Greatly enhanced enantioselectivity by an apparently remote steric effect in the 1,1′-binaphthyl-catalyzed alkynylzinc addition to aldehydes

Article abstract of DOI:10.1016/S0040-4039(02)02211-6

An unusual steric effect in the binaphthyl-catalyzed asymmetric alkynylzinc addition to aldehydes is observed. Increasing the steric bulkiness at the para-position of the 3,3′-anisyl groups of the 1,1′-binaphthyl ligands, though apparently remote from the

Full text of DOI:10.1016/S0040-4039(02)02211-6

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TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8831–8834
Greatly enhanced enantioselectivity by an apparently remote
steric effect in the 1,1%-binaphthyl-catalyzed alkynylzinc
addition to aldehydes
David Moore, Wei-Sheng Huang, Ming-Hua Xu and Lin Pu*
Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA
Received 24 September 2002; accepted 7 October 2002
Abstract—An unusual steric effect in the binaphthyl-catalyzed asymmetric alkynylzinc addition to aldehydes is observed.
Increasing the steric bulkiness at the para-position of the 3,3%-anisyl groups of the 1,1%-binaphthyl ligands, though apparently
remote from the Lewis acid coordination sites, has greatly enhanced the enantioselectivity as well as catalytic activity. Propargyl
alcohols with ees up to 92% have been produced from the reaction of a terminal alkyne with aromatic aldehydes by using the
binaphthyl catalysts. © 2002 Elsevier Science Ltd. All rights reserved.
Optically active propargyl alcohols are versatile precur-
sors to many chiral organic compounds.1–7 Recently,
significant progress has been made in the asymmetric
alkynylzinc addition to aldehydes for the synthesis of
chiral propargyl alcohols (1) (Scheme 1).8–16 Among the
catalysts developed, those based on ephedrine11 and
1,1%-bi-2-naphthol12,13 have shown the most general
enantioselectivity.
In 2000, we reported that the binaphthyl compound
(S)-2 was highly enantioselective for the diphenylzinc
addition to aldehydes.17 It is believed that all the four
oxygen atoms in (S)-2 participate in the coordination
with the Lewis acidic zinc centers to catalyze the reac-
tion. In order to develop enantioselective catalysts for
the alkynylzinc addition, we prepared a series of
analogous binaphthyl compounds (S)-2-(S)-11 that
Keywords: alkynylzinc; 1,1%-binaphthyl; enantioselective; propargyl alcohols; aldehydes.
* Corresponding author. E-mail: lp6n@virginia.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02211-6

