University of Groningen

Catalytic enantioselective conjugate addition of organometallic reagentsde Vries, Andreas Hendrikus Maria

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1

Chapter 1

Introduction

1.1 Routes to enantiomerically pure compounds

The synthesis of optically active compounds is a subject that has fascinated chemistsfor more than a century. Since the pioneering work of Pasteur, van 't Hoff and Le Bell,1

the area of stereochemistry began to evolve into the major field of research that it isnowadays. In recent years, the synthesis and isolation of enantiomerically pure2

compounds has gained new impetus, due to the realization that a chiral compoundinteracts with enantiomers in different ways as a result of a diastereomericrelationship. A well known example of the dramatic difference in activity of3

enantiomers is thalidomide, commercially known as Softenon. Only one enantiomergives the desired therapeutic effect, whereas the other enantiomer causes severe fetaldamage. The search for efficient syntheses of enantiomerically pure compounds is4

going on, largely stimulated by the requirements for new bioactive materials.In general there are three main routes to obtain pure enantiomers (Scheme 1.1):5

- resolution of a racemic mixture- synthesis with compounds from the chirality pool- asymmetric synthesisAlthough significant advances in other routes to obtain enantiomerically purecompounds have been reported, the 'classical' resolution of racemates bydiastereomeric crystallisation still constitutes the most important method in industry. 6

However, the maximum theoretical yield of one enantiomer is 50%, unless theunwanted enantiomer can be recycled. In a kinetic resolution the two enantiomers ofa racemic mixture react at different rates with a chiral entity, preferably used incatalytic amounts. Excellent kinetic resolutions have been reported by employing7

enzymes.8

Naturally occurring chiral compounds (referred to as the chirality pool) can be used asstarting materials for enantiomerically pure compounds or may be employed as9

enantioselective agents (catalysts or ligands) in organic synthesis. The lack of10

availability of both enantiomers of most natural compounds often is a limiting factor.Therefore many desired enantiomers have to obtained by synthesis.In the early days, synthesis to enantiomerically pure compounds from prochiralprecursors was considered possible only by using biochemical methods. Althoughpowerful, those methods using enzymes, cell cultures, or (living) microorganisms are11

in most cases substrate specific. Organic synthesis, on the other hand, has revealed12

Racemates

Synthesis

Chirality Pool

Enzymatic Chemical

Diastereomercrystallisation

Kineticresolution

Enantiomerically pure compound

Biocatalysis

Asymmetricsynthesis

ProchiralSubstrates

Catalysis

Chapter 1

2

a variety of versatile stereoselective reactions that complement biological processes. 13

Optically active compounds can be obtained using either a stoichiometric or a catalyticamount of chiral auxiliary. All stereoselective syntheses are based on the principle thatthe products are formed via diastereomeric transition states that differ in Gibbs freeenergy of activation. If this energy difference is sufficient ($ 3 kcal/mol, RT) oneenantiomer will be formed, preferentially.

Scheme 1.1 Routes to enantiomerically pure compounds.

Asymmetric catalysis is the most promising and attractive form of stereoselectivesynthesis, since a small amount of enantiomerically pure material produces largequantities of enantiomerically enriched, or in the ideal situation, enantiomerically purematerial. A wide variety of highly successful reactions with enantiomeric excesses(e.e.'s) > 95% have been reported. In most cases chiral transition metal complexes,14

often prepared in situ, are employed as the catalysts. The reactions involved are15

generally asymmetric reduction, asymmetric oxidation and asymmetric carbon-carbonbond formation. Especially the last category has a tremendous synthetic utility and inthe next Section selected examples of successful catalytic asymmetric carbon-carbonbond formations will be highlighted. For other supplementary information concerningchirality and (catalytic) asymmetric synthesis, the interested reader is referred to thereferences throughout this Chapter and to five of the six last Ph.D. theses from theOrganic Department of this University.16

