University of Groningen

Synthetic applications of the catalytic asymmetric 1,4-additionNaasz, Robert

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2002

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Naasz, R. (2002). Synthetic applications of the catalytic asymmetric 1,4-addition. s.n.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 28-03-2021

19

Chapter 2

The catalytic enantioselective 1,4-addition of organometallicreagents: copper catalyzed addition of organozinc reagents

and related approaches

2.1 Introduction

The discovery of the successful phosphoramidite ligand (S,R,R)-L1 as described in Section1.3, has led to an increasing interest in the conjugate addition of organometallics. Theattention of research in the field of enantioselective 1,4-additions was focussed on the coppercatalyzed 1,4-addition of organozinc reagents. In the present chapter, the development ofnew ligands and catalysts for the copper catalyzed enantioselective 1,4-addition oforganozinc reagents and their application from 1997 onwards, in our research group and byothers, is reviewed.1 Additionally, the information known to date about the mechanism ofthese 1,4-additions is summarized in Section 2.3. Finally, the recent development of anothercatalytic system, the highly enantioselective rhodium-BINAP catalyzed 1,4-addition oforganoboronic acids developed by Hayashi et al., is discussed briefly (Section 2.4).

2.2 Copper catalyzed enantioselective 1,4-addition of organozinc reagents

As mentioned in the introduction, a variety of successful catalytic systems have beendeveloped since 1997. The majority of the ligands in use are based on phosphorus, such asphosphoramidites (PO2N, Section 2.2.1), phosphites (PO3, Section 2.2.2), phosphonites(PO2C, Section 2.2.3) and phosphines (PC3, Section 2.2.4), and other phosphorus containingligands (Section 2.2.5), but other ligands have also been applied; they are discussed inSection 2.2.6.

2.2.1 Phosphoramidites

As described in the previous chapter, the copper catalyzed 1,4-addition to 2-cyclopentenone(2.1) in the presence of (S,R,R)-L1 resulted in a low enantioselectivity of only 10% ee.2

Therefore, one of the priorities in our group was to develop phosphoramidite ligands thatwould display high enantioselectivity in the 1,4-addition to 2-cyclopentenone. TADDOL3

based phosphoramidite (R,R)-2.4 (Figure 2.1) was found to give a moderate ee of 37% in the

Chapter 2

20

tandem 1,4-addition-aldol reaction (Scheme 2.1).4 The reactions were carried out in thepresence of benzaldehyde to prevent undesired oligomerization by in situ trapping of thereactive zinc enolate that is formed by the 1,4-addition of Et2Zn to 2.1.

O O

Ph

OHH

O

Ph

OH

2.1 2.2 2.3

Et2ZnCu(OTf)2 (1.2 mol%)

L* (1.3 or 2.4 mol%)PhCHOtoluene, −30 °C

PCC

Scheme 2.1 Tandem 1,4-addition-aldol reaction on 2-cyclopentenone.

The addition of 4 Å molsieves to the reaction mixture had a beneficial effect on the ee,which went up from 37% to 62%. The exact nature of the influence of the molecular sieves isnot understood.

OP

O

Ph Ph

Ph Ph

O

O

H

H

NMe2

O

OP N N

O

OPn

OO

P NPh

Ph

(S,R,R)-L1 (R,R)-2.4

2.5 n=02.6 n=1

Ph Ph

Figure 2.1 Phosphoramidite ligands.

Initial experiments with BINOL based phosphoramidites revealed a dramatic increase in theee obtained in the 1,4-addition to 2-cyclopentenone when going from monodentate ligandsto the structurally related C2-symmetric bidentate ligands. The preparation and testing of avariety of such bidentate ligands, e.g. 2.5 and 2.6, eventually led to an ee of 83% for 2.3,obtained with (S,S)2-2.5 in the presence of 4 Å molsieves (79% ee without molsieves).5,6

A different approach to solve the problem of the moderate ee’s obtained in the 1,4-additionto cyclopentenones is modification of the substrates. It was found that the use ofcyclopenten-3,5-dione monoacetals such as 2.7 as substrates led to very satisfactory ee’sranging from 87% to 97%, with the use of ligand (S,R,R)-L1.7 The usefulness of these

The catalytic enantioselective 1,4-addition of organometallic reagents

21

substrates has been demonstrated by the total synthesis of prostaglandin E1 methyl ester(2.9) in seven steps (Scheme 2.2).

O O

COOCH3

OHH

OO

PhPh

6

C5H11

SiMe2Ph

OO

PhPh

H C5H11

O SiMe2Ph

(MeOOC(CH2)6)2ZnCu(OTf)2 (3 mol%)(S,R,R)-L1 (6 mol%)

toluene, −40 °Cc.y. 60%

O

OH

C5H11

OH

COOCH36

2.7 2.8 2.994% optical purity7% c.y. (7 steps)

6 steps

Scheme 2.2 Total synthesis of PGE1 methyl ester (2.9).

Further variation of the amine moiety and modification of the BINOL part led to thesynthesis of a variety of phosphoramidite ligands, which were tested on both cyclohexenoneand various acyclic enones.8 However, (S,R,R)-L1 remains the best phosphoramidite ligandfor cyclic enones and the diisopropyl BINOL-phosphoramidite 1.34b (Chapter 1) generallygives the best results with chalcones.The copper-phosphoramidite catalyst based on L1 was also tested on other substrates, in ourgroup and by others. Sewald and Wendisch successfully used both (R,S,S)-L1 and (S,S,S)-L1

in the 1,4-addition to nitroolefins, obtaining ee’s up to 86% (Scheme 2.3).9

NO2

R

Et2ZnCu(OTf)2 (2 mol%)(R,S,S)-L1 (4.1 mol%)

toluene, −30 °CNO2

R

2.10a: R = Phb: R = CH(OMe)2

2.11a: 48% ee (−78 °C)b: 86% ee

Scheme 2.3 1,4-Addition to nitroolefins.

