Enantioselective Organocatalytic Diels-Alder Reactions

REVIEW 1

Enantioselective Organocatalytic Diels–Alder ReactionsOrganocatalytic Diels–Alder ReactionsPedro Merino,*a Eugenia Marqués-López,b Tomás Tejero,a Raquel P. Herrera*a,c

a Laboratorio de Síntesis Asimétrica, Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza, CSIC, 50009 Zaragoza, Aragón, SpainFax +34(976)762075; E-mail: [email protected]; E-mail: [email protected]

b Technische Universität Dortmund, Organische Chemie, Otto-Hahn-Str. 6, 44227 Dortmund, Germanyc Fundación ARAI+D, Gobierno de Aragón, 50009 Zaragoza, SpainReceived 1 September 2009; revised 30 September 2009Dedicated to Professor Alfredo Ricci on the occasion of his 70th birthday

SYNTHESIS 2010, No. 1, pp 0001–0026xx.xx.2009Advanced online publication: 20.11.2009DOI: 10.1055/s-0029-1217130; Art ID: E25409SS© Georg Thieme Verlag Stuttgart · New York

Abstract: Enantioselective organocatalytic asymmetric Diels–Alder reactions provide a facile and efficient route to optically ac-tive functionalized cyclohexenes, which can be further transformedinto a variety of important organic compounds. A variety of smallorganic molecules such as prolines, imidazolidinones, chiralBrønsted acids, guanidines, carbenes and Cinchona alkaloids can beused as different catalyst systems to induce enantioselectivity in thereaction. This review provides an overview of the history of theasymmetric organocatalyzed Diels–Alder reaction.

1 Introduction2 Chiral-Base-Catalyzed Diels–Alder Reactions2.1 Chiral Secondary Amines2.2 Chiral Primary Amines2.3 Cinchona Alkaloids2.4 Heterocyclic Carbenes2.6 Chiral Guanidines3 Hydrogen-Bond-Catalyzed Diels–Alder Reactions4 Concluding Remarks

Key words: Diels–Alder reactions, asymmetric catalysis, cycload-ditions, organocatalysis

1 Introduction

The Diels–Alder reaction is one of the most importantatom-economic reactions. Since the publication by Otto P.H. Diels and Kurt Alder of their famous paper1 in 1928 theDiels–Alder reaction is still one of the most studied2 andmost utilized reactions in organic synthesis.3 This monu-mental investigation extended over more than sixty yearsand it provided detailed information about a wide varietyof dienes and dienophiles4 as well as the factors that influ-ence the mechanism of their addition to unsaturated sys-tems.5 The Diels–Alder reaction is also one of the oldestorganic transformations to employ chiral auxiliaries in or-der to obtain enantiomerically pure compounds.6 The firstasymmetric Diels–Alder reaction was reported in 1948 byKorolev and Mur.7 After the discovery by Walborsky andco-workers in 1963 that the reaction could be efficientlycatalyzed by Lewis acids,8 the catalytic asymmetricDiels–Alder reaction has been extensively investigated9

and the synthetic relevance of the formation of the cyclo-

hexene framework with four contiguous stereocenters be-came an active field of research.10 A very elegantalternative to the construction of the cyclohexene frame-work in an enantioselective way was recently describedby Enders and co-workers11 through a triple organocata-lyzed cascade reaction through a new methodology thathas been further applied by other authors.12

In addition to Lewis acids, other catalytic approacheshave been investigated as well. Several Diels–Alder reac-tions have been reported to have a considerable rate en-hancement in water as a solvent13 or in a hydrogen-bonding environment.14 The synthetic versatility of theDiels–Alder reaction has been further emphasized by bio-catalytic approaches15 which offer the possibility of carry-ing out the reaction in a metal-free environment at anacceptable rate under mild conditions and with good se-lectivities. In this context, small organic molecules actingas organocatalysts emerged as a good alternative to theuse of enzymes, which can be somewhat too specific andmore complex to use. The rapid development of organo-catalysis during the last decade16 is impressively reflectedin the advances that have been achieved with a great vari-ety of organic transformations.17 Among those processesare important reactions such as aldol condensation,Friedel–Crafts, Mannich, Strecker and Henry reactions,and of course, Diels–Alder cycloadditions. Although anumber of authoritative reviews, cited throughout this in-troduction, have been written on the catalytic Diels–Alderreaction, a separate compilation concerning exclusivelyorganocatalytic approaches has, to the best of our knowl-edge, still not appeared.18 Some examples are collected intwo general reviews concerning domino reactions19 andthe use of proline in organic catalysis.20 The present re-view therefore focuses on recent developments in organo-catalyzed Diels–Alder cycloadditions.

2 Chiral-Base-Catalyzed Diels–Alder Reactions

The use of chiral amines as organocatalysts has receivedconsiderable attention in enantioselective synthesis.21

Typical reactive intermediates are iminium ions22 orenamines23 formed by the reversible reaction of the aminecatalyst with a carbonyl compound. This type of aminoca-talysis has been broadly employed with a wide range of

2 P. Merino et al. REVIEW

Synthesis 2010, No. 1, 1–26 © Thieme Stuttgart · New York

reactions including, among others, cycloadditions, conju-gate additions, and domino processes.

2.1 Chiral Secondary Amines

MacMillan and co-workers were pioneers in this field, ap-plying successfully for the first time24 their imidazolidino-ne organocatalyst25 3·HCl to provide Diels–Aldercycloadducts 4 in very good yield and with excellentenantioselectivities (Scheme 1, Table 1).26

Scheme 1

Pedro Merino was born inZaragoza (Spain) and grad-uated with an HonoursM.Sc. degree in chemistryfrom University of Zarago-za where he also receivedhis Ph.D. with ProfessorEnrique Meléndez in 1989.After two years of a post-doctoral stay in the group ofProfessor AlessandroDondoni (University of Fer-rara, Italy) working on ap-

plications of thiazolechemistry in the area ofasymmetric synthesis, hewas appointed AssistantProfessor at the Universityof Zaragoza in 1992. In1994 he was promoted toAssociate Professor and in2005 he got his habilitationas Full Professor in OrganicChemistry. In 2006 heearned a Chair in OrganicChemistry at the Depart-

ment of Organic Chemistryof the University of Zarago-za. His research interests in-clude the development ofnovel synthetic methodolo-gies as well as target-orient-ed synthesis, the applicationof heterocycles in synthesisand the use of organic andmetal-based catalysts inasymmetric synthesis.

Eugenia Marqués-Lópezwas born in Seville (Spain).She graduated in chemistryfrom University of Sevillein 2002. She completed herPh.D. (2007) in organicchemistry under the super-vision of Professor RosarioFenández and Dr. José M.Lassaletta at the same uni-

versity. During her Ph.D.she worked on the field ofN,N-dialkylhydrazones asN,N-dialkylamino iminesurrogates and its applica-tion to Staudinger, Mannichand Strecker-type reactions.She also worked on the syn-thesis of novel diene com-plexes in the laboratory of

Dr. John M. Brown at theUniversity of Oxford (UK)(2005). She is currently inthe laboratory of ProfessorMathias Christmann work-ing on organocatalysis as anAlexander von Humboldtpost-doctoral fellow (Tech-nische Universität Dort-mund, Germany).

Tomás Tejero was born inZaragoza (Spain). He stud-ied chemistry at the Univer-sity of Zaragoza where hereceived his Ph.D. with ho-nours working with Profes-sor E. Meléndez. In 1984 hebecame Assistant Professorand in 1986 he spent a year

as a postdoctoral researchassociate in the UniversityPierre et Marie Curie (Paris)under the supervision ofProfessor J. Normant. In1987 he returned to Zarago-za and received his habilita-tion as Senior Lecturer inthe same year. In 2009, he

got his habilitation as FullProfessor in Organic Chem-istry. His research interestspans asymmetric synthesisincluding asymmetric catal-ysis and nuclear magneticresonance techniques.

Raquel P. Herrera wasborn in Alicante (Spain) in1977. She received herB.Sc. from University of Al-icante in 1999 and her M.Sc.from the same university in2000. From 1999 to 2003she completed her Ph.D. un-der the supervision of Pro-fessor Albert Guijarro andProfessor Miguel Yus at

University of Alicante.Then, she took up a Europe-an postdoctoral contractwith Professor Ricci (Bolo-gna, Italy) in the IndustrialChemistry Faculty untilMarch 2006, at which timeshe joined Dr. José M. Las-saletta’s group at the IIQ-CSIC (Seville, Spain) as anI3P postdoctoral fellow. She

was appointed to her presentposition at ICMA (Institutode Ciencia de Materiales deAragón) CSIC-Universityof Zaragoza in January 2008as a permanent ARAI+D(Gobierno de Aragón) re-searcher. Her research inter-ests focus on asymmetricorganocatalysis and its ap-plications.

Biographical Sketches

R O

+1

2 endo-4exo-4

MeOH–H2O23 °C

NH

NO Me

Ph3

·HCl

(5 mol%)

CHO

R

R

CHO +

REVIEW Organocatalytic Diels–Alder Reactions 3


The reaction was tolerant of different a,b-unsaturated al-dehydes. Notably, it was also general with respect to thediene structure, thus allowing access to a number of cyclo-hexenyl building blocks, such as 6, that incorporated dif-ferent substituents with high levels of regio- andenantioselectivity (Scheme 2 and Table 2).26a

Scheme 2

The authors proposed a mechanism based in their preced-ing work. It was reasoned that LUMO-lowering activationmight also be available with a carbogenic system that ex-ists as a rapid equilibrium between an electron-deficientand a relatively electron-rich state. With this in mind, theyenvisioned that condensation of aldehyde 1 with catalyst3 would lead to the formation of an iminium ion A that issufficiently activated to engage a diene reaction partner.Accordingly, Diels–Alder cycloaddition would lead to

iminium ion B, which upon hydrolysis would provide theenantioenriched cycloaddition product C liberating thecatalyst which re-enters the catalytic cycle (Scheme 3).The proposal illustrated in Scheme 3 has been further sup-ported by theoretical calculations at a B3LYP/6-31G*level.27

Scheme 3

The utility of the iminium activation to provide LUMO-lowering catalysis outside the mechanistic confines oflone-pair coordination28 was applied by MacMillan’s re-search group for carrying out enantioselective Diels–Alder reactions with simple ketone dienophiles.29 A seriesof imidazolidinone perchloric acid salts were studied assuitable catalysts from which compound 8 arose as themore effective (Scheme 4, Table 3).