(S)-1.1Cl3C

Cl3C COOEt+ N2CHCOOEt

NCu

OO

RR

2 (S)-1.1

R =

C8H17O

t-Bu cis / trans = 85/15e.e. (cis) 91%

Introduction

3

1.2 Catalytic asymmetric carbon-carbon bond formations:selected examples

Asymmetric cyclopropanationAn early example of metal-based homogeneous asymmetric catalysis dates from 1966.It involves an asymmetric cyclopropanation catalysed by a complex of copper (II) anda chiral Schiff base derived from salicylaldehyde and "-phenylethylamine. Although17

enantiomeric excesses were low, the principle was elaborated by Aratani and co-workers and has led to high enantioselectivities in selected cyclopropanationreactions. An example is given in Scheme 1.2.18

Scheme 1.2

Recent advances in the development of catalysts for enantioselective intra- andintermolecular cyclopropanation reactions were achieved with dinuclear rhodium (II)complexes of chiral pyrrolidone or oxazolidinone ligands and copper complexes19

derived from a chiral C -symmetric semicorrin ligand 1.2 or structurally related220

bis(oxazoline) ligands, for example 1.3. Some results obtained with these copper21

catalysts in the cyclopropanation of styrene with ethyl diazoacetate are compiled inScheme 1.3. The mechanism of these highly selective reactions presumably involvesa cycloaddition of a metal-carbenoid species to the olefin.18,19

1.31.2

+Ph COOEt

N2CHCOOEt+PhPh COOEt

CuII

1.2 or 1.3

N N

O O

t-Bu t-Bu

NH

N

CN

OH HO99%73 / 27

85%75 / 25

1.3

1.2

trans / cis e.e. (trans)

Chapter 1

4

Scheme 1.3

Asymmetric Diels-Alder reactionsThe Diels-Alder reaction is a classical reaction in organic synthesis and especially thevery recent progress in the design of chiral Lewis acids has led to the development ofeffective catalysts for asymmetric Diels-Alder reactions. Most efforts were focussed16e

on the use of boron, aluminium, and titanium as the Lewis acidic center, however,successful catalysis was alo achieved with catalysts based on copper and lanthanides.22

Since Knol has recently reported extensively on this subject, only two examples are16e

shown in Scheme 1.4.

1.5

Ph NHSO2CF3

NHSO2CF3Ph

e.e. 96%

e.e. 99%

1.4

OO

O

OB -H+

1.4CHO

+O

H

H

BnO

NO

O

OOBnON

O O+

1.5AlMe3

1) chiral cat.2) H3O

+/ H2O Ph

OHEt2Zn+

Ph H

O(1.1)

Introduction

5

Scheme 1.4 The Brøndsted acid-assisted chiral Lewis acid 1.4 as chiral catalyst fora D-A reaction of ",$-enals with cyclopentadiene and the aluminium /22c

chiral bis-sulfonamide 1.5 catalysed Diels-Alder reaction of a bidentatedienophile and a substituted cyclopentadiene. 22e

Asymmetric 1,2-additionThe addition of carbon-nucleophiles to aldehydes (or other carbonyl compounds) togive secondary alcohols is one of the basic reactions of organic synthesis. Asymmetricvariations of this reaction have been developed by addition of dialkylzinc reagents toaldehydes in presence of catalytic amounts of chiral amino alcohols or cinchona23

alkaloid bases (Eq. 1.1). At present, the 1,2-addition of (functionalised) dialkylzinc15

reagents to aldehydes is one of the most studied catalytic asymmetric transformations,in particular to examine whether a novel chiral ligand is capable of asymmetricinduction.24

Analogous catalytic enantioselective 1,2-additions to carbonyl compounds wereachieved with silyl enol ethers and allyl silanes and allyl stannanes, furnishing chiral25 26

e.e. 80 - 98%

1.6

OO

TiCl2

dr. 73 / 27 - 99 / 1e.e. 77 - 99%

R2 COOR

OH

R1

OR'Me2Si

1.6R2

OSiMe2R'

R1

+H COOR

O

Bu3SnR H

O+ 1.6

R

OH

Chapter 1

6

alcohols with possibilities to extend the carbon framework. A breakthrough in this areawas achieved with chiral titanium complex 1.6 and examples of highly enantioselectivealdol and allyl transfer reactions catalysed by 1.6 are shown in Scheme 1.5.27 28

Scheme 1.5 Enantioselective aldol and allyl transfer reactions.

