity varied from d.r. (endo/exo) ¼ 1.1:1 to 14.1. A representative

example is shown in Scheme 8.6. Results obtained by use of solid-supported

catalysts were usually equal or superior to those obtained with the analogous

‘‘free’’ solution-phase catalyst, 13. The solid-supported catalysts can be easily recov-

ered by filtration, and re-using the recovered catalysts gives similar results. In addi-

tion, recently a chiral pyrrolidine derivative has been used as an efficient organo-

catalyst for the hetero-Diels–Alder reaction by the Jørgensen group, achieving

high enantioselectivities of up to 94% ee [10].

8.1.3

Diels–Alder and hetero-Diels–Alder Reactions Using C2-symmetric Organocatalysts

Chiral amidinium organocatalysts also have been shown to be suitable catalysts for

the Diels–Alder reaction, and have been applied in the formation of the skeleton of

estrone and norgestrel [11]. The Gobel group first designed suitable axially chiral

mono-amidinium ions for this reaction (Scheme 8.7, Eq. 1); the type 27 product

was obtained highly enantioselectively [11a,b]. A drawback of these organocata-

lysts, however, is the length of the synthetic route required to prepare them. Very

dienophile

O

diene

R1

NR2

R1

NH

R2

H NR1R2

chiral organo-catalyst, e.g. 13: product

H O

II

•HCl

I

Scheme 8.5


recently, Gobel and Tsogoeva et al. designed an C2-symmetric bis-amidinium salt

26 which is more accessible, because this organocatalyst can be synthesized by a

short synthetic route [11c]. In the presence of bis-amidinium catalyst 26, the prod-

uct 27 was formed with enantioselectivity up to 47% ee. A representative example

is shown in Scheme 8.7, Eq. 1 [11c]. The rate of reaction with the C2-symmetric

bis-amidinium salts is much higher than that with the mono-amidinium salts.

Substitution of the phenyl group in the catalyst structure by bulkier groups is re-

garded as a strategy for further optimization of the catalyst. The Rawal group re-

ported a highly efficient asymmetric hetero-Diels–Alder reaction using 20 mol%

of TADDOL (a,a,a 0,a 0,tetraaryl-1,3-dioxolan-4,5-dimethanol) 29 as an organocatalyst

[12]. After hetero-Diels–Alder reaction and subsequent derivatization, the desired

final products of type 30 were obtained in yields of 52–97%, and with enantioselec-

tivities of 92 to >98% ee. A selected example is shown in Scheme 8.7, Eq. 2. This

reaction has been successfully carried out with a range of aldehydes. Notably, the

monomethyl and dimethylether derivatives of 29 were poor catalysts, indicating

that the hydrogen bonding capability of 29 is a prerequisite for the catalytic func-

tion [12].

In conclusion, the organocatalytic asymmetric Diels–Alder reaction is a highly

efficient process, in particular when using TADDOL 29, as shown by the Rawal

group, as well as the imidazolidinone-type catalysts, e.g. 13 and 18, developed by

the MacMillan group. In this connection a specific highlight is certainly the appli-

cation of this concept in the first highly enantioselective catalytic Diels–Alder reac-

tion with a,b-unsaturated ketones as dienophiles. Furthermore, suitable organo-

catalyst have been found for the hetero-Diels–Alder reaction as demonstrated by

the Jørgensen group.

8.2

[3B2]-Cycloadditions: Nitrone- and Electron-deficient Olefin-based Reactions

In addition to [4þ2]-cycloadditions, the asymmetric [3þ2]-cycloaddition reaction of

a nitrone, 31, with an a,b-unsaturated carbonyl compound, 32, is of wide interest

[13]. The resulting isoxazolidine products of type 33 are intermediates in the prep-

73% yielddr(endo/exo ) = 6.6:1

91% ee

25CH3CN,

aqueous HCl,room temperature

+

23

O

NH

NO

CH3

CH3

Ph

24(3.3 mol%)

11

CHOH

Scheme 8.6


aration of a wide range of biologically important compounds, e.g. b-lactams and

non-natural amino acids [13, 14]. The concept of this [3þ2]-cycloaddition – with

regard to organocatalytic application – is shown schematically in Scheme 8.8.