Scheme 4

Table 1 Organocatalyzed Diels–Alder Cycloadditions between Cyclopentadiene and Representative Dienophiles

R Time (h)

Yield (%)

Ratio exo/endo

ee (%) exo

ee (%) endo

Me 16 75 1:1 86 90

Pr 14 92 1:1 86 90

i-Pr 14 81 1:1 84 93

Ph 21 99 1.3:1 93 93

2-furyl 24 89 1:1 91 93

Table 2 Organocatalyzed Diels–Alder Cycloadditions between Acrolein or Crotonaldehyde and Representative Dienes

Diene R Product Yield (%)

Ratio exo/endo

ee (%) endo

H 82 1:14 94

H 84 – 89

HMe

9075

––

8390

H 75 1:5 90

H 72 1:11 85

R O +

1 5

3 (20 mol%)

MeOH–H2O23 °C

XX

CHO

R

endo-6

CHO

CHO

Ph

CHO

Ph R

CHO

OAc

CHO

OAc

Table 3 Organocatalyzed Diels–Alder Cycloaddition between Cyclopentadiene and Acyclic Enones

R1 R2 Yield (%) Ratio endo/exo ee (%) endo

Me Me 85 14:1 61

Me Et 89 25:1 90

Me n-Bu 83 22:1 92a

Me i-amyl 86 20:1 92

Me i-Pr 24 8:1 0

n-Pr Et 84 15:1 92

i-Pr Et 78 6:1 90

a Reaction performed without solvent.

NH

R2R1

·HClcatalyst =

N

R2

R1

O

CHO

H NR1R2

diene

dienophile

A

B

C

+

2

R1

7 (20 mol%)

H2O, 0 °C

NH

NO Me

8

· HClO4

R2

O

OPh

R1

R2 Oendo-9



The reaction showed high enantiocontrol for differentsubstituted ketones, with the exception of the methyl ke-tone, which only showed moderate levels of enantioselec-tivity, and the isopropyl ketone, which afforded racemiccycloadducts in poor yield, presumably as a result of stericinhibition of iminium formation.

The reaction with acyclic enones was also quite generalwith respect to diene structure, allowing enantioselectiveaccess to a range of alkyl-, alkoxy-, amino-, and aryl-substituted cyclohexenyl ketones (Scheme 5, Table 4).29

Scheme 5

A computational study showed that trans-iminium isomer12 (Scheme 6) was energetically disfavored since bothenantiofacial sites are shielded by structural impediment.On the other hand, the cis-iminium isomer 13 showed theSi face to be rather accessible to cycloaddition, thus ex-plaining the observed enantioselectivity. Moreover, thecomputational prediction based on accessibility of enan-tiofaces in 12 and 13 also predicts the absence of selectiv-ity observed for methyl and isopropyl ketones listed inTable 3 and is in a complete agreement with the disparityin enantiocontrol observed between methyl ketone (61%ee) and ethyl ketone (90% ee).

The organocatalytic Diels–Alder reaction between cinna-maldehyde and cyclopentadiene catalyzed by imidazolid-inone 3 has been used as a model for mass spectrometricscreening of enantioselective Diels–Alder reactions. Themethod, reported by Pfaltz and Teichert30 allows the si-

multaneous evaluation of mixtures of catalysts, thus pro-viding the possibility of screening catalyst librariesprepared by combinatorial methodologies.

Kinetic studies on the imidazolidinone-catalyzed Diels–Alder reactions showed that iminium ion formation andhydrolysis of the cycloadducts are fast, and that the rate-determining step of the reaction is the carbon–carbonbond formation.31 Energy barriers calculated by usingDFT methods are in agreement with experimental results.

Reactive intermediates between MacMillan’s catalyst 3and aldehydes have been isolated and characterized by X-ray crystallography.32 The obtained structures confirm thecommonly accepted catalytic cycles proposed for organo-catalytic processes.

MacMillan and co-workers also applied their LUMO-lowering organocatalytic strategy to develop the first or-ganocatalytic intramolecular Diels–Alder reaction.33 Thisproved to be effective in the cycloisomerization of a rangeof trienals 14 using imidazolidinones 3a–c and 15a–c(Scheme 7, Table 5).

Scheme 7

In general, catalyst 15 resulted in superior yields andenantioselectivities in comparison with 3, but both afford-ed bicyclic product 16 in high yield, good diastereoselec-tivity and with excellent enantioselectivity. Unexpectedly,substitution at the b-position of the a,b-unsaturated carbo-nyl system afforded a complete inversion in the endo/exoselectivity.

The synthetic utility of this new organocatalytic strategywas demonstrated in the total synthesis of the marine me-tabolite solanapyrone D (20) (Scheme 8),33 a phytotoxicpolyketide isolated from the fungus Altenaria solani.34

Table 4 Organocatalyzed Diels–Alder Cycloaddition between Ethyl Vinyl Ketone and Representaive Dienes

Diene Product Yield (%)

Ratio endo/exo

ee (%) endo

88 >200:1 96

91 >200:1 98

92 >200:1 90

90 >200:1 90

79 >200:1 85a

a Reaction performed without solvent at –20 °C.

10

8 (20 mol%)

EtOH, –30 °C

O

+

5R

R

COEt

Et

11

OMe

OMe

COEt

NHCbz

NHCbz

COEt

PhCOEt

Ph

COEt

COEt

Scheme 6

N

NO Me

RPh

N

NO Me

RPh

NH

NO Me

R

Me

Ph

O

= Me or Htrans-iminium 12 cis-iminium 13

R = 5-methyl-2-furyl

NH

NO Me

Ph3

CHO

X

R

3a–c or 15a–c

co-catalysta: HClb: TFAc: HClO4 N

H

NO Me

Ph15

(20 mol%)X

R

CHOH

H14 16



The organocatalytic approach allowed its synthesis inonly six steps and 15% overall yield from 17.35

MacMillan’s catalyst has also been employed by othergroups in intramolecular Diels–Alder methodologies di-rected toward the synthesis of interesting natural products.Koskinen and co-workers36 and Jacobs and Christmann37

have employed such a methodology for the synthesis ofbicyclic amaminols A (21) and B (22), respectively(Scheme 9).

A similar strategy was employed by Hong and co-work-ers.38 Both compounds show remarkable resemblance tocrucigasterin 277 and exhibit moderate cytotoxicityagainst P388 murine leukemia cells.39

Decalin 28, a key intermediate in the total synthesis of te-lomerase inhibitor UCS1025A (25)40 and maleimide ana-logue 2641 was obtained in a similar way (Scheme 10) tothat described for constructing the dihydroindane systempresent in 22.

The organocatalytic intramolecular Diels–Alder strategywas applied to the synthesis of eunicellin core 30 presentin many natural products.42 Preparation of 30 has been re-ported by Burton, Holmes and co-workers using imidazo-lidinone ent-3a as a catalyst (Scheme 11).43 An exo-selective intramolecular Diels–Alder reaction of a,b-un-saturated aldehyde 29 successfully delivered the tricyclic

Table 5 Organocatalyzed Intramolecular Diels–Alder Cycloaddition

Aldehyde Catalyst Product Yield (%) Ratio endo/exo ee (%) endo

3b15b

8485

>20:1>20:1

7793

3b15b

4775

4:1>20:1

8794

3a15c

7670

<1:201:2.5

9497

3c15c

7984

>20:1>20:1

9493

3c15c

<1070

–>20:1

–92

CHO

Ph

Ph

CHOH

H

CHO

CHOH

H

CHO

Ph

Ph

CHO

H

O CHO

PhO

Ph

CHOH

H

Ph

CHOH

CHO

Ph

H

Scheme 8

CHO 3 (20 mol%)

MeCN, 5 °C

CHO

H

H

17

18(71%, >20:1 dr, 90% ee)

H

H

OH O

OMeO

H

H

solanapyrone D, 20

O

O

H

O

OMe 4 steps

(28.5%)

19

OSiMe3

MeO OSiMe3

TiCl4CH2Cl2, –78 °C

(75%)

Scheme 9

CHO

Et

(E/Z ~ 7:1)23

ent-15 (10 mol%)·TFA

MeCN–H2O (98:2)–18 °C, 12 h

71% (2 steps)

Et

CHO

H

H

24(98% ee)

Et

H

H

amaminol A, 21

NH2

OH

Et

H

H

amaminol B, 22

NH2

OH

amaminol B, 22



core of eunicellin 30 containing all the requisite function-alities to allow synthesis of the natural product 31.

Kinsman and Kerr prepared44 key intermediate endo-34for the synthesis of (+)-hapalindole Q (35), an alkaloidfirst isolated by Moore and co-workers from the terrestrialblue-green alga Hapalosiphon fontinalis,45 by using orga-nocatalyst 3a (Scheme 12). Although the reaction showedgood enantioselectivity, a substoichiometric amount ofcatalyst (40 mol%) was needed for a low chemical yieldand a moderate diastereomeric ratio in favor of the endoisomer.

