catalytic enantioselective michael addition reactions of α ... · catalytic enantioselective...

CHAPTER

Catalytic Enantioselective Michael Addition Reactionsof α-Nitroesters to α,β-Unsaturated Ketones1

91

6

6.1 Abstract1

Enantioselective Michael additions of α-nitroesters 6.4a-d with α,β-unsaturated

ketones were carried out in the presence of a catalytic amount of chiral Al-Li-(R)- 2,2’-

dihydroxy-1,1’-binaphthyl (“AlLiBINOL”) complex prepared in situ from LiAlH4 and 2.45

equiv of (R)-BINOL. The enantioselectivity of the Michael addition proved to be extremely

temperature dependent: Michael adduct 6.7a was obtained in 7% e.e. when the reaction was

performed at RT, whereas 72% e.e. of the opposite enantiomer of 6.7a was found when the

1,4-addition was performed at -23 °C. Solvent variation showed that tetrahydrofuran gave the

highest selectivity (up to 80% e.e.), while the highest enantioselectivity for the opposite

enantiomer was found in dichloromethane (up to 25%). X-Ray structure analysis of the

AlLi 3BINOL3 complex 6.10 in combination with 27Al NMR studies showed that

“AlLiBINOL” is a mixture of aluminium complexes in solution.

6.2 Introduction

Modified peptides not only open a way to understand biological phenomena, but also

offer opportunities for drug discovery.2 The incorporation of conformational constraints is

used to probe the molecular structure of receptors. By preorganizing the optimum

conformation for binding, significant enhancements of biological activity can be expected.

Introduction of alkyl groups at the α-carbon of α-amino acids might introduce such

conformational constraints and, furthermore, enhance metabolic stability.3 As a result, the

synthesis of α-alkylated α-amino acids has attracted considerable attention and provides a

challenging synthetic problem.4 The major method for catalytic asymmetric synthesis of

amino acids,5 i.e. hydrogenation of dehydro-α-amino acids, is, however, not suitable for this

class of compounds. Among the possible ways to obtain these α−amino acids, asymmetric

carbon-carbon bond formation is obviously the method of choice. Virtually all methods

involve the use of a chiral auxiliary.4 The most famous among these methodologies are

Schöllkopf's bis-lactim ether,6 Seebach's imidazolones and oxazolidinones procedures7 or

1 Part of this work has been published previously: Keller, E., Veldman, N., Spek, A.L., Feringa, B.L.

Tetrahedron Asymm. 1997, 8, 3403.2 Burger, A., Wolff M.E. in Burger's Medicinal Chemistry and Drug Discovery, Wiley, New York, 1995.3 Williams, R.M. Synthesis of Optically Active α-Amino Acids, Pergamon Press, Oxford, 1989,

Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238.4 For a recent review see: Wirth, T. Angew.Chem., Int. Ed. Engl. 1997, 36, 225.5 Noyori, R., Hashiguchi, S. in Applied Homogeneous Catalysis with Organometallic Compounds,

Cornils, B., Herrmann, W.A. Eds., VCH Publishers, Vol. 1, Weinheim, 1996, 564.6 Schöllkopf, U. Pure Appl. Chem. 1983, 55, 1799.7 Blank, S., Seebach, D. Angew. Chem., Int. Ed. Engl. 1993, 32, 1765; Seebach, D., Gees, T., Schuler, F.

Liebigs Ann. Chem. 1993, 785; and references cited therein.

Chapter 6

92

variants thereof. In addition, Ojima has developed an elegant and efficient route to attain

these compounds via the "β-lactam synthon method" (Scheme 6.1).8,9

N

PhN

Ph

O

O Ph

H2N

R Ph

NHO

OH

R = CH2=CHCH2R = CH3 H2N

R Ph

OHO

Scheme 6.1 α-Alkylated α−amino acids via the "β-lactam route".

Furthermore, Seebach reported a method based on chiral proline derivatives using

the principle of "self reproduction of chirality".10,11 Racemic α-alkylated α-amino acids can

also be subjected to enzymatic resolution. Different microorganisms have been applied and

the products are obtained with very high enantiomeric excess.12

Although α-nitroesters have large synthetic potential,13 owing to the nitro and ester

functionalities, they have scarcely been used in asymmetric catalysis. The nitro group can

activate the adjacent methylene group for reaction, and furthermore, since the nitro

functionality can be easily transformed into an amine, an oxime, a hydroxylamine, a ketone,

or a carboxylic acid, etc. (Figure 6.1),14 optically active α-nitroester derivatives can function

as potential starting materials for a large range of highly functional, optically active

compounds.

8 Ojima, I. Acc. Chem. Res. 1995, 28, 383.9 Ojima, I., Chen, H.-J.C., Nakahashi, K. J. Am. Chem. Soc. 1988, 110, 278.10 Seebach, D., Boes, M., Naef, R., Schweizer, W.B. J. Am. Soc. Chem. 1983, 105, 5390; and references

cited therein.11 See also: Genin, M.J., Baures, P.W., Johnson, R.L. Tetrahedron Lett. 1994, 35, 4967; Ferey, V.,

Vedrenne, P., Toupet, L., Le Gall, T., Mioskowski, C. J. Org. Chem. 1996, 61, 7244.12 Kruizinga, W.H., Bolster, J., Kellogg, R.M., Kamphuis, J., Boesten, W.H.J., Meijer, E.M., Schoemaker,

H.E. J. Org. Chem. 1988, 53, 1826; Liu, W., Ray, P., Benezra, S.A. J. Chem. Soc., Perkin Trans. I1995, 553; J. Kamphuis., Boesten, W.H.J., Kaptein, B., Hermes, H.F.M., Sonke, T., Broxterman, Q.B.,van den Tweel, W.J.J., Schoemaker, H.E. in Chirality in Industry Collins, A.N., Sheldrake, G.N.,Crosby, J., Eds., Wiley, Chichester 1992, 187.

13 Shipchandler, M.T. Synthesis 1979, 666.14 Seebach, D., Colvin, E.W., Lehr, F., Weller, T. Chimia 1979, 33, 1.

Catalytic Enantioselective Michael Addition Reactions of α-Nitroesters to α,β-UnsaturatedKetones

93

R'

CO2RO2N

Amino acids

Amines

Hydroxylamines

Ketones

Carboxylic acids

Oximes

Figure 6.1 Synthetic potential of α-nitroesters.

Rajappa and co-workers reported the synthesis of optically active dipeptide

precursors with diastereomeric excesses ranging from 33 to 51%. Optically pure N-nitroacetyl

proline derived amides were used in the Michael reaction to several Michael acceptors

(Scheme 6.2), i.e. proline acts as the chiral auxiliary.15 Furthermore using enzymatic

resolutions, Wong et al. obtained alkylated α-nitroacetate ester derivatives with high

enantioselectivity. These are considered to be α-methyl-α-amino acids analogues in which the

nitro group functions as a latent primary amino group.16

N

O

O2N

CO2Et

N

O

O2N

CO2Et

O

OEtKF, DMF

18-crown-6

72%, 51% de

EtOO

N

O

AcHN

CO2Et

EtOO

HZn, AcOH, Ac2O

40-60 °C

Scheme 6.2 Synthesis of dipeptides via N-nitroacetyl proline amide derivatives.

