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University of Groningen

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

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Publication date:1996

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Citation for published version (APA):de Vries, A. H. M. (1996). Catalytic enantioselective conjugate addition of organometallic reagents. s.n.

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1

Chapter 5

Towards a New Catalytic System for Enantioselective Conjugate Addition of Organometallic Reagents

5.1 Introduction

As was shown in the preceding Chapters all successful reports on catalyticenantioselective conjugate addition of organometallic reagents are limited to onespecific type of substrate. In spite of the introduction of novel tri- and tetradentateamino alcohols, the nickel catalysed alkyl transfer from diethylzinc is onlyenantioselective for acyclic enones so far (Chapter 4). In this Chapter attempts will be described to develop a catalyst which is effective forcyclic and acyclic enones. Three main variations have been investigated: - The reactivity of diethylzinc towards enones in the presence of metal salts other

than Ni(acac) .2

- Tuning of the copper catalysed alkyl transfer from diethylzinc to enones withchiral ligands.

- Tuning of the copper catalysed methyl transfer to enones withtrimethylaluminium as organometallic reagent.

5.2 The reactivity of diethylzinc towards enones in the presence of metalsalts

Organozinc compounds (R Zn and RZnY, I) react extremely sluggish with carbonyl2

compounds. The high covalent character of the carbon-zinc bond and the relativelymoderate Lewis acidity of Zn(II) are responsible for this inertness. The reactivity can1

be enhanced by the use of (chiral) ligands and/or by transmetalation to a second metal.2

The empty low-lying 4p orbitals of zinc allow many transmetalation reactions withmetallic salts to proceed as long as they are thermodynamically favoured. This ability1

permits the conversion of organozinc reagents into more reactive organometallicreagents RML (II) (Eq. 5.1). The synthetic utility of this approach has beenn

1b

demonstrated with nickel, copper, palladium and titanium salts.1,3 1,4 1,5 1,6

Y = R, halideM = Ti, Pd, Ni, CuX = halide

YX

MLnR

Zn (5.1)

II

X Zn Y+R MLn

I

R Zn Y + X MLn

Chapter 5

2

With this knowledge we have examined several metal salts as catalysts in the conjugateaddition of diethylzinc to chalcone (Table 5.1, entries 1-7). As chiral ligand aminoalcohol (-)-DAIB (5.3, Figure 5.1), successfully applied in the nickel catalysedconjugate addition, was employed. The catalytic conjugate addition reactions were runon a 1 mmol scale. In general, a solution of 7 mol% of metal salt and 16 mol% of (-)-DAIB in 2 ml of acetonitrile was heated at reflux for 1 h. Except for CuBr, all in situprepared complexes gave clear solutions, indicating the homogeneous nature of thecatalytic system. The three palladium salts gave a dark green solution and CuBr, ZnI ,2Fe(acac) , and Co(acac) afforded orange, colourless, red, and purple solutions,3 2

respectively. Chalcone (5.1) was added at room temperature followed by 1.5 ml ofdiethylzinc in hexane (1 M) at -30EC. After 16 h at -30EC the conversion wasdetermined by GC analysis. The results of these reactions are shown in Table 5.1.

PhPh

O

5.1 5.2

CH3CN, hexane-30°C

metal salt (cat.)chiral ligand (cat.)

Ph Ph

O

*+ Et2Zn

N

OH

N

NHO

NOH

N OH

PhPh

5.3 5.4 5.5 5.6


3

Table 5.1 Enantioselective conjugate addition of diethylzinc to chalcone ( 5.1)using various metal complexes. a

entry metal salt chiral ligand conv. (%) e.e. (%) abs. conf.b c d

1 Pd(OAc) 5.3 < 52

2 Pd(CH CN) Cl 5.3 < 53 2 2

3 PdCl 5.3 < 52

4 CuBr 5.3 60 41 R 5 ZnI 5.3 < 52

6 Fe(acac) 5.3 < 53

7 Co(acac) 5.3 70 67 R2

8 Co(acac) 5.4 80 83 S2

9 Co(acac) 5.5 48 33 R2

10 Co(acac) 5.6 58 28 S2

a. Reactions at -30EC in 2 ml of acetonitrile and 1.5 ml of hexane using an in situ prepared catalyst from 7 mol%of metal salt and 16 mol% of chiral ligand (Figure 5.1). Reaction time 16 h. b. Conversion to the 1,4-product,determined by GC analysis. c. Determined by HPLC analysis: Daicel, Chiralcel OD; 0.25% iPrOH in hexane,flow rate 1.0 ml/min, UV detector (254 nm). d. Comparison of retention times of (R)- and (S)-5.2 with knowndata gave the absolute configuration.7

Figure 5.1 Chiral ligands used in the Co(acac) catalysed addition of diethylzinc to2

5.1.

Chapter 5

4

In most cases the conjugate addition reaction appears not to proceed. (In all entries no1,2-addition was observed either.) Only with CuBr and Co(acac) conversions to the2

1,4-product higher than 50% were achieved. In comparison to the nickel catalysedreaction (> 95% conversion to the 1,4-product after 2 h at -30EC) the copper and cobaltcatalysed conjugate additions are slow and a considerable amount (ca. 5%) of a reducedbyproduct (1,3-diphenylpropan-1-one) has been detected. In spite of the relatively low8

conversion, product 5.2 was isolated and the e.e.'s were determined by HPLC analysis.With the CuBr and Co(acac) catalysed addition enantioselectivities were achieved of2

41% and 67%, respectively. These e.e. values indicate that (-)-DAIB is capable ofcreating selective catalysts with other metal salts, as well.A number of other chiral amino alcohols were examined with Co(acac) in the model2

reaction (Figure 5.1 and Table 5.1, entries 8-10). Employing (+)-DAB (5.4) as chiralligand, again the same enantioselectivity (83% e.e.) as in the nickel catalysed versionwas found for product 5.2. Amino alcohols (+)-diphenyl(1-methylazetidin-2-yl)-methanol (5.5) and (2S,2'S)-2-(hydroxymethyl)-1-[(1-methylpyrrolidin-2yl)methyl]-9

pyrrolidine (5.6) gave substantial lower conversions to the 1,4-product, moderate e.e.'s,and the reduced byproduct was detected in higher amounts (ca. 20%).Although reasonable yields and e.e.'s were found in the Co(acac) / chiral amino alcohol2

catalysed additions, no further experiments were performed for the following reasons:- The addition shows lower regioselectivity for the 1,4-product compared to the

Ni(acac) / chiral amino alcohol catalysed reaction.2

- With cyclohexenone (5.7) as substrate and (-)-DAIB as chiral ligand the reactionproceeds sluggish and no enantioselectivity was found.