Barbas and co-workers reported46 the first organocatalyticdiastereo- and enantioselective direct asymmetric dominoKnoevenagel/Diels–Alder reactions47 that produced high-ly substituted spiro[5.5]undecane-1,5,9-triones 40(Scheme 13, Table 6).

The reaction takes place smoothly in methanol at ambienttemperature in the presence of 10 mol% of chiral 5,5-di-methylthiazolidinium-4-carboxylate (39). Compounds 40are attractive intermediates in the synthesis of naturalproducts and in medicinal chemistry.48 Spirotriones 40were obtained as single diastereomers, with good yields

and excellent enantiomeric excess values, together withthe corresponding acetals 41 which were obtained in lowyields.

Imidazolidinone 42 has been used as a catalyst for the for-mation of the central tetracyclic framework of (+)-min-fiensine through an organocascade sequence starting witha Diels–Alder reaction (Scheme 14).49

The origin of the enantiocontrol exerted by 42 is proposedto arise from the tert-butyl group of the catalyst which in-duces an endo-selective Diels–Alder cycloaddition of in-

Scheme 10

NO

O

OO

OH

H

H

H

H

UCS1025A, 25

NBn

O

O

O

TBSO

H

H

H

H

26

O

27

3 (10 mol%)·TfOH

MeNO2–H2O (98:2)0 °C, 48 h

(74% yield, 84% ee)

O

H

H

28

26

Scheme 11

OOBn

PhMe2Si

O

O OBn

PhMe2Si

O

HHH

29 exo-30

ent-3a (5 mol%)

MeCN–H2O (95:5)

(67%)

OHH

eunicellin, 31

AcO

OAc

AcO

AcO

HH

HH

Scheme 12

NH

CHO

+

32 33

CHONTs

3a (40 mol%)

DMF–MeOH (1:1)(5% H2O), 1.5 h

endo-34

CHO

exo-34

TsN

+

93% ee 92% ee

NH

NCS

(+)-hapalindole Q, 35

(35%, 70% dr)

Scheme 13

O

Ar

36

+ RCHO

37

+O O

O O

38

S

NH

CO2H

39 (10 mol%)

MeOH, r.t.

OO

O

O

Ar

RO

40

OO

O

O

Ar

R

41

MeOMeO

+



dole 43 with the iminium salt formed in situ frompropynal and the catalyst (Figure 1).

Recently, Gotoh and Hayashi have reported an exo- andenantioselective Diels–Alder reaction of a,b-unsaturatedaldehydes catalyzed by diarylprolinol silyl ether 46 underacidic conditions (Scheme 15, Table 7).50

Scheme 15

Under the best conditions, the authors found that in thepresence of an acid catalyst, the Diels–Alder reaction af-forded the exo isomer with high diastereoselectivities andexcellent enantioselectivities for aromatic, hetoaromaticand aliphatic substituents as described above in Table 7.The diastereoselectivities are better than those reported byMacMillan and co-workers (Table 1) and though 10mol% of the catalyst 46 was used in the above reactions,the catalyst loading could be reduced to 2 mol% while af-fording similar yields and enantioselectivities.

Jørgensen and co-workers reported the first organocata-lytic enantioselective inverse-electron-demand hetero-Diels–Alder (HDA) reaction51 between aliphatic alde-hydes 47 and b,g-unsaturated a-keto esters 48 catalyzedby 49 (Scheme 16, Table 8). The resulting highly func-tionalized cycloadducts 50 were obtained with excellentdiastereo- and enantioselectivity.52 The stoichiometricHDA reaction between non-chiral enamines with b,g-un-saturated a-keto esters had been reported earlier53 andSchreiber and Meyers had described a stoichiometricasymmetric enamine–enal cycloaddition.54

Scheme 16

Table 6 Asymmetric Three-Component Diels–Alder Catalyzed by 5,5-Dimethylthiazolidinium-4-carboxylate 39

Ar R Time (h)

Yield (%)

Ratio 40/41

ee (%) 40

Ph 4-O2NC6H4 72 95 13:1 86

Ph 4-NCC6H4 96 85 16:1 84

1-naphthyl 4-O2NC6H4 72 93 >100:1 99

2-furyl 4-O2NC6H4 72 92 12:1 88

2-thienyl 4-O2NC6H4 72 80 15:1 99

Scheme 14

Et2O, –50 °C, 24 h

42 (15 mol%)N

NHBoc

SMePMB

N

PMB

NOH

SMeBoc

NH

NOH

(+)-minfiensine, 45

CHO

(87%, 96% ee)

N

NH

O

t-Bu

Me

then NaBH4, MeOH

· CBr3CO2H

43

44

Figure 1

N

BocHN

SPMB

Me

endo-selectiveN

N

O

t-Bu

Me

Ar

R O1

endo-(4S) exo-(4S)

+

CHO

R

R

CHO+

2

(10 mol%)

CF3CO2H(20 mol%)toluene, r.t.

NH

46

Ar

Ar Ar = 3,5-(F3C)2C6H3

OTES

Table 7 Organocatalyzed Diels–Alder Cycloaddition between Cyclopentadiene and Representative Dienophiles Catalyzed by 46

R Time (h) Yield (%) Ratioexo (ee, %)/endo (ee, %)

Ph 26 quant. 85 (88):15 (97)

2-naphthyl 28 94 86 (82):14 (96)

2-MeOC6H4 78 71 78 (96):22 (96)

4-BrC6H4 24 quant. 86 (84):14 (96)

4-O2NC6H4 6 93 87 (82):13 (96)

2-furyl 100 67 80 (78):20 (94)

c-hexyl 17 78 85 (93):15 (97)

n-Bu 3 65 78 (91):22 (94)

CO2Et 17 92 70 (64):30 (84)

4-O2NC6H4a 17 quant. 86 (73):14 (94)

a Catalyst 46 (2 mol%) and CF3CO2H (4 mol%) were used.

O

R1

+

R2

O

CO2R3

OO CO2R3

R2

R1

NH

Ar

Ar

47

48

49

50

CH2Cl2, 17 h–15 °C to r.t.

then PCC, CH2Cl2

(10 mol%)

Ar = 3,5-Me2C6H3



It was suggested that the corresponding chiral enaminesgenerated from aldehydes 47 and chiral pyrrolidine 49could act as electron-rich alkenes undergoing the HDA re-action with enones via the catalytic cycle outlined inScheme 17.

Scheme 17

The observed absolute and relative stereochemistry in thefinal products 50 is consistent with the proposed transi-tion-state model depicted in Figure 2. The electronicproperties of the enamine would govern the regioselectiv-ity, while the 2,2-diarylmethyl substituent on the pyrroli-dine ring would shield the Si face of the enamine. As aconsequence, the 2,2-diarylmethyl substituent of theenamine intermediate induces the addition of the enone tothe Re face of the alkene fragment in an endo-selectivefashion.

Following the seminal work of Jørgensen and co-workersin organocatalytic HDA reactions, several important con-tributions have been reported by other authors.55 Zhao andco-workers reported a novel prolinal dithioacetal deriva-tive 55 as a catalyst for the HDA reaction between enoliz-able aldehydes and b,g-unsaturated-a-ketophosphonates54 (Scheme 18, Table 9).56

Scheme 18

During the initial screening of conditions and catalysts itwas found than the more hindered catalyst 55 led to a bet-ter enantiomeric excess value than the others. In order tostudy the scope of this reaction, several enolizable alde-hydes and b,g-unsaturated a-ketophosphonates were em-ployed under the optimized conditions. The resultscollected in Table 9 show that products 56 were obtained

Table 8 Organocatalytic Inverse-Demand Hetero-Diels–Alder Reaction Catalyzed by 49

R1 R2 R3 Yield (%) ee (%)

Et Ph Me 69 84

i-Pr Ph Me 93 89

Bn Ph Me 65 86

Et 4-ClC6H4 Me 79 85

i-Pr 4-ClC6H4 Me 70 90

Bn 4-ClC6H4 Me 62 80

Et Me Et 81 86

i-Pr Me Et 75 94

Bn Me Et 72 89

N R4

R1

R2 CO2R3

O

O CO2R3

R2

R1

N

R4

H2OO CO2R3

R2

R1

HO

NH

R4

R1

O

H2O

49

48

47

53

51

52


R1 R2 Time (h) Yield (%) ee (%)

Me Me 30 79 87

Me Me 28 87 82

n-Bu Me 30 88 83

n-pentyl Me 36 87 89

n-octyl Me 30 91 85

i-Pr Me 40 69 89

Ph Me 36 82 68

Bn Me 72 69 94

Me Et 48 72 80

Et Et 48 71 89

Me Ph 29 41 19

Figure 2

R1

N

ArAr

MeO2C O

Ph

O

R1

+

R2

O

P(O)(OEt)2

OO P(O)(OEt)2

R2

R1

NH

SAr

SAr47

54

55

56

CH2Cl2, SiO2

then PCC, CH2Cl2

(10 mol%)

Ar = 2,6-Me2C6H3



in good enantiomeric excess values (up to 94% ee) andgood yields. Only when R2 was a phenyl group did thesystem lead to a detrimental decrease in reactivity andenantioselectivity, probably owing to electronic effects.

Liu and co-workers have described57 the HDA reaction ofa,b-unsaturated trifluoromethyl ketones 57 with enoliz-able aldehydes 47 using prolinol derivative 58 as a cata-lyst in combination with 4-fluorophenol. This reactionprovided a practical synthesis of trifluoromethyl-substi-tuted dihydropyranones 61 with high diastereo- and enan-tioselectivities but moderate chemical yields (Scheme 19,Table 10). The mechanism for the formation of 59 wasproposed according to the catalytic cycle previouslyreported51 by Juhl and Jørgensen and illustrated inScheme 17. In this case, however, additional treatmentwith methanesulfonyl chloride was necessary to promotethe formation of the double bond in the dihydropyranonesystem.