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D. Moore et al. / Tetrahedron Letters 43 (2002) 8831–8834
mol%) was used to catalyze the reaction of phenyl-
acetylene (2.1 equiv.) with benzaldehyde in the presence
of Ti(OiPr)4 (20 mol%) and diethylzinc (2.0 equiv.) in
THF, very good enantioselectivity (85% ee) was
observed as shown in entry 1 of Table 1. Other solvents
were not as effective as THF (entries 2–4). Reducing
the temperature to 0°C increased the ee to 88% but
decreased the yield (entry 5). In all these reactions, a
solution of diethylzinc (2.0 equiv.) and phenylacetylene
(2.1 equiv.) was heated at reflux under nitrogen for 5 h
before the addition of (S)-14, Ti(OiPr)4, and
benzaldehyde.
Scheme 1. Asymmetric alkynylzinc addition to aldehydes for
the synthesis of propargyl alcohols.
contain 3,3%-anisyl groups with a variety of electron-
withdrawing substituents.18 However, all of these com-
pounds showed low enantioselectivity for the reaction
of phenylacetylene with benzaldehyde in the presence of
diethylzinc with or without Ti(OiPr)4. The ee of the
resulting propargyl alcohol product was observed in the
range of 0–67%. Ligand (R)-12 that contains the elec-
tron-donating alkoxy groups at the 3,3%-anisyls,
although highly enantioselective for the alkylzinc addi-
tion to aldehydes,19 was found not good for the
alkynylzinc addition.
We also found that the reflux step could be avoided by
stirring a solution of (S)-14, phenylacetylene and
diethylzinc at room temperature for 12 h followed by
the addition of Ti(OiPr)4 and benzaldehyde. Appar-
ently, the zinc complex generated from the reaction of
(S)-14 with diethylzinc catalyzed the formation of an
alkynylzinc reagent from phenylacetylene and diethyl-
zinc. Table 2 summarizes the results obtained from this
procedure. The temperature and reaction time in Table
2 are for the step involving Ti(OiPr)4 and benzaldehyde.
As shown in entry 2, up to 92% ee was observed for the
reaction at room temperature. Entry 3 indicates that
there was a slight reduction in ee as the reaction
proceeded to 83% yield. At 0°C, the reaction became
much slower and the longer reaction time also led to
reduction in ee (entries 4–6). This suggests that racem-
ization of the propargyl alkoxide could take place,
though slow, under the reaction condition.
We then synthesized the binaphthyl compound (S)-13
that contains para-phenyl-substituted 3,3%-anisyl
groups.18,20 This compound was used to catalyze the
reaction of phenylacetylene with benzaldehyde. In the
presence of diethylzinc (2.0 equiv.) and Ti(OiPr)4 (1.0
equiv.), (S)-13 (20 mol%) catalyzed the reaction in
THF at room temperature with 80% ee. Since both
electron-donating and electron-withdrawing groups at
the 3,3%-anisyls of the binaphthyl ligands gave relatively
poor results, we suspected that the significantly
improved enantioselectivity of (S)-13 over ligands (S)-
2-(R)-12 might be due to an unusual steric effect at the
remote para-position of the 3,3%-anisyls. Therefore, we
introduced the more bulky tertiary butyl groups to
make compound (S)-14.18,21 When this compound (10
The enantiomer of (S)-14, (R)-14, was prepared. Com-
pound (R)-14 was used to catalyze the reaction of
phenylacetylene with benzaldehyde in the presence of
diethylzinc and Ti(OiPr)4. The following gives the opti-
mized procedure for the reaction catalyzed by (R)-14.
Table 1. Reaction of phenylacetylene with benzaldehyde catalyzed by (S)-14 in the presence of Ti(OiPr)4 and diethylzinc
Entry
Solvent
Temperature
Isolated yield (%)
ee (%)
t (h)
1
2
3
4
5
THF
r.t.
r.t.
r.t.
r.t.
0°C
ꢀ70
ꢀ70
ꢀ70
ꢀ70
50
85
83
40
40
88
12
12
12
12
35
CH2Cl2
Toluene
Ether
THF

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D. Moore et al. / Tetrahedron Letters 43 (2002) 8831–8834
8833
Table 2. Reaction catalyzed by (S)-14 without refluxing
yield. No side product was observed in this reaction. The
enantiomeric purity of the product was determined to be
89% ee by using HPLC-ChiralDiacel OD column.
phenylacetylene with diethylzinc
Entry
Temperature
Time (h)
Yield (%)a
ee (%)
We prepared another ligand (S)-15 that has a smaller
methyl group at the para-position of the 3,3%-anisyl
substituents of the binaphthyl.18 Its catalytic properties
are compared with those of (R)-14 by using the optimized
procedure and the results are summarized in Table 3. The
reactionscatalyzedby(R)-14proceededwithmuchhigher
enantioselectivity than (S)-15. The speed of the reactions
catalyzed by (R)-14 was also much faster than that by
1
2
3
4
5
6
r.t.
r.t.
r.t.
0°C
0°C
0°C
0.5
1.0
2.0
2.3
7.5
53
66
83
12
27
58
88
92
89
89
87
84
22.0
a Measured by 1H NMR.
1
(S)-15. For example, H NMR study showed 83% yield
Under nitrogen, (R)-14 (0.05 mmol, 30 mg), phenyl-
acetylene (1.1 mmol,121 mL) and diethylzinc (1.0 mmol,
102 mL) were added to a 10 mL flask containing THF
(5 mL, dried over sodium). This solution was stirred at
room temperature for 12 h. Then, Ti(OiPr)4 (0.25 mmol,
74 mL) was added. After stirred for an hour, benzaldehyde
(0.5 mmol, 50 mL) was added, and the reaction mixture
was stirred at room temperature for additional 3 h.
Concentrated ammonium chloride was added to quench
the reaction. The mixture was extracted with methylene
chloride and dried with sodium sulfate. After column
chromatographic purification on silica gel eluted with
2–10% ethyl acetate in hexanes, the propargyl alcohol
product 1,3-diphenyl-prop-2-yn-1-ol was isolated in 80%
in 2 h for the reaction using (R)-14, but only 45% yield
for using (S)-15 under the same condition.
Table 3. Asymmetric addition of phenylacetylene to aromatic aldehydes catalyzed by (R)-14 and (S)-15
Entrya
1
Aldehyde
Catalyst
ee (%)
84
Configuration
(R)-14
R
2
3
4
(R)-14
(R)-14
(R)-14
84
85
89
R
R
R
5
6
7
8
(S)-15
(S)-15
(S)-15
(S)-15
56
73
81
83
S
S
S
S
a Reactions carried out at room temperature with 10% catalyst, 25% Ti(OiPr)4, 2 equiv. ZnEt2, and 2.1 equiv. phenylacetylene in 5 mL THF at
room temperature.