- Copper salts showed to be more promising in an attempt to achieve catalyticenantioselective conjugate additions to cyclic and acyclic enones (vide infra ).

5.3 Copper catalysed enantioselective addition of diethylzinc to enones

IntroductionAs was shown in the preceding Section the catalyst derived in situ from CuBr and (-)-DAIB is capable of catalysing the conjugate addition of diethylzinc to chalcone. Theregioselective conversion to the 1,4-product is slow (compared to Ni(acac) / (-)-DAIB)2

and a moderate enantioselectivity was found (41% e.e., Table 5.1, entry 4). Althoughthis result supposes quite the contrary, copper salts seem to be the metal salt of choicefor achieving catalytic enantioselective conjugate addition to both cyclic and cyclicenones for the following reasons: (1) Probably due to the affinity of the (chiral) nickelcenter for the carbonyl oxygen, only enantioselective alkyl transfer occurs in the case

VIVIII

ONiL*n

R R

ONiL*n

CuL*nR''

O

R R'


5

of s-cis enones, i.e. chalcone, as is shown in Figure 5.2 (III). For cyclohexenone,probably intermediate IV will be formed with the chiral nickel complex too far awayfrom the $-position and therefore not able to introduce any asymmetry (see precedingChapters). Copper complexes, on the other hand probably coordinate to the carbon-carbon double bond of the enone, furnishing intermediates like V, with possibilities10

for enantioselective alkyl transfer to both cyclic and acyclic enones (i.e. s-trans and s-cis enones).

Figure 5.2 Possible intermediates in the nickel catalysed alkyl transfer to acyclic(III) and cyclic enone ( IV) and the copper catalysed reaction ( V).

(2) Preliminary investigations on the CuI catalysed addition of diethylzinc tocyclohexenone (5.7) have revealed that this reaction is slow and not regioselective. SeeGC diagram A in Figure 5.3, which shows besides the 1,4-product (5.8, retention timeof 5.88 min), several other products, and a substantial amount of unreacted substrate(retention time of 2.88 min). With an additional (chiral) ligand, for example (+)-DAB(5.4), the conversion is faster and a higher regioselectivity to the 1,4-product wasfound. (ca. 80%, GC diagram B, Figure 5.3). This is a typical example of ligand-accelerated catalysis and "the gate to successful metal catalysed asymmetricreactions". In reactions with transition metals, however, a variety of metal complexes11

often exists simultaneously in solution. These molecular assemblies form12

spontaneously and the composition of the mixtures is dictated by thermodynamicfactors. The goal in the development of efficient asymmetric catalysis is to find thatparticular, active and highly enantioselective complex.(3) Furthermore, a switch to copper salts was stimulated by a report of Alexakis and co-workers, of an in situ prepared complex of CuI and a chiral trivalent phosphorus ligand,which catalyses the enantioselective conjugate addition of diethylzinc tocyclohexenone (5.7, Scheme 5.1). However, with chalcone as substrate no e.e. for the13

1,4-product was found.With this knowledge we have examined three different classes of chiral ligands in theCuI (10 mol%) catalysed addition of diethylzinc to cyclohexenone (5.7) and tochalcone (5.1).

L* =

5.7

NP

OPh

N

i-Pr5.9

70 % yield32 % e.e. (S)

O

Et

O

5.8

*+ Et2Zn CuI (cat.)L* (cat.)

toluene20°C


7

Figure 5.3 GC diagrams of the CuI catalysed (A, after 5 days at -10 EC in toluene)and the CuI / (+)-DAB ( 5.4) catalysed (B, after 24 h at -20 EC in toluene)addition of diethylzinc to cyclohexenone.

Scheme 5.1 CuI catalysed addition of diethylzinc to 5.7, reported by Alexakis and co-workers. 13

Amino alcohol ligandsAs already mentioned the chiral tertiary amino alcohol (+)-DAB or (-)-DAIB (20 mol%)showed a substantial ligand-acceleration in the copper catalysed conjugate addition ofdiethylzinc to 5.7 (Figure 5.3). The reaction time was shortened and the regioselectivityto the 1,4-product has been improved to ca. 80%. Unfortunately, with both chiral aminoalcohol ligands, the 1,4-product 5.8 was isolated without any enantioselectivity, incontrast to the copper catalysed addition to chalcone (Table 5.1, entry 4). The e.e. of theresulting 1,4-product was determined by the formation of diastereomeric aminals withcommercially available optically pure 1,2-diphenylethylene diamine. This method is14

much faster than the routinely accomplished formation of diastereomeric ketalsaccording to the Hiemstra-Wynberg method.15

Phosphorus ligandsTraditionally phosphorus compounds are considered one of the best soft base ligandsfor copper(I) and a significant number of complexes of known crystal structure,primarily with trivalent monodentate ligands, has been described. In general, the16

monomeric phosphorus ligands only coordinate as single ligand donors and are notinvolved in any bridging role. Furthermore, trivalent phosphorus compounds areknown as (chiral) ligands for stoichiometric conjugate organocopper additions to cyclicenones.17,18,19

benzeneRT, 3 h

HMPT+OO

P NOHOH

(5.2)

5.10

Chapter 5

8

Recently, Hulst has synthesised quite easily from (S)-2,2'-binaphthol and HMPT, anovel chiral trivalent phosphorus compound (5.10, Eq. 5.2). Phosphorus amidites have20

been applied extensively as improved capping reagents for the synthesis ofoligonucleotides, however, they represent a class of compounds, hardly recognized21 22

as ligands for catalytic transformations.23

When ligand 5.10 (20 mol%) was examined in the CuI (10 mol%) catalysed addition ofdiethylzinc to cyclohexenone (5.7, Scheme 5.1) the above mentioned ligand-acceleration is even more pronounced. Within 24 h the catalytic reaction, in toluene /hexane at -10EC, results in selective formation of the 1,4-product (> 90%, GC analysis).Only traces of reduced products were detected. Product 5.8 was isolated in 75% yieldwith an e.e. of 35% (Table 5.2, entry 1).