Several asymmetric versions of cycloaddition reactions with nitrones in the pres-

ence of optically active metal complexes as Lewis-acid catalysts have been reported

[15]. Because of a lack of suitable chiral catalysts, however, the asymmetric design

of this reaction was found to be difficult when using a,b-unsaturated aldehydes as

substrates, because these compounds are poor substrates for metal catalysts, prob-

ably because of preferential coordination of the Lewis acid catalyst to the nitrone in

the presence of monodentate carbonyl compounds. Consequently, inhibition of the

catalyst occurs.

A solution addressing this synthetic issue is an extension of the recently devel-

80% yield (27 + 28)ratio (27:28)=22:1

47% ee

27

CH2Cl2,-70 °C

+

26(100 mol%)

O

OHH

Me

HH3CO

OHH

H

MeH3CO

O

+

t-Bu

N

NN

NH

H

H

H

Ph

Ph

Ph

Ph

28

H3C

H3CO

O

(1)

TBSO

N

O

H Ph

O

O

OHOH

Ar Ar

Ar Ar

29 (Ar=1-naphthyl)(20 mol%)

+O O

TBSO OPh

N

Ph(2)

3070% yield>98% ee

TFPB TFPB

Scheme 8.7

+

31 32

N OR2

R1R3

OR4

NO

R1

R2 R3

O

R4

33

organocatalyst

[3+2]-cycloadditionreaction

Scheme 8.8

8.2 [3þ2]-Cycloadditions: Nitrone- and Electron-deficient Olefin-based Reactions 263

oped organocatalytic Diels–Alder reaction reported by the MacMillan group. This

concept has now been successfully applied to [3þ2]-cycloadditions with nitrones

[16, 17]. This transformation is also the first example of an organocatalytic 1,3-

dipolar cycloaddition. Conversion of N-benzylidene benzylamine N-oxide, 31a,

with (E)-crotonaldehyde, 32a, to the isoxazolidine product 35a was investigated as

an initial model reaction. Detailed catalyst screening revealed that, in accordance

with the Diels–Alder reaction, the phenylalanine-derived imidazolidinone acid salt

34�HCl was the preferred organocatalyst. Study of different types of Brønsted acid

component showed that 34�HClO4 was most effective. The scope of the organo-

catalytic [3þ2]-cycloaddition of nitrones, e.g., 31a–g, to a,b-unsaturated aldehydes

32a–b was investigated using this catalyst. Selected examples are shown in Scheme

8.9.

The resulting isoxazolidines endo-35 were obtained in yields of up to 98%, with

diastereomeric ratios of d.r. (endo/exo) of 80:20 to 99:1, and with enantioselectivity

of 90–99% ee. The endo product was always formed as preferred diastereomer.

This 1,3-dipolar cycloaddition not only gave excellent results but was also found

to be very general with regard to the nitrone component. Several types of aryl- and

alkyl-substituted nitrone have been applied successfully. Irrespective of the substi-

tution pattern, high diastereomeric ratios and enantioselectivity were obtained (see

Scheme 8.9, products 35a,d,f,g). Variation of the N-alkyl group is also possible. As

can be see from Scheme 8.9 (see, e.g., products 35a–c), the reactions also proceed

well when an N-allyl and N-methyl-substituted nitrone is used. Acrolein, 32b, and

crotonaldehyde, 32a, were used as the aldehyde component. It is noteworthy that

this reaction is also suitable for use on a larger scale, as has been demonstrated

by the 25 mmol-scale preparation of endo-35a (98% yield, 94% ee) starting from ni-

trone 31a and crotonaldehyde.

The reactions can be performed under an aerobic atmosphere using wet sol-

vents, which makes this procedure even more attractive. Another advantage is the

easy access to the catalyst, which is based on the inexpensive amino acid phenyl-

alanine.