Scheme 19

Concurrently, Chen and co-workers58 employed the sameamine 58 as a catalyst for a highly stereoselective inverse-electron-demand aza-Diels–Alder reaction between N-sulfonyl-1-azabuta-1,3-dienes 62 and aldehydes(Scheme 20). Excellent diastereomeric ratios (>99:1) andenantioselectivities were observed for a broad scope ofsubstrates under the optimized conditions (Table 11). Thesynthetic utility of the strategy depicted in Scheme 20 wasdemonstrated by conversion of hemiaminal 63 into a num-ber of valuable compounds of synthetic interest, includingsaturated highly substituted pyridines, tetrahydropy-ridines and piperidines (Scheme 21).

Scheme 20


R1 R2 Time (h)

Yield (%)

Ratio cis/trans

ee (%)

Me Ph 64 63 >95:5 97

Me 4-ClC6H4 72 62 >95:5 97

Me 4-BrC6H4 72 63 >95:5 95

Me 3-BrC6H4 96 63 96:4 92

Me 4-MeC6H4 106 76 96:4 94

Me 4-MeOC6H4 90 57 >95:5 93

Me 2-MeOC6H4 77 54 98:2 83

Me 1-naphthyl 96 50 >95:5 92

i-Pr Ph 120 71 96:4 93

Bn Ph 142 51 94:6 46

NH

Ph

PhOTMS

O

R1

+OHO OH

R2

R1

47

57

58

59

CH2Cl2, SiO2

(20 mol%)

R2

O

CF3

OO OH

R2

R1

60

CF3Et3N

CH2Cl2, –10 °C

MeSO2ClOO CF3

R2

R1

61

4-fluorophenol

PCCacetone

CF3 Table 11 Diels–Alder Reaction between 47 and 62 Catalyzed by 58

R1 R2 R3 Yield (%) ee (%)

Ph Ph Et 88 97

Ph 4-ClC6H4 Et 85 98

Ph 3-ClC6H4 Et 92 99

Ph 3-MeOC6H4 Et 81 95

Ph 4-MeC6H4 Et 78 96

Ph 1-naphthyl Et 40 99

Ph 2-furyl Et 83 98

Ph 2-thienyl Et 87 98

Ph Me Et 83 93

Ph CO2Et Et 95 99

4-MeC6H4 Ph Et 85 99

4-ClC6H4 Ph Et 82 98

2-ClC6H4 Ph Et 74 99

3-BrC6H4 Ph Et 86 99

1-naphthyl Ph Et 83 94

PhCH=CH Ph Et 91 99

Ph Ph Me 92 98

Ph Ph Ph(CH2)2 72 99

Ph Ph Et 82 96

NH

Ph

PhOTMS

O

R3

+

4758

MeCN, H2O

(10 mol%)

r.t., 24 hR2

N

R1

N

R2

62

AcOH (10 mol%)

63

Ts

Ts

R1

R3

OH



Scheme 21 Reagents and conditions: (a) PCC, 40 °C, 6 h; (b)Et3SiH, BF3·OEt2, –78 °C, 4 h; (c) Et3SiH, BF3·OEt2, r.t., 12 h; (d)FeCl3·6H2O, CH2Cl2, 0 °C, 8 h; (e) MnO2, CHCl3, r. t., 12 h.

Similarly, prolinol derivative 58 also catalyzed the con-densation between 62 and a,b-unsaturated aldehydes, inthe presence of 10 mol% of benzoic acid, to afford hemi-aminals 72 in which a migration of the double bond tookplace (Scheme 22, Table 12).59 Compounds 72 were ob-tained in good yields, excellent enantioselectivity and ex-clusive a-regioselectivity.

Scheme 22

In the case of linear enals 73, the reaction proceeded witha very good E-selectivity for the newly formed doublebond (Scheme 23, Table 13).59 The resulting hemiaminalswere oxidized in situ to afford lactams 74 with excellentenantiomeric excess values. Scale-up (1 mmol) of this di-enamine-catalyzed reaction gave rise to similar resultsand no loss of enantioselectivity was observed.

Scheme 23

Catalyst 58 also catalyzed the formation of enantiomeri-cally pure hydroquinoxalines of interest in medicinalchemistry through the hetero-Diels–Alder reaction of al-dehydes 75 with o-benzoquinone diimide 76 (Scheme 24,Table 14).60 The reaction was carried out in the presenceof water and with 10 mol% of benzoic acid as a co-cata-lyst. In all cases, excellent selectivities were obtained.

Scheme 24

Chiral secondary amines different from proline or imida-zolidinone derivatives can also be used as suitable organo-catalysts for the Diels–Alder reaction. Bonini and co-workers developed a series of aziridin-2-yl methanols 78which catalyzed the reaction between a,b-unsaturated al-dehydes 1 and cyclopentadiene (2) (Scheme 25). Both hy-

N

Ph

64 96% ee

Ts

Ph OH

N

Ph

Ts

Ph O

N

Ph

Ph

Ph

O Ph

CHO

65 67%, 98% ee

66 62%

67 91%, 95% ee

N

Ph

Ts

Ph

68 72%, 99% ee

N

Ph

Ts

Ph

69 55%, 99% ee

a

b

cd

e

NH

Ph

PhOTMS

+58

MeCN, H2O

(10 mol%)

r.t., 2–6 hR2

N

R1

N

R2

62

PhCO2H (10 mol%)Ts

Ts

R1 OH

CHO

71

72

Table 12 Reaction between 62 and a,b-Unsaturated Aldehydes 71

R1 R2 Yield (%) ee (%)

Ph CO2Et 95 99

2-thienyl CO2Et 91 99

CO2Et Ph 95 >99

CO2Et 2-BrC6H4 91 >99

CO2Et 4-MeOC6H4 96 >99

Ph Ph 89 99

Ph Me 85 98

CO2Et Ph 92 99

Table 13 Reaction between 62 and Linear Enals 73

R1 R2 Yield (%) Ratio E/Z ee (%)

Ph Et 68 8.1:1 99

Ph Me 66 5.8:1 98

Ph n-Pr 70 6.7:1 97

4-ClC6H4 Et 71 7.5:1 98

4-BrC6H4 Et 68 8.9:1 98

4-MeC6H4 Et 72 7.6:1 98

NH

Ph

PhOTMS

+58

MeCN, H2O

(10 mol%)

–10 °C, 8–12 hCO2Et

N

R1

N

CO2Et

PhCO2H (10 mol%)Ts

Ts

R1 O

R2 CHO

73

R2

7462 then PCC, CH2Cl2

NH

Ph

PhOTMS

+58

THF, H2O

(10 mol%)

r.t., 12 h

PhCO2H (10 mol%)

R2 CHO

75

77

NBz

NBz

76 then PCC, CH2Cl2

NBz

BzN O

R2



drochloride and perchlorate salts of aziridines 78 weretested and only moderate enantiomeric excesses wereachieved (Table 15).

The observed low enantiomeric excess values were ratio-nalized on the basis of the observed background reactionin the absence of aziridine but in the presence of catalytic

amounts of hydrochloric acid (5 mol%) or perchloric acid(10 mol%).61 Interestingly, in the case of the exo-4 ad-ducts, catalyst 78 afforded preferentially the enantiomerof those obtained with MacMillan’s catalyst (Scheme 1).

Lemay and Ogilvie reported62 the same reaction catalyzedby hydrazine 79 in higher yields and enantioselectivities(Scheme 26, Table 16). Both aryl and alkyl substituentsfurnished similar results. In this case the enantiomer of theendo-4 adduct was obtained with respect to that obtainedin the reaction depicted in Scheme 21; accordingly, cata-lyst 79 can be considered complementary to MacMillan’scatalyst 3 since both enantiomeric endo-4 and exo-4 ad-ducts are obtained.

The reaction illustrated in Scheme 26 was also carried outwith 2-phenylbuta-1,3-diene and 2-methylpenta-1,3-di-ene to afford the corresponding adducts in moderate selec-tivities. The authors found a negligible background(<5%), with a slight preference (1.3:1) for the endo adductwhen the reaction was carried out in the only presence of20 mol% of trifluoromethanesulfonic acid.

Scheme 26

In a similar way to MacMillan’s catalyst 3, the proposedmechanism for catalyst 79 is based on the generation ofactive iminiun ion 80 (Scheme 27).63 This intermediatewould lower the energy of the dienophile LUMO, accel-erating the addition to diene 2. After the cycloaddition hastaken place, hydrolysis by water, present in the solvent or

Table 14 Reaction between Aldehydes 75 and 76 Catalyzed by 58

R1 Yield (%) ee (%)

Et 85 98

Me 82 94

i-Pr 90 99

Bn 78 99

n-Pent 92 99

BnO(CH2)2 82 96

PhS(CH2)2 63 95

O2N(CH2)2 79 95

Scheme 25

R1 O1

endo-4exo-4

+

CHOR1+

2

78

NH

R2

OH

R3

R3

78a78b78c

R2 = HR2 = MeR2 = H

R3 = PhR3 = PhR3 = 4-F3CC6H4

R1

CHO

Table 15 Organocatalytic Diels–Alder Reaction Catalyzed by 78

R1 Catalyst Time (h)

Yield (%)

Ratioexo (ee, %)/endo (ee, %)

Ph 78a·HClb 48 33 1.8 (37):1 (36)

Ph 78a·HClO4c 48 74 1.7 (57):1 (66)

Ph 78b·HClb 48 16 1.4 (38):1 (43)

Ph 78b·HClb 48 35d 1.4 (48):1 (51)

Ph 78c·HClb 48 35 1.5 (24):1 (28)

Me 78a·HClb 24 85 1 (22):1 (24)

Me 78a·HClO4c 24 88 1 (11):1.4 (10)

Me 78b·HClb 24 83 1 (25):1.6 (37)

Me 78b·HClb 18 88d 1 (35):1 (45)

a The reaction was carried out at 18 °C unless otherwise indicated.b As a preformed salt, using 95:5 MeOH–H2O as the reaction medium.c Prepared in situ, using H2O as the reaction medium.d Reaction performed at 30 °C.


