Efficient chirality switching in the addition of diethylzinc to aldehydes in the presence of simple chiral α-amino amides

DOI: 10.1002/anie.200702259

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Angewandte Chemie - International Edition p. 9002 - 9005 (2007)

Update date:2022-08-30

Topics:

Authors:

Burguete, M. Isabel

Collado, Manuel

Escorihuela, Jorge

Luis, Santiago V.

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Article abstract of DOI:10.1002/anie.200702259

(Chemical Equation Presented) It works both ways: A very simple and efficient dual enantioselective control in the addition of diethylzinc to benzaldehyde can be achieved by using nickel complexes of chiral α-amino amide derivatives. Whereas complexes with 1:1 stoichiometries afford the S alcohol as the major enantiomer, 1:2 (metal/ligand) complexes lead to the predominant formation of the R enantiomer (see scheme).

Full text of DOI:10.1002/anie.200702259

Communications

DOI: 10.1002/anie.200702259

Asymmetric Catalysis

Efficient Chirality Switching in the Addition of Diethylzinc to

Aldehydes in the Presence of Simple Chiral a-Amino Amides**

M. Isabel Burguete,* Manuel Collado, Jorge Escorihuela, and Santiago V. Luis*

Dedicated to Professor Miguel Yus on the occasion of his 60th birthday

Chiral catalysis is one of the most efficient approaches for the

preparation of enantiopure compounds.^[1]For practical appli-

cations, the chiral ligands need to be accessible from simple

starting materials and the process has to provide access to

both enantiomers of the product, to guarantee that the

desired isomer can be obtained.^[2]This last condition can be

fulfilled through the preparation of both enantiomers of the

corresponding ligand. A more challenging approach is the

dual stereocontrol over the outcome of the reaction by

modification of the reaction conditions or the nonchiral

structural components, thereby allowing the preparation of

either of the enantiomers from a single configuration of the

chiral elements of the catalyst.^[3]This chirality switching has

been achieved by using different Lewis acids coordinated to

the ligands,^[4]by modification of the solvent system,^[5]and by

introduction of structural features that modify the catalytic

mechanism or the structure of the catalytic site,^[6]including

variations in the nature of the support in heterogeneous

catalysis.^[7]An example has recently been reported in which

the reversal of topicity is obtained by a change in the

molecularity of the catalytic species formed by the ligand and

a Gd center.^[8]This is a promising possibility as many catalytic

systems showa significant sensitivity to the molecularity of

the catalysts and the catalytic complexes.^[9]

The formation of the active complexes requires basic

media and is accompanied by deprotonation of the amide

(NH) group and the generation of square-planar Ni species

(color change from blue to orange). The stoichiometry of the

complexes was determined by the continuous variations

method (Job plot).^[14]For this purpose, amino amides 1a

(R = CH₂Ph, R’ = 1-anthryl) and 1b (R = CH₂Ph, R’ = 2-

methylnaphthyl) containing strong chromophoric groups

were selected: one derives from an aromatic amine and the

second from a benzylic one. The results obtained from the

absorbance at approximately 400 nm (MeOH, ca. 10^À5m)

revealed the existence of complexes with two different

stoichiometries, namely 1:1 and 1:2 (M/L).

Nickel complexes of different a-amino amides were

prepared in MeOH/KOH for both M/L stoichiometries. The

data obtained on complexes obtained from 1:1 metal/ligand

ratios suggested the presence of monomeric and oligomeric

species in equilibrium (Scheme 2). However, the presence of

Starting from natural amino acids, a-amino amides 1

(Scheme 1) can be easily obtained through N protection,

Scheme 2. Structures of monomeric and oligomeric species for 1:1

nickel complexes of a-amino amides.

the correct M/L ratio was confirmed through acidic treatment

of the complex and separate UV determination of the ligand

and the metal. For the 1:2 complexes, the structure was

confirmed by elemental analysis and ESI MS. The square-

planar complexes also allowed their study by NMR spectros-

copy. All data indicate that the 1:2 complexes are of higher

stability than the 1:1 complexes, in particular those derived

from aromatic amines, but interconversion is very slowunder

normal conditions.