Methods by which the asymmetric centre in α-alkyl-α-amino acid derivatives is

introduced in a catalytic manner were unknown at the beginning of these studies.17 In this

chapter we describe the use of alkylated nitroacetyl esters as Michael donors in a catalytic

enantioselective fashion. In this way the rich chemistry of α-nitroesters is combined with

15 Thomas, A., Manjunatha, S.G., Rajappa, S. Helv. Chem. Acta 1992, 75, 715; see also Manjunatha,

S.G., Rajappa, S. J. Chem. Soc., Chem. Commun. 1991, 372.16 Lalonde, J.J., Bergbreiter, D.E., Wong, C.-H. J. Org. Chem. 1988, 53, 2323.17 Shortly after we published our initial results, Trost claimed the first catalytic asymmetric reaction to

yield α-alkylated α−amino acids: Trost, B.M., Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36, 2635.

Chapter 6

94

asymmetric Michael additions and the nitroacetyl group is used as a synthetic equivalent of an

α−amino acid ester anion.

Conjugate addition reactions of carbon nucleophiles to α,β-unsaturated compounds

are among the most widely used methods far carbon-carbon bond formation in organic

synthesis.18 Major efforts have been made to achieve catalytic enantioselective conjugate

addition and considerable progress has been seen recently, despite the often complicated

nature of many 1,4-addition reactions.19,20 Although the catalytic enantioselective Michael

addition reaction of dialkyl malonates and β-ketoesters has been widely studied,19,21,22 to the

best of our knowledge, only one example of an enantioselective Michael addition of an α-

nitroester has been described in the literature.

EtO2C

O2N+

O

6.2

N

OCH3

OHN

6.1

toluene, 89%

EtO2C

O2NO

*

[α]365 = -7.1 ° (c=1.0, toluene)

6.3

Scheme 6.3 Quinine catalyzed Michael addition of ethyl nitropropionate.

Shortly after the first catalytic enantioselective Michael addition was reported,23

Wynberg and Helder published a series of enantioselective catalytic Michael additions using

several donors including ethyl nitropropionate 6.2.24 Using quinine 6.1 as a chiral base, 6.2was allowed to react with MVK in toluene at room temperature. The corresponding Michael

adduct 6.3 was isolated in 89% yield, however, the e.e. was not reported (Scheme 6.3).

Subsequently van Aken studied this reaction and attempts were made to determine the e.e. by

18 Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry

Series, No. 9, Pergamon: Oxford 1992.19 Feringa, B.L., de Vries, A.H.M. in Carbon-Carbon Bond Formation by Catalytic Enantioselective

Conjugate Addition; in Advances in Catalytic Processesi, JAI Press Inc., Vol. 1, 151, 1995.20 Smalz, H.-G. in Comprehensive Organic Synthesis, Trost, B.M., Fleming, I., Eds., Pergamon, Oxford

1991.21 For a very efficient enantioselective Michael addition (MA) of dialkylmalonates, see: a) Sasai, H., Arai,

T., Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571; b) Sasai, H.,,Arai, T., Satow, Y., Houk, K.N.,Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194; see also Chapter 1.

22 For a recent example of an enantioselective MA of β-ketoesters, see: Sasai, H., Emori, E., Arai, T.,Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561, see also Chapter 1.

23 Långström, B., Bergson, G. Acta Chem. Scand. 1973, 27, 3118.24 Wynberg, H., Helder, R. Tetrahedron Lett. 1975, 46, 4057.


95

various methods. Based on partly separated absorptions in the 1H NMR spectrum of 6.3 in the

presence of a chiral europium shift reagent, the o.p. of 6.3 was estimated to be 26%.25

6.2.1 “Two centre catalysis”

Many catalytic systems contain one active metal centre in a suitable ligand

environment. During catalysis one substrate is bound to the metal centre and possibly

activated in such a way that a reactant can attack selectively and the product is formed. The

special features of “two centre catalysis”, however, is currently attracting considerable

interest in the field of asymmetric catalysis. In this case the reactants are bound to two

different centres, which often results in both high selectivity and reactivity.26,27 Urease

Klebsiella aerogenes, an enzyme for hydrolysis of urea, provides a clear example of this

principle.28

Recently Shibasaki and co-workers introduced a new class of heterobimetallic BINOL

complexes as effective catalysts for carbon-carbon bond formations, such as the Henry

reaction of aliphatic nitro compounds29 and the Michael addition reaction of dialkyl

malonates,21 as already shown in Chapter 1. In these catalytic reactions one of the metal

centres of the heterobimetallic complex acts as a Lewis acid and the second metal centre

functions as a Brönsted base. Using the concept of “two centre catalysis” high selectivities

were obtained in several carbon-carbon bond forming reactions. Stimulated by these elegant

reports we examined these chiral Lewis acid complexes in the Michael addition reaction of

nitroesters to α,β-unsaturated ketones (Scheme 6.4).

6.3 Enantioselective Michael additions of α-nitroesters

In the initial attempts the Michael addition of 6.4a to MVK (6.5a) provided the

desired Michael adduct 6.7a with high chemoselectivity when lanthanide based BINOL

complexes29 were employed as the catalyst. However, no enantioselectivity was found using

either a LaLiBINOL complex or the alkali metal free LaBINOL complex.30 In contrast an

”AlLiBINOL” complex 6.6, prepared by using a modification of the method reported by

Shibasaki31 for reasons given later, yielded 6.7a with 7% e.e.,

32 when the reaction was

25 Van Aken, E. Aliphatic Nitro Compounds in Stereoselective Synthesis, Ph.D. Thesis, University of

Groningen, 1992.26 Steinhagen, H., Helmchen, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2339.27 Van den Beuken, E.K., Feringa, B.L. Tetrahedron 1998, in press.28 Jabri, E., Carr, M.B., Hausinger, R.P., Karplus, P.A. Science 1995, 268, 998; Lippard, S.J. Science

1995, 268, 996.29 Sasai, H., Suzuki, T., Arai, S., Arai, T., Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418; Sasai, H.,

Suzuki, T., Itoh, N., Shibasaki, M. Tetrahedron Lett. 1993, 34, 851; Sasai, H., Itoh, N., Suzuki, T.,Shibasaki, M. Tetrahedron Lett. 1993, 34, 855; Sasai, H., Suzuki, T., Itoh, N., Arai, S., Shibasaki, M. Tetrahedron Lett. 1993, 34, 2657; Sasai, H., Suzuki, T., Itoh, N., Tanaka, K., Tadamasa, D., Okamura,K., Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372.

30 The optical purity of 6.7a was determined by HPLC analysis on chiral stationary phase (DAICELCHIRALPAK OJ), after conversion to the corresponding 1,3-dioxolane.

31 Arai, T., Sasai, H., Aoe, K.-i., Okamura, K., Date, T., Shibasaki, M. Angew. Chem., Int. Ed. Engl.1996, 35, 104; Arai, T., Bougauchi, M., Sasai, H., Shibasaki, M. J. Org. Chem. 1996, 61, 2926.

32 The absolute configuration of the major enantiomer has not been established so far.

Chapter 6

96

performed overnight at room temperature using 10 mol%33

of the in situ prepared catalyst.

Moreover, when the same reaction was performed at -23 °C, 6.7a was isolated with 72% e.e..