Related classes of substrates, α,β-unsaturated nitroesters and nitrocoumarins, wereinvestigated in our laboratory and with the use of (S,R,R)-L1 ee’s of up to 92% werereached.10 Also very successful were the enantioselective 1,4-additions to a variety ofcyclohexadienones and related compounds.11 An elegant feature of these substrates, e.g. 2.12,is the possibility of performing two sequential 1,4-additions, in which the stereochemicaloutcome of the second 1,4-addition is solely dependent on the enantiomer of L1 that is usedin each step and is not influenced by the presence of stereogenic centres at the 4- and 5-position of 2.13 (Scheme 2.4). Phosphoramidite (S,R,R)-L1 was employed also by Alexakis etal. for the catalytic asymmetric synthesis of muscone in 75% ee (see also Scheme 1.8, Chapter

Chapter 2

22

1) and the 1,4-addition to acyclic enones.12 They also used (S,R,R)-L1 in enantioselectivetandem 1,4-addition-electrophile trapping reactions.13

O

O

O

O

Et2Zn

'(S,R,R)-cat'

2.12 2.1397% ee

2.14a98% trans

O

O

O

O

Et2Zn'(S,R,R)-cat'

Et2Zn'(R,S,S)-cat'

2.14b98% cis(meso)

Scheme 2.4 Sequential 1,4-additions to cyclohexadienone 2.12.

Following the initial reports,2a,14 a variety of phosphoramidites has been prepared and testedin the 1,4-addition to various substrates. Some of these phosphoramidite ligands aredepicted in Figure 2.2.

OOP

OOP

N N

N

ClO O

PO

OP N

Ph

Ph OP

O

Ph Ph

Ph Ph

O

O

H

H

HN

(S,S)-2.15 (R,R)-2.16

(R,R)-2.18

(Sa,RC)-2.17

OOP

O N

(R)-2.19

Figure 2.2 Phosphoramidite ligands.

The catalytic enantioselective 1,4-addition of organometallic reagents

23

Phosphoramidite (S,S)-2.15 and related ligands were recently reported by Alexakis et al.15

They claim that the atropoisomerism of the biphenol unit is induced by the chiral amine,although this claim is not supported by experimental proof. An advantage of these ligands isthat the biphenol used for the synthesis of (S,S)-2.15 is cheaper than enantiomerically pureBINOL and for some substrates higher enantioselectivities are obtained than with (S,R,R)-L1.Alexakis also reported the synthesis and use of a variety of TADDOL based phosphoramitesand reached the same conclusion that Erik Keller in our group had previously,4 that bulkysubstituents on the nitrogen in these ligands are detrimental for high enantioselectivities.16

The best result was indeed obtained with the sterically least hindered (R,R)-2.16, giving 49%ee in the 1,4-addition of diethylzinc to benzalacetone. Quinoline based phosphoramidite(Sa,RC)-2.17 was reported by Faraone et al. and was tested in the 1,4-addition of Et2Zn to 2-cyclohexenone providing a maximum ee of 70%.17 Waldman et al. reported on the synthesisof C2-symmetric phosphoramidite (R,R)-2.18 and the related monodentate (R)-2.19.18 Ofthese two, the bidentate (R,R)-2.18 proved to be the superior ligand for cyclic enones, giving82% ee in the 1,4-addition of Me2Zn to 2-cyclohexenone and 2-cycloheptenone. For acyclicsubstrates such as chalcone, (R)-2.19 gave slightly better results, reaching 82% ee in the 1,4-addition of n-Bu2Zn against 60% ee as obtained with (R,R)-2.18. Chan et al. reported on theuse of a diisopropylamino phosphoramidite with a H8-binaphthoxy moiety as the chiralbackbone instead of BINOL with ee’s up to 88%.19 8,8’-BINOL derived phosphoramiditesand their application in the copper catalyzed enantioselective 1,4-addition have also beenreported, albeit with moderate enantioselectivities of up to 50%.20

2.2.2 Phosphites

The first successful chiral phosphite ligands were reported by the group of Pfaltz in 1997.21

Using phosphinooxazoline ligands (R,S)-2.20a and b, ee’s up to 96% were obtained in theCu(OTf)2 catalyzed 1,4-addition of Me2Zn to 2-cyclohexenone and 50% ee in the addition ofEt2Zn to chalcone (Figure 2.3).

O

OP

O

N

O

R

R

OP

O

OO

P O

PhPhPh

PhPh

O

OO

PhH

H

(R,S)-2.20a: R = Hb: R = Mec: R = 3,5-di-t-butylphenyld: R = biphenyl

2.21 2.22

Figure 2.3 Chiral phosphite ligands.

Chapter 2

24

Very encouraging were the results obtained with 2-cyclopentenone as the substrate, forwhich an ee of 72% was obtained with (R,S)-2.20b. Further modification of these ligands,and, especially, introduction of bulky substituents at the 3,3’ position of the BINOLbackbone, led to the synthesis and testing of, among others, (R,S)-2.20c and (R,S)-2.20d.22

(R,S)-2.20c gave an impressive ee of 94% in the 1,4-addition to 2-cyclopentenone and highenantioselectivities were obtained in the 1,4-addition of Et2Zn to 2-cyclohexenone (90%), 2-cycloheptenone (94%) and chalcone (87%).Alexakis et al. reported on a series of phosphites based on tartrate,23 TADDOL,24 andBINOL.12 The tartrate phosphites gave only moderate results, the maximum ee being 65%obtained with benzalacetone as the substrate. TADDOL based phosphite 2.21 was the mostsuccessful one of the tested series, giving 96% ee in the addition of Et2Zn to 2-cyclohexenone,although only racemic material was obtained with benzalacetone as the substrate. The bestresult obtained with the corresponding BINOL phosphite 2.22 was 87% ee in the 1,4-addition of Me2Zn to 2-cyclopentadecenone, producing muscone (see Chapter 1).

OOP

OOP

O O

OOP

OOP

O O t-Bu

t-But-Bu

t-Bu

(S,S)-2.23 (S,S,S)-2.24

Figure 2.4 Phosphite ligands reported by Chan et al.

The BINOL based phosphites (S,S)-2.23 and (S,S,S)-2.24 have been reported by Chan et al.(Figure 2.4).25 These phosphites were especially successful in 1,4-additions to 2-cyclopentenone, an ee of 89% being reached using (S,S)-2.23. An interesting effect of the

temperature of the reaction mixture on the enantioselectivity was observed. At 20 °C a

higher ee (88%) was obtained than at 0 °C (84%) and at –20 °C only moderate conversion

with an ee of 8% was found. The optimum temperature seems to be 10 °C resulting in theaforementioned 89% ee. Other cyclic enones also gave good results with these ligands withee’s up to 90% for 2-cyclohexenone, but chalcone only gave a maximum ee of 17%. Chan etal. were the first to report the copper catalyzed enantioselective 1,4-addition of organozinc

reagents to α,β-unsaturated lactones using the same phosphite ligands (Scheme 2.5).26 The1,4-addition of Et2Zn to the 6-membered lactone 2.25b proceeded with 92% ee and amoderate ee of 56% was obtained for the 5-membered lactone 2.25a.