Very recently, highly enantioselective allylations of a wide variety of non-enolisablealdehydes (aromatic and unsaturated) with allyltributyltin using catalytic amounts ofBINAP and AgOTf have been reported (e.e. > 88%).26, 29

Optically active cyanohydrins have been recognized to be versatile compounds sincethey can be easily converted to a variety of chiral molecules. Therefore, much effort hasbeen focussed on asymmetric cyanohydrin syntheses using enzymes, chiral cyclic30

dipeptides, chiral Lewis acids, and chiral Schiff bases of dipeptides. Promising31 32 33

results were achieved with cyclic dipeptide 1.7 and Schiff base 1.8 in the presence31 33

of Ti(Oi-Pr) as catalyst in the addition of hydrogen cyanide to several aromatic and4

aliphatic aldehydes (Scheme 1.6).34

R = aromatic, aliphatic e.e. 50 - 97%

1.8

N

OH

N COOMeR1

O R2

H

1.7

HNNH

O

O

N

NH

R H

O+ HCN

R CN

OHH

Ti(Oi-Pr)4

1.7 or 1.8

R = Me, n-Bu, vinyl e.e. 79 - 91%

(1.2)N RLi+ 1.3

R

NHH

Introduction

7

Scheme 1.6

Compared to the addition to carbonyl compounds, successful examples of asymmetricaddition of carbon nucleophiles to imines has been reported only scarcely. Twocontributions need to be emphasised. Nucleophilic additions of organolithium reagentsto N-arylimines are promoted by C -symmetric bis(oxazoline) ligands (for example 1.3)2

with high asymmetric induction and decreasing the ligand loading to 20 mol% retainsmost of the ceiling e.e.'s (Eq. 1.2).35

Another very recent communication illustrates an effective catalytic Strecker synthesis.Employing cyclic dipeptide 1.9 as catalyst, the conversion of aldehydes to amino acidsprecursors occurs in high yield and in some cases exceptionally high e.e.'s (Scheme1.7). The basic guanidine side chain, accelerating proton transfer in the Strecker36

synthesis, was essential for asymmetric induction since the structural resembling cyclicdipeptide 1.7 failed to afford any enantioselectivity.

R = benzyl

1.9

HNNH

O

O

N

NH

NH2H

e.e. 80 - 99%

+ HCN 1.9

NR

X

NR

CN

H

X

Chapter 1

8

Scheme 1.7

Asymmetric allylic alkylationThe earliest examples of palladium catalysed enantioselective allylic alkylationscreating a stereogenic center at the allylic or homoallylic position, were achieved37 38

employing chiral phosphine ligand 1.10 (DIOP) (e.e. 22-46%). Although enantiomericexcesses were low to moderate, this principle had lead to the synthesis of a wide varietyof bisphosphines and to successful application in the allylic alkylation to acyclicsubstrates (e.e. 30-90%).39

Recent advances in the catalytic enantioselective allylic alkylation of the model acyclicsubstrate (R' = phenyl) have been achieved using C -symmetric ligands, such as chiral2

semicorrin 1.2 and bis(oxazoline) 1.3, with enantioselectivities up to 97% (Scheme1.8). Ligand 1.11 (Ar and Ar = Ph; R = i-Pr or Ph), representing a new class of40

1 2 1

ligands, showed record enantioselectivities not only for the substitution of the modelacyclic subtrate (e.e. up to 99%), but for the first time also with 1,3-dialkyl-2-propenyl41

acetates (R' = alkyl).41a

1.11

O

NR1

P Ar1

Ar2

e.e. 22 - 99%

1.10

O

O PPh2

PPh2

H

H

R' R'

C(CO2R)2Hchiral ligand

[Pd(C3H5)Cl]2BSA, KOAc

R' R'

OAcH2C(CO2R)2+

Nu

Pd

ON P

PhPh

Introduction

9

Scheme 1.8

X-Ray structures of the allylic chiral palladium complexes and mechanistic studies ofthis asymmetric allylic substititution have been reported. Attack of the nucleophile42

must occur trans to the Pd-P bond, shown in Figure 1.1, furnishing the observedenantiomer.Furthermore, when ligand 1.11, with a stereogenic phosphorus center (Ar … Ar ), were1 2

employed as catalyst, cycloalkenyl acetates could for the first time be alkylated withrelatively high enantioselectivities (up to 85%).43

Figure 1.1

Chapter 1

# Throughout this thesis a distinction have been made between the conjugate addition reaction of organiccompounds, for instance diethyl malonate (Michael addition) and the conjugate addition reaction oforganometallic reagents (1,4-addition).