R Yield (%) Ratio exo/endo ee (%) exo

Ph 96 1.9:1 90

4-O2NC6H4 93 2.2:1 92

4-ClC6H4 92 2:1 90a

4-i-PrC6H4 84 1.7:1 90a

2-O2NC6H4 86 – 85

3-O2NC6H4 71 1.9:1 69a

n-Pr 90 1.2:1 87

i-Pr 88 2.1:1 94a

a The endo isomer.

CF3SO3H (20 mol%)

H2O, 20 ºC

N

NH

OBn

79R O

1

endo-4exo-4

++

2

R

CHOR

CHO

(20 mol%)



supplied by the formation of 79 releases products 4 and re-generates the catalyst for the next cycle.

A suitable explanation for the observed diastereo- andenantioselectivity arose from theoretical calculationswhich showed 80a to be the lowest energy conformer.64

Approach of the diene 2 to the bottom face of that favorediminium ion would lead to the major stereoisomers in allcases (Scheme 28). According to this hypothesis, theenantioselectivity is a consequence of the position of thebenzyl side-chain of the catalyst that determines the pre-ferred orientation in compounds 80. Additional supportfor this rationale was obtained from X-ray crystal struc-ture analysis and additional experiments with catalystsbearing large side chains.64

Lee and co-workers have demonstrated that cyclic sulfo-nyl hydrazine 82 in the presence of 10 mol% of trichloro-acetic acid is also an efficient organocatalyst for thereaction, giving rise to good chemical yields and highenantioselectivities for both aliphatic and aromatic a,b-unsaturated aldehydes 1 (Scheme 29, Table 17).65

Scheme 29

The enantioselectivity of the endo products was slightlybetter than that of the exo products. To address the stere-ochemical course of this reaction, a molecular model ofthe transition state for the iminium ion formed between 82and 1 similar to those illustrated in Scheme 24 was pro-posed. In the case of compound 82 the N-ethyl group is re-sponsible for the favorable approach by the bottom face asin 80a.

In general, endo selectivity is considered to be an attributeof the Diels–Alder family of reactions. However, exo se-lectivity can be enabled readily by the deliberate modifi-cation of existing methodologies, especially with simplea,b-unsaturated aldehydes and ketones.66 In this context,Maruoka and co-workers have developed an importantexo-selective Diels–Alder reaction between 1 and 2 usingbinaphthyl-based diamine 83 as an organocatalyst, afford-ing unprecedented levels of exo selectivity in some cases.The reaction was carried out in trifluoromethylbenzeneand in the presence of 10 mol% of p-toluenesulfonic acid(Scheme 30, Table 18).67

Scheme 27

R O

R

N

NH

O

Ph

·TfOH

N

N

O

Ph

R

N

N

O

Ph

ROHC

79

1

80

2

81

4

H2O

H2O

Scheme 28

2N

N

OBn

Ph

80a

H

TfOPh

CHO

Ph

CHO

(1R,2R,3R,4S)-exo-4

(1S,2R,3R,4R)-endo-4

N

N

OBn

H

Ph

280b CHO

Ph

Ph

CHO

(1R,2S,3S,4S)-endo-4

(1S,2S,3S,4R)-exo-4

TfO



Me 6 92 1 (–):1.5 (83)

n-Pr 6 71 1 (66):1.3 (90)

Ph 12 92 1 (78):1.1 (93)

4-MeOC6H4 24a 82 1 (81):0.9 (91)

4-O2NC6H4 8 99 1 (81):1.1 (91)

2-O2NC6H4 24a 94 1 (72):2.5 (90)

4-ClC6H4 24 81 1 (84):1.1 (96)

4-BrC6H4 12 81 1 (86):1.1 (96)

a Reaction carried out at room temperature.

N

NHS

O OEt

CCl3CO2H (10 mol%)

brine, 0 °C

82

R O1

endo-4exo-4

++

2

R

CHOR

CHO

(20 mol%)



In most cases, under the appropriate reaction conditions,the corresponding cycloadducts 4 were obtained withgood to excellent exo enantioselectivity. Although the useof acrolein and 2-nitrocinnamaldehyde as dienophiles re-sulted in a significant decrease in diastereoselectivity, theexo cycloadducts were still dominant. Unfortunately,however, this reaction system was found to be suitableonly for a limited combination of a,b-unsaturated alde-hydes 1 with cyclopentadiene (2).

Scheme 30

On the basis of experimental details and the catalytic cy-cle previously proposed by MacMillan and co-workers forreactions with iminium intermediates,26 the authors68 pro-posed the mechanism illustrated in Scheme 31 for the exo-selective Diels–Alder reaction. This was recently the sub-ject of theoretical studies by Houk and co-workers, whoused DFT methods including single-point calculations atMP2/6-31G*//B3LYP6-31G* level.69

According to this mechanism, the free methylamino groupin the diamine·TfOH catalyst A would initially react withthe a,b-unsaturated aldehyde to form the iminium inter-mediate D in equilibrium with the protonated aminal E.The more reactive intermediate D would react with cyclo-pentadiene to give the exo adduct F under the influence ofthe sterically hindered binaphthyl moiety. The resulting

iminium intermediate F would finally be hydrolyzed togive the exo cycloadduct and regenerate the di-amine·TfOH catalyst A.

2.2 Chiral Primary Amines

In addition to the most intensively used chiral secondaryamines as organic catalysts, primary amines have recentlyemerged as a new and powerful sort of organocatalyststhat find application in a variety of reactions.70

The enantioselective organocatalytic Diels–Alder reac-tion of a-acyloxyacroleins – synthetic equivalents of theirritant and unstable a-haloacroleins71 – was developed byIshihara and Nakano.72 The reaction between 2,3-dimeth-ylbuta-1,3-diene (84) and a-(p-methoxybenzoyloxy)ac-rolein (85) catalyzed by triamine 86 in the presence of aBrønsted acid afforded the corresponding cycloadduct 87in quantitative yield and excellent enantioselectivity(Scheme 32). The generality and scope of the reaction il-lustrated in Scheme 32 were demonstrated by extendingthe process to other dienes, including cyclopentadiene,cyclohexadiene, 5-(benzyloxymethyl)cyclopentadieneand isoprene; enantiomeric excess values ranging from 74to 92% were obtained.

The same authors reported the use of BINAM 89 as a cat-alyst for the Diels–Alder reaction between cyclopentadi-ene (2) and a-(cyclohexylcarbonyloxy)acrolein (88)(Scheme 33).73 The reaction was carried out in the pres-ence of trifluoromethanesulfonimide and it was extendedto other dienes such as cyclohexadiene.



H 45 93 1.9 (86):1 (68)

Me 160 72 >20 (88):1 (–)

CO2Et 144a 90 5.5 (83):1 (56)

Ph 160 80 12.8 (92):1 (91)c

4-ClC6H4 96 99 7.8 (92):1 (96)

4-O2NC6H4 40 99 7.4 (95):1 (98)

3-O2NC6H4 144 98 1.3 (87):1 (81)

4-i-PrC6H4 144b 84 6.3 (82):1 (73)

a Reaction carried out at –60 °C in toluene as a solvent.b Reaction carried out at 0 °C.c The (2S,3S)-isomers were obtained.

pTsOH·H2O (10 mol%)

PhCF3, –20 °C

83

R O1

endo-4exo-4

++

2

R

CHOR

CHO

(12 mol%)

Ar

NHMe

NHMe

Ar

Ar = 4-t-BuC6H4

Scheme 31

NH

HN

HMe

Me

HO

R

N

HN H

Me

Me

OH

R

H

NH

Me

N Me

R

NH

Me

N Me

R

R

CHO

HN

NH

Me

Me

H

O

R

N

HN

Me

Me

R

H

TfO

TfO

H2O

TfO

TfO

TfO

A

B

C

D

E

F

TfO



According to an X-ray structural analysis of a-(cyclohex-ylcarbonyloxy)acrolein (88) and on the basis of the 1HNMR study, two transition states were proposed in orderto explain the enantioselectivity of the reaction(Figure 3).74

Figure 3

Whereas in the trifluoromethanesulfonimide-activatedTS-1 the diene should approach the Si face of the dieno-phile from the less hindered side to give the (2S)-exo ad-duct, in TS-2 both the aldimine and the acyloxy group areactivated by the ammonium protons although through aweak non-linear hydrogen bond that confers some insta-bility. Consequently, the former transition structureshould be more reactive than the latter and thus it is sug-gested that the reaction depicted in Scheme 29 proceedspreferentially via TS-1.