Much to our surprise the opposite enantiomer32 of Michael adduct 6.7a was obtained. To the

best of our knowledge this is the first example of a metal complex mediated enantioselective

Michael addition of an α-nitroester.

O

OAl

O

O

Li

NO2

R2 CO2R1

O

R3 , THF

O2N

R1O2C

R2

O

R3

6.4a R1=Et, R2=Me6.4b R1=Bn, R2=Me6.4c R1=Bn, R2=Et6.4d R1=menthyl, R2=Me

6.5a R3=Me6.5b R3=Et6.5c R3=Ph

6.7a R1= Et, R2= R3= Me6.7b R1= Bn, R2= R3= Me6.7c R1= Bn,R2= Et, R3= Me6.7d R1= Bn,R2= Me, R3= Et6.7e R1= Bn, R2= R3= Et6.7f R1= Bn,R2= Me, R3= Ph6.7g R1= menthyl, R2=R3= Me

6.6

Scheme 6.4

6.3.1 Temperature dependence

For practical reasons34

the remarkable temperature dependence of the enantioselectivity

was further studied using benzyl ester 6.4b. In all cases Michael adduct 6.7b was isolated in

satisfactory yield (81-86%). The temperature dependence of the enantioselectivity is shown in

Figure 6.2. As can be seen from the figure 6.7b could be obtained with an e.e. up to 74%

when the reaction was performed at -30 °C. The highest selectivity for the opposite

enantiomer is seen at RT albeit with very low e.e. (7%).

33 The amount of catalyst is based upon the assumption of the complete conversion of LiAlH4 to 6.6 (with

the stoichiometry Li:Al:BINOL=1:1:2), giving one well defined complex in solution, according toShibasaki et al.31 Since “AlLiBINOL” appears to be a mixture of aluminium complexes in equilibriumand because the nature and consistency of these complexes is not fully known, a more accurate figurecannot be given.

34 The e.e. of Michael adduct 6.7b could be determined directly by HPLC analysis on a chiral stationaryphase (DAICEL CHIRALPAK AD).


97

The results of the temperature dependance study seem to indicate that competing

enantioselective Michael additions take place, most probably due to different chiral

“AlLiBINOL” complexes in solution. Therefore several reaction parameters were studied in

more detail. First the influence of the amount of catalyst on the enantioselectivity of the

Michael addition was tested. The reaction of 6.4b with MVK under the influence of 10 mol%

of “AlLiBINOL” at -30 °C gave 6.7b with 74% e.e. after 72 h, while when 5 mol% of

“AlLiBINOL” was used 6.7b was isolated with 80% e.e. after 96 h. These data show that a

decrease in the amount of catalyst used results in an increase in enantioselectivity of the

Michael addition. A further decrease of the amount of catalyst led to excessively long reaction

times.

6.3.2 Solvent dependence

Next the effect of various solvents on the reaction was investigated. The results are

depicted in Table I. THF gave the best results providing (-)-6.7b in good yield with an e.e. of

71% at -20 °C and was therefore used in the further investigations. Noteworthy is the result

obtained with dichloromethane as the solvent. The Michael addition performed in THF

furnished (+)-6.7b with an e.e. of 7% at RT, whereas the same reaction in dichloromethane

yielded (+)-6.7b with 20% e.e.. The selectivity could even be improved to 25% e.e. by

performing the reaction in refluxing dichloromethane (at -20 °C 6% e.e. was found in this

solvent). Furthermore it should be noted that the reaction is much slower in dichloromethane

-30 -20 -10 0 10 20 30-20

0

20

40

60

80

°C

Figure 6.2 Temperature dependence of the enantioselectivity of

the Michael addition of 6.4b with 6.5a.

e.e.

of 6

.7b

Chapter 6

98

and dichloroethane compared to the reaction in THF, resulting in only low conversions to the

desired Michael adduct low temperatures (entries 4 and 8).

O

OAl

O

O

Li

NO2

CO2Bn

O, THF

O2N

BnO2CO

6.6

6.4b

6.5a

6.7b

Table 1 Solvent effect on the asymmetric Michael addition of 6.4b with 6.5aEntry Solvent Catalyst amount

(mol%)T (°C) time (h)a e.e. (%)

1 Tetrahydrofuran 10 -20 72 71(-)

2 Toluene 10 -30 72 7(-)

3 Diethylether 10 -30 72 19(-)

4 dichloromethane 10 -20 72b 6(+)

5 dichloromethane 10 RT 72 20(+)

6 dichloromethane 10 40 72 25(+)

7 Dioxane 10 RT 18 4(+)

8 Dichloroethane 10 -30 72b 4(-)a Complete conversion of starting material in the specified time was found except for entries 4 and 8. b Low

conversion <40%, even after 72 h.

6.3.3 Substrate variation

In order to examine the scope of this new enantioselective Michael addition catalyzed

by 6.6 several substrates were tested. The results are listed in Table 2. The in situ prepared

catalyst 6.6 (5-10 mol%)33 provided Michael adducts 6.7c-f in good yields with enantiomeric

excesses ranging from 5% to 55% when β-unsubstituted enones were used (Table 2).

However, β-substituted enones and cyclic enones were unreactive under the present

conditions (entries 9 and 10), and starting materials were recovered, even after prolonged

reaction times. Furthermore, ethyl acrylate (entry 11) and acrolein (entry 12) were not

converted into the Michael adducts under these conditions since polymerisation of the

Michael acceptor was observed.

The presence of sterically demanding substituents often results in an increase of the

enantioselectivity. However, in the reactions tested here this effect was not observed. The

introduction of larger substituents either in the Michael donor or the Michael acceptor

resulted in a lower enantioselectivity. This was most striking when 1-phenyl-propenone (6.5c)was used in the reaction with 6.4b, in which the desired Michael adduct 6.7f was isolated

with very low e.e. (5-8%, entries 7,8).


99

O

OAl

O

O

Li

NO2

R2 CO2Bn

O

R3 , THF

O2N

BnO2C

R2

O

R3

6.6

R4 R4

Table 2 Substrate variation in "AlLiBINOL" catalyzed asymmetric Michael addition.

Entry R2 R3 R4 Temp.(°C) “AlLiBINOL”

(mol%)

Time (h) Yield (%)a e.e. (%)

1 Me Me H -30 10 72 83 74

2 Me Me H -30 5 96 81 80

3 Me Et H -23 10 72 84 49

4 Me Et H -24 5 72 n.d.b 55

5 Et Me H -21 10 72 86 47

6 Et Et H -23 10 72 84 33

7 Me Ph H RT 10 18 87 8

8 Me Ph H -24 10 72 86 5

9 Me Me Me RT or -20 10 72 0 -

10 Me (CH2)3 RT or -20 10 72 0 -

11 Me OEt H RT or -20 10 72 0 -

12 Me H H RT 10 18 0 - a Isolated yield, b n.d.= not determined.

6.3.4 Chiral nitroester in "AlLiBINOL" catalyzed Michael additions

The addition of (1R,2S,5R)-menthyl-2-nitropropionate 6.4d to 6.5a under the

influence of in situ prepared catalyst 6.6 furnished 6.7g with diastereoselectivities comparable

to the values obtained for 6.7a and 6.7b (RT: d.e. = 7%, -25 °C: d.e. = 70%, Scheme 6.5).35

These results show that the asymmetric induction is exclusively accomplished by the chiral

catalyst as the chiral auxiliary did not significantly influence the selectivity of the Michael

addition.