The catalytic enantioselective 1,4-addition of organometallic reagents

25

O

O

n

O

OEt2Zn (1.5 equiv)(S,S)-2.23 (2 mol%)Cu(OTf)2 (1 mol%)

toluene, 0 °C

2.25a: n = 0b: n = 1

2.26a: 56% eeb: 92% ee

n

Scheme 2.5 Enantioselective 1,4-addition to lactones using (S,S)-2.23.

Pàmies et al. reported a series of sugar derived phosphites.27 Initially they synthesizedphosphites based on ribose and different biphenols but the ee’s obtained were moderate,with a maximum ee of 53% in the 1,4-addition of Et2Zn to 2-cyclohexenone. Furthermodification led to the synthesis of 2.27, a very bulky phosphite that gave 81% ee in the 1,4-

addition of Et2Zn to 2-cyclohexenone at 0 °C in CH2Cl2. With this ligand they observed ahigh initial turnover frequency of 1200 h-1 and full conversion was reached within 5 minusing 1 mol% of ligand and Cu(OTf)2.

OO

OOP

O

O

SiMe3

SiMe3

OP O

O

Me3Si

Me3Si t-But-Bu

t-But-Bu

O

OPOP

Ph

Ph

t-Bu

2.27 2.28

Figure 2.5 Ribose derived phosphite 2.27 and phosphine-phosphite 2.28.

Together with the group of Van Leeuwen they also reported the use of phosphine-phosphiteligands, e.g. 2.28, in the catalytic enantioselective 1,4-addition.28 Although these ligands gavehigh turnover frequencies, very low enantioselectivities were obtained in the 1,4-addition ofEt2Zn to 2-cyclohexenone with a maximum ee of 22%. Beter results were obtained using aEt3Al/Cu(MeCN)4BF4 system instead of Et2Zn/Cu(OTf)2, reaching 62% ee in the addition to2-cyclohexenone.

2.2.3 Phosphonites

Only a few successful applications of chiral phosphonites in enantioselective 1,4-additionshave been reported. Interestingly, all the phosphonite ligands reported so far were initiallyprepared for applications in other catalytic enantioselective reactions. Reetz et al. prepared

Chapter 2

26

the C2-symmetric ferrocene based phosphonite 2.29 that was originally successfully appliedin the rhodium catalyzed hydrogenation. (Figure 2.6).29 When applied in the 1,4-addition ofEt2Zn to 2-cyclohexenone, an impressive ee of 96% was obtained.30 Unfortunately, nosystematic screening of different substrates has been reported, although 98% ee has beenreported for the 1,4-addition to lactone 2.25b.31

OP

O

PhPh

PhPh

O

O

H

H

OO

PFe

OO

P

OO

P t-Bu

OO

P t-Bu

(R,R)-2.29 (S,S)-2.30

(S)-2.31 (S)-2.32

Figure 2.6 Chiral phosphonite ligands.

Alexakis et al. described the successful application of TADDOL phosphonite 2.30, usedoriginally in catalytic enantioselective hydrosilylation and hydroformylation reactions,32 inthe 1,4-addition to nitroolefines (see also Scheme 2.3).33 Ee’s ranging from 31% to 86% werereached using various nitroolefins. In contrast, the use of (S,S)-2.30 in the 1,4-addition tochalcone and 2-cyclohexenone resulted in 7% ee and 54% ee, respectively.16

In a cooperation between us and the group of Pringle, the BINOL and biphenanthrol basedphosphonites with various exocyclic substituents previously used in the catalyticenantioselective hydrogenation,34 were tested in the 1,4-addition of Et2Zn to 2-cyclohexenone and chalcone.35 Only moderate results were obtained using 2-cyclohexenoneas a substrate with a maximum ee of 41%, but an ee of 82% was obtained in the 1,4-additionof Et2Zn to chalcone using (S)-2.31. With the related phenanthrol phosphonite (S)-2.32, 80%ee was reached under the same conditions. The phosphonites were also tested in the 1,4-addition to nitroolefins, but in contrast to TADDOL based phosphonite 2.30, only lowenantioselectivities were observed (<20% ee).36

The catalytic enantioselective 1,4-addition of organometallic reagents

27

2.2.4 Phosphines

In 1997 Alexakis reported on the accelerating effect that both alkyl and aryl phosphines hadon the copper catalyzed 1,4-addition of organozinc reagents.37 A wide variety ofcommercially available diphosphines were tested but no satisfactory levels ofenantioselectivity were obtained (0-44% ee) on either cyclic or acyclic enones.

PPh2

NH

N

O

R

N PPh2

N

PPRMe

R Me

2.33a: R = Cyb: R = t-Bu

(S)-2.34a: R = Hb: R = Me

(S)-2.35

NH PPh2

O

(S)-2.36

Figure 2.7 Chiral phosphines used in the enantioselective 1,4-addition.

The first really successful application of phosphines was reported in 1999 by Imamoto et al.38

In the presence of 1 mol% Cu(OTf)2 and 1 mol% 2.33a in toluene at −80 °C, 83% ee wasobtained in the 1,4-addition of Et2Zn to 2-cyclohexenone. For 2-cycloheptenone andchalcone, phosphine 2.33b gave better results with 97% and 71% ee, respectively.A milestone was reached by Zhang et al. using (S)-2.34a and b.39 They employed theseligands for the first time and obtained high ee’s (>90%) with both cyclic and acyclic enoneswith the same catalytic system. Ee’s of 98% were reached, also for the first time, in the 1,4-addition to chalcones. In the 1,4-addition to 2-cyclohexenone, 91% and 92% ee were obtainedusing (S)-2.34a and (S)-2.34b, respectively. For chalcones (S)-2.34b clearly was the superiorligand, giving 96% ee with chalcone and 98% ee with 4-methoxy substituted chalcone.Morimoto et al. reported on the use of several new P,N ligands of which (S)-2.35 was themost successful, giving 91% ee in the 1,4-addition of Et2Zn to 2-cyclohexenone.40 (S)-2.36 wasreported by Tomioka et al., but only moderate results were obtained in the 1,4-addition to 2-cyclohexenones with ee’s ranging from 7-64%.41

Recently, the group of Hoveyda reported the use of highly modular peptide-basedphosphines in the copper catalyzed 1,4-addition of organozinc reagents (Figure 2.8).42

N

HN

NHBu

PPh2O

Ph

O

N

HN

NH

PPh2O

O

Ot-Bu

OMe

O

(S,S)-2.37 (S,S)-2.38

Figure 2.8 Modular peptide-based phosphines.