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D. Moore et al. / Tetrahedron Letters 43 (2002) 8831–8834
In summary, we have observed an unusual steric effect
in the binaphthyl-catalyzed asymmetric alkynylzinc
addition to aldehydes. Increasing the steric bulkiness at
the para-position of the 3,3%-anisyl groups of the 1,1%-
binaphthyl ligands, though apparently remote from the
Lewis acid coordination sites, has greatly enhanced the
enantioselectivity as well as catalytic activity. Propargyl
alcohols with ee’s up to 92% have been produced from
the reaction of a terminal alkyne with aromatic alde-
hydes by using the binaphthyl catalysts.
11. Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687–9688.
12. (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855–1857; (b)
Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002,
in press.
13. Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. J. Chem. Soc.,
Chem. Commun. 2002, 172–173.
14. (a) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990,
937–943; (b) Tombo, G. M. R.; Didier, E.; Loubinoux, B.
Synlett 1990, 547–548.
15. (a) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.;
Reider, P. Synthesis 1999, 1453–1458; (b) Lu, G.; Li, X.;
Zhou, Z.; Chan, W. L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2001, 12, 2147–2152.
16. Jiang, B.; Chen, Z.; Xiong, W. J. Chem. Soc., Chem.
Commun. 2002, 1524–1525.
Acknowledgements
We thank the partial support for this research from the
donors of the Petroleum Research Fund—administered
by the American Chemical Society.
17. Huang, W.-S.; Pu, L. Tetrahedron. Lett. 2000, 41, 145–149.
18. For the synthesis of the 3,3%-anisyl substituted 1,1%-binaph-
thyl compounds, see Ref. 17 and Huang, W.-S.; Hu, Q.-S.;
Pu, L. J. Org. Chem. 1999, 64, 7940–7956.
19. Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1998, 63,
1364–1365.
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1
20. Characterization of (S)-13: H NMR (300 MHz, CDCl3)
l 8.00 (s, 2H), 7.92–7.89 (m, 2H), 7.78 (d, 2H, J=2.31 Hz),
7.67-7.62 (m, 6 H), 7.47–7.31 (m, 12H), 7.11 (d, 2H, J=8.47
Hz), 5.80 (s, 2H), 3.88 (s, 6H). 13C NMR (75 MHz, CDCl3)
l 155.48, 150.77, 140.69, 134.64, 133.65, 131.70, 131.09,
129.48, 128.98, 128.67, 128.51, 128.18, 127.73, 127.08,
125.00, 124.09, 114.73, 111.82, 56.37. HRMS (DEI) calcd
for C46H34O4: 650.2457; found: 650.2442.
1
21. Characterization of (S)-14: H NMR (300 MHz, CDCl3)
l 7.93–7.88 (m, 4H), 7.53 (d, 2H, J=2.69 Hz), 7.44–7.40
(m, 2H), 7.38–7.29 (m, 6H), 6.964 (d, 2H, J=8.47 Hz), 5.93
(s, 2H), 3.81 (s, 6H), 1.37 (s, 9H). 13C NMR (75 MHz,
CDCl3) l 154.30, 150.39, 144.18, 133.43, 131.15, 129.49,
129.24, 129.19, 129.21, 126.50, 126.16, 124.94, 123.68,
115.35, 110.88, 56.10, 31.57. Anal. calcd for C42H40O4: C,
82.59; H, 6.93. Found: C, 82.31; H, 7.38. HRMS (DEI)
calcd for C42H42O4: 610.3083; found: 610.3096.