A detailed investigation of the potential of this organocatalytic [3þ2]-

cycloaddition for application to cyclic a,b-unsaturated aldehydes was conducted by

the Karlsson group [18]. A broad range of organocatalyst comprising a MacMillan-

type imidazolidine salt, 34�HCl, and pyrrolidine derivatives, e.g. 41�2HCl, were

used. The [3þ2]-cycloaddition of nitrone 31c with cyclopent-1-ene carboxaldehyde

was chosen as model reaction. In this reaction the imidazolidine salt 34�HCl led

to the desired product in low yield (19%) and enantioselectivity (5% ee) only after

144 h. When azabicyclo[3.3.0]octane-derived salts, e.g. 40, were used the desired

isoxazolidine cycloadduct 38 was obtained in yields up to 61% and with enantio-

selectivity up to 76% ee. Diastereoselectivity obtained with this type of catalyst was

in the range d.r. ¼ 72:28 to 89:11. A selected example is shown in Scheme 8.10.

Diastereoselectivity and enantioselectivity were observed to increase substantially

when proline-derived diamine salts were used as organocatalysts. In particular,

the pyrrolidinium salt 41�2HCl was found to be very useful, furnishing the target

molecule 38 in 70% yield with diastereoselectivity of d.r. ¼ 95:5 and enantioselec-


tivity of 91% ee (reaction time 144 h; Scheme 8.10). The amount of catalyst was 13

mol% for all the catalysts tested. The reaction also proceeds in the presence

of smaller amounts of catalyst, although the rate of reaction is low. Use of only

1 mol% 41�2HCl led to the formation of the cycloadduct 38 with d.r. ¼ 97:3 and

91% ee. The yield, however, was 21% only after 120 h. It should be noted that

proline-derived amino alcohols or their O-methylated derivatives were not suitable

catalysts.

NH

NO CH3

CH3

CH3

Ph

34(20 mol%)

+

31a-g 32a,b

N OR2

R1R3

OH

NO

R1

R2 R3

O

H

35a-h (endo)

nitromethane/water, -20 °C

N OR2

R1R3

OH

36a-h (exo)

+

N OCH3

OH

35a (endo )98% yield

dr(endo/exo )=94:694% ee

Ph

N OCH3

OH

35b (endo )73% yield


N OH3CCH3

OH

35c (endo )66% yield


Selected examples

N OCH3

OH

35d (endo )78% yield


Ph

majordiastereomer

minordiastereomer

N OH3CCH3

OH

35e (endo )76% yield


N OCH3

OH

35f (endo )93% yield


Ph

N OCH3

OH

35g (endo )70% yield


N OH

OH

35h (endo )72% yield


Ph

Cl

Cl

Ph

H3CO

(31a: R1=Ph, R2=Bn;

31b: R1=Ph, R2=allyl;

31c: R1=Ph, R2=Me;

31d: R1=p-Cl-C6H4, R2=Bn;

31e: R1=p-Cl-C6H4, R2=Me;

31f: R1=p-MeO-C6H4, R2=Bn;

31g: R1=cyclohexyl, R2=Bn)

(32a: R3=CH3;

32a: R3=H)

•HClO4

•HClO4

Scheme 8.9

8.2 [3þ2]-Cycloadditions: Nitrone- and Electron-deficient Olefin-based Reactions 265

Another type of asymmetric [3þ2]-cycloaddition catalyzed by organocatalysts

is the cycloaddition of 2,3-butadienoates and electron-deficient olefins [19]. Such

an approach has been reported by the Zhang group using novel phosphabicy-

clo[2.2.1]heptanes as catalysts. This new type of phosphine with a rigid phosphabi-

cyclic structure gave better results than were obtained with several known chiral

phosphines. For example, in the presence of 10 mol% phosphine 45 the [3þ2]-

cycloaddition of 2,3-butadienoate 42 and acrylate 43 gives one regioisomer only, 44

(Scheme 8.11); yield (88%) and enantioselectivity (93% ee) are both high.

A study of the range of substrates revealed regioselectivity was usually high, in

the range 94:6 to 100:0. This [3þ2]-cycloaddition developed by the Zhang group is

a powerful method for asymmetric synthesis of optically active cyclopentene prod-

ucts. A reaction mechanism has also been proposed. The initial step is formation

of an adduct between the phosphine catalyst and the 2,3-butadienoate, followed by

cycloaddition with the acrylate component as a key step.

In conclusion, new types of [3þ2]-cycloaddition have been developed which

are based on use of organocatalysts. The [3þ2]-cycloaddition of nitrones and

organocatalyst(13 mol%),

DMF/water+

31c 37

N OH3CN

O CH3

O

H

38

2. NaBH4, MeOH

39

+

majordiastereomer

minordiastereomer

H

OH

N OH3C H

OH

1.