35 The diastereomeric ratio of 6.7g was determined by 13C-NMR (125 MHz).

Chapter 6

100

O

OAl

O

O

Li

NO2

CO2Men*

O, THF

O2N

*MenO2CO

6.6

6.4d

6.5a

6.7g

Men*=

Scheme 6.5

6.3.5 Catalyst variation

In contrast with the results reported by Shibasaki and co-workers31 on the Michael

addition of dialkyl malonates to cyclic enones the use of the “AlNaBINOL” complex (instead

of “AlLiBINOL”), prepared in situ from NaAlH4 and 2 equivalents of BINOL, in the reaction

of 6.4b with 6.5a resulted in nearly racemic 6.7b, albeit, with high chemoselectivity.

Furthermore the use of (R)-3,3’-dimethyl-2,2’-dihydroxy-1,1’-binaphthyl36 as chiral ligand

resulted in a poorly soluble catalyst complex. When this heterogeneous system was utilized in

the reaction of 6.4b with enone 6.5a, Michael adduct 6.7b was isolated in 89% yield but with

low enantioselectivity (e.e. <5%). The steric bulk at the 3 position of the substituted BINOL

ligand might prevent the formation of a complex similar to that prepared from BINOL. The

reduced solubility of this catalyst might be explained by the formation of, for example,

oligomeric structures.

As an alternative chiral C2-symmetric diol, an in situ prepared catalyst from 2

equivalents of α,α,α′,α′-tetraphenyl-2,2'-dimethyl-1,3-dioxolane-4,5-dimethanol

(TADDOL)37,38 and LiAlH4 was tested.39 Although again an excellent yield of the desired

Michael adduct 6.7b was obtained, no asymmetric induction was accomplished using this

type of ligand. A heterobimetallic complex ("AlLiTADDOL", 6.8) which is probably

responsible for the efficient catalysis of the Michael addition (Scheme 6.6). The chirality of

the complex is apparently not capable of effecting the stereochemical outcome of the Michael

addition.

36 de Vries, A.H.M. Catalytic Enantioselective Conjugate Addition of Organometallic Reagents, Ph. D.

Thesis, University of Groningen, 1996, 129.37 Narasaka, K. Synthesis 1991, 1.38 Dahinden, R., Beck, A.K., Seebach, D. in Encyclopedia of Reagents for Organic Synthesis, Paquette,

L.A. Ed., Wiley, Chichester, 1995, Vol. 3, 2167.39 Using this ligand Seebach prepared a chiral LiAlH4 derivative for the enantioselective reduction of

ketones.38


101

NO2

CO2Bn

O, THF

O2N

BnO2CO

6.8

6.4b

6.5a

6.7b

O

O

O

O O

O

O

OAl

Ph Ph Ph

PhPhPhPh

PhLi

Scheme 6.6 AlLiTADDOL catalyzed Michael addition.

NO2

R2 CO2R1

O2N

R1O2C

R2

O

O2N

R1O2C

R2

O

O2N

R1O2C

R2

O

O

10 mol% AlLiBINOL2MVK

10 mol% AlLiBINOL2.45MVK

6.7 < 40 % 6.9 > 60 %

+

isolated yield > 81 %6.7

Scheme 6.7

6.4 Catalyst formationWhen we used the in situ prepared catalyst, according to the procedure described by

Shibasaki an co-workers (using 2.0 equiv. of BINOL),31 the yields of the Michael adducts 6.7were low because the 1,4-addition reaction was accompanied by the formation of tandem

Michael adducts 6.9 (Scheme 6.7). Apparently the solution is too basic to accomplish

efficient quenching of the intermediate enolate that is formed in the Michael addition and

therefore the enolate reacts with an additional equivalent of MVK. The yields of the desired

mono-Michael adducts could be improved by using larger amounts of BINOL for the

formation of the catalyst, and in this way reduce the basicity of the reaction medium. Careful

adjustment of the stoichiometry of the reagents showed that the highest yields of Michael

adducts 6.7 were obtained when 2.45 equiv. of BINOL and 1.0 equiv. of LiAlH4 in THF were

used for the catalyst preparation. Using this stoichiometry a homogeneous catalyst solution

was obtained, whereas larger amounts of BINOL resulted in a white precipitate from the

reaction mixture probably because of the formation of oligomeric structures40 in which the

BINOL can act as a bridging ligand.

40 Apbett, A.W. in Encyclopedia of Inorganic Chemistry, King, R.B. Ed., Wiley, Chichester, 1994, Vol.

1., 115.

Chapter 6

102

6.5 Mechanistic and structural aspects of the "AlLiBINOL" catalyzed Michael additions

of α-nitroesters

The 1,4-addition reaction is proposed to proceed via double coordination of the

Michael donor as well as coordination of the Michael acceptor to the heterobimetallic catalyst

in accordance with the mechanism proposed by Shibasaki and co-workers.41 The lithium

naphthoxide moiety can function as a Brönsted base and the aluminium alkoxide functions as

a Lewis acid. The reaction of the α-nitroester with the “AlLiBINOL” complex gives the

corresponding lithium enolate (I ). This enolate then reacts with the enone, which is activated

by coordination to the aluminium Lewis acid centre, to give the aluminium enolate (II ) after

1,4-addition. The resulting alkoxide then reacts with an acidic hydrogen of a Michael donor

to generate the desired Michael adduct and the “AlLiBINOL” complex is regenerated to react

in the next catalytic cycle (Scheme 6.8).

OAl

OOO

* *

OAl

OOO

* *

Li

H

ON

O

OR1OR2

NO2

R2 CO2R1O2N

R1O2C

R2

O

6.46.7

Li

H

O

R2

NO2R1O2C

II

O+

6.5

I

O

"AlLiBINOL"complex 6.6

O

OAl

O

O

Li

Scheme 6.8 Possible reaction path for the Michael addition.

The catalytic enantioselective Michael addition in which the chirality is introduced at

the Michael donor site often imparts lower selectivity than the catalytic enantioselective

Michael additions in which the chiral centre is introduced at the Michael acceptor site.42 A

possible explanation for this phenomenon can be found in the fact that the Michael donor is

chiral itself, whereas for the second class of reactions both the Michael donor and the Michael

acceptor are achiral.

41 Shibasaki, M., Sasai, H., Arai, T. Angew. Chem., Int Ed. Engl. 1997, 36, 1236.42 For a more detailed discussion on this subject, see Chapter 1.


103

The chirality of the Michael donor can influence the stereochemical outcome of the

reactions in several ways. It can be imagined that opposite enantiomers of the racemic

Michael donor bind to the catalyst in a different manner (Scheme 6.9). In this way two

diastereomeric intermediate complexes I or II are produced. These two different

diastereomeric complexes can subsequently react to give the desired product, with different

rates and selectivity since one complex can have a good match and give high selectivity

whereas the other complex imparts lower selectivity. So if one path gives high

enantioselectivity but the other is less selective, the overall e.e. is lower than the selectivity

that is found in case of an achiral Michael donor.