9

Table 5.2. Enantioselective conjugate addition of diethylzinc to cyclohexenone andchalcones catalysed by ligand 5.10 and copper(I) salts. a

entry substrate CuX (mol%) mol% of 5.10 solvent e.e. (%) b c

abs. conf.d

1 5.7 CuI (10) 20 toluene / hexane 35 S 2 5.7 CuI (10) 20 THF / hexane 22 S 3 5.7 CuI (10) 20 diethylether / hexane 0

4 5.7 CuI (10) 20 acetonitrile / hexane 5S

5 5.7 CuBr (10) 20 toluene / hexane 35 S 6 5.1 CuI (10) 20 toluene / hexane 14 R 7 5.1 CuI (10) 20 toluene 47 R 8 5.7 CuI (10) 20 toluene 38 S 9 5.7 CuI (10) 50 toluene 18 Se

10 5.7 CuI (10) 10 toluene 25 S11 5.7 CuI (10) 15 toluene 35 S12 5.7 CuI (50) 100 toluene 40 Sf

a. Reactions at 1 mmol scale at -10EC. Reaction time 24 h. Conversion to the 1,4-product (5.8) > 90% (basedon GC analysis). b. 1.5 Equivalent of diethylzinc added as solution in hexane (1M) or toluene (1.1M) c.Enantiomeric excess of 3-ethylcyclohexanone (5.8) determined by derivatisation with optically pure 1,2-diphenylethylene diamine. E.e. determination of 5.2, see Table 5.1. d. Comparison of the optical rotation of14

5.8 with known data gave the absolute configuration. For e.e. determination of 5.2, see Table 5.1. e.24

Conversion to the 1,4-product (95%) only achieved after an additional 3 days at RT. f. At 0.5 mmol scale in15 ml of toluene.

The enantioselectivity in the formation of the 1,4-product showed to be stronglydependent on the solvent used. Although the reaction is also very selective to the 1,4-product in THF, diethyl ether, and acetonitrile significant lower (or no) e.e.'s werefound (22, 0, and 5%, respectively, entries 2-4). With CuBr instead of CuI the samereaction rate and enantioselectivity was found.When the most selective reaction conditions, found for 5.7, were employed with theacyclic substrate chalcone (5.1) a very regioselective 1,4-addition occurred.Unfortunately, for 5.2, isolated in 87% yield, a disappointing e.e. of 14% was found(entry 6). At this stage all conjugate addition reactions described in this Chapter wereperformed with a solution of diethylzinc in hexane. When a solution of diethylzinc in

Chapter 5

10

toluene was added to the reaction mixture a remarkable increase in e.e. for 5.2 wasfound (entry 7). With cyclohexenone this variation had a minor influence (entry 8). Apossible explanation is B-stacking of the chiral catalyst and the aromatic substratepromoted by toluene into a more enantioselective aggregate.Employing 50 mol% of 5.10 and 10 mol% of CuI, furnished a chiral catalyst which isonly active at room temperature, less regioselective and hardly enantioselective (entry9). Better results were obtained with 5.10 / CuI ratios of 1 and 1.5 (entries 10 and 11).At higher concentration of the chiral catalyst no significant enhancement was found inreactivity and enantioselectivity (entry 12). These remarkable results indicate the highactivity of the enantioselective catalyst, prepared in situ of appropriate amounts of CuIand 5.10, compared to the other possible complexes in solution.Although moderate enantioselectivities were found for 5.2 and 5.8 these preliminaryexperiments represent the first example of catalytic enantioselective conjugate additionof an organometallic reagent to both a cyclic and acyclic substrate and provide severalapproaches for further investigation (see Chapter 6).

Sulfur ligandsConsistent with the soft base behaviour of sulfur ligands, a considerable number ofcopper(I) complexes of sulfur ligands has been reported. In general, it is a goodmonodentate ligand in trigonal planar and tetrahedral complexes, but it is equally wellfunctioning as a bridging ligand in dinuclear and polynuclear aggregates. Sulfur16

containing compounds are known as chiral ligands for stoichiometric and catalytic25

enantioselective conjugate addition reactions of Grignard reagents to enones. 26

Furthermore, the research group of Prof. Kellogg has shown that optically pure thiolsand sulfides are successful catalysts in the enantioselective addition of diethylzinc tobenzaldehyde. Therefore, several (novel) sulfur containing compounds were27

examined as chiral ligands in the copper catalysed addition of diethylzinc tocyclohexenone and chalcone.First, thiophosphonate 5.11 (see Figure 5.3), known as a chiral equivalent of H S,28 29

2

was tested in the CuI catalysed addition of diethylzinc to cyclohexenone. A mixture ofCuI (10 mol%) and of 5.11 (15 mol%) in toluene furnished a catalyst which is ratherslow and less regioselective to the 1,4-product (compared to 5.10). After 4 days at -10EC, 88% of the substrate was converted to 5.8 with an e.e. of 15%. Probably due tosolubility problems this is not the chiral ligand of choice under these reactionconditions.

5.13

S N

O

5.11

OO

PS

SH

5.12

N

S

OPh

R1N

R2

a R1 = Me, R2 = Hb R1 = Me, R2 = Mec R1 = i-Pr, R2 = H

N

S

OPh

N

5.12d

*

5.8

O O

5.7

+ Et2ZnCuOTf (cat.)5.12 (cat.)

toluene-10°C


11

Figure 5.3 Sulfur containing ligands used in the copper catalysed addition o fdiethylzinc to cyclohexenone and chalcone .

Later on in this project, solubility of the in situ prepared chiral catalysts was enhancedwith CuOTf or Cu(OTf) as the copper source (see Chapter 6). When a mixture of2

Cu(OTf) (3 mol%) and of 5.11 (6.5 mol%) in toluene was employed as chiral catalyst,2

the addition of diethylzinc to cyclohexenone proceeds within 16 h at -15EC and withgood selectively to the 1,4-product. Product 5.8 was isolated in 65% yield, however,no significant e.e. (< 10%) was found. For chalcone (5.1) this Cu(OTf) / 5.11 catalyst2

was less reactive (55% isolated yield after 2 days at -15EC) and a disappointing e.e of7% was found.

Table 5.3 Enan tioselective 1,4-addition of diethylzinc to cyclohexenon ecatalysed by CuOTf and sulfur containing ligands 5.12. a

entry ligand e.e. of 5.8 (%) abs. conf.b b

1 5.12a 47 R 2 5.12b 39 R 3 5.12c 62 R 4 5.12d 49 R

Chapter 5

12

a. Reactions at 1 mmol scale at -10EC in 5 ml of toluene. Reaction time 2-14 h (see text). Conversion to the 1,4-product > 95% (based on GC analysis). Isolated yields > 70%. b. Determination of e.e. and absoluteconfiguration of 3-ethylcyclohexanone (5.8), see Table 5.2.