10

1.3 Aims of this thesis and survey of its contents

As outlined in the last Section, several examples are known of catalytic asymmetriccarbon-carbon bond formations for a wide variety of substrates, furnishing valuableproducts in high yields and with excellent enantioselectivities. However, the carbon-carbon bond formation by conjugate addition of carbon nucleophiles to ",$-unsaturatedcompounds (1,4-addition), being one of the basic reactions in organic synthesis, stilllacks a highly regioselective and enantioselective catalyst with a broad scope. Thisthesis describes the development of several catalytic systems capable ofenantioselective conjugate addition reactions of organometallic reagents to enones.A number of examples are currently known of both Michael type additions and 1,4-additions of organometallic reagents catalysed by chiral metal complexes withenantioselectivities exceeding 80%. In Chapter 2 a comprehensive survey of all#

catalytic enantioselective conjugate addition reactions is given.Chapter 3 details the investigation on the nickel / chiral amino alcohol catalysedaddition of dialkylzinc reagents to several chalcones. Preliminary experiments werealready performed by Jansen. In Chapter 4 the synthesis of several novel chiral tri-44

and tetradentate amino alcohol ligands and the results of their examination in the nickelcatalysed conjugate addition of diethylzinc to chalcone and cyclohexenone aredescribed.Chapter 5 describes the development of a catalytic system capable of enantioselectiveconjugate addition reactions of organometallic reagents to cyclic and acyclicsubstrates. Cobalt and copper catalysed conjugate additions of diethylzinc as well asthe copper catalysed addition reactions of trimethylaluminium were investigated.In Chapter 6 several novel phosphorus amidites, representing a new class of chiralligands, are presented. The synthesis and application as chiral ligand in the coppercatalysed conjugate addition of dialkylzinc reagents to cyclic and acyclic enones, arereported. The results of the application of representatives of this new class of ligands in severalother catalytic addition reactions are described in Chapter 7.Parts of this thesis have already been published, or will be published.45 46

Introduction

11

1. For the early history of optical isomerism, see Eliel, E.L. Stereochemistry of Carbon Compounds;McGraw-Hill: New York, 1962.

2. For extensive reviews on stereoselective reactions, see: a) Asymmetric Synthesis; Morrison, J.D. Ed.;Academic Press: Orlando, 1983-1985, Vol. 1-5. b) Topics in Stereochemistry; Eliel, E.L.; Wilen, S.H.Eds.; Wiley and Sons: New York, 1967-1990, Vol 1-20.

3. a) Pfeiffer, C.C. Science 1956, 124, 29. b) Sheldon, R. A. Chirotechnology; Marcel Dekker, Inc., NewYork, 1993, Chapter 2 and references therein.

4. Merck Index, Budavari, S. ed., 11 ed. Merck 1990, No. 9182, p. 1458. Recently, the actions of racemicth

and enantiomerically pure thalidomide were reinvestigated. Probably racemisation in vivo occurs, see:Eriksson, T.; Björkman, S.; Roth, B.; Fyge, Å.; Höglund, P. Chirality 1995, 7, 44 and references therein.

5. Reference 2a, Vol 1, Chapter 1.

6. Jacques, J.; Collet, A.; Wilen, S.H. Enantiomers Racemates and Resolutions; Wiley: New York, 1981.See also reference 3b, Chapter 6.

7. Kagan, H.B.; Fiaud, J.C. Topics in Stereochemistry; Eliel, E.L.; Wilen, S.H. Eds.; Wiley and Sons: NewYork, 1988, 18, 249.

8. a) Wong, C.-H.; Whitesides, G.M. Enzymes in Synthetic Organic Chemistry; Tetrahedron OrganicChemistry Series, No. 12; Pergamon: Oxford, 1994. b) Van der Deen, H.; Cuiper, A.D.; Hof, R.P.; VanOeveren, A.; Feringa, B.L.; Kellog, R.M. J. Am. Chem. Soc. 1996, 118, 3801 and references therein.