Scheme 1. General structure for a-amino amides.

activation of the carboxy group, coupling with a variety of

amines, followed by N deprotection.^[10]We have also shown

that the corresponding Ni complexes are able to efficiently

catalyze the addition of diethylzinc to benzaldehyde.^[11–13]

The ligands in the 1:2 species can adopt either cis or trans

dispositions (Figure 1). Theoretical calculations (RB3LYP/

LACVP* level) using a simplified model derived from

methylamine and alanine indicated the trans conformations

to be more stable than those corresponding to cis isomers (by

7–9 kcalmol^À1, Figure 2).

[*] Prof. Dr. M. I. Burguete, Dr. M. Collado, J. Escorihuela,

Prof. Dr. S. V. Luis

Department of Inorganic and Organic Chemistry. UAMOA

University Jaume I/CSIC

Avda. Sos Baynat s/n. 12071 Castellón (Spain)

Fax: (+34)964-728-214

E-mail: burguete@qio.uji.es

The prevalence of trans dispositions in solution was

confirmed by NOE experiments. The complex derived from

1c (see Figure 1) showed positive NOE contacts between the

aromatic protons at the 2-position of the tert-butylphenyla-

luiss@qio.uji.es

[**] Financial support was provided by the MEC and Fundació Caixa

Castelló-UJI (projects CTQ2005-08016-C03 and P1B2004-13). J.E.

thanks the MEC-CSIC for a predoctoral fellowship.

9002

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 9002 –9005

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Angewandte

Chemie

Table 1: Addition of ZnEt₂to benzaldehyde using 1:1 and 1:2 Ni/1d

complexes.

Complex Catalyst loading Conversion [%]^[a]Selectivity [%]^[a]ee [%]^[b]

[mol%]

1:1

1:2

0.5

0.1

0.05

97 (S)

96 (S)

93 (S)

62 (S)

92 (R)

93 (R)

96 (R)

91 (R)

90 (R)

47 (R)

0.5

0.1

0.05

[a] Yields after 24 h; conversions and selectivities were determined by

NMR spectroscopy. Selectivity: 100[1-phenylpropanol]/[benzyl alco-

hol]+[1-phenylpropanol]. [b] Determined by chiral HPLC (Chiralcel

OD); the major enantiomer obtained is indicated in parenthesis.

Figure 1. Alternative cis and trans disposition of the ligands in the 1:2

complex of amino amide 1c (R=CH₂Phe; R’=4-tBuC₆H₄). Experimen-

tal NOE effects are shown for the trans configuration.

Both complexes are active catalyts at lowloadings, and

reach turnover numbers (TONs) of almost 10³. Longer

reaction times are required for complete conversion with

catalyst concentrations below1%, but the selectivity and

enantioselectivity remain essentially unaffected. Only with

catalyst loadings of about 0.05% were effects on the

selectivity and ee values detected. The catalysts obtained

from 1:1 stoichiometries are more active than the 1:2

complexes. In the first case, conversion is complete after 8 h

at RT for a 1% molar ratio while, under the same conditions,

the 1:2 complexes require 16–18 h. In the 1:2 complexes the

Ni center achieves a more efficient coordination sphere and,

accordingly, it is expected to be less active for coordination of

additional ligands.

Nevertheless, the most significant observation is that the

1:2 complex affords (R)-1-phenylpropanol as the major

enantiomer whilst the complex prepared with a 1:1 metal/

ligand ratio produces (S)-1-phenylpropanol as the predom-

inant species. Thus, a very effective chirality switching is

achieved with this simple ligand just by using the correspond-

ing Ni complexes with 1:1 or 1:2 stoichiometries as catalysts.