Next, several novel substituted thiazolidin-4-ones 5.12a-d (Figure 5.3), synthesised byHof, were examined in the CuOTf catalysed addition of diethylzinc to cyclohexenone30

(Table 5.3). The synthesis of 5.12a-d is based on cyclocondensation of an "-mercaptoacid, aniline, and the corresponding carboxaldehyde furnishing the thiazolidin-4-onesin quantitative yield as a mixture of diastereoisomers. Diastereomerically pure cis-5.12a-d were obtained by recrystallisation. With ligand 5.12a (11 mol%) and 5 mol%30

of CuOTf a very selective reaction to the 1,4-product (> 90%, GC analysis) was found.Isolation, purification, and derivatisation of 5.8 revealed an e.e. of 47% (entry 1).In order to improve the observed enantioselectivity sterically demanding groups onboth the pyridyl group (5.12b and 5.12d) and the "-position (5.12c) were introduced.Clearly, a methyl substituent on the pyridine ring reduces the e.e. (5.12b, 39%, entry2), probably by inducing the formation of another aggregate of the copper complex insolution. Quinoline, instead of pyridine (5.12d), had a minor influence, whereas asterically demanding group at the "-position in ligand 5.12c gave the best results. After2 h quantitative conversion to the 1,4-product was achieved and an enantiomeric excessof 62% was observed.For comparison, the chiral oxazoline substituted thiophene 5.13 was also examined31

in the model reaction given in Table 5.3. Again a high selectivity of 95% to the 1,4-product was observed. However, the low enantiomeric excess of 5.8 (5%) found withthis chiral thiophene, indicates the necessity of the chiral cavity created by the cisconfiguration of both substituents in ligands 5.12. Furthermore, the role of the amidefunctionality in ligands 5.12 is not clear at this moment.With chalcone as substrate complete 1,4-selectivity was observed as well in the CuOTf/ 5.12 catalysed addition, however, low e.e.'s for 5.2 (up to 11% for ligand 5.12c) wereobserved. In cooperation with the group of Prof. Kellogg, optimisation of the structureof this novel type of sulfur containing ligands is under progress. The scope of thisreaction and possible other asymmetric transformations will be explored.

5.4 Enantioselective copper catalysed methyl transfer to enones withtrimethylaluminium as organometallic reagent

IntroductionThe 1,4-addition of hydrocarbon substituents to ",$-unsaturated carbonyl compoundsis usually achieved by using organocuprate reagents. Asymmetric conjugate addition32

Ph Ph

O

*

5.25.1

PhPh

O

+ EtMgBr


13

of organocuprates is well established with chiral and prochiral substrates. In an effort33

to create a system capable of catalytic enantioselective conjugate addition of Grignardreagents, preliminary experiments were performed in the presence of (-)-DAIB (5.3).Contrary to other substrates, the addition of EtMgBr to chalcone in diethyl ether at34

room temperature proceeded quite selective to the 1,4-product. (GC analysis revelaeda regioselectivity of ca. 90%, Table 5.4, entry 1). In the presence of catalytic amounts35

of 5.3 and KOt-Bu or Ni(acac) in diethyl ether / propionitrile at -50EC, this 1,4-addition2

is even more regioselective (> 90%, GC analysis) and 5.2 could be isolated in 86% and92%, respectively (entries 2 and 3). Unfortunately, in both cases no enantioselectivealkyl transfer occurred.Since there is no enantioselectivity at all in the presence of (-)-DAIB and secondly, theenantioselective transfer of alkyl groups from Grignard reagents to enones is stilllimited to one type of substrate (see Section 2.3), the main point of our research hasbeen shifted to other organometallic reagents.

Table 5.4 Conjugate addition of EtMgBr to chalcone .a

entry chiral ligand (mol%) metal source (mol%) yield (%) e.e.b

(%)c

1 - - nd -c

2 5.3 (16) KOt-Bu (16) 86 0 3 5.3 (16) Ni(acac) (7) 92 22

a. Reaction conditions see text. b. Isolated yield. c. Yield not determined. GC analysis revealed a 1,4-selectivity of 90% at 100% conversion.

Trimethylaluminium as organometallic reagentThe 1,4-addition of hydrocarbon substituents to ",$-unsaturated carbonyl compoundshas also been reported with organomanganese reagents, organotitanates,36 37

organoaluminium halides and trialkylaluminium reagents. Especially the highly38 39,40

selective copper(I) catalysed alkyl transfer from aluminium compounds to several

PhPh

O

Ph Ph

O

*+ Me3Al

L* (cat.)CuBr (cat.)

solvent-30°C5.1 5.2a

Chapter 5

14

cyclic and acyclic enones, reported by the research group of Kabbara andWestermann, catched our attention. Screening of chiral ligands with affinity for40c,d

copper(I), should furnish a novel catalytic enantioselective conjugate addition method.Therefore, amino alcohols 5.3, 5.4 and 5.6, phosphorus amidite 5.10 and thioephedrines5.14 and dimer 5.15 were examined in the CuBr catalysed addition of30a

trimethylaluminium (TMA) to chalcone. The results are summarised in Table 5.5. Withligands 5.3, 5.4 and 5.6 the addition reaction in ethyl acetate is highly regioselectiveto the the 1,4-product, and comparable with those found in the literature withoutadditional ligand. Enantioselectivities for 5.2a of 5%, 30%, and 5% were observed,40c,d

respectively. Although the e.e. found for 5.2a, when ligand 5.4 was employed, ismoderate, this is to our knowledge the first example of a catalytic enantioselective alkyltransfer from aluminium compounds to an enone.41

Table 5.5 CuBr catalysed enantioselective conjugate addition of Me Al to3

chalcone. a

entry ligand solvent conv. (%) e.e. (%)b c

1 5.3 ethyl acetate 91 5 2 5.4 ethyl acetate 94 30 3 5.6 ethyl acetate 90 5 4 5.10 ethyl acetate 68 ndd e

5 5.14 ethyl acetate 55 < 5d

6 5.15 ethyl acetate 66 ndd e

7 5.4 THF 98 8 8 5.4 acetonitrile 96 0

a. Reactions at 1 mmol scale in 2 ml of solvent using an in situ prepared catalyst from 7 mol% of CuBr and 20mol% of chiral ligand; 0.7 ml of 2M solution of TMA in hexane (or toluene) was added. Reaction time 48 h.b. Conversion to the 1,4-product, determined by GC analysis. c. Determined by HPLC analysis, see Table 5.1.d. Reaction proceeds only at RT. Conversion after 3 days. e. E.e. could not be determined due to isolation andpurification problems.