Triamine 86 has also been used in the Diels–Alder reac-tion of cyclic and acyclic dienes with a-(phthalimido)ac-rolein 91 providing cyclic a-quaternary a-amino acid

precursors 93. The combination of 86 with pentafluo-robenzenesulfonic acid provided good yields, very highendo selectivity and very good enantioselectivities(Scheme 34, Table 19).75

Scheme 34

The synthetic utility of the methodology outlined inScheme 34 was demonstrated by converting the corre-sponding major endo adduct of the cycloaddition with cy-clopentadiene into the a-amino ester 95 (Scheme 35), akey intermediate for the preparation of interesting com-pounds such as norbornane-2-amino-2-methanol deri-vatives76 and (–)-altemicidin.77

Chiral primary amines derived from natural cinchona al-kaloids have recently been reported to catalyze the forma-tion of highly substituted cyclohexanones throughorganocascade processes, consisting of a double Michaelsequence, that are complementary to the classical Diels–Alder reaction.78

Scheme 32

84 (10 mol%)

Bn NH2

NH

t-BuN

87

86

CHORO2C

85 R = 4-MeOC6H4

C6F5SO3H (27.5 mol%)

EtNO2, r.t., 8 h

CO2R

CHO

(quant., 90% ee)

Scheme 33

+

CHOO

88

(5 mol%)

H2O (10 mol%)EtCN, –75 °C

90

89

O

2O

CHO

O

NH2

NH2

exo/endo = 92:891% ee (1S,2S,4S)

Tf2NH (9.5 mol%)

NH

NO

O

H

HH

TS-1

N

NO H

HH

TS-2

O

Table 19 Cycloaddition between 79 and Dienes 80

Diene Time (h)

Yield (%)

Ratio endo/exo

ee (%) endo

48a 55 – 83

32 82 – 96

48 82 >99:1 94

48 80 >99:1 88

48 73 >99:1 94

48 89 >99:1 94

36 86 62:38 87

84a 52 – 67

a The reaction was carried out at room temperature.

CHON92

9174 (10 mol%)

C6F5SO3H (27.5 mol%) 93

RO

O

R

N(phth)

CHO

EtNO2, 0 °C

Ph



2.3 Cinchona Alkaloids

Cinchona alkaloids have been widely used in asymmetricorganic catalysis.79 Their utility in modern asymmetricsynthesis is well documented in numerous reports con-cerning a variety of organic processes,80 in particularthose related with asymmetric phase-transfer catalysis.81

One of the main advantages of cinchona alkaloids consistsof their abundance in Nature existing as pseudoenantio-meric pairs, as exemplified by quinine and quinidine,which gives access to either enantiomer of a given productof interest. The ready accessibility of cinchona alkaloidsalso promotes their use in the construction of more com-plex bifunctional organocatalysts, which have also beenused in a variety of organic reactions.82

In 1989, Riant and Kagan83 provided the first example ofa base-catalyzed asymmetric Diels–Alder reaction be-tween N-methylmaleimide (96) and anthrone (97) in thepresence of a catalytic amount of quinidine (98)(Scheme 36).

Scheme 36

On the basis of previous experimental results,84 the au-thors proposed a model of addition in which the hydroxygroup in 98 is necessary for achieving better enantioselec-tivities (Figure 4). According to this model, catalyst 98acts in a dual manner by activating maleimide 96 throughhydrogen-bonding and by forming an ionic pair with an-throne (97).

The Diels–Alder condensation between 3-hydroxy-2-py-rone (100) and N-benzylmaleimide (101) promoted bycatalyst 102 led to adduct 103, which was used to preparecompound 104 (Scheme 37),85 a key intermediate in thesynthesis of RPR 107880 (105),86 a P antagonist which

behaves as a neurotransmitter. The authors based theirwork on previous related research.87

In the Diels–Alder reaction of 2-pyrones 106 with a,b-un-saturated carbonyl derivatives 107 the 6¢-OH cinchona al-kaloid 108 afforded much better catalytic efficiency thandid natural cinchona alkaloids (Scheme 38, Table 20).88

The results illustrated in Scheme 38 were extended to

Scheme 35

NaOClO, NaH2PO4·H2Ot-BuOH–THF–H2Or.t., 90 min

TMSCHN2, MeOHtoluene, r.t., 10 min94 95H2NNH2, EtOH

NH2

CO2Me

N

CHO

O

O

1)

2)

3)

O

+

N Me

O

O

HO

N Me

O

O

N

OH

N

OMe

97

96 98 (10 mol%)

CHCl3, –50 °C

9997%, 61% ee

Figure 4

O

N Me

O

O

N

O

NH

OMe

H

Scheme 37

O

O

OH

+ NBn

O

O

100 101

O

OHBnN

O

O102 (30 mol%)

103

NBn

OHOMe

N

OHOMe

O

OMe

RPR 107880, 105104

CH2Cl2, 5 h

N

OH

N

OMe

R S

S

Scheme 38

O

HO

N

OR

N

OH

108 (5 mol%)

Et2O, r.t.O

OR4

OH

R1

O

R3

R2

107

106

exo-109

O

R4

R2

R3

R1

O

R =



simple a,b-unsaturated methyl ketones with excellentchemical yields and enantioselectivities.89

Very interestingly, the authors also demonstrated88 thepossibility of using bifunctional catalysts to control theendo/exo selectivity. Thus, the Diels–Alder condensationbetween 2-pyrone 100 and a-chloroacrylonitrile (110)was carried out in the presence of catalysts 108 and 111(Scheme 39). Whereas the former was found to be endoselective, the latter afforded preferentially the exo adduct.As a consequence of the opposite sense of chiral inductionexerted by quinine and quinidine-derived catalysts, selec-tive pathways to each of the four possible stereoisomersthat could be generated from 100 and 110 can be access-ed.88

Scheme 39

Bernardi, Ricci and co-workers have developed an inter-esting catalytic asymmetric Diels–Alder reaction between3-vinylindoles 114 and maleimides 115, furnishing a di-rect approach to optically active tetrahydrocarbazole de-

rivatives 117. The reaction was catalyzed by bifunctionalacid–base organocatalyst 116a (Scheme 40, Table 21).90

The quasi-enantiomeric catalyst 116b, derived from hyd-roquinidine, gave access to the enantiomeric products ent-117 with comparable results. The reaction was also car-ried out with quinones as dienophiles and excellent enan-tioselectivities (96–99% ee) were obtained.

Scheme 40

The dual interaction between the basic moiety of the cat-alyst and the N-H group of the diene, and the thioureafunctionality with the dienophile, were invoked as beingresponsible for the enhancement of the reactivity. Accord-ing to this hypothesis, the authors proposed the model de-picted in Figure 5 to explain the observedenantioselectivity. A similar model can be proposed forthe cycloaddition between 114 and quinones. The modelillustrated in Figure 5 is also in complete agreement withthe inversion observed with catalyst 116b.

Table 20 Reaction between 2-Pyrones 106 and Compounds 107

R1 R2 R3 R4 Yield (%)

Ratio exo/endo

ee (%)

Ph H CO2Et H 87 93:7 94

4-BrC6H4 H CO2Et H 91 91:9 91

Ph H COPh H 100 93:7 90

Me Me H H 65 24:76 91

Ph H CO2Et Ph 84 95:5 85

Ph H CO2Et Me 87 88:12 82

Ph H CO2Et Cl 77 86:14 84

Ph H CO2Et Br 75 85:15 83

a The reaction was carried out in EtOAc as a solvent.

O

O

OH

100

O

OH

113

O

CN

Cl

Cl

CN

110

O

OH

O

Cl

NC

112

85% ee

87:13 dr

85% ee

91:9 dr

108(5 mol%)

Et2O

(90%)

111(5 mol%)

THF

(90%)

N

MeO

NH

S

NH

Ar

N

H

Ar = 3,4-(F3C)2C6H3

111

Table 21 Organocatalytic Diels–Alder Reaction Catalyzed by 116a

R1 R2 R3 R4 Yield (%) ee (%)

H H H Ph 91 98

Br H H Ph 86 90

MeO H H Ph 77 96

H Me H Ph 79 96

H H Me Ph 58 92

H H H Me 89 98

H H H Bn 89 96

H H H t-Bu 81 88

H H H H 72 52

NH

R1

+

N

O

O

R4

114

115

116a (20 mol%)CH2Cl2, –55 °C, 48 h

2) TFAA

endo/exo > 95:5

NN

O

O

H

H

F3CO

R1

117

H

N

MeO

NH

S

NH

ArN

H

N

MeO

NH

S

NH

Ar

N

H

116a 116b

1)

Ar = 3,4-(F3C)2C6H3

R2R3

R4

R2 R3



Figure 5

Lectka and co-workers reported91 the organocatalyticDiels–Alder reaction between ketene enolates generatedin situ from the corresponding acyl chlorides and o-qui-nones. The reaction was catalyzed by benzoylquinidine120 and excellent enantioselectivities were obtained wheno-chloranil (118) was used as a substrate (Scheme 41,Table 22). The reaction was extended to other quinones,but lower enantioselectivities were obtained. The samecatalytic system was applied to the cycloaddition of theketene enolates with o-benzoquinone imides92 and o-ben-zoquinone diimides,93 affording the corresponding 1,4-benzoxazinones and quinoxalinones, respectively, in ex-cellent enantioselectivities.

Similarly, the formal Diels–Alder cycloaddition betweeno-quinone methides 123 and silyl ketene acetals 122 wasinitiated by the chiral cinchona alkaloid derived ammoni-um fluoride precatalyst 124 (Scheme 42, Table 23).

Scheme 42

Actually, the reaction consists of a two-step process start-ing with a Michael-type addition of the ketene acetalformed in situ by the action of the precatalyst, to the exo-cyclic double bond. In a second step, a, intramolecular nu-cleophilic attack to the carbonyl group forms the final 3,4-dihydrocoumarin derivatives 125. Such a stepwise mech-anism resembles that recently demonstrated for polarDiels–Alder reactions.5a

2.4 Heterocyclic Carbenes

Carbon–carbon bond-forming processes mediated by N-heterocyclic carbene (NHC) organocatalysts have wit-nessed recent and impressive progress in the discovery ofnew reaction manifolds and the development of asymmet-ric processes.94 They act as excellent organic catalysts ina variety of reactions including enantioselective intermo-lecular homodimerization of aryl aldehydes,95 intramolec-ular aldehyde–ketone benzoin cyclizations96 and theStetter reaction,97 among others.