To our knowledge, this represents the first example of this

approach to dual stereocontrol, and the first case in which a

single ligand allows both enantiomers to be obtained in the

addition of dialkylzinc to aldehydes.

The relationship between the enantiomeric composition

of the chiral complex derived from 1d and that of the product

arising from the addition of diethylzinc to benzaldehyde was

investigated. The presence of very strong negative nonlinear

effects for the 1:1 complex confirms the importance of

aggregated species for this stoichiometry.^[17]Such nonlinear

effects are completely absent for the 1:2 complex (Figure 3),

which shows that, in this case, aggregate formation is not

significant.^[18]

Figure 2. Calculated minimum energy structures for the cis and trans

configurations in the model structure of the 1:2 complexes. Axial and

equatorial refer to the disposition of the methyl group of alanine in the

five-membered ring formed upon chelation to the nickel center.

mino fragment and the methine hydrogen atom at the

stereogenic center as well as with one of the two amino

hydrogen atoms. A small NOE interaction was also detected

for the tert-butyl group and the aromatic protons of the side

chain. Similar observations were found in other systems. This

finding agrees with the structures of 1:2 nickel complexes

reported for related ligands.^[15]The presence of the C₂axis

within these complexes can serve the important function of

dramatically reducing the number of possible competing

diastereomeric transition states.^[16]

Nickel complexes prepared under both metal/ligand

stoichiometries (1:1 and 1:2) were efficient catalysts for the

addition of diethylzinc to benzaldehyde. Initial studies were

carried out with ligand 1d (R = R’ = CH₂Ph).^[11]Table 1 shows

the results obtained after 24 h for the 1:1 and 1:2 complexes at

different catalyst loadings.

This dual stereocontrol seems to be quite general. A few

examples with other a-amino amides and for other aldehydes

are given in Table 2. The last two entries in Table 2 confirm

that it also applies to other reagents such as ZnMe₂.

Angew. Chem. Int. Ed. 2007, 46, 9002 –9005

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org 9003

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Communications

In summary, the results presented herein reveal that

efficient dual stereocontrol can be achieved by using simple

a-amino amides derived from natural amino acids for the

addition of ZnR₂to aromatic aldehydes just by a straightfor-

ward adjustment of the stoichiometry of the Ni complexes.

Thus, 1:1 Ni complexes provide the S enantiomer while the 1:2

Ni complexes afford the R enantiomer. Both catalytic systems

are very active and can be used at very lowconcentrations

(1% or lower). Further studies are in progress to study the

scope of this process and the potential application of these

catalytic systems to other processes.

Figure 3. Enantioselectivity of the product as a function of the optical

purity of the ligand 1d.

Experimental Section

General procedure for the preparation of nickel complexes: A

solution of nickel(II) acetate (1 equiv or 0.5 equiv) in methanol

(ca. 10^À2m) was added to a solution of 1 (1 equiv) in methanol

(ca. 10^À2m). After stirring the mixture for 20 min at RT, KOH

(ca. 3 equiv) in methanol (1m solution) was added and the solution

was maintained at RT overnight. The orange precipitate formed was

isolated by filtration, washed, and dried to afford the complexes in

almost quantitative yields.

Table 2: Addition of ZnEt₂to benzaldehydes and 1-naphthaldehyde

using 1:1 and 1:2 Ni/1d–f complexes.^[a]

Ligand M/L Aldehyde

Conv. Select. ee [%]^[c]

[%]^[a]

[%]^[b]

1 f

1:1

1:2

1:1

1:2

1:1

1:2

1:1

1:2

1:1

1:2

1:1

1:2

1:1

1:2

1:1

1:2

1:1

1:2

benzaldehyde

4-chlorobenzaldehyde

4-methylbenzaldehyde

80 (S)

85 (R)

68 (S)

85 (R)

90 (S)

92 (R)

83 (S)

85 (R)

90 (S)

88 (R)

85 (S)

92 (R)

78 (S)

82 (R)

76 (S)

84 (R)

87 (S)

87 (R)

General procedure for the addition of ZnR₂to aldedyhes: The Ni

complex (1 mmol) was dissolved in anhydrous toluene (10 mL) in a

Schlenk tube. The solution was stirred and cooled at 08C for 30 min,

and then a 1.1m solution of ZnEt₂in toluene (21 mmol) was added.