S N

Ph

H(

2HS N

Ph

H.HCl

5.14 5.15

(5.3)

5.1

PhPh

O

+ Me3Al

L* (cat.)CuBr (cat.)

toluene Ph Ph

OH

5.16

5.185.175.8a

O

OO OH

+ +

TMA5.4 (cat.)CuBr (cat.)

O

5.7

(5.4)ethyl acetate


15

When phosphorus amidite 5.10 or thiolephedrines 5.14 and 5.15 were employed aschiral ligands, the addition of TMA to 5.1 proceeded very sluggish and no significante.e. for 5.2a was observed (entries 4-6). The transfer of the methyl group of TMA to thecopper atom and subsequently to the enone is apparently hampered by these chiralligands. Furthermore, the copper catalysed addition of TMA to enones showed a remarkablesolvent dependency. The conjugate addition of TMA to 5.1, in the presence of ligand5.4 and CuBr, proceeded smoothly in other polar solvents like THF or acetonitrile.However, hardly any enantioselectivity was observed. Coordinative solvents open thedimeric structure of organoaluminium compounds to form monomeric complexes witha significantly reduced electronegativity of aluminium. The weak nucleophilicity of40d

the organometallic reagent and as a result complete 1,4-addition can be attributed tothis property.On the other hand, reaction of TMA with enones in apolar solvents like toluene orhexane results in fast 1,2-addition to the carbonyl group (Eq. 5.3; see also ref. 40d).Compound 5.16 was isolated in 90% yield. In spite of the presence of 5.4, this carbonyladdition proceeded without any enantioselectivity.

Chapter 5

16

Employing the most successful conditions found in the reaction with chalcone, thecopper catalysed addition of TMA to cyclohexenone (5.7) resulted in a mixture ofproducts. Besides traces of reduced products, 5.8a, the 1,2-product 5.17, and a dimericstructure, probably 5.18, were detected by GCMS analysis (Eq. 5.4). Apparently, withcyclic substrates the 1,4-addition of TMA is competing with several other reactionsincluding a tandem reaction of the enolate with unreacted starting material. Since40d

there is no selectivity to a single product with 5.7 was usedas substrate no furtherexperiments were performed using other cyclic substrates.

5.5 Summary and concluding remarks

It has been demonstrated that transmetalation of alkyl group from dialkylzinc to copperor cobalt and subsequently to the ",$-unsaturated ketone is possible. However, with thechiral amino alcohol ligands 5.3-5.6 no new general catalysts were obtained capableof enantioselective conjugate addition to both cyclic and acyclic enones. Better catalysts were obtained with the combination of CuI and phosphorus amidite5.10 or sulfur containing ligands 5.12. With both ligands a remarkable ligand-acceleration was observed, resulting in very regioselective conjugate additions ofdiethylzinc to cyclohexenone and chalcone. The system, derived of CuI and twoequivalents of 5.10, is the first catalyst reported so far, capable of enantioselectiveconjugate addition to both cyclic and acyclic enones. Also, with the substitutedthiazolidin-4-ones 5.12 relatively high enantioselectivities were observed for theconjugate addition of diethylzinc to cyclohexenone.Interesting results were achieved with the CuBr catalysed enantioselective methyltransfer from trimethylaluminium (TMA) to chalcone. With chiral amino alcohol (+)-DAB (5.4) the highly regioselective 1,4-addition of TMA to chalcone proceeded with30% e.e. Unfortunately, with cyclohexenone no regioselective addition occurred. Especially the preliminary experiments on the copper / phosphorus amidite catalysedasymmetric 1,4-addition of diethylzinc to cyclohexenone and chalcone, although e.e.'sare moderate, provide several approaches for further investigation.

5.6 Experimental section

For general remarks, see Section 3.8.

Materials


17

The following compounds were commercially available and used without purification:All metal salts shown in Table 5.1 (Aldrich), 1,2-diphenylethylene diamine (Fluka), andtrimethylaluminium (2 M in hexane or toluene, Aldrich). Hexamethylphosphorustriamide (HMPT) was purchased from Aldrich and distilled before use.O,O'-(1,1'-Dinaphthyl-2,2'-diyl)dithiophosphoric acid (5.11) was prepared accordingto a published procedure. Chiral ligands (+)-diphenyl(1-methylazetidin-2-yl)-28

methanol (5.5), substituted thiazolidin-4-ones 5.12, (4S)-4-i-propyl-2-(2-thienyl)-9 30

1,3-oxazoline (5.13) and thiolephedrines 5.14 and 5.15 were kindly provided by31 30a

Prof. Martens, R. Hof, C. Zondervan, and R. Hof, respectively. For all other materials,see Section 3.8.

Conjugate addition of diethylzinc to chalcone (5.1) using catalytic amounts of metalsalts and chiral amino alcoholsThis procedure is typical for all entries in Table 5.1. A solution of 0.07 mmol of metalsalt and 0.16 mmol of chiral amino alcohol in 2 ml of acetonitrile was stirred andrefluxed for 1 h under nitrogen. The solution was cooled to room temperature and 208mg (1.0 mmol) of 1,3-diphenyl-2-propen-1-one (5.1) was added. The mixture wascooled to -35EC and 1.5 ml of diethylzinc in hexane (1 M, 1.5 mmol) was added.Stirring was continued at -30EC for 16 h. An aliquot of the solution (0.1 ml) was drawnand quenched with 1 ml of 3 N HCl. After extraction with 1 ml of diethyl ether theconversion was determined by GC analysis. Retention times (oven temperature 225EC,flow 101 ml/min He): 1,3-diphenyl-2-propenone (5.1), 5.66 min; 1,3-diphenylpentan-1-one (5.2), 4.93 min. If the conversion to 5.2 was higher than 50%, the mixture waspoured into 25 ml of aqueous 3 N HCl and extracted with diethyl ether (3 x 20 ml). Forpurification and e.e. determination of 5.2, see Section 3.8. Conversions and e.e. valuesare given in Table 5.1.