ON+

O

OR1O-

ON+

O

RO O-

or

catalyst

R2

R2

ON+

O

OR1O-

R2

+*

*

*

O

R3

O2N

R1O2C

R2

O

R3

O

R3

O2N

R1O2C

R2

O

R3

e.e. = X

e.e. = Y

diastereomeric complex I

*

*

ML

ML

ML

diastereomeric complex II

Scheme 6.9

6.6 Catalyst structureShibasaki has proposed a dimeric structure of the heterobimetallic catalyst 6.6 with a

ratio of Li:Al:BINOL=1:1:2, based on the amount of reagents used for the preparation of the

catalyst and the X-ray structure of a complex of AlLi(BINOL)2 and cyclohexenone. 31,43

Furthermore Shibasaki recently reported an X-ray structure of a dimeric complex of

AlLi(BINOL) 2 and three additional THF molecules.44

However, since we found some

unexpected results such as the temperature dependence of the Michael additions and the

reversal of enantioselectivity, we decided to investigate the nature of the catalyst in more

detail.

43 Also three THF molecules were present in the crystal structure.44 Arai, T., Yamada, Y.M.A., Yamamoto, N., Sasai, H., Shibasaki, M. Chem. Eur. J. 1996, 2, 1368.

Chapter 6

104

Figure 6.3 Pluton drawing of molecular structure of AlLi3BINOL3.6THF 6.10. a: Top view;

b: side view

In our hands a solution of “AlLiBINOL” (LiAlH4:BINOL=1:2.45) in THF also

provided crystals suitable for X-ray analysis. The molecular structure of the trimeric complex

6.10 is shown in Figure 6.3. The complex consists of one aluminium and three lithium atoms

and three BINOL and six THF molecules. The aluminium is surrounded by three BINOL

molecules stabilised by three lithium ions. The six THF molecules are present to complete the

lithium coordination sites. The complex has a slightly distorted octahedral geometry around

the aluminium centre, with a Al-O-distance of 1.891(3) Å and a Li-O-distance of 1.944(11)

Å. This trimeric structure, in fact, resembles the structure of the heterobimetallic lanthanide-

tris-lithium-tris-BINOL complexes described recently by Shibasaki.21b The crystalline

complex 6.10 efficiently promoted the Michael reaction of 6.4b with 6.5a at -20 °C in THF to


105

give 6.7b with 65% e.e.. This indicates that complex 6.10 is indeed involved in the

enantioselective catalytic process, or can at least function as a precursor for the actual active

catalyst.

-60-40-20020406080100120140 -80 ppm

Figure 6.5 27Al NMR spectrum of AlLiBINOL2 in dry THF.

Since the ratio of Al and Li found in the structure of 6.10 did not correspond with the

ratio of the reagents used for the formation of the, most efficient, in situ prepared catalyst, we

set out to examine the catalyst further using 27Al NMR.45,46,47,48

Based on the X-ray structure of the AlLi3BINOL3.6THF and the stoichiometry of the

reagents used we expected at least two signals in the 27Al NMR spectrum for the different

complexes in solution. To our surprise both for the solution of “AlLiBINOL” prepared from 1 45 Benn, R., Janssen , E., Lehmkuhl, H, Rufiñska, A. J. Organomet. Chem. 1987, 333, 181; Delpuech, J.-

J., Khaddar, M.R., Peguy, A.A., Rubini, P.R. J. Am. Chem. Soc. 1975, 97, 3373.46 Apbett, A.W., in Encyclopedia of Inorganic Chemistry, King, R.B. Ed., John Wiley & Sons,

Chichester, Vol. 1., 1994, 104.47 Hinton, J.F., Briggs, R.W. in NMR and the Periodic Table, Harris, R.K., Mann, B.E. Eds., Acad. Press,

London, 1978, 279.48 Taylor, M.J. in Comprehensive Coordination Chemistry, Wilkinson, G. Ed., Pergamonn Press, London,

1987, Vol. 3., 105.

ppm-80-60-40-20020406080100120140

a

b

Figure 6.4 27Al NMR spectra of a) “AlLiBINOL” and b) AlLi3BINOL3.6THF

in CDCl3.

Chapter 6

106

equiv of LiAlH4 solution in THF and 2 equiv of BINOL and for the solution prepared from 1

equiv of LiAlH4 solution in THF and 2.45 equiv of BINOL we obtained nearly identical

spectra in dry CDCl3 (ratio’s Li:Al:BINOL=1.0:1.0:2.0 and Li:Al:BINOL=1.0:1.0:2.45,

respectively, Figure 6.4a).49 The spectra consisted of three overlapping signals; one sharp

absorption at 18.8 ppm and two broader signals at 35 ppm and 53 ppm. In contrast Shibasaki

observed only one broad signal for the catalyst (Li:Al:BINOL=1.0:1.0:2.0) in THF, prepared

from LiAlH 4 powder.51 Shibasaki concluded from this observation that AlLiBINOL2 is the

only complex in solution and that the structure of the catalyst was unequivocally determined.

The sharp signal at 18.8 ppm is characteristic for a symmetrical octahedral

arrangement of the complex, whereas the signals at lower field probably originate from

tetrahedral complexes with lower symmetry.45,46 The sharp signal at 18.8 ppm was also found

in the 27Al NMR spectrum in CDCl3 of a trimeric complex prepared from 1 equiv. of LiAlH4

solution in THF and 2 equiv. of BuLi and 3 equiv. of BINOL (ratio Li:Al:BINOL=3:1:3,

AlLi 3BINOL3)(Figure 6.4b) equivalent to trimeric complex 6.10. Based on the 27Al NMR

data it appears that AlLi3BINOL3.6THF is indeed present in CDCl3 solution, although it is

reasonable to believe that this is not the only active complex in solution responsible for

enantioselective catalysis, because at least three aluminium complexes are observed in

chloroform by 27Al NMR using in situ preparation. Furthermore, the complexes can readily

exchange their ligands in solution and it is assumed that the different complexes are in

equilibrium with each other (Scheme 6.10).

Since different results are obtained by performing the catalytic reactions in

dichloromethane or in THF (Table 1) the complex composition in different solvents was

studied in more detail. The 27Al NMR of the catalyst solution in THF, prepared according to

the procedure described by Shibasaki (ratio Li:Al:BINOL=1.0:1.0:2.0), was recorded.50 The

LiAlH 4 powder was weighed under dry argon in a glove box to prevent reaction with water

and the catalyst solution was prepared using BINOL dried in vacuo. Again, in sharp contrast

with the results obtained by Shibasaki51 two peaks were observed, as depicted in Figure 6.5.

Although the relative intensities showed large differences in dry THF or dry CDCl3 and the

signals shifted to lower field in THF, this experiment indicated that also in THF more than

one complex is present in solution. Although complex 6.10 is probably present both in THF

and CDCl3, the different complexes are probably in equilibrium in solution. First of all pure

6.10 is poorly soluble in THF and furthermore the fact that opposite enantiomers of the

Michael adducts are isolated in THF or dichloromethane and the observed temperature

dependence (Figure 6.2), indicate that not a single catalyst structure is responsible for the

observed selectivity.

49 27Al NMR spectra were recorded after evaporation of the THF, the residual white powder was dissolved

in dry CDCl3 under dry N2 atmosphere.50 Using an internal tube containing THF-d8 for locking.51 Shibasaki, M. personal communication, see also ref. 31.