Bode and co-workers reported98 the first Diels–Alder re-action catalyzed by heterocyclic carbenes between enones126 and aza-dienes 127. The catalyst was generated in situfrom 128 and Hünig’s base (Scheme 43, Table 24). Underthe optimized conditions, the process tolerated a broadrange of aza-dienes 127, including those bearing electron-rich and electron-deficient substituents. Heterocyclic and

N

R1

N

O

OR3

N

OMe

N

S

N

CF3

CF3N

H

H

H H

Scheme 41

O

Cl

118

N

OCOPh

N

OMe

O

Cl

119

R

O

Cl

Cl

Cl

120 (10 mol%)

DIPEA

THF, –78 °C Cl

Cl

Cl

Cl O

O

R

O

121

Table 22 Organocatalytic Diels–Alder Reaction of o-Chloranil (118) and Ketene Acetals Catalyzed by Benzoylquinidine 120

R1 Yield (%) ee (%)

Et 91 99

i-Pr 75 93

Ph 90 90

Bn 72 99

4-MeOC6H4 58 99

4-MeC6H4 75 93

Table 23 Condensation between 122 and 123 Catalyzed by 124

R1 Yield (%) dr ee (%)

Me 85 7.5:1 72

Et 87 15.4:1 80

i-Pr 88 10.2:1 79

i-Bu 91 11.3:1 81

ClCH2CH2 88 15.2:1 90

MeSCH2 84 9.5:1 85

Bn 86 13.7:1 80

122

N

OH

N

OMe

123

124 (10 mol%)

THF, –78 °C

O

R

O

125

NO2

F

O

O

O

PMP

O

O

PMP

R

OTMSNpO

Np = 2-naphthyl

PMP = 4-MeOC6H4



aliphatic substrates can also be employed. The yieldsranged from moderate to high and the enantiomeric excessvalues observed were close to >99% in all cases. Variationin the enal reactant 126 was also possible, affording thedesired product with the same good results.

Scheme 43

To explain the exceptional and high diastereo- and enan-tioselectivities, the authors postulated the stereochemicalmodel depicted in Figure 6 where the high preference foran endo transition state in the NHC-catalyzed systemwould be reinforced by the presence of the bulky triazoli-um moiety in the active dienophile.

Supported by the experimental data and previous investi-gations into NHC-catalyzed transformations, the catalyticcycle shown in Scheme 44 was postulated.

Scheme 44

The methodology was extended99 to a-halo aldehydes 135acting as 1-oxodienes100 in order to prepare cycloadducts137 through a hetero-Diels–Alder reaction (Scheme 45,Table 25). The NHC was generated in situ from 129 bythe action of triethylamine and only 0.5 mol% was neededto achieve excellent results.

Scheme 45

A range of aromatic and aliphatic enones was employed,as was a variety of a-chloro aldehydes; in all cases the de-sired product was obtained in good yield and excellentenantioselectivity. The high cis diastereoselectivities ob-served were postulated to arise from the stereoselectiveformation of a (Z)-enolate in the redox reaction of enals inconjunction with a high preference for an endo cycloaddi-tion as depicted in Figure 6.

Table 24 Organocatalytic Diels–Alder Reaction Catalyzed by Carbene Derived from 129

R1 R2 Yield (%) ee (%)

EtO Ph 90 99 (S,S)

EtO Ph 90 99 (R,R)a

EtO 4-MeOC6H4 81 99 (S,S)

EtO 4-MeCOC6H4 55 99 (S,S)

EtO 2-furyl 71 99 (S,S)

EtO n-Pr 58 99 (S,S)

t-BuO Ph 70 97 (S,S)

Me Ph 51 99 (S,S)

Me n-Pr 71 98 (S,S)

Ph 4-MeOC6H4 52 99 (S,S)

a Reaction carried out with 10 mol% of ent-129.

H

O

R1

O

+

H

N

R2

ArO2SN

O

R2

R1O

ArO2S126

127

130

129 (10 mol%)

DIPEA (10 mol%)toluene–THF (10:1), r.t.

O

N

NN

Mes

Cl

Mes = mesityl

Figure 6

ON

N NAr

–O

H

R2

NSOO

PMP

H N

Ph

SO2Ar

N

O

Ph

SO2Ar

126

N

NN

Mes

131

NN

N

MesOH

NN

N

MesOH

EtO2C

NN

N

MesOH

homoenolate H+ transfer

128

EtO2C

N

NN

ArO2S

N

Ph

SO2Ar

O

EtO2C EtO2C

132a 132b

133

134

130

CHO

EtO2C

EtO2C

H

O

Cl

R1

+

R2

O

CO2Me

O

O

R1

CO2MeR2

135

136

129 (0.5 mol%)Et3N (1.5 equiv)

137

EtOAc 0.2 M, r.t.



2.5 Chiral Guanidines

Although the potential of chiral guanidines in organicsynthesis101 and as organocatalytic Brønsted bases hasbeen demonstrated in several reactions, including theStrecker reaction,102 the Henry reaction,103 epoxida-tions,104 and conjugate addition reactions,105 their use incycloaddition reactions has been scarcely explored.

Tan and co-workers utilized chiral bicyclic guanidine 139for promoting the Diels–Alder reaction between an-thrones 138 and N-substituted maleimides 115(Scheme 46, Table 26).106

Compound 139 was found to be an excellent catalyst for arange of both anthrones and maleimides, furnishing cy-cloadducts 140 in very good yields and high enantioselec-

tivities. The reaction was also extended to N-hydroxyphthalimides,107 thus leading to the correspond-ing cycloadducts which were easily converted into the N-hydroxy derivatives, as exemplified in Scheme 47 forcompound 141. These sorts of compounds have been rec-ognized as valuable catalysts for the aerobic oxidation oforganic compounds under mild conditions.108

Scheme 47

3 Hydrogen-Bond-Catalyzed Diels–Alder Reactions

In recent years, small organic molecules capable of form-ing hydrogen-bond interactions have become a useful toolin asymmetric organocatalysis. Examples of this sort ofmolecule are chiral thioureas, amidinium ions and di-

Table 25 Organocatalytic Hetero-Diels–Alder Reaction Catalyzed by Carbene Derived from 129

R1 R2 Yield (%) Ratio cis/trans ee (%)

Ph Ph 88 >20:1 99 (S,S)

Ph Ph 91 8:1 99 (R,R)

Ph 4-BrC6H4 98 15:1 99 (S,S)

Ph 4-BrC6H4 80 6:1 99 (S,S)

Ph c-hexyl 76 >20:1 86 (S,S)

Ph 2-furyl 94 8:1 99 (S,S)

n-C9H19 Me 71 >20:1 99 (S,S)

n-C9H19 Ph 90 >20:1 99 (S,S)

TBSO Ph 80 3:1 97 (R,S)

Ph 4-MeC6H4 74 >99:1 97 (S,S)

Ph n-Pr 84 >99:1 98 (S,S)

Ph c-hexyl 85 >99:1 95 (S,S)

n-C9H19 4-MeC6H4 70 >99:1 99 (S,S)

TBSO 4-MeC6H4 83 >99:1 95 (S,S)

a 24 mmol scale, 2 h.b 2 mol% of 129.

Scheme 46

O

+

N

R5

OO

138

115

139 (10 mol%)

CH2Cl2 –20 °C, 4–8 h

140

R1

R3

R2

R4

N

N

HN

Bn

Bn

N

O

O

R1

R3

R2

R4

R5

OH

Table 26 Organocatalytic Diels–Alder Reaction Catalyzed by Bicyclic Guanidine 139

R1 R2 R3 R4 R5 Yield (%) ee (%)

H H H H 2-O2NC6H4 87 98

H H H H 2,5-Cl2C6H3 88 95

Cl Cl H H Bn 92 95

Cl Cl H H c-hexyl 88 98

Cl Cl H H t-Bu 87 93

Cl Cl H H t-Bu 92 91

Cl Cl H H 4-ClC6H4CH2 85 98a

H H Cl Cl Ph 92 99

H H Cl Cl 2,6-F2C6H3 92 99

H H Cl Cl 2-MeOC6H4 90 98

H Cl Cl H Ph 87 99

H Cl Cl H 2,4,6-Me3C6H2 85 99

H H MeNH H Et 95 98

H H MeNH H c-hexyl 96 85

Cl Cl H H MeCO2 86 92

Cl Cl H H PhCO2 85 12

H H Cl Cl MeCO2 83 64

H H Cl Cl PhCO2 84 87

a Reaction performed at –40 °C.

141

NO

O

ClCl

O

OEtNH2

142

NO

O

ClCl

OH

MeOH

(92%)

OH OH



ols.109 In addition, chiral Brønsted acids have been fre-quently utilized in asymmetric catalysis and their use hasbecome a rapidly growing area of interest within the fieldof organocatalysis.110 In particular, after the first concur-rent reports by Akiyama et al.111 and Uraguchi andTerada,112 chiral phosphoric acids have emerged as a pow-erful class of organic catalysts for the activation of imineand related functional groups towards a number of asym-metric additions of various nucleophiles.113

Gong and co-workers developed114 the first chiral Brønstedacid catalyzed asymmetric direct aza-hetero-Diels–Alder115 reaction between cyclohexenone 143 and imines144 generated in situ from the corresponding aldehydesand 4-methoxyphenylamine (Scheme 48). Chiral phos-phoric acid 145 promoted the reaction for a range of dif-ferentially substituted aromatic aldimines in high yields.In all cases good diastereomeric ratios were obtained,with the endo isomer being obtained predominantly. Goodenantioselectivities were also achieved (Table 27).