O,O'-(1,1'-Dinaphthyl-2,2'-diyl)-N,N-dimethylphosphorus amidite (5.10)The synthesis of 5.10 is somewhat improved compared to the published procedure. 20

To a mixture of (S)-(-)-1,1'-bi-2-naphthol (1.81 g, 6.3 mmol) in 10 ml of dry benzenehexamethylphosphorus triamide (1.14 g, 7.0 mmol) was added. After 1 min a whitesolid precipitated. The mixture was stirred for 3 h at ambient temperature and the solidwas collected by filtration, washed with diethyl ether (10 ml) and dried in vacuo to give1.99 g (5.5 mmol, 88%) of pure 5.10. An optical rotation of ["] = +593E (c 0.90,20

D

CHCl) was found contrary to an earlier report. All other spectroscopic data ( H NMR,320 1

C NMR, P NMR, HRMS) were in good agreement with reported values.13 31 20

Conjugate addition of diethylzinc to cyclohexenone (5.7) or chalcone (5.1) using

Chapter 5

18

catalytic amounts of CuI and chiral amino alcohols, phosphorus amidite 5.10 orsulfur containing ligands 5.11-13This procedure is typical for all conjugate addition reactions described in Section 5.3.A solution of copper salt and of chiral ligand in 5 ml of toluene was stirred at ambienttemperature for 1 h under nitrogen (for amounts of chiral catalyst, see text in Section5.3 and Tables 5.2 and 5.3). In general this results in a clear solution. If not, anappropriate amount of CH Cl was added untill a clear solution was obtained. Substrate2 2

was added (1.0-2.0 mmol), the mixture was cooled to -30EC and diethylzinc in hexane(1 M) or toluene (1.1 M) (1.5 equivalent) was added. Stirring was continued atappropriate temperature (see text) for 24 h. An aliquot of the solution (0.1 ml) wastaken and quenched with 1 ml of aqueous 1 N HCl. After extraction with 1 ml of diethylether the conversion was determined by GC analysis. Retention times (oventemperature 100EC, flow 101 ml/min He): cyclo-2-hexen-1-one (5.7), 2.87 min; 3-ethylcyclohexan-1-one (5.8), 5.88 min. For retention times of 5.1 and 5.2, see above.When complete conversion was achieved the mixture was poured into 25 ml of aqueous1 N HCl and extracted with diethyl ether (3 x 20 ml). If the conversion was notcomplete, longer reaction times and / or higher temperatures were required (see text).The combined organic layers were washed with brine (25 ml), dried (MgSO ), filtered4

and evaporated to give the crude 1,4-products. (Caution: compound 5.8 is volatile andlong evaporation times should be avoided.) After purification by columnchromatography (SiO , hexane:diethyl ether 5:1) the e.e.'s were determined. For 3-2

ethylcyclohexan-1-one (5.8): Derivatisation with optically pure 1,2-diphenylethylenediamine in CDCl (10 min, with some 4Å mol sieves) followed by C NMR analysis.3

13 14

For 1,3-diphenylpentan-1-one (5.2): HPLC analysis (see Section 3.8). H NMR and C1 13

NMR data of 5.2 and 5.8 were in good agreement with the data found in Chapters 3 and4. E.e. values are given in Section 5.3 and Tables 5.2 and 5.3.

Conjugate addition of EtMgBr to chalcone (5.1) using catalytic amounts of KOt-Buor Ni(acac) and (-)-DAIB (5.3)2

A solution of 0.16 mmol of KOt-Bu or 0.07 mmol of Ni(acac) and 0.16 mmol of (-)-2

DAIB (5.3) in 5 ml of propionitrile was stirred for 1 h under nitrogen. Chalcone (208mg, 1.0 mmol) was added and the mixture was cooled to -50EC and EtMgBr in diethylether (0.4 M, 2.0 mmol) was added. After 16 h at -50EC the reaction mixture was pouredinto 50 ml of saturated NH Cl solution, separated and extracted with diethyl ether (2 x4

25 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ),4

filtered and evaporated to give the crude 1,4-product. For purification and e.e.determination of 5.2, see Section 3.8.


19

Conjugate addition of trimethylaluminum (TMA) to chalcone (5.1) using catalyticamounts of CuBr and chiral amino alcohols, phosphorus amidite 5.10 orthiolephedrines 5.14 or 5.15This procedure is typical for all conjugate addition reactions described in Table 5.5. Asolution of 0.07 mmol of CuBr and 0.20 mmol of chiral ligand in 2 ml of solvent wasstirred at ambient temperature for 1 h under nitrogen. Chalcone was added (1.0-2.0mmol), the mixture was cooled to -30EC and TMA in hexane (2 M) or toluene (2 M) (1.5equiv.) was added. Stirring was continued at -30EC for 48 h. An aliquot of the solution(0.1 ml) was taken and quenched with 1 ml of aqueous 1 N HCl. After extraction with1 ml of diethyl ether the conversion was determined by GC analysis. Retention times,see above. When complete conversion was achieved the mixture was poured into 25 mlof aqueous 1 N HCl and extracted with diethyl ether (3 x 25 ml). If conversion was notcomplete, longer reaction times and / or higher temperatures were required (see text).The combined organic layers were washed with brine (25 ml), dried (MgSO ), filtered4

and evaporated to give the crude 1,4-products. For purification and e.e. determinationof 5.2a, see Section 3.8. Conversions and e.e. values are given in Table 5.5.

1,3-Diphenyl-1-buten-3-ol (5.16)A solution of 0.07 mmol of CuBr and 0.20 mmol of (+)-DAB (5.4) in 2 ml of toluenewas stirred at ambient temperature for 1 h under nitrogen. Chalcone was added (1.0mmol), the mixture was cooled to -30EC and TMA in toluene (2 M, 1.5 equivalent) wasadded. Stirring was continued at -10EC for 16 h and the mixture was poured into 50 mlof aqueous 1 N HCl and extracted with diethyl ether (3 x 25 ml). The combined organiclayers were washed with brine (25 ml), dried (NaSO ), filtered and evaporated to give4

5.16, which was purified by column chromatography (SiO , hexane:diethyl ether 3:1).2

Yield 90%. H NMR (300 MHz, CDCl ) * 1.81 (s, 3H), 2.19 (bs, 1H), 6.54 (d, J = 16.0 13

Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H), 7.27-7.56 (m, 10H). C NMR * 29.82 (q), 74.68 (s),13

125.29 (d), 126.59 (d), 127.09 (d), 127.64 (d), 127.70 (d), 128.33 (d), 128.59 (d), 136.36(d), 136.71 (s), 146.61 (s). HRMS calcd for C H O: 224.120, found 224.120.16 16

E.e. of 5.16 was determined by HPLC analysis; Daicel (Chiralcel OD), 10% iPrOH inhexane, flow rate 1.0 ml/min, UV detector (254 nm); retention times 10.93 min and13.54 min.