107

OAl

O

O

O

Li

**

AlLiBINOL2

*

*OAl

O O

OO

O

Li

Li

Li *

AlLi3BINOL3

Oligomeric complexes?

Scheme 6.10

6.7 Conclusions

In conclusion, we have developed a new asymmetric Michael addition reaction of α-

nitroesters to α,β-unsaturated ketones using “AlLiBINOL” as a heterobimetallic chiral

catalyst. Enantioselectivities as high as 80% were achieved. Since the nitro group can be

easily converted into an amino or an N-hydroxylamino group, the Michael addition products

obtained in this reaction are considered to be useful synthetic intermediates for optically

active α-alkylated α-amino acids. These molecules occur frequently in natural products and

the new synthetic route might be applied for the preparation of peptide mimetica. Contrary to

the initial reports of Shibasaki who found that the heterobimetallic "AlLiBINOL" catalyst is a

dimeric BINOL complex and is formed as a single species, our investigations show that the

"AlLiBINOL" can also adopt a trimeric structure, similar to the structures of several

lanthanide derived BINOL catalysts.21b

6.8 Experimental section

Instruments and materials

The following compounds were commercially available and used without purification:

LiAlH 4 solution in THF (1 M, Aldrich, Fluka), NaAlH4 solution in THF (1M, Aldrich),

LiAlH 4 (Merck), 2-cyclopentenone (Aldrich), 2-cyclohexenone (Aldrich), mesityloxide

(Aldrich), (R)-BINOL (Syncom), d-menthol (Janssen). Methyl vinyl ketone (MVK, Aldrich

or Fluka) and ethyl vinyl ketone (Aldrich) were distilled immediately prior to use. Ethyl-2-

nitropropionate 6.4a was prepared according to a literature procedure.52 27Al NMR spectra

were recorded on a Varian-300 (78.12 MHz) spectrometer. Chemical shifts are denoted in δ-

units (ppm) relative to Al(OH2)63+ as an external standard: δ(Al(OH2)6

3+) = 0.0 ppm for the

measurements in CDCl3. In THF, THF-d8 was used as an external standard. HPLC analysis

were carried out using a Waters 600E system controller equipped with a Waters 991

photodiode array detector. Chromatographic purification of the Michael adducts 6.7 was

performed by rotating disk chromatography with Chromatotron model 7924T, by Harrison

research, equipped with a FMI lab pump RP-G150. All catalytic reactions were performed in

oven dried glassware under dry N2 atmosphere and solvents were dried using standard

procedures.

52 Kornblum, N., Blackwood, R.K. Organic Synthesis, Wiley, New York, 1963, Collect. Vol. 4, 454.

Chapter 6

108

Preparation of “AlLiBINOL” complex 6.6.

To a stirred solution of dry (R)-BINOL (700 mg, 2.45 mmol) in 9.0 mL dry THF (Na) at 0 °Cwas slowly added 1.0 mL of LiAlH4 (1.0 M) solution in THF, and the mixture was stirred at

this temperature for 30 min at 0 °C. The residual homogeneous catalyst solution (0.10 M in

THF) was used as such for the enantioselective reactions.

Benzyl 2-nitropropionate (6.4b)

Prepared in 65% yield according to the literature procedure52 for the preparation of a related

compound and purified using flash chromatography (SiO2, hexane:ethyl acetate = 4:1). 1H-

NMR (CDCl3, 200 MHz) δ = 1.79 (d, J = 7.1 Hz, 3H, CH3), 5.23 (q, J = 7.1 Hz, 1H, CH),

5.25 (s, 2H, CH2Ar), 7.35 (m, 5H, Ar); 13C-NMR (CDCl3, 50 MHz) δ = 15.45 (q), 68.28 (t),

82.97 (d), 128.22 (d), 128.62 (d), 128.72 (d), 134.12 (s), 164.87 (s).

Benzyl 2-nitrobutyrate (6.4c)

Prepared in 62% yield according to the literature procedure52 for the preparation of a related

compound and purified using flash chromatography (SiO2, hexane:ethyl acetate = 4:1). 1H-

NMR (CDCl3, 200 MHz) δ = 1.02 (t, J = 7.3 Hz, 3H, CH3), 2.25 (m, 2H, CH2), 5.07 (dd, J =

5.6 Hz, J = 9.0 Hz, 1H, CH), 5.24 (s, 2H, CH2Ar), 7.35 (m, 5H, Ar);13C-NMR (CDCl3, 50

MHz) δ = 9.86 (q), 23.67 (t), 68.17 (t), 89.16 (d), 128.23 (d), 128.61 (d), 128.71 (d), 134.17

(s), 164.28 (s).

l-(-)(1R,2S,5R)-Menthyl 2-(R,S)-nitropropionate (6.4d)

Prepared in 56% yield, according to the literature procedure52 for the preparation of a related

compound, from l-(-)-(1R,2S,5R)-menthyl 2-(R,S)-bromopropionate53

and purified using flash

chromatography (SiO2, hexane:diethylether = 9:1). [α]D -62.4 (c 1.00, CHCl3); 1H-NMR

(CDCl3, 200 MHz) δ = 0.75 (d, J = 7.1 Hz, 3H, CH3), 0.90 (dd, J = 6.1 Hz, J = 4.9 Hz, 6H,

2xCH3), 0.84 - 1.73 (m, 8H), 1.78 (d, J = 7.1 Hz, 3H, CH3), 1.99 (m, 1H, CH), 4.77 (dt, J1 =

4.4 Hz, J2 = 10.7 Hz, OCH), 5.19 (q, J = 7.1 Hz, 1H, CH3); 13C-NMR (CDCl3, 50 MHz) δ =

15.45 (q), 15.72 (q), 20.41 (q), 21.62 (q), 22.91 (t), 25.88 (d), 25.79 (d), 31.10 (d), 39.87 (t),

40.00 (t), 46.47 (d), 46.53 (d), 77.32 (d), 83.14 (d), 164.45 (s)

General procedure for the synthesis of Michael adducts 6.7.

To 1.0 mmol of α-nitroester 6.4 was added 1.0 mL of “AlLiBINOL” solution in THF at

ambient temperature. The resulting solution was then brought to the desired temperature and

the Michael donor 6.5 (2.2 mmol) was added in one portion. The reaction mixture was stirred


109

at the indicated temperature and the progress of the reaction was monitored by TLC (SiO2,

hexane:acetone = 9:1) until all of the starting α-nitroester was converted.54 The reaction

mixture was then treated with 1N HCl (1.0 mL) followed by extraction with dichloromethane

(2x10 mL). The combined organic extracts were washed with water (5 mL) and concentrated.

Toluene (10 mL) was added and the solution was again concentrated to give a nearly

colourless residue. Purification by rotating disk chromatography (SiO2, hexane:acetone = 9:1)

gave the Michael adducts 6.7 as nearly colourless analytical pure oils. Yields and e.e.’s are

compiled in tables I and II.