Organocatalyst Yield [%]

19

61

70

d.r.

86:14

80:20

95:5

ee [%]

-5

70

91

NH

NO CH3

CH3

CH3

Ph

34

S

NH

p-MeO-C6H4

p-MeO-C6H4

HO

O O

NH N

•2HCl

41•2HCl

H

•HCl

•HCl

•HCl

40 •HCl

Scheme 8.10


a,b-unsaturated carbonyl compounds proceeds very efficiently, particularly if chiral

imidazolidine and pyrrolidine salts are used as catalysts. The [3þ2]-cycloadditions

proceed with high diastereo- and enantioselectivity, and are an attractive route

for preparation of enantiomerically pure isoxazolidines. Furthermore, [3þ2]-

cycloaddition of 2,3-butadienoates with electron-deficient olefins is catalyzed with

high enantioselectivity by chiral phosphines with a rigid phosphabicyclic structure.

References

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Corey, Angew. Chem. 2002, 114, 1724–1741; Angew. Chem. Int. Ed. 2002, 41,1650–1667.

2 For the original work on the Diels–

Alder reaction, see: O. Diels, K.

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10 K. Juhl, K. A. Jørgensen, Angew.Chem. 2003, 115, 1536–1539; Angew.Chem. Int. Ed. 2003, 42, 1498–1501.

11 (a) T. Schuster, M. Kurz, M. W.

Gobel, J. Org. Chem. 2000, 65, 1697–1701; (b) T. Schuster, M. Bauch,

G. Durner, M. W. Gobel, Org. Lett.2000, 2, 179–181; (c) S. B. Tsogoeva,G. Durner, M. Bolte, M. W. Gobel,

Eur. J. Org. Chem. 2003, 1661–1664.12 Y. Huang, A. K. Unni, A. N. Tadani,

V. H. Rawal, Nature 2003, 424, 140.13 For a review of [3þ2]-cycloaddition

reactions, see: K. V. Gothelf, K. A.

Jorgensen, Chem. Rev. 1998, 98, 863–910.

14 For example, see: M. Frederickson,

Tetrahedron 1997, 53, 403–425.

15 For selected contributions to the field

45(10 mol%)

+

42

4344

toluene, 0 °C

88% yield93% ee

(only this regioisomer is formed)

CH

H

H

CO2Et

CO2i-Bu

CO2i-Bu

CO2Et

PPh

i-Pr i-Pr

Scheme 8.11

References 267

of enantioselective metal-catalyzed

cycloadditions with nitrones, see: (a)

D. Keirs, D. Moffat, K. Overton, R.

Tomanek, J. Chem. Soc., Perkin Trans1 1991, 1041–1051; (b) K. B. Jensen,

M. Roberson, K. A. Jørgensen, J.Org. Chem. 2000, 65, 9080–9084; (c) S.Iwasa, S. Tsushima, T. Shimada, H.

Nishiyama, Tetrahedron Lett. 2001,

42, 6715–6717; (d) X. Ding, K.Taniguchi, Z. Ukata, K. Inomata,

Chem. Lett. 2001, 468–469; (e) S.Iwasa, S. Tsushima, T. Shimada, H.

Nishiyama, Tetrahedron 2002, 58,227–232; (f ) S. Murahashi, Y.

Imada, T. Kawakami, K. Harada,

Y. Yonemushi, N. Tomita, J. Am.Chem. Soc. 2002, 124, 2888–2889;(g) F. Viton, G. Bernardinelli, E. P.

Kundig, J. Am. Chem. Soc. 2002, 124,4968–4969.

16 W. S. Jen, J. J. M. Wiener, D. W. C.


17 D. W. C. MacMillan, PCT Int. Appl.

WO 2003002491, 2003.

18 S. Karlsson, H.-E. Hogberg,

Tetrahedron: Asymmetry 2002, 13, 923–936.

19 G. Zhu, Z. Chen, Q. Jiang, D. Xiao,

P. Cao, X. Zhang, J. Am. Chem. Soc.1997, 119, 3836–3837.


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Asymmetric Organocatalysis (From Biomimetic Concepts to Applications in Asymmetric Synthesis) || Cycloaddition Reactions