Chiral pyrrolidine derivatives as catalysts in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(98)00497-2

A series of pyrrolidine derivatives with β-amino alcohol moieties prepared from (S)-proline were found to catalyze the enantioselective addition of diethylzinc to aldehydes to yield optically active secondary alcohols with high enantioselectivities. A mec

Full text of DOI:10.1016/S0957-4166(98)00497-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 133–138
Chiral pyrrolidine derivatives as catalysts in the enantioselective
addition of diethylzinc to aldehydes
Xiaowu Yang,a Jianheng Shen,a Chaoshan Da,a Rui Wang,a,∗ Michael C. K. Choi,b
Liwei Yang b and Kwok-yin Wong b
aUnion Laboratory of Asymmetric Synthesis and Department of Biology, Lanzhou University, Lanzhou 730000,
People’s Republic of China
bUnion Laboratory of Asymmetric Synthesis and Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hong Kong, People’s Republic of China
Received 6 November 1998; accepted 8 December 1998
Abstract
A series of pyrrolidine derivatives with β-amino alcohol moieties prepared from (S)-proline were found to
catalyze the enantioselective addition of diethylzinc to aldehydes to yield optically active secondary alcohols with
high enantioselectivities. A mechanism accounting for the configurational change with the bulkiness of chiral
ligands is proposed. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Catalytic asymmetric carbon–carbon bond formation is one of the most active research areas in organic
synthesis.1 In this field, asymmetric addition of diethylzinc (Et2Zn) to aldehydes using a catalytic amount
of chiral catalyst has attracted much attention.2 In recent years, numerous efforts have been made to
search for new effective chiral ligands such as chiral β-amino alcohols,3 chiral amino thiols,4 pyridyl
alcohols,5 amines6 and titanium complexes7 and to investigate the reaction mechanism.8 It has been
found that β-amino alcohols and titanium complexes are efficient in the reaction. Mechanistic studies
show that the enantioselectivity of the addition of dialkylzincs to aldehydes is very sensitive to the steric
and electronic properties of chiral catalysts. In this paper, we report the catalytic asymmetric addition of
Et2Zn to aldehydes using chiral pyrrolidine derivatives having β-amino alcohol moieties 1–79 in order to
elucidate the steric effect of chiral ligands on the enantioselectivity.
∗
Corresponding author. E-mail: wangrui@lzu.edu.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00497-2

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2. Results and discussion
2.1. Effect of the amount of catalysts and reaction temperature on the asymmetric reaction
Our first effort was to investigate the effect of the amount of catalysts 1, 2 and 3 and reaction
temperature on the catalyzed addition of Et2Zn to benzaldehyde. The results are listed in Table 1. When
5 mol% of ligands (relative to benzaldehyde) was used, the optical purity (op) of 1-phenylpropan-1-ol
was lower than those using 10 mol% chiral ligands (runs 1–2, 4–5, 7–8, and 10–11). The op decreased
but the yields were nearly quantitative when the amount of the catalysts was increased to 15 mol% (runs
3, 6, 9, and 12). For example, the addition of Et2Zn to benzaldehyde in hexane catalyzed by 5 mol%,
10 mol% and 15 mol% of β-amino alcohol 2 afforded (R)-1-phenylpropan-1-ol in 81.9%, 95.7% and
94.1% op, respectively, with high yields (runs 7–9). We attempted to lower the reaction temperature for
higher enantioselectivity, but there was almost no reaction below 0°C. Thus, the optimum amount of
chiral catalysts was 10 mol% relative to benzaldehyde and reaction temperature was 0°C.
Table 1
The effect of the amount of chiral ligands on asymmetric addition of Et2Zn to benzaldehyde

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135
2.2. Effect of solvents on the asymmetric reaction
It has been reported that solvents have a great effect on the enantioselectivity and yields.7b Thus, our
second effort was to examine the effect of solvents using 10 mol% of chiral ligands 1, 2, and 3 on the
reaction. As shown in Table 2, when 1 was used as a ligand, an identical op of 99.2% was obtained in
benzene and cyclohexane with 97.7% and 97.2% yields (runs 2, 5).
Although a similar op could be obtained using mixed solvents, the yields were relatively low (runs
6–8). The highest op of 95.7% was obtained by employing hexane as a solvent in the presence of ligand
2 (runs 9–12). Using ligand 3 bearing the bulky diphenylmethanol moiety, up to 81.8% op was obtained
of phenyl propanol with S configuration in hexane (runs 13–16). From the results, toluene and THF as
solvents retarded the reaction and lowered the enantioselectivities and yields to some extent. Thus, the
best solvents for the reaction are benzene and hexane.
Table 2
The effect of solvents on the asymmetric addition of Et2Zn to benzaldehyde
2.3. Enantioselective addition of Et2Zn to benzaldehyde and 4-methoxybenzaldehyde
Under the above optimum reaction conditions, the asymmetric catalytic capability of chiral ligands
1–7 was investigated (Scheme 1). The results are shown in Table 3. β-Amino alcohol 1 possessing a
dimethylmethanol moiety at the α-position of the pyrrolidine ring (R1=Me) gave (R)-1-phenylpropan-
1-ol in 99.2% op and (R)-1-(4-methoxyphenyl)propan-1-ol in 95.3% op (runs 1–2). Chiral ligand 2
(R1=Et) also provided good results (runs 3–4). However, on ligand 3 (R1=Ph), while the bulkiness of