Chapter 2

28

Excellent results with ee’s of 98% or higher were obtained with the use of a catalyst preparedin situ from (S,S)-2.37 (2.4 mol%) and Cu(OTf)2•C6H6 (1 mol%) in toluene for 2-cyclopentenone, 2-cyclohexenone, and 2-cycloheptenone with different organozinc reagents.Unfortunately, 1,4-additions to acyclic enones using these phosphine ligands have not beenreported as yet. Since the phosphines are constructed from two or three amino acids,numerous variations in ligand structure are possible using readily available compounds. Todemonstrate this, the problem of the somewhat lower enantioselectivity (72% ee) using i-Pr2Zn in the 1,4-addition to 2-cyclohexenone in the presence of (S,S)-2.37 was addressed. Byusing a positional optimization strategy,43 (S,S)-2.38 was identified as a superior ligand,giving 91% ee in the addition of i-Pr2Zn. The authors mention that by carrying out acomplete ligand screening, a different optimal chiral phosphine construct may emerge foreach particular enone. Additionally, a synthetic application of this highly enantioselective1,4-addition is presented in the same paper; the total synthesis of clavularin B (2.40, Scheme2.6).42 The zinc enolate resulting from the 1,4-addition of Me2Zn to 2-cycloheptenone wasquenched with 4-iodo-1-butene in the presence of HMPA yielding 2.39 with 97% ee. Thiscompound was subsequently converted to clavularin B (2.40) in three steps.

O O

Me

Me2Zn (3 equiv)Cu(OTf)2 (1 mol%)(S,S)-2.37 (2.4 mol%)toluene, −30 °C

1)

I (10 equiv)

HMPA (10 equiv)

0 °C

2)

O

Me

O

2.39trans/cis: 15:197% ee

2.40c.y. 42% (4 steps)

3 steps

Scheme 2.6 Catalytic enantioselective synthesis of clavularin B (2.40).

2.2.5 Other phosphorus containing ligands

Aminophosphines (S,S)-2.41a and b were reported by Tomioka et al. and tested in the 1,4-addition of Et2Zn to 2-cyclohexenones (Figure 2.9).44 Only moderate ee’s were obtained,ranging from 40 to 70% and 5 mol% of Cu(OTf)2 and 10 mol% of ligand were required toreach these enantioselectivities.

NP

N

R

PhPhN

O PN

N

Ph(S,S)-2.41a: R = Phb: R = Me

(S)-2.42

Figure 2.9 Chiral phosphorus ligands.

The catalytic enantioselective 1,4-addition of organometallic reagents

29

Quinoline based phosphane ligand (S)-2.42 was reported by Buono et al.45 Although onlymoderate ee’s were reported, an interesting effect of water was observed. Using similarconditions the ee could be raised from 7% to 61% by adding a small amount of water. Sincethe addition of Zn(OH)2 also has a beneficial effect, this is probably formed in situ byhydrolysis of Et2Zn and acts as a Lewis acid, although the precise role of water has not beenelucidated. Note that the beneficial effect of a trace of water might also be an explanation forthe higher enantioselectivity observed in the 1,4-addition to 2-cyclopentenone in thepresence of (R,R)-2.4 and molecular sieves, which may contain some water (Section 2.2.1).

2.2.6 Non-phosphorus containing ligands

Although most of the attention in the development of new ligands for the copper catalyzedenantioselective 1,4-addition has been devoted to phosphorus ligands, due to the highaffinity of these soft Lewis bases for copper, some interesting and successful chiral ligandsthat do not contain phosphorus have been developed. Following initial reports by Noyori etal.46 about the copper catalyzed 1,4-addition in the presence of achiral sulfonamides, Sewaldreported the first enantioselective version of this reaction in 1997, using various chiralsulfonamides.47 Although a clear ligand accelerating effect was observed, lowenantioselectivities were obtained in the 1,4-addition of Et2Zn to 2-cyclohexenone (ee < 30%).Tomioka et al. also had little succes in the application of chiral disulfonamides, reporting amaximum ee of 28%.44

Successful examples of sulfonamide ligands for the copper catalyzed asymmetric 1,4-addition to alkenones were found by Gennari et al. by high-throughput screening of aparallel library of ligands.48

NS

NHR2

R1OO

OHR3

2.43

NS

NH

OO

OH

2.44 2.45

Cl

Cl

Cy

NS

NH

OO

OH

t-Bu

t-Bu

Cy

Figure 2.10 Chiral Schiff base sulfonamide ligands.

A variety of sulfonamides with the general structure 2.43 was prepared by condensation of

salicylaldehydes with enantiomerically pure β-amino sulfonamides (which in turn wereprepared by reaction of different primary amines with sulfonylchlorides) using solution-phase parallel synthesis and solid-phase extraction techniques. Through screening of alibrary of 100 ligands, 2.44 was identified as the best ligand for the 1,4-addition of Et2Zn to 2-cyclohexenone and 2-cycloheptenone, with 90% and 91% ee, respectively. Sulfonamide 2.45was identified as the best ligand to promote the 1,4-addition of Et2Zn to 2-cyclopentenonewith an ee of 80%. Enantioselective 1,4-addition to chalcone proved to be more difficult. A

Chapter 2

30

maximum ee of 50% was obtained by screening a large library of ligands. The sameprocedure was applied also to nitroalkenes as substrates and a chiral sulfonamide ligandwas identified that gave a maximum ee of 58%.49

Surprisingly high ee’s were obtained by Pàmies et al. using a very simple sugar-based thiolligand, with ee’s up to 62% in the 1,4-addition of Et2Zn to 2-cyclohexenone.50 Woodward etal. reported on the use of BINOL-derived thiols displaying up to 77% ee in the 1,4-additionto acyclic enones.51

Alexakis and Mangeney recently reported the use of diaminocarbenes as ligands in thecopper catalyzed 1,4-addition, although the obtained enantioselectivities were onlymoderate with a maximum ee of 51%.52

2.2.7 Other applications

As mentioned in Section 2.2.3, many ligands originally intended for application in othercatalytic enantioselective processes have successfully been used in the catalyticenantioselective 1,4-addition. But the reverse is also true and ligands used in the 1,4-additionare being used in other reactions with much success. Examples are the use ofphosphoramidites in hydrogenations,53 Heck reactions,54 and SN2’ substitutions55 in ourgroup and by others. Phosphoramidites also found successful application in the ringopening of vinylic epoxides and related compounds.56 Pàmies et al. reported extensively onthe use of their phosphite and phosphine ligands in hydrogenation57 and hydroformylationreactions.58 Reports on the phosphoramidite catalyzed borane reduction of ketones withcomplete enantioselectivity have also appeared, although one of the papers wassubsequently retracted.20,59