After stirring the mixture for 30 min at RT, a solution of the aldehyde

(10 mmol) in toluene was added slowly. The mixture was stirred at RT

for 18 h, quenched with HCl (1m), and the product was extracted into

Et₂O (3 10 mL). The combined extracts were washed with KHCO₃,

dried with anhydrous MgSO₄, and evaporated under vacuum.

Purification by column chromatography (silica gel, 9:1 hexanes/

AcOEt as the eluent) gave the pure alcohol as a colorless oil. The

conversion and the selectivity of the reaction were determined by

NMR spectroscopy, and the ee value was determined by HPLC or GC

on a chiral stationary phase.

4-methoxybenzaldehhyde 99

4-methoxybenzaldehyde

1-naphthaldehyde

benzaldehyde^[d]

Determination of the ee values: Chiralcel OD column, hexanes/2-

propanol (95:5; 1.0 mLmin^À1), UV detection (210 nm). Phenyl-1-

propanol: t_R= 9.45 min (R) and 11.35 min (S); 1-(1’-naphthyl)-1-

propanol: t_R= 17.26 min (R) and 8.61 min (S); 4-methylphenyl-1-

propanol: t_R= 7.84 min (R) and 11.47 min (S); 4-chlorophenyl-1-

propanol: t_R= 36.21 min (R) and 39.57 min (S); 4-methoxyphenyl-1-

propanol: t_R= 13.69 min (R) and 14.85 min (S). Phenylethanol: GC,

capillary column VF-5 ms; 30 m 0.25 mm, 0.25 mm, 15 psi; temper-

benzaldehyde^[d]

[a] 1d: R=R’=CH₂Ph, 1e R=R’=4-CH₂(C₆H₄)CH₃, and 1 f R=CH₂Ph,

R’=4-CH₂(C₆H₄)OCH₃. [b] Yields after 24 h; conversions and selectiv-

ities were determined by NMR spectoscopy. Selectivity: 100[1-phenyl-

propanol]/[benzyl alcohol]+[1-phenylpropanol]. [c] Determined by

HPLC on a chiral stationary phase (Chiralcel OD); the major enantiomer

obtained is indicated in parenthesis. [d] Addition of ZnMe₂.

atures: injector 2308C, detector 3008C, oven 60–1308C, 10 8Cmin^À1

t_R= 12.18 min (R) and t_R= 12.51 min (S).

;

Received: May 22, 2007

Revised: July 30, 2007

Published online: September 24, 2007

Explaining the observed enantioselectivities is difficult

without calculating the relative energies of all reasonable

transition states. For 1:1 complexes, the coordination of

benzaldehyde at one square-planar position, by substituting

one weakly coordinating ligand, or at one octahedral position

allows a transition state to be considered that is similar to that

described by Noyori and co-workers for the process catalyzed

by amino alcohols. A tricyclic transition state with an anti–

trans disposition could favor the formation of the S enan-

tiomer.^[19]For 1:2 complexes, coordination must occur at one

of the octahedral positions. Actually, an octahedral green

complex is obtained by dissolving the complex in benzalde-

hyde. In this case, the presence of the R’ substituent can favor

a syn–trans disposition of the tricyclic transition state, thereby

affording the R enantiomer.

Keywords: amino acids · asymmetric catalysis · chirality ·

homogeneous catalysis · ligand design

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9004 www.angewandte.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Angew. Chem. Int. Ed. 2007, 46, 9002 –9005

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org 9005

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