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the α-position of the pyrrolidine ring was gradually increased, the op of the product decreased and the S
configuration of the product was observed (runs 5–6). The ligand 5 (R2=Me, R3=PhCH2) shows higher
enantioselectivity than 3 (runs 5–6, 10–11) and the catalytic capability of 6 (up to 93.7% op, runs 12–13)
containing the methoxy group (R2=Me) is higher than 4 with the hydroxyl group (R2=H, up to 55% op,
runs 7–9). Chiral C2-symmetric alcohol 7 also gave good results with the product having S configuration
(91% op, 95% yield, run 15). Though the structure of the chiral ligands is very similar, the absolute
configuration of the product and the enantioselectivity are very different, which prompts us to rationalize
the mechanism of the addition reaction.
Scheme 1.
Based on our experimental findings and related mechanistic studies by Soai and Noyori,8a,b we
proposed a mechanism as shown in Scheme 2. First, Et2Zn reacts rapidly with the ligand to give the
corresponding zinc monoalkoxide 8, which does not ethylate benzaldehyde, and is then converted to
the zinc monoalkoxide–diethylzinc complexes 9 and 10.11 The coordination geometry of the zinc atom
is essentially tetrahedral12 and this complex 10 is more stable than complex 9. The nucleophilicity of
the ethyl group of Et2Zn would be increased by coordination of the zinc atom with the oxygen or the
nitrogen atom of the catalyst.13 Second, the re or si face of benzaldehyde may be reacted to give six-
center transition states (TS) 11 and 12, respectively. The TS 11 should be more stable than TS 12 because
Table 3
Enantioselective addition of Et2Zn to aldehydes

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137
the phenyl group is disposed equatorially in 11.14 Third, the six-center transition states 11 and 12 may
explain the stereochemical course of the addition. When the α-substituent of the pyrrolidine ring is Me
or Et (ligands 1 or 2), the re face of benzaldehyde is attacked, leading to the R isomer (Table 3, runs 1–4).
However, with the increase of the bulkiness of the α-substituent of the pyrrolidine ring, steric factors
have to be taken into consideration. The bulky phenylmethanol moiety and bulky N-group in ligands 3
and 5 block the approach of benzaldehyde from the re face, and the ethyl group at complex 10 attacks
benzaldehyde mainly from the si face through the transition state 12, leading to the S-isomer.14a Owing
to transition state 12 being unstable, less asymmetric induction was observed (runs 5–6, 10–11, 14–17).
On the other hand, in case where the N-substituent is small (H in 4 and 6), the steric effect is not sufficient
to hinder attack of the re face of benzaldehyde, resulting in the R-isomer (runs 7–9, 12–13). The same
trend was observed by Soai8a using β-amino alcohols with different N-substitutents as chiral catalysts in
the reaction.
Scheme 2.
3. Experimental
3.1. General methods
Optical rotation ([α]D) was taken on a WZZ automatic polarimeter using CHCl3 as a solvent. All
reactions were carried out under a nitrogen atmosphere with dry, freshly distilled solvent under anhydrous
condition. Hexane, benzene, cyclohexane, THF and toluene were distilled from sodium. Benzaldehyde
and 4-methoxybenzaldehyde were distilled from calcium hydride under an argon atmosphere.
3.2. Typical procedure of asymmetric addition of Et2Zn to benzaldehyde
To a solution of chiral β-amino alcohol (1) (14 mg, 0.064 mmol) in benzene (1.2 mL) was added
dropwise a solution of Et2Zn (1.28 mL, 1 M in benzene solution) at 0°C. After stirring for 0.5 h,

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X. Yang et al. / Tetrahedron: Asymmetry 10 (1999) 133–138
benzaldehyde (67.8 mg, 0.64 mmol) was added at 0°C, and the reaction was stirred for 2 h at 0°C and for
13 h at room temperature. The reaction mixture was quenched by 5% cold aqueous HCl solution and the
mixture was extracted with ether (4×10 mL). The combined organic extracts were washed with brine (10
mL), dried (Na2SO4), and evaporated under reduced pressure to give an oily residue. The residue was
purified by silica gel TLC to give optically active 1-phenylpropan-1-ol (84.3 mg, 97.7%).
Acknowledgements
We thank the Hong Kong Polytechnic University, the National Natural Science Foundation of China,
Fok Ying Tung Education Foundation (Hong Kong), and the Ministry of Education of China for financial
support.
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