2.3 Mechanism of the copper catalyzed 1,4-addition of diorganozincs

The mechanism of the 1,4-addition of cuprates and the structure of cuprates in solution hasbeen investigated extensively but remains a subject of considerable debate.60 Differentmechanisms have been proposed and rejected, such as the single electron transfer (SET)mechanism proposed by House et al.61 and the 1,2-addition mechanism over the C=C doublebond.62 Extensive theoretical studies by Nakamura, in combination with experimental dataof others, have led to the proposal of the reaction mechanism shown in Scheme 2.7 for the1,4-addition of cuprates to enones.60 The central feature of this mechanism is the 3-cuprio(III)enolate (CPop) which has an open, dimeric structure. In this complex copper/olefin(soft/soft) and lithium/carbonyl (hard/hard) interactions are achieved. The three limitingstructures of the intermediate CPop are shown in the box in Scheme 2.7. Stable copper-enone

π-complexes have been observed using NMR techniques by several research groups.63 Therelative stability of the trialkylcopper species can be understood with the “3-cuprio(III)enolate” structure where the internal enolate anion acts as a strong stabilizing ligand. Therate determining step of the reaction (to form TScc) is the C-C bond formation caused by

The catalytic enantioselective 1,4-addition of organometallic reagents

31

reductive elimination of CuIII to CuI. This proposed mechanism is in accordance with kineticdata obtained previously by Krauss and Smith,64 who showed that the 1,4-additions ofcuprates are first-order in both cuprate dimer and enone.

Scheme 2.7 Mechanism for the 1,4-addition of cuprates as proposed by Nakamura.

It must be kept in mind that this mechanism is proposed for cuprates, i.e. with Li as thecounter cation, and it is not clear whether these results can be readily transposed to thecopper catalyzed 1,4-addition of organozinc reagents where zinc is the counter cation.Interestingly, Nakamura et al. suggest, on the basis of their calculations on cuprates (!), thatthe role of the effective chiral ligands in the 1,4-addition of organozinc reagents is toselectively accelerate reductive elimination of one of the diastereomeric CPop intermediates,through complexation of the phosphorus moiety of the ligand to the CuIII in TScc (Scheme2.8).65 Note that this view is different from previous suggestions that focus on the copper-olefin complexation step as the crucial face-selective step.66

O

+ R2CuM P*

O

CuR

R

P*

‡

O

CuR

R

P*

‡

O

R

O

R

favored

disfavoredP* = chiral phosphorus ligand

M

M M

M

Scheme 2.8 Enantioselection through selective reductive elimination.

O

H H

LiR

CuIR

Li

X O

H H

Li

CuIII

RR

LiX

O

H H

CuIII

RR

Li

LiX O

H H

CuIIIRR

Li

LiX

O

H H

CuIR

R

Li

LiX

CuIIIR R

OO CuIIIR R

OCuI

R R

‡

CPcl CPop TScc

PD3-cuprio(III) enolatecupracyclopropane olefin π-complex

−−

X = CuR2, halogen, etc.

Chapter 2

32

In contrast to the large amount of research related to the mechanism of the 1,4-addition ofcuprates, little is known about the mechanism of the copper catalyzed 1,4-addition oforganozinc reagents. The only extensive mechanistic studies were published by Noyori et al.dealing with achiral sulfonamide ligands (vide infra).67 In 1997, the catalytic cycle depicted inScheme 2.9 was postulated by our group,2,68 based on results obtained so far. After in situreduction of Cu(II) to Cu(I),69 a copper ethyl species (L2CuEt) is formed by alkyl transferfrom zinc to copper.70 The proposal of participation of two phosphoramidite ligands in thecatalytically active complex was based on the optimum ligand-to-copper ratio of 2 and theobservation of nonlinear effects.2,8 Indication for the existence of an electron rich CuEtspecies was later provided by Chan et al.25a Recording a 31P-NMR spectrum of a 2:1 solution

of (S,S,S)-2.24 and Cu(OTf)2 in toluene–d8, a peak was observed at δ 149.0 ppm (free 2.24)and a peak at 231.6 ppm, which they ascribe to a (S,S,S)-2.24-Cu(OTf)2 species. Uponaddition of an excess of Et2Zn, the peak at 231.6 ppm disappeared quickly and a new peak at

δ 124.0 was observed which was ascribed to an Et-CuI complex containing a molecule of(S,S,S)-2.24.

Et2Zn

L2CuEt

+

EtZnX O

OXZn

Et

CuL

L Et

Et

OZnEt

L2CuX

2.46

2.47

Scheme 2.9 Proposed catalytic cycle.

Complexation of the alkylzinc fragment to the carbonyl of the enone and formation of the π-complex of the copper with the enone results in 2.46, that might be compared with CPop inScheme 2.7. Subsequent addition of the ethyl group, possibly via a 3-cuprio(III) enolate (seeScheme 2.7) generates the zinc enolate 2.47. After reaction the zinc enolate is released andthe copper catalyst (L2CuX) is available for the next catalytic cycle. Release of the zincenolate from the catalyst is facilitated by the formation of a stable dimeric structure of thezinc enolate 2.47 in toluene, as demonstrated by Noyori using cryoscopic molecular weightmeasurements.67

The catalytic enantioselective 1,4-addition of organometallic reagents

33

Noyori et al. also reported extensive kinetic studies using a CuCN/sulfonamide 2.48catalyst, following the reaction by measuring the intensity of the C-O stretching band of thezinc enolate in the IR-spectrum.67 The reaction turned out to proceed with first-order kineticsin both Et2Zn and 2-cyclohexenone and also in CuCN and sulfonamide 2.48. These studiesled to the conclusion that this particular catalytic system can be simply viewed as abisubstrate-uniproduct system. The catalyst reversibly captures Et2Zn and 2-cyclohexenoneto form a 2.48/Et2Zn/cyclohexenone complex (A, Figure 2.11, compare with CPop inScheme 2.7), in which alkyl transfer occurs (B, Figure 2.11). The catalyst/product complexformed releases the product thus regenerating the catalyst and completing the cycle. Becausethe reaction proceeds with first-order kinetics in Et2Zn and 2-cyclohexenone, the turnoverrate is only limited by the alkyl-transfer step and not the product releasing step. Since thesulfonamide 2.48 is structurally and electronically very different from phosphoramidites andother phosphorus containing ligands, different kinetics could be observed with theseligands, but kinetic studies are required to establish this.