9. Hanessian, S. Total Synthesis of Natural products: The 'Chiron' Approach; Pergamon Press: Oxford,1983. See also reference 3b, Chapter 5.

10. Blaser, H.-U. Chem. Rev. 1992, 92, 935.

11. See reference 3b, Chapter 4.

12. Reference 8a, Chapter 4.

13. Atkinson, R.S. Stereoselective Synthesis; Wiley: Chichester, 1995. See also reference 2.

14. a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993. b) Brunner, H.;Zettlmeier, W. Handbook of Enantioselective Catalysis; VCH Publishers: New York, 1993. c) Noyori,R. Asymmetric Catalysis in Organic Chemistry; Wiley: New York, 1994. d) Advances in CatalyticProcesses, Asymmetric Chemical Transformations; Doyle, M.P., Ed.; Jai Press: Connecticut, 1995.

15. For non-metal based chiral catalysts, see for example Wynberg, H. Topics in Stereochemistry; Eliel,E.L.; Wilen, S.H. Eds.; Wiley and Sons: New York, 1988, 16, 87.

16. a) Hof, R.P. Enantioselective Synthesis and (Bio)catalysis, Ph.D. Thesis, University of Groningen, 1995.b) Xianming, H. Chiral Nonracemic 1-Aryl-2,2-dimethyl-1,3-propanediols: Reactions and Applicationsin Asymmetric Synthesis, Ph.D. Thesis, University of Groningen, 1995. c) Rispens, M.T.Enantioselective Oxidation Using Transition Metal Catalysts, Ph.D. Thesis, University of Groningen,1996. d) Vries, T.R. Chiral Cyclic Derivatives of C-Symmetrical Butanedioic Acids, Ph.D. Thesis,2

University of Groningen, 1996. e) Knol, J. Chiral Lewis Acid Catalyzed Diels-Alder Reactions, Ph.D.Thesis, University of Groningen, 1996.

17. Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1966, 5239.

18. Aratani, T. Pure Appl. Chem. 1985, 57, 1839 and references therein.

19. Doyle, M.P. Recl. Trav. Chim. Pays-Bas 1991, 110, 305.

1.4 References and notes

Chapter 1

12

20. a) Fritschi, H.; Leuteneggar, U.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1986, 25, 1005. b) Fritschi, H.;Leuteneggar, U.; Siegmann, K.; Pfaltz, A.; Keller, W.; Kratky, Ch. Helv. Chim. Acta 1988, 71, 1541.

21. a) Müller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232. b) Lowenthal, R.E.;Abiko, A.; Masamune, S. Tetrahedron Lett. 1990, 31, 6005. c) Evans, D.A.; Woerpel, K.A.; Hinman,M.M. J. Am. Chem. Soc. 1991, 113, 726. d) Evans, D.A. Woerpel, K.A.; Scott, M.J. Angew. Chem., Int.Ed. Engl. 1992, 31, 430.

22. Only leading references are noted. Boron: a) Furuta, K.; Shimizu, S.; Miwa, Y. Yamamoto, H. J.Org. Chem. 1989, 54, 1481. b) Corey, E.J.;Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966. c) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994,116, 1561.Aluminium: d) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. J. Am. Chem. Soc.1988, 110, 3588. e) Corey, E.J.; Imai, N.; Pikul, S. Tetrahedron Lett. 1991, 32, 7517. f) Corey, E.J.;Sarshar, S.; Lee, D.-H. J. Am. Chem. Soc. 1994, 116, 12089. g) Bao, J.; Wulff, W.D. J. Am. Chem. Soc.1993, 115, 3814.Titanium: h) Narasaka, K.; Inoue, M.; Yamada, T. Chem. Lett. 1986, 1967. i) Mikami, K.; Motoyama,Y.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812. Copper: j) Evans, D.A.; Miller, S.J.; Leckta, T. J. Am. Chem. Soc. 1993, 115, 6460.Lanthanide: k) Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994, 116, 4083.