Copper catalysed addition of trimethylaluminum (TMA) to cyclohexenone (5.7) A solution of 0.07 mmol of CuBr and 0.20 mmol of (+)-DAB (5.4) in 2 ml of ethylacetate was stirred at ambient temperature for 1 h under nitrogen. Cyclohexenone wasadded (1.0 mmol), the mixture was cooled to -30EC and TMA in toluene (2 M, 1.5equivalent) was added. Stirring was continued at -30EC for 2 days and the mixture was

Chapter 5

20

1. a) Boersma, J. In Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F.G.A.; Abel, E.W.,Eds.; Pergamon: Oxford, 1982, Vol. 2, Chapter 16. b) Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93,2117.

2. Reviews on catalytic asymmetric diethylzinc addition to aldehydes, see: a) Noyori, R.; Kitamura, M.Angew. Chem. Int. Ed. Engl. 1991, 30, 49. b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.

3. a) Kumada, M. Pure Appl. Chem. 1980, 52, 669. b) Greene, A.E.; Lansard, J.P.; Luche, J.L.; Petrier, C.J. Org. Chem. 1984, 49, 931. c) Petrier, C.; de Souza Barbosa, J.C.; Dupuy, C.; Luche, J.-L. J. Org. Chem.1985, 50, 5761. See also reference 5c.For nickel catalysed asymmetric conjugate addition reactions of dialkylzincs, see Section 2.5 andChapters 3 and 4.

4. a) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056. b)Knochel, P.; Yeh, M.C.P.; Berk, S.C. Talbert, J. J. Org. Chem. 1988, 53, 2390. c) Tamaru, Y.; Tanigawa,H.; Yamamoto, T.; Yoshida, Z. Angew. Chem., Int. Ed. Engl. 1989, 28, 351. d) Zhu, L.; Wehmeyer, R.M.;Rieke, R.D. J. Org. Chem. 1991, 56, 1445. e) Rozema, M.J.; AchyuthaRao, S.; Knochel, P. J. Org. Chem.1992, 57, 1956. See also reference 13.

5. a) Negishi, E.; King, A.O.; Okuda, N. J. Org. Chem. 1977, 42, 1821. b) Negishi, E.; Valente, L.F.;Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298. c) Negishi, E. Acc. Chem. Res. 1982, 15, 340.

6. a) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30, 1657. b) Seebach, D.; Behrendt,L.; Felix, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1008. c) Duthaler, R.O.; Hafner, A. Chem. Rev.1992, 92, 807. d) Rozema, M.J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.Tetrahedron Lett. 1993, 34, 3115.These publications report about chiral titanium complexes, capable of catalysing the addition of(functionalised) dialkylzinc reagents to aldehydes. In the presence of catalytic amounts of trans-1(R),2(R)-bis(trifluoromethanesulfonamido)cyclohexane and Ti(Ot-Bu) this protocol can be6a,d

4

extended to enantioselective conjugate addition reactions to chalcone (5.1, see below). For the

poured into 50 ml of aqueous 1 N HCl, separated and extracted with diethyl ether (2 x25 ml). The combined organic layers were washed with brine (25 ml), dried (NaSO ),4

filtered and evaporated. GC and GCMS analysis revealed several products with noselectivity to one single product.

Acknowledgement

The pleasant cooperation with Dr. R. Hof to examine sulfur containing ligands in thecopper catalysed conjugate addition reactions is gratefully acknowledged. Dr. R. Hulstis thanked for the synthesis of 5.10 and A. Arnold for the performance of someexperiments described in this Chapter. The research group of Prof. Martens, Universityof Oldenburg and C. Zondervan are acknowledged for the synthesis of 5.5 and 5.13,respectively. Mr. M. Suijkerbuijk and Mr. W. Kruizinga are thanked for assistance withthe many e.e. determinations of 5.2(a) and 5.8, respectively.

5.7 Refererences and notes

43% e.e.

Ph Ph

O( )5

toluene, -15°C

(10 mol%)

N

N

Tf

Tf

Ti(Ot-Bu)2

Oct2Zn+5.1


21

preparation of dioctylzinc, see Chapter 6.

7. Bolm, C.; Ewald, M. Felder, M. Chem. Ber. 1992, 125, 1205.

8. Confirmed by GCMS analysis. Nickel catalysed conjugate reduction of ",$-unsaturated ketones is aknown process, see: Caporusso, A.M.; Giacomelli, G.; Lardicci, L. J. Org. Chem. 1982, 47, 4640. Seealso reference 3c.

9. Kindly provided by Prof. J. Martens. For synthesis, see: Behnen, W.; Mehler, T.; Martens, J.Tetrahedron: Asymmetry 1993, 4, 1413.

10. a) Ullenius, C.; Christenson, B. Pure Appl. Chem. 1988, 60, 57. b) Krause, N.; Wagner, R.; Gerold, A.J. Am. Chem. Soc. 1994, 116, 381.

11. For a discussion about ligand accelerated asymmetric catalysis, see: Berrisford, D.J.; Bolm, C.;Sharpless, K.B. Angew. Chem. Int. Ed. Engl. 1995, 34, 1059.

12. Van Koten, G.; Noltes, J.G. in Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F.G.A.;Abel, E.W., Eds.; Pergamon: Oxford, 1982, Vol. 2, Chapter 14.

13. Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry 1993, 4, 2427.

14. Alexakis, A.; Frutos, J.C.; Mangeney, P. Tetrahedron: Asymmetry 1993, 4, 2431.

15. Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 2183.

16. Hathaway, B.J. In Comprehensive Coordination Chemistry; Wilkinson, G.; Gillard, R.D.; McLeverty,J.A., Eds.; Pergamon: Oxford, 1987, Vol. 5, Chapter 53.