HN S

O

O

OZn

R

NS

O

O

Ph

CuZnR3

2.48

R

OZnR

ZnR

NS

O

O

Ph

CuR

A B

BzBz

Figure 2.11 Sulfonamide 2.48 and proposed intermediates in the catalytic cycle (A and B).

In line with observations in our group, Noyori et al. also found that Me2Zn is considerablyless reactive than Et2Zn. In a competition experiment using equimolar amounts of both zincreagents less than 10% of methylated product was formed. To study the influence ofdifferent possible conformers of enone systems, s-trans, s-cis, and flexible enones also werecompared. The results led to the conclusion that the reactivity of these substrates increasesgoing from s-cis (e.g. 2.49) to flexible (e.g. 2.50) to s-trans (e.g. 2.51), the relative initial rate of

reaction with a CuCN/2.48 system at 0 °C being 1 : 4 : 80. It should be mentioned thatcomparison of 2.49 with the other two purely based on its conformation may not be

appropriate since 2.49 also has two substituents on the α-position, which is known to makeenones less reactive.

Chapter 2

34

OO

s-trans s-cis

O

C5H11

OO

2.49 2.50 2.51

Figure 2.12 Conformers of enones.

The extra conformational degrees of freedom in flexible enones such as 2.50 and chalcones(compared to 2-cyclohexenone) make them a problematic class of substrates to obtain highenantioselectivity as can also be seen from the result presented in the previous section.Additionally, complexation of a Lewis acid to the carbonyl functionality can occur in either asyn or anti fashion. The influences of these conformational effects on the enantioselectivitywere studied in some detail by Woodward et al.51a

So far, no working model has been developed to explain the high enantioselectivitiesobtained with some of the ligands mentioned in Sections 2.2.1 to 2.2.6. Possibly, molecularmodeling using X-ray structures of chiral copper complexes (see Figure 1.5) as the startingpoint could provide valuable information in this area.71

2.4 Rh-catalyzed enantioselective 1,4-addition of organoboronic acids

Besides the enantioselective copper catalyzed 1,4-addition of organozinc reagents, by far themost successful approach to achieve highly enantioselective conjugate addition has been therhodium catalyzed addition of aryl- and alkenylboronic acids to enones, as developed byHayashi et al.72 Using 3 mol% of a Rh source and 3 mol% of BINAP, 97% ee was obtained inthe 1,4-addition of a phenyl group to 2-cyclohexenone (Scheme 2.10). The 1,4-addition to 2-cyclopentenone and 2-cycloheptenone proceeded with 96% and 93% ee, respectively.Furthermore, linear enones also gave good results with ee’s of over 90% and a variety ofalkenyl boronic acids could also be used as nucleophiles with high enantioselectivity (>90%).

Recently, the successful 1,4-addition of boronic acids to a variety of substrates, such as α,β-unsaturated esters and lactones, 1-alkenylphosphonates and nitroolefins has been reportedwith ee’s ranging from 84% to 98%.73 Since these initial reports others have also applied therhodium catalyzed 1,4-addition of organoboronic acids.74

O

+ PhB(OH)2

O

Ph

Rh(acac)(C2H4)2 (3 mol%)(S)-BINAP (3 mol%)

dioxane/H2O100 °C

(S)-2.5297% ee

Scheme 2.10 Rhodium catalyzed enantioselective 1,4-addition of phenylboronic acid.

The catalytic enantioselective 1,4-addition of organometallic reagents

35

Advantages of this catalytic system are the stability of the organoboronic acids, allowing theuse of protic solvents and water, and the fact that organoboronic acids in the absence of arhodium catalyst are far less reactive towards enones than most other organometallicreagents and no 1,2-addition takes place. Since aryl- and vinyl-organozinc reagents do notperform well in the copper catalyzed 1,4-addition,75 the ‘Hayashi method’ is fullycomplementary to the copper catalyzed 1,4-addition of organozinc reagents.

2.5 Summary

In conclusion, since the first examples of highly enantioselective 1,4-additions usingCu(OTf)2 and (S,R,R)-L1, a wide variety of different ligands has been developed to catalyzethe 1,4-addition of organozinc reagents to enones. Phosphoramidite (S,R,R)-L1 remains oneof the best ligands for cyclic substrates (see also next chapter) with >98% ee in the 1,4-addition to 2-cyclohexenone, although low ee’s were obtained for 2-cyclopentenone. Highee’s with this notoriously difficult substrate were obtained using phosphites (R,S)-2.20c (94%ee) and (S,S)-2.23 (89%) and phosphoramidite (S,S)2-2.5 (83% ee). For acyclic substrates suchas chalcone by far the best ligand is phosphine (S)-2.34b, giving up to 98% ee. Very versatileis phosphine ligand (S,S)-2.37, giving ee’s of 98% or higher with 2-cyclopentenone, 2-cyclohexenone, and 2-cycloheptenone. Because of the modularity of these ligands, they alsohave good potential in the 1,4-addition to other substrates and in catalyzing other reactions.

The scope of substrates has also been extended and nitroolefins, α,β-unsaturated lactones,cyclopenten-3,5-dione monoacetals and cyclohexadienones can now be used withoutproblems. For the introduction of aryl or vinyl groups, the Rh-BINAP catalyzed 1,4-additionof organoboronic acids is the method of choice, with high enantioselectivities being obtainedon a variety of substrates.

2.6 References and notes

1 Recent reviews on the catalytic asymmetric 1,4-addition in general: a) N. Krause, A.Hoffmann-Röder, Synthesis 2001, 171; b) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033.2 a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. de Vries, Angew. Chem., Int.Ed. Engl. 1997, 36, 2620; For an account of the research done in our group see: b) B. L.Feringa, Acc. Chem. Res. 2000, 33, 346.3 TADDOL = α,α,α’,α’-tetraphenyl-2,2’-dimethyl-1,3-dioxolane-4,5-dimethanol.4 a) E. Keller, J. Maurer, R. Naasz, T. Schrader, A. Meetsma, B. L. Feringa, Tetrahedron:Asymmetry 1998, 9, 2409; b) E. Keller, Catalytic Enantioselective Conjugate Addition Reactions,With a Focus on Water, PhD thesis, Groningen, 1998, chapter 7.5 A. Mandoli, L. A. Arnold, A. H. M. de Vries, P. Salvadori, B. L. Feringa, Tetrahedron:Asymmetry 2001, 12, 1929.