23. a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823. b) Kitamura, M.; Suga, S.; Noyori, R. J. Am.Chem. Soc. 1986, 108, 6071. c) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109,7111.

24. a) Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49. b) Soai, K.; Niwa, S. Chem. Rev.1992, 92, 833. c) Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93, 2117. See also reference 14c, Chapter5 and reference 16a, Chapter 4.

25. For a brief review, see: Bach, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 417.

26. Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723 andreferences therein.

27. Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039.

28. a) Costa, A.L.; Piazza, M.G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993,115, 7001. b) Keck, G.E.; Tarbert, K.H.; Geraci, L.S. J. Am. Chem. Soc. 1993, 115, 8467.

29. See also: a) Faller, J.W.; Sams, D.W.I.; Liu, X. J. Am. Chem. Soc. 1996, 118, 1217. b) Sawamura, M.;Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. c) Evans, D.A.; Murry, J.A.; Kozlowski, M.C. J.Am. Chem. Soc. 1996, 118, 5814.

30. Becker, W.; Freund, H.; Pfeil, E. Angew. Chem., Int. Ed. Engl. 1966, 4, 1079.

31. Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181 and references therein.

32. Reetz, M.T.; Kunisch, F.; Heitmann, P. Tetrahedron Lett. 1986, 39, 4721.

33. Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am. Chem. Soc. 1992, 114, 7969 and referencestherein.

34. For a mechanistic study on this reaction, see: Shvo, Y.; Gal, M.; Becker, Y.; Elgavi, A. Tetrahedron:Asymmetry 1996, 7, 911.

35. Denmark, S.E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc. 1994, 116, 8797.

36. Iyer, M.S.; Gigstad, K.M.; Namdev, N.D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910.

Introduction

13

37. Trost, B.M.; Strege, P.E. J. Am. Chem. Soc. 1977, 99, 1649.

38. Fiaud, J.C.; Hibon de Gournay, A.; Larcheveque, M.; Kagan, H.B. J. Organomet. Chem. 1978, 154, 175.

39. Reviews: a) Frost, C.G.; Howarth, J.; Williams, J.M.J. Tetrahedron: Asymmetry 1992, 4, 1089. b) Reiser,O. Angew. Chem., Int. Ed. Engl. 1993, 32, 547.

40. Pfaltz, A. Acc. Chem. Res. 1993, 26, 339 and references therein.

41. a) Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566. b) Sprinz, J.; Helmchen, G.Tetrahedron Lett. 1993, 34, 1769. c) Dawson, G.J.; Frost, C.G.; Williams, J.M.J. Tetrahedron Lett. 1993,34, 3149.

42. a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.; Walter, O.; Zsolnai, L. TetrahedronLett. 1994, 35, 1523. b) Von Matt, P.; Lloyd-Jones, G.C.; Minidis, A.B.E.; Pfaltz, A.; Macko, L.;Neuburger, M.; Zehnder, M.; Rüegger, H.; Pregosin, P.S. Helv. Chim. Acta 1995, 78, 265.

43. Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994, 35, 8595.

44. Jansen, J.F.G.A.; Feringa, B.L. Tetrahedron: Asymmetry 1992, 3, 581.

45. Chapter 2: Feringa, B.L.; de Vries A.H.M. in Advances in Catalytic Processes, Vol 1: AsymmetricChemical Transformations; Doyle, M.P., Ed.; JAI Press, Connecticut, 1995, p. 151.Chapter 3: de Vries, A.H.M.; Jansen, J.F.G.A.; Feringa, B.L. Tetrahedron 1994, 50, 4479.Chapter 6: de Vries, A.H.M.; Meetsma, A.; Feringa, B.L. Angew. Chem., Int. Ed. Engl. in press.

46. Chapter 4: de Vries, A.H.M.; Imbos, R.; Feringa, B.L. manuscript in preparation for Tetrahedron:Asymmetry.Section 5.2: de Vries, A.H.M.; Feringa, B.L. manuscript in preparation for Tetrahedron: Asymmetry.Section 5.3: de Vries, A.H.M.; Hof, R.P.; Staal, D.; Kellogg, R.M.; Feringa, B.L. submitted toTetrahedron: Asymmetry.