17. a) House, H.O. Fischer, Jr., W.F. J. Org. Chem. 1968, 33, 949. b) Corey, E.J.; Beames, D.J. J. Am. Chem.Soc. 1972, 94, 7210. c) M. Suzuki, T. Suzuki, T. Kawagishi, Y. Morita, R. Noyori, Isr. J. Chem. 1984,24, 118. d) A. Alexakis, S. Mutti, J. F. Normant, J. Am. Chem. Soc. 1991, 113, 6332.

18. Recently enantioselective 1,4-additions of Grignard reagents to cyclic enones, catalysed by a CuI /chiral bidentate phoshine complex, has been reported: M. Kanai, K. Tomioka, Tetrahedron Lett. 1995,36, 4275.

19. Organophosphorus ligands have played a dominant role in the development of synthetic methodologyfor the preparation of chiral products by asymmetric hydrogenation using transition metal catalysts;for an extensive review, see: Morrison, J.D. Asymmetric Synthesis, Chiral Catalysis; Academic Press:New York, 1985, Vol. 5.

20. R. Hulst, N. K. de Vries, B. L. Feringa, Tetrahedron: Asymmetry 1994, 5, 699.

21. For a review see: Beaucage, S.L.; Iyer, R.P. Tetrahedron 1992, 48, 2223.

22. a) Gagnaire, D.; Robert, J.B.; Verrier, J. Bull. Soc. Chim. Fr. 1968, 6, 2392. b) Mosbo, J.A.; Verkade,J.G. J. Am. Chem. Soc. 1973, 95, 4659. c) Schiff, D.E.; Richardson, Jr., J.W.; Jacobson, R.A.; Cowley,A.H., Lasch, J.; Verkade, J.G. Inorg. Chem. 1984, 23, 3373 and references therein.

Chapter 5

22

23. a) Pastor, S.D.; Hyun, J.L.; Odorisio, P.A.; Rodebaugh, R.K. J. Am. Chem. Soc. 1988, 110, 6547 andreferences therein. b) van Rooy, A. Rhodium Catalysed Hydroformylation with Bulky Phosphites asModifying Ligands, Ph.D. Thesis, University of Amsterdam, 1995, Chapter 7.

24. Posner, G.; Frye, L.L. Isr. J. Chem. 1984, 24, 88.

25. a) Leyendecker, F.; Laucher, D. Tetrahedron Lett. 1983, 24, 3517. b) Leyendecker, F.; Laucher, D.Nouv. J. Chim. 1985, 9, 13.

26. See Section 2.3.

27. a) Hof, R.P.; Poelert, M.A.; Peper, N.C.M.W.; Kellogg, R.M. Tetrahedron: Asymmetry 1994, 5, 31. b)Fitzpatrick, K.; Hulst, R.; Kellogg, R.M. Tetrahedron: Asymmetry 1995, 6, 1861.

28. Hoffmann, E.W.; Kuchen, W.; Poll, W.; Wunderlich, H. Angew. Chem., Int. Ed. Engl. 1979, 18, 415.

29. Fabbri, D.; Delogu, G.; De Lucchi, O. Tetrahedron: Asymmetry 1993, 4, 1591.

30. a) Hof, R.P. Enantioselective Synthesis and (Bio)catalysis, Ph.D. Thesis, University of Groningen, 1995.b) de Vries, A.H.M.; Hof, R.P.; Staal, D.; Kellogg, R.M.; Feringa, B.L. Submitted to Tetrahedron:Asymmetry.

31. Kindly provided by Charon Zondervan. Synthesis according to: Frost, C.G.; Williams, J.M.J.Tetrahedron Lett. 1993, 34, 2015.

32. a) Posner, G.H. Org. React. 1972, 19, 1. b) Lipshutz, B.H. Synthesis, 1987, 325.

33. Rossiter, B.E.; Swingle, N.M. Chem. Rev. 1992, 92, 771. For catalytic enantioselective conjugateadditions of organocuprates, see Section 2.3.

34. Kharasch, M.S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances, Prentice-Hall, NewYork, 1954.

35. For a discussion on uncatalysed 1,4-addition of Grignard reagents, see Jansen, J.F.G.A. Stereoselective1,4-Additions, Ph.D. Thesis, University of Groningen, 1991.

36. Cahiez, G.; Alami, M. Tetrahedron Lett. 1989, 30, 3541.

37. Arai, M.; Lipshutz, B.H.; Nakamura, E. Tetrahedron 1992, 48, 5709.

38. Rück, K.; Kunz, H. Synthesis, 1993, 1018.

39. For transition metal catalysed vinyl and alkynyl transfer, see: a) Hooz, J.; Layton, R.B. J. Am. Chem.Soc. 1971, 93, 7320. b) Bernardy, K.F.; Floyd, M.B.; Poletto, J.F.; Weiss, M.J. J. Org. Chem. 1979, 44,1438. c) Schwartz, J.; Carr, D.B.; Hansen, R.T.; Dayrit, F.M. J. Org. Chem. 1980, 45, 3053. d) Lipshutz,B.H.; Dimock, S.H. J. Org. Chem. 1991, 56, 5761. e) Wipf, P.; Smitrovich, J.H.; Moon, C.-W. J. Org.Chem. 1992, 57, 3178.

40. For trimethylaluminium additions, see: a) Ashby, E.C.; Noding, S.A. J. Org. Chem. 1979, 44, 4792. b)Fuijwara, J.; Fukutani, Y.; Hasegawa, M.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1984, 106,5004. c) Westermann, J.; Nickisch, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1368. d) Kabbara, J.,Flemming, S.; Nickisch, K.; Neh, H.; Westermann, J. Tetrahedron 1995, 51, 743 and references therein.

41. The high potential to develop a enantioselective version of this selective copper(I) catalysed alkyltransfer from TMA to enones has very recently also been noticed by another research group: Takemoto,Y.; Kuraoka, S.; Hamaue, N.; Iwata, C. Tetrahedron: Asymmetry 1996, 7, 993.They have reported a CuOTf catalysed 1,4-addition of TMA to 3,4,4-trimethylcyclohexa-2,5-dienone(5.19) with enantioselectivities up to 68% in the presence of 20 mol% of oxazoline 5.21 and 120 mol%of tert-butyldimethylsilyl triflate (TBDMSOTf).

O

5.19

+ TMA5.21 (20 mol%)CuOTf (5 mol%)

TBDMSOTfTHF, 0°C

O

88% yield68% e.e.

5.20

N

O

O

O

5.21


23

university of groningen catalytic enantioselective conjugate ...workers, of an in s itu prepared...

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