Ethyl 2-methyl-2-nitro-5-oxohexanoate (6.7a)

The e.e. of 6.7a was determined by HPLC analysis on a chiral stationary phase (DAICEL

CHIRALPAK OJ, iPrOH:hexane 1:9) after conversion to the corresponding 1,3-dioxolane.55

6.7a: 1H-NMR (CDCl3, 200 MHz) δ = 1.29 (t, J = 7.2 Hz, 3H, CH3), 1.77 (s, 3H, CH3), 2.16

(s, 3H, CH3), 2.41-2.59 (m, 4H, 2xCH2), 4.26 (q, J = 7.2 Hz, 2H, CH2); 13C-NMR (CDCl3, 50

MHz) δ = 13.52 (q), 21.76 (q), 29.69 (q), 29.94 (t), 37.63 (t), 62.74 (t), 91.64 (s), 166.97 (s),

205.73 (s). MS(CI):235[M++NH4+]; Anal. calcd. for C9H15NO5: C 49.76, H 6.96, N 6.45,

found: 49.50, H 6.84, N 6.27.

Benzyl 2-methyl-2-nitro-5-oxohexanoate (6.7b)

According to the general procedure 6.7b was obtained as a nearly colourless oil. [α]D -1.87 (c

0.48, CHCl3) (75% e.e.); The e.e. of 6.7b was determined by HPLC analysis on a chiral

stationary phase (DAICEL CHIRALPAK AD, iPrOH:hexane 1:39). 1H-NMR (CDCl3, 200

MHz) δ = 1.78 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.48 (m, 4H, CH2), 5.22 (s, 2H, CH2Ar), 7.34

(m, 5H, Ar); 13C-NMR (CDCl3, 50 MHz) δ = 21.91 (q), 19.64 (q), 30.00 (t), 27.55 (t), 68.19

(t), 91.67 (s), 128.20 (d), 128.60 (d), 128.67 (d), 134.25 (s), 166.78 (s), 205.66 (s);

MS(CI):297[M++NH4+]; Anal. calcd. for C14H17NO5: C 60.21, H 6.14, N 5.01, found: C

60.18, H 6.14, N 4.88.

Benzyl 2-ethyl-2-nitro-5-oxohexanoate (6.7c)

According to the general procedure 6.7c was obtained as a nearly colourless oil. [α]D +2.65 (c

0.64, CHCl3) (47% e.e.); The e.e. of 6.7c was determined by HPLC analysis on a chiral


MHz) δ = 0.88 (t, J = 7.4 Hz, 3H, CH3), 2.06 (s, 3H, CH3), 2.11-2.46 (m, 6H, 3xCH2), 5.22

(s, 2H, CH2Ar), 7.34 (m, 5H, Ar); 13C-NMR (CDCl3, 50 MHz) δ = 7.67 (q), 27.00 (t), 28.17

53 Lau, H.-H., Schöllkopf, U. Liebigs Ann. Chem. 1981, 137854 Mixture for TLC staining: o-anisaldehyde dip: (mix at 0 °C) anis aldehyde 7.4 mL; ethanol (96%) 383

mL; sulfuric acid 10 mL; acetic acid 3.0 mL.55 Dann, A.E., Davis, J.B., Nagler, M.J. J. Chem. Soc., Perkin I 1979, 158.

Chapter 6

110

(t), 29.62 (q), 37.39 (t), 51.95 (t), 95.55 (s), 128.38 (d), 128.58 (d), 128.69 (d), 134.31 (s),

166.37 (s), 205.72 (s); MS(CI):311[M++NH4+]; Anal. calcd. for C15H19NO5: C 61.42, H 6.53,

N 4.78, found: C 61.36, H 6.59, N 4.58.

Benzyl 2-methyl-2-nitro-5-oxoheptanoate (6.7d)

According to the general procedure 6.7d was obtained as a nearly colourless oil. [α]D + 3.04.

(c 0.29, CHCl3) (49% e.e.); The e.e. of 6.7d was determined by HPLC analysis on a chiral


MHz) δ = 1.02 (t, J = 7.32 Hz, 3H, CH3), 1.77 (s, 3H, CH3), 2.36 (q, J = 7.32 Hz, CH2), 2.45

(m, 4H, 2xCH2), 5.22 (s, 2H, CH2Ar), 7.34 (m, 5H, Ar); 13C-NMR (CDCl3, 50 MHz) δ = 7.44

(q), 21.86 (t), 30.07 (t), 35.68 (t), 36.19 (t), 68.17 (t), 91.75 (s), 128.17 (d), 128.58 (d), 128.65

(d), 134.27 (s), 167.11 (s), 208.47 (s); MS:311[M++NH4+]; Anal. calcd. for C15H19NO5: C

61.42, H 6.53, N 4.78, found: C 61.50, H 6.58, N 4.66.

Benzyl 2-ethyl-2-nitro-5-oxoheptanoate (6.7e)

According to the general procedure 6.7e was obtained as a nearly colourless oil. [α]D -1.23 (c

0.73, CHCl3) (33% e.e.); The e.e. of 6.7e was determined by HPLC analysis on a chiral


MHz) δ = 0.87 (t, J = 7.3 Hz, 3H, CH3), 1.01 (t, J = 7.3 Hz, 3H, CH3), 2.00-2.45 (m, 8H,

4xCH2), 5.22 (s, 2H, CH2Ar), 7.34 (m, 5H, Ar); 13C-NMR (CDCl3, 75 MHz) δ = 7.67 (q),

7.90 (q), 27.29 (t), 28.30 (t), 35.68 (t), 36.22 (t), 68.18 (t), 95.77 (s), 128.43 (d), 128.64 (d),

128.74 (d), 134.40 (s), 166.43 (s), 208.51 (s); MS(CI):325[M++NH4+]; Anal. calcd. for

C16H21NO5: C 62.51, H 6.89 N 4.56, found: C 62.71, H 7.12, N 4.78.

Benzyl 2-methyl-2-nitro-5-oxophenylpentanoate (6.7f)

According to the general procedure 6.7f was obtained as a nearly colourless oil. [α]D + 0.65.

(c 0.62, CHCl3) (8% e.e.); The e.e. of 6.7f was determined by HPLC analysis on a chiral


MHz) δ = 1.85 (s, 3H, CH3), 2.65 (m, 2H, CH2), 3.02 (m, 2H, CH2), 5.24 (s, 2H, CH2Ar),

7.33-7.58 (m, 2H, Ar); 13C-NMR (CDCl3, 50 MHz) δ = 22.10 (q), 30.56 (d), 32.79 (t), 68.23

(t), 91.91 (s), 127.86 (d), 128.24 (d), 128.54 (d), 128.59 (d), 128.65 (d), 133.30 (d), 134.24

(s), 136.07 (s), 166.86 (s), 197.30 (s); MS(CI): 359[M++NH4+]; Anal. calcd. for C19H19NO5:

C 66.84, H 5.61 N 4.10, found: C 66.84, H 5.73, N 3.92.

(1R,2S,5R)-Menthyl 2-methyl-2-nitro-5-oxohexanoate (6.7g)

According to the general procedure 6.7g was obtained as a nearly colourless oil as a

inseparable 1:1 mixture of diastereoisomers, see text. 1H-NMR (CDCl3, 200 MHz) δ = 0.75


111

(d, J = 7.1 Hz, 3H, CH3), 0.89 (t, J = 6.35 Hz, 6H, 2xCH3), 0.80-1.80 (m, 8H), 1.95-2.02 (m,

1H, CH), 1.74 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.41-2.55 (m, 4H, 2xCH2), 4.30 (dt, J = 10.74

Hz, J = 4.39 Hz, 1H, CH); 13C-NMR (CDCl3, 125 MHz) δ = 15.66 (q), 15.72 (q), 20.61 (q),

21.77 (q), 22.84(q), 28.90 (q), 25.84 (q), 25.91 (q), 31.24 (t), 33.85 (t), 37.75 (t), 39.83 (t),

39.90 (t), 46.58 (q), 77.30 (d), 91.79 (s), 91.84 (s), 166.43 (s), 205.47 (s), 205.51 (s);

MS(CI): 345[M++NH4+]; Anal. calcd. for C17H29NO5: C 62.36, H 8.93, N 4.28, found: C

62.40, H 9.05, 4.14.