Chapter 2

36

6 For the preparation of optically active 3-alkylcyclopentanones through catalyticasymmetric conjugate reduction see: Y. Moritani, D. H. Appella, V. Jurkauskas, S. L.Buchwald, J. Am. Chem. Soc. 2000, 122, 6797.7 L. A. Arnold, R. Naasz, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2001, 123, 5841.8 L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries, R. Naasz, B. L. Feringa, Tetrahedron2000, 56, 2865.9 a) N. Sewald, V. Wendisch, Tetrahedron: Asymmetry 1998, 9, 1341; b) An achiral version ofthis reaction had already been published previously: A. Alexakis, J. Vastra, P. Mangeney,Tetrahedron Lett. 1997, 38, 7745; See also: c) H. Schäfer, D. Seebach, Tetrahedron 1995, 51, 2305.10 a) J. P. G. Versleijen, A. M. van Leusen, B. L. Feringa, Tetrahedron Lett. 1999, 40, 5803; b) J.Versleijen, Isocyanomethylboranes, Isocyanomethylphosphonates and Phosphoramidites for Use inOrganic Synthesis, PhD thesis, Groningen, 2001, chapters 6 and 7.11 a) R. Imbos, A. J. Minnaard, B. L. Feringa, Tetrahedron 2001, 57, 2485; b) R. Imbos, M. H. G.Brilman, M. Pineschi, B. L. Feringa, Org. Lett. 1999, 1, 623.12 A. Alexakis, C. Benhaïm, X. Fournioux, A. van den Heuvel, J.-M. Levêque, S. March, S.Rosset, Synlett 1999, 1811.13 A. Alexakis, G. P. Trevitt, G. Bernardinelli, J. Am. Chem. Soc. 2001, 123, 4358.14 A. H. M. de Vries, A. Meetsma, B. L. Feringa, Angew. Chem., Int. Ed. Engl. 1996, 35, 2374.15 A. Alexakis, S. Rosset, J. Allamand, S. March, F. Guillen, C. Benhaim, Synlett 2001, 1375.16 A. Alexakis, J. Burton, J. Vastra, C. Benhaim, X. Fournioux, A. van den Heuvel, J.-M.Levêque, F. Mazé, S. Rosset, Eur. J. Org. Chem. 2000, 4011.17 C. G. Arena, G. Calabrò, G. Franciò, F. Faraone, Tetrahedron: Asymmetry 2000, 11, 2387.18 O. Huttenloch, J. Spieler, H. Waldmann, Chem. Eur. J. 2000, 6, 671.19 F.-Y. Zhang, A. S. C. Chan, Tetrahedron: Asymmetry 1998, 9, 1179.20 P. Müller, P. Nury, G. Bernardinelli, Helv. Chim. Acta 2000, 83, 843.21 A. K. H. Knöbel, I. H. Escher, A. Pfaltz, Synlett 1997, 1429.22 a) I. H. Escher, A. Pfaltz, Tetrahedron 2000, 56, 2879; b) G. Helmchen, A. Pfaltz, Acc. Chem.Res. 2000, 33, 336.23 A. Alexakis, J. Vastra, J. Burton, P. Mangeney, Tetrahedron: Asymmetry 1997, 8, 3193.24 A. Alexakis, J. Vastra, J. Burton, C. Benhaim, P. Mangeney, Tetrahedron Lett. 1998, 39, 7869.25 a) M. Yan, L.-W. Yang, K.-Y. Wong, A. S. C. Chan, Chem. Commun. 1999, 11; b) M. Yan, A.S. C. Chan, Tetrahedron Lett. 1999, 40, 6645.26 M. Yan, Z.-Y. Zhou, A. S. C. Chan, Chem. Commun. 2000, 115.27 a) O. Pàmies, G. Net, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 1999, 10, 2007; b) O.Pàmies, M. Diéguez, G. Net, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 2000, 11, 4377.28 M. Diéguez, S. Deerenberg, O. Pàmies, C. Claver, P. W. N. M. van Leeuwen, P. Kamer,Tetrahedron: Asymmetry 2000, 11, 3161.29 M. T. Reetz, A. Gosberg, R. Goddard, S.-H. Kyung, Chem. Commun. 1998, 2077.30 M. T. Reetz, Pure Appl. Chem. 1999, 71, 1503.31 See ref. 17b in ref. 1a.

