Enantioselective addition of diethylzinc to aldehydes with novel chiral C2-symmetric dimeric ligands

Article abstract of DOI:10.1016/S0040-4039(99)02230-3

Novel (S)-valinol-based chiral C₂-2,2'-ethylenediiminodiethanol derivatives 4a and 4b have been synthesized and used as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. (R)-1- Phenylpropanol has been obtained in up

Full text of DOI:10.1016/S0040-4039(99)02230-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1047–1050
Enantioselective addition of diethylzinc to aldehydes with novel
chiral C2-symmetric dimeric ligands
Masanori Okaniwa, Reiko Yanada ∗ and Toshiro Ibuka ∗
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 18 October 1999; revised 15 November 1999; accepted 26 November 1999
Abstract
Novel (S)-valinol-based chiral C2-2,20-ethylenediiminodiethanol derivatives 4a and 4b have been synthesized
and used as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. (R)-1-Phenylpropanol has
been obtained in up to 91% enantiomeric excess. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aldehyde; alkylation; organozinc; enantioselective; C2-symmetric 2,20-ethylenediiminodiethanol derivatives.
Development of catalytic asymmetric synthesis is important for synthetic chemistry.1 In the past
decade, a number of efficient chiral ligands have been reported in this field.2 Among the possible
reactions, catalytic enantioselective addition of organozinc to aldehydes is a typical reaction to construct a
chiral center. A number of aminoalcohols,3 diamines,4 and diols5 have been used successfully to promote
this enantioselective reaction.
Uemura and co-workers demonstrated that chiral imines bearing a tricarbonylchromium group undergo
highly diastereoselective coupling reactions with samarium diiodide to give coupling products in high
chemical and optical yields.6 Recently, we also succeeded in preparation of (S)-valinol-based chiral
C2-2,20-ethylenediiminodiethanol (C2-dimeric aminoalcohol) derivatives by a highly diastereoselective
intermolecular pinacol-like coupling reaction using optically active imines and metallic samarium.7 In
this report, we describe the synthesis and use of novel chiral C2-dimeric aminoalcohols as catalysts for
the enantioselective addition of diethylzinc to aldehydes. We anticipated that enantioselective addition re-
action of diethylzinc to arylaldehydes in the presence of a catalytic amount of C2-dimeric aminoalcohols
could occur to yield chiral aryl ethyl carbinol in high yields and high enantioselectivities.
The chiral compounds 2a and 2b were prepared according to our imine coupling method in 70–80%
yield.7 Compounds 3a and 3b were obtained in quantitative yield by five-membered ring formation
with aqueous formaldehyde in methanol. Demethylation of these compounds gave the C2-dimeric
aminoalcohols 4a8 and 4b9 with BBr3 in hexane–chloroform at room temperature in 70–80% yields
∗
Corresponding authors. E-mail: ryanada@pharm.kyoto-u.ac.jp (R. Yanada), tibuka@pharm.kyoto-u.ac.jp (T. Ibuka)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02230-3
tetl 16158

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(Scheme 1). A monomeric ligand 5 was prepared in order to compare the difference in asymmetric
induction ability between the C2-dimeric aminoalcohol ligand 4a and the monomeric ligand 5a.
Scheme 1.
Table 1
Enantioselective addition of diethylzinc to benzaldehyde with chiral ligandsa
The enantioselectivity of chiral ligand-catalyzed reactions of benzaldehyde with diethylzinc was studi-
ed by varying the amount of catalyst, the temperature, and the reaction time. Exposure of benzaldehyde
to diethylzinc (2 equiv.) and the chiral ligand 4a (5 mol%) at 0°C for 24 h afforded alcohol 8a in 75%
yield and 88% ee (Table 1, entry 1). When the same reaction was run for 84 h under otherwise identical
reaction conditions, the chemical yield was considerably improved (entry 2). The yield and enantiomeric
excess of the reactions increased with an increase in the amount of the chiral catalyst 4a (entries 3–5).
The highest enantiomeric excess (90% ee) was realized by reacting in hexane at 0°C (compare entry 6

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with entries 5 and 7). Hexane is the solvent of choice rather than toluene (compare entries 5 and 6 with
entries 8 and 9). Next, we used the chiral ligand 4b as a catalyst. The ligand 4b also catalyzed the addition
reaction effectively in hexane to afford (R)-1-phenylpropanol (97% yield, 91% ee) (entry 10). However,
the chiral aminoalcohol 5a was found to be a less effective catalyst. Thus, reaction of benzaldehyde with
diethylzinc in the presence of 20 mol% of the ligand 5a afforded an alcohol with only 10–13% ee (entries
12 and 13).
The substituents at the α- or β-position of chiral aminoalcohol play an important role in asymmetric
induction.2a,10 It is known that the α-position of aminoalcohol becomes more bulky, the degree of asym-
metric induction becomes higher.10 Thus far, the addition reaction of diethylzinc to benzaldehyde using
chiral C2-primary aminoalcohol gave 1-phenylpropanol in low to moderate enantiomeric excess.3d,11 In
spite of our ligands 4a and 4b having primary alcohol moiety, 1-phenylpropanol was obtained in high
enantiomeric excess (90 and 91% ee). As shown in Fig. 1, the anti-transition state is predominant. The
steric hindrance between the methylene bridge of the ligand and the hydrogen of the aldehyde carbon
would disfavor a syn-transition state, leading to a decrease in the enantioselectivity. Consequently, it is
thought that diethylzinc attacked predominantly from the re-face of benzaldehyde.
Fig. 1. Plausible mechanism of asymmetric induction using ligand 4a
Table 2
Enantioselective addition of diethylzinc to aldehydes with chiral ligand 4aa
The chiral ligand 4a was found to be an effective catalyst in the addition reaction of diethylzinc to
various aldehydes to afford good enantiomeric excess (Table 2, entries 1–7). Due to the low solubility of
aldehydes to hexane, toluene was used as a solvent (entries 5–9). The reaction using aromatic aldehydes
bearing an electron-donating group (6c and 6d) increased the isolated yields. On the other hand, the
reaction using aromatic aldehyde bearing an electron-withdrawing group (6e) reduced the isolated

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yield. The reaction using α,β-unsaturated aldehyde (6f) or aliphatic aldehyde (6g) proceeded in low
enantioselectivity.
Next, we examined an asymmetric amplification. A slightly positive non-linear relationship was
observed between the enantiomeric excess of the product and the enantiomeric excess of the ligand 4a in
the addition reaction (Fig. 2).
Fig. 2. Correlation between % ee of 4a and % ee of (R)-1-phenylpropanol
In conclusion, this paper is the first report of high enantiomeric excess that was obtained in the reaction
of diethylzinc to aromatic aldehyde using C2-dimeric aminoalcohols 4a and 4b bearing primary alcohols.
The good enantioselectivity apparently arises from their stereostructural rigidity and bulkiness.
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4.6, 7.6 Hz), 3.74 (dd, 2H, J=4.6, 11.9 Hz), 3.77 (s, 6H), 3.82 (dd, 2H, J=4.3, 11.9 Hz), 4.00 (s, 2H), 4.23 (s, 2H), 6.78 (d,
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