Crystal data for: AlLi 3BINOL 3.6THF (6.10)Colourless transparent block shaped crystals were obtained when a 0.01 M solution of

"AlLiBINOL" in THF was slowly evaporated. X-ray data were collected on an Enraf-Nonius

CAD4T diffractometer on a rotating anode (MOKα, λ = 0.71073 &) at 150 K for a transparent

colourless crystal [0.18x0.25x0.50].56 The structure solved by direct methods

(SHELXS96/TREF) and refined on F2 using SHELXL96 to a final R = 0.0704 (wR2 = 0.158)

for 2113 reflections and 152 parameters. Hydrogens were taken into account on calculated

positions. A final difference map showed no density excursions outside -0.29 and 0.26 e/Å3.

Anal. calcd. for AlLi3BINOL3.6THF (C84H84O12AlLi 3): Al 1.99, Li 1.54 found: Al 1.95, Li

1.52. Crystal data and experimental details of the structure determination are compiled in

Table 3. For additional references and experimental details, see Chapter 7.

Table 3 Crystal data, data collection, structure solution, and refinement for

AlLi 3BINOL3.6THF 6.10Empirical formula C84H84AlLi 3O12

Formula weight 1333.39

Crystal system Hexagonal

Space Group P6322

a (Å), b (Å), c (Å) 14.4753(15), 14.4753(15), 19.6929(11)

α,β,χ (°) 90, 90, 120

V (Å3) 3573.5(6)

Z 2

D (calc,) (g/cm3) 1.239

F (000) (electrons) 1412

µ(Mo Kα) (cm-1) 0.9

Crystal size (mm) 0.18 x 0.25 x 0.5

Data collectionTemperature (K), exposure time (H) 150, 24.5

Radiation (Å) Mo Kα (0.71073 Å)

Θ range (°) 1.6 - 25.0

Total data, Unique data, Observed data ( I > 2.0 σ (I)) 9190, 2213, 1071

RefinementNumber of reflections 2113

Number of refined parameters 152

Final agreement factors

RF, wR 0.0704, 0.158

Chapter 6

112

Table 4 Bond lengths (Å) for AlLi3BINOL3.6THFa 6.10Al (1)-O(1) 1.891(3) C(5)-C(6) 1.347(8) C(6)-H(6) 0.9312

O(1)-C(1) 1.331(6) C(6)-C(7) 1.387(8) C(7)-H(7) 0.9299

O(1)-Li(1) 1.944(11) C(7)-C(8) 1.367(9) C(8)-H(8) 0.9301

O(2)-C(11) 1.408(5) C(8)-C(9) 1.412(8) C(11)-H(11a) 0.9702

O(2)-C(14) 1.409(11) C(9)-C(10) 1.436(7) C(11)-H(11b) 0.9704

O(2)-Li(1) 2.006(10) C(10)-(C10_d) 1.515(6) C(12)-H(12a) 0.9694

C(1)-C(2) 1.417(6) C(11)-C(12) 1.500(12) C(12)-H(12b) 0.9699

C(1)-C(10) 1.388(7) C(12)-C(13) 1.402(13) C(13)-H(13a) 0.9707

C(2)-C(3) 1.362(8) C(13)-C(14) 1.420(12) C(13)-H(13b) 0.9688

C(3)-C(4) 1.407(9) C(2)-H(2) 0. 9305 C(14)-H(14a) 0.9709

C(4)-C(5) 1.431(8) C(3)-H(3) 0.9295 C(14)-H(14b) 0.9704

C(4)-C(9) 1.413(8) C(5)-H(5) 0.9310a Standard deviations in the last decimal are given in parentheses

Table 5 Selected bond angles (°) forAlLi3BINOL3.6THFa 6.10O(1)-Al(1)-O(1-a) 94.97(18) O(1-a)-Al(1)-O(1-e) 81.31(17) Al(1)-O(1)-Li(1) 100.0(3)

O(1)-Al(1)-O(1-b) 94.97(17) O(1-b)-Al(1)-O(1-c) 88.97(18) C(1)-O(1)-Li(1) 123.1(4)

O(1)-Al(1)-O(1-c) 174.82(18) O(1-b)-Al(1)-O(1-d) 81.31(17) C(1)-C(10)-C(10-d) 119.5(4)

O(1)-Al(1)-O(1-d) 88.97(16) O(1-b)-Al(1)-O(1-e) 174.8(2) C(1)-C(10)-C(10-d) 121.6(4)

O(1)-Al(1)-O(1-e) 81.31(17) O(1-c)-Al(1)-O(1-d) 94.97(18) O(1)-Li(1)-O(2) 98.92(16)

O(1-a)-Al(1)-O(1-b) 95.0(2) O(1-c)-Al(1)-O(1-e) 94.97(19) O(1)-Li(1)-O(1-e) 78.6(5)

O(1-a)-Al(1)-O(1-c) 81.31(19) O(1-d)-Al(1)-O(1-e) 94.97(16) O(1)-Li(1)-(O(2-e) 163.4(2)

O(1-a)-Al(1)-O(1-d) 174.8(2) Al(1)-O(1)-C(1) 124.0(4) O(1-e)-Li(1)-O(2-e) 98.9(2)a Standard deviations in the last decimal are given in parentheses

27 Al NMR of "AlLiBINOL"

In CDCl3 under nitrogen atmosphere: a sample of a solution of "AlLiBINOL" in THF (0.10

M) prepared according to the general procedure (1.0 equiv. LiAlH4 solution in THF and 2.45

equiv. BINOL) or according to the stoichiometry used by Shibasaki (1.0 equiv. LiAlH4

solution in THF and 2.0 equiv. BINOL)31 was evaporated to dryness, the residual white

powder was dissolved in dry CDCl3 and the spectra were recorded under N2 atmosphere

(Figure 6.4).

In THF: BINOL (2.864 g, 10.0 mmol) was heated to 60 °C under vacuum for 4 h. The

reaction flask was put under argon and dry THF (freshly distilled from Na, 30.0 mL) was

added. LiAlH4 was weighted under dry nitrogen atmosphere in a glove box and dry THF

(freshly distilled from Na, 20.0 mL) was added and the resulting grey suspension was cooled

to 0 °C. The BINOL solution was slowly added via a canulum. The resulting greyish

suspension was stirred for 1 h at 0 °C. The solid material was allowed to settle and a sample

of the supernatant was transferred to a flame dried NMR tube under argon atmosphere. A dry

internal tube containing THF-d8 was placed in the tube and the spectrum was recorded

directly (Figure 6.5).

56 Performed by N. Veldman, University of Utrecht.

catalytic enantioselective michael addition reactions of α ... · catalytic enantioselective...

Documents