Scheme 48

In order to explain the observed reactivity, the authors hy-pothesized the activation of the imine through protonationand reaction of the resulting reactive intermediate with theenolized enone (Scheme 49).

Scheme 49

Concurrently, Akiyama and co-workers reported116 thechiral Brønsted acid catalyzed aza-Diels–Alder reactionof aldimines 148 with Brassard’s diene117 (149) to affordpiperidinone derivatives 151 in high yields and with ex-cellent enantioselectivities (Scheme 50). Under the opti-mized reaction conditions, a broad range of aldiminesderived from aromatic and heteroaromatic aldehydes un-derwent the aza-Diels–Alder reaction to afford the cy-clization products with excellent enantioselectivities andmoderate to high yields (Table 28). Aliphatic aldimines,which were generated in situ, also gave the correspondingcycloadducts with excellent enantiomeric excess valuesbut with moderate yields.

Scheme 50

The synthetic utility and applicability of catalyst 150 wasdemonstrated by performing the reaction depicted inScheme 42 on a one-gram scale. The corresponding cy-cloadduct (R = Ph) was obtained in 95% chemical yieldand 94% ee.

The authors postulated that the presence of the hydroxygroup on the N-aryl moiety was essential for achievinghigh enantioselectivity, as it was demonstrated that bycarrying out the reaction with an imine that had no suchgroup, a low enantioselectivity was observed.

On the basis of this data it was assumed that the processproceeded via a nine-membered cyclic transition state(Figure 7),118 in which the phosphoryl oxygen atom formsa hydrogen bond with the hydrogen atom of the hydroxygroup. Under these conditions the nucleophile shouldpreferentially attack the less-hindered Re face of the ald-imine.

Table 27 Organocatalytic Aza-Diels–Alder Reaction Catalyzed by Phosphoric Acid 145

R Yield (%) Ratio endo/exo ee (%)

Ph 76 84:16 87

3-ClC6H4 74 81:19 83

4-ClC6H4 82 82:18 85

2-ClC6H4 73 81:19 77

4-FC6H4 72 80:20 85

3-FC6H4 76 82:18 84

4-BrC6H4 81 82:18 85

3-BrC6H4 79 81:19 87

4-MeC6H4 81 83:17 83

4-NCC6H4 70 83:17 76

O

+

143

144

145 (5 mol%)

toluene, 20 °CNPMP

H R

N

N

O

O

H

R

R

H

PMP

PMP

endo-146

exo-147

+

Ar

Ar

O

P

OO

OH

Ar = 4-ClC6H4

OH

H+

NHR2

H R1

N

HO H

R1

R2H

N

HO R1

H

R2H

H+

endo-146

exo-147

O

NR2

H R1

+

148

149

150 (3 mol%)mesitylene, –40 °CN

Ar1

HR

Ar2

Ar2

O

P

OO

OOTMS

OMeOMe

N

O

OMeR

Ar1

151Ar2 = 9-anthryl

HN

PhCO2H (1 equiv)

Ar1 = 2-HO-5-MeC6H3



By using Danishefsky’s diene (152) and catalyst 153,functionalized piperidones 154, precursors of importantbiologically active compounds (alkaloids, iminosugars,etc.), were prepared (Scheme 51, Table 29).116

Göbel and co-workers reported119 that chiral amidiniumion 157 promoted the cycloaddition reaction between di-ene 155 and cyclopentene-1,2-dione 156, leading to a3.2:1 mixture of compounds 158 and 159.120 Despite thereaction being conducted in the presence of stoichiometricamounts of 157, only moderate enantioselectivities wereobtained (Scheme 52).

TADDOL derivative 161 was reported to catalyze theHDA reaction between aminodiene 160 and aldehydes 37(Scheme 53).121 The reaction took place with moderate to


R Yield (%) ee (%)

Ph 87 94

4-BrC6H4 86 96

4-ClC6H4 90 97

4-FC6H4 76 98

4-MeC6H4 90 95

4-MeOC6H4 84 99

2-BrC6H4 83 98

2-ClC6H4 86 98

4-MeC6H4 76 96

1-naphthyl 79 98

2-naphthyl 91 97

2-furyl 63 97

PhCH=CH 76 98

c-hexyl 69 99

i-Pr 65 93

Figure 7

Ar

Ar

O

PO O

ON

HR

O

Me

H

H

Re attack

Scheme 51

+

149

NAr1

HR

Ar2

Ar2

O

P

OO

OH

Ar2 = 2,4,6,-(i-Pr)3C6H2

Ar1 = 2-HO-5-MeC6H3

152 153 (5 mol%)CH3CO2H (1.2 equiv)

N

O

toluene, –78 °C

OMe

OTMS

R

Ar1

154


R Time (h) Yield (%) ee (%)

Ph 18 99 80

4-IC6H4 24 86 84

4-BrC6H4 13 100 84

4-ClC6H4 35 72 84

4-FC6H4 13 77 78

4-F3CC6H4 21 82 81

2-BrC6H4 10 96 80

2-ClC6H4 12 100 76

1-naphthyl 12 100 91

Scheme 52

MeO

O

OEt

MeO

O

OH

Et

H

MeO

OH

H

Et O

MeO

O

OHH

Et

H

MeO

OHH

H

Et O

155

156

157 (1 equiv)

158a 159a

158b 159b

Ar

O

NHH

NH2

CH2Cl2, –27 °C

158/159 = 3.2:143% ee 50% ee

(94%)

Ar = 2,5-(HO)2C6H3

MeCN–H2O



good chemical yields and high enantiomeric ratios(Table 30).122 The main factor governing this reaction ap-pears to be a single hydrogen-bond activation of the car-bonyl group enhanced by intramolecular hydrogen-bonding interactions of the catalyst (Figure 8).

Scheme 53

Figure 8

Computational investigations of the mode of activation byTADDOL in this asymmetric reaction confirmed thatsuch a cooperative catalysis is favored.123 These resultswere improved by using catalyst 164, which led to theenantiomeric adducts ent-163 in high yield and enantiose-lectivity (Scheme 54, Table 31).124

Scheme 54

An X-ray structural analysis carried out on an inclusioncomplex of 2,2¢-bis(diphenylhydroxymethyl)binaphthyl-ene and benzaldehyde revealed the presence of an in-tramolecular hydrogen bond between the two hydroxygroups and an intermolecular hydrogen bond to the carbo-nyl oxygen of benzaldehyde, as represented and proposedearlier in Figure 8.

4 Concluding Remarks

The Diels–Alder reaction has been growing in importancein organic synthesis since its discovery. The numeroussynthetic applications of the Diels–Alder adducts andtheir derivatives for the generation of highly functional-ized cyclic compounds, in addition to a variety of other

Table 30 Organocatalytic Diels–Alder Reaction Catalyzed by TADDOL 162

R Yield (%) er (%)

Ph 70 >99:1

4-MeOC6H4 68 97:3

1-naphthyl 69 >99:1

2-naphthyl 97 97:3

4-F3CC6H4 68 97:3

2-furyl 67 96:4

c-hexyl 64 93:7

PhCH=CH 52 97:3

TBSO

NMeMe R

O

H

O

O OH

OH

Ar Ar

ArAr

Ar = 1-naphthyl

O

TBSO R

NMe Me

O

O R AcCltoluene–CH2Cl2

–78 °C, 15 min

160 37

161 (10 mol%)

toluene

162

163

O O

OO

ArArAr

Ar

HH

R1

O

R2

Table 31 Organocatalytic Diels–Alder Reaction Catalyzed by Diol 164

R Yield (%) ee (%)

Me 75 97

n-Pr 76 94

Ph(CH2)2 95 95

PhS(CH2)2 76 94

Phth(CH2)3 67 92

1-propynyl 42 98

i-Bu 79 90

c-hexyl 99 84

Ph 84 98

3-MeOC6H4 86 98

2-O2NC6H4 93 98

1-naphthyl 67 97

2-furyl 96 99

O

O R

–40 or –80 °C, 1 or 2 d

ent-163

then AcCl, CH2Cl2–toluene–78 °C, 30 min

Ar

OHAr

OH

ArAr

Ar = 4-F-3,5-Me2C6H2

TBSO

NMe Me R

O

H

160 37

164 (20 mol%)

toluene



products, clearly establish this reaction as a standard in thearsenal of synthetic methodologies. Increasing concern inthe chemical community about efficient organocatalysishas diverted attention towards the fascinating use of smallorganic molecules for promoting highly selective Diels–Alder reactions. In addition to prolines, imidazolidinonesand other pyrrolidine-derived reagents capable of promot-ing the reaction through enamine catalysis, chiral basesincluding N-heterocyclic carbenes and chiral guanidineshave also been utilized in combination with aldehydes andimines to promote inverse-demand hetero-Diels–Alder re-actions. Hydrogen-bond activation is also possible with avariety of reagents such as chiral Brønsted acids and diols.Because of the ready access to those small organic mole-cules, the mild reactions, the easy work-up and the excel-lent yields and selectivities observed, organocatalyzedDiels–Alder reactions can now be considered to be eco-friendly, simple and efficient processes to be taken intoaccount in many synthetic problems.

Acknowledgment

We thank the Ministry of Science and Education (MEC, Madrid,Spain; Projects CTQ2007-67532-C02-01 and CTQ2009-09028),the Government of Aragón (Zaragoza, Spain; Project PI064/09 andConsolidated Groups, ref. E-10) and Spanish Council of Research(CSIC; Project PIE 200880I260) for financial support of ourresearch. E.M.-L. thanks the Alexander von Humboldt Foundationfor a postdoctoral fellowship. R.P.H. thanks ARAI+D Foundationfor a permanent position.

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