The catalytic enantioselective 1,4-addition of organometallic reagents

37

32 a) D. Seebach, M. Hayakawa, J.-I. Sakaki, W. B. Schweizer, Tetrahedron 1993, 49, 1711; b) J.-I. Sakaki, W. B. Schweizer, D. Seebach, Helv. Chim. Acta 1993, 76, 2654.33 A. Alexakis, C. Benhaim, Org. Lett. 2000, 2, 2579.34 C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J. Hyett, A. Martorell, A. G. Orpen, P. G.Pringle, Chem. Commun. 2000, 961.35 A. Martorell, R. Naasz, B. L. Feringa, P. G. Pringle, Tetrahedron: Asymmetry 2001, 12, 2497.36 A. Martorell, R. Naasz, unpublished results.37 A. Alexakis, J. Burton, J. Vastra, P. Mangeney, Tetrahedron: Asymmetry 1997, 8, 3987.38 Y. Yamanoi, T. Imamoto, J. Org. Chem. 1999, 64, 2988.39 X. Hu, H. Chen, X. Zhang, Angew. Chem., Int. Ed. 1999, 38, 3518.40 T. Morimoto, Y. Yamaguchi, M. Suzuki, A. Saitoh, Tetrahedron Lett. 2000, 41, 10025.41 Y. Nakagawa, K. Matsumoto, K. Tomioka, Tetrahedron 2000, 56, 2857 and references citedtherein.42 S. J. Degrado, H. Mizutani, A. H. Hoveyda, J. Am. Chem. Soc. 2001, 123, 755.43 For a detailed example of a positional optimization strategy see: B. M. Cole, K. D. Shimizu,C. A. Krueger, J. P. A. Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem., Int. Ed. Engl.1996, 35, 1668.44 T. Mori, K. Kosaka, Y. Nakagawa, Y. Nagaoka, K. Tomioka, Tetrahedron: Asymmetry 1998,9, 3175.45 G. Delapierre, T. Constantieux, J. M. Brunel, G. Buono, Eur. J. Org. Chem. 2000, 2507.46 M. Kitamura, T. Miki, K. Nakano, R. Noyori, Tetrahedron Lett. 1996, 37, 5141.47 V. Wendisch, N. Sewald, Tetrahedron: Asymmetry 1997, 8, 1253.48 a) I. Chataigner, C. Gennari, U. Piarulli, S. Ceccarelli, Angew. Chem., Int. Ed. 2000, 39, 916;b) I. Chataigner, C. Gennari, S. Ongeri, U. Piarulli, S. Ceccarelli, Chem. Eur. J. 2001, 7, 2628.49 S. Ongeri, U. Piarulli, R. F. W. Jackson, C. Gennari, Eur. J. Org. Chem. 2001, 803.50 O. Pàmies, G. Net, A. Ruiz, C. Claver, S. Woodward, Tetrahedron: Asymmetry 2000, 11, 871.51 a) C. Börner, W. A. König, S. Woodward, Tetrahedron Lett. 2001, 42, 327; b) C. Börner, M. R.Dennis, E. Sinn, S. Woodward, Eur. J. Org. Chem. 2001, 2435; c) S. M. W. Bennet, S. M. Brown,A. Cunningham, M. R. Dennis, J. P. Muxworthy, M. A. Oakley, S. Woodward, Tetrahedron2000, 56, 2847.52 a) F. Guillen, C. L. Winn, A. Alexakis, Tetrahedron: Asymmetry 2001, 12, 2083; b) J.Pytkowicz, S. Roland, P. Mangeney, Tetrahedron: Asymmetry 2001, 12, 2087.53 M. van den Berg, A. J. Minnaard, E. P. Schudde, J. van Esch, A. H. M. de Vries, J. G. deVries, B. L. Feringa, J. Am. Chem. Soc. 2000, 122, 11539.54 R. Imbos, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2001, accepted for publication.55 a) H. Malda, A. W. van Zijl, L. A. Arnold, B. L. Feringa, Org. Lett. 2001, 3, 1169; b) A.Alexakis, C. Malan, L. Lea, C. Benhaim, X. Fournioux, Synlett 2001, 927.56 a) F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, B. L. Feringa, Angew. Chem., Int. Ed. 2001,40, 930; b) F. Bertozzi, P. Crotti, B. L. Feringa, F. Macchia, M. Pineschi, Synthesis 2001, 483; c)F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold, B. L. Feringa, Org. Lett. 2000, 2, 933;d) F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold, B. L. Feringa, Tetrahedron Lett.

Chapter 2

38

1999, 40, 4893; e) F. Badalassi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold, B. L. Feringa,Tetrahedron Lett. 1998, 39, 7795.57 O. Pàmies, M. Diéguez, G. Net, A. Ruiz, C. Claver, Chem. Commun. 2000, 2383 andreferences cited therein.58 a) M. Diéguez, O. Pàmies, G. Net, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 2001, 12, 651;b) M. Diéguez, O. Pàmies, A. Ruiz, S. Castillón, C. Claver, Chem. Eur. J. 2001, 7, 3086.59 a) M. F. P. Ma, K. Li, Z. Zhou, C. Tang, A. S. C. Chan, Tetrahedron: Asymmetry 1999, 10,3259; This paper was retracted after we failed to reproduce the reported results: b) M. F. P.Ma, K. Li, Z. Zhou, C. Tang, A. S. C. Chan, Tetrahedron: Asymmetry 2000, 11, 2435; c) R.Naasz, E. P. Schudde, R. Hulst, A. J. Minnaard, B. L. Feringa, unpublished results.60 For a review and historical overview of structure and reaction mechanisms oforganocuprates see: a) E. Nakamura, S. Mori, Angew. Chem., Int. Ed. 2000, 39, 3751; See also:b) S. Woodward, Chem. Soc. Rev. 2000, 29, 393; c) N. Krause, A. Gerold, Angew. Chem., Int. Ed.Engl. 1997, 36, 187.61 H. O. House, Acc. Chem. Res. 1976, 9, 59.62 J. Berlan, K. Koosha, J. Organomet. Chem. 1978, 153, 107 and references cited therein.63 a) B. Christenson, T. Olsson, C. Ullenius, Tetrahedron 1989, 45, 523 and references citedtherein; b) S. H. Bertz, R. A. J. Smith, J. Am. Chem. Soc. 1989, 111, 8276; c) S. Sharma, A. C.Oehlschlager, Tetrahedron 1991, 47, 1177; d) A. S. Vellekoop, R. A. J. Smith, J. Am. Chem. Soc.1994, 116, 2902; e) N. Krause, R. Wagner, A. Gerold, J. Am. Chem. Soc. 1994, 116, 381.64 S. R. Krauss, S. G. Smith, J. Am. Chem. Soc. 1981, 103, 141.65 S. Mori, E. Nakamura, Chem. Eur. J. 1999, 5, 1534.66 B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771.67 M. Kitamura, T. Miki, K. Nakano, R. Noyori, Bull. Chem. Soc. Jpn. 2000, 73, 999.68 See also: A. H. M. de Vries, Catalytic Enantioselective Conjugate Addition of OrganometallicReagents, PhD thesis, Groningen, 1996, Chapter 6.69 This reduction might be achieved by Et2Zn or by another reducing agent, see also ref. 26.70 For a comparison between the different properties of zinc and copper see: S. Mori, A.Hirai, M. Nakamura, E. Nakamura, Tetrahedron 2000, 56, 2805.71 Apart from the X-ray structure shown in Figure 1.5 in Chapter 1, the only X-ray structureof a copper complex with one of the ligands discussed in section 2.2 was reported by Chan etal.; a [Cu(S,S)-2.23(MeCN)2OTf] complex. See ref 26.72 a) Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai, N. Miyaura, J. Am. Chem. Soc. 1998, 120,5579; b) Y. Takaya, M. Ogasawara, T. Hayashi, Chirality 2000, 12, 469.73 T. Hayashi, Synlett 2001, 879.74 a) M. Kuriyama, K. Tomioka, Tetrahedron Lett. 2001, 42, 921; b) M. T. Reetz, D. Moulin, A.Gosberg, ESOC 12 Programme and Abstracts, Groningen, 2001, Poster 2-2.75 For the nickel catalyzed enantioselective 1,4-addition of vinylic zinc reagents prepared insitu from Me2Zn and alkynes with ee’s up to 81%, see: S.-I. Ikeda, D.-M. Cui, Y. Sato, J. Am.Chem. Soc. 1999, 121, 4712.