From Highly Enantioselective Monomeric Catalysts to Highly Enantioselective Polymeric Catalysts: Application of Rigid and Sterically Regular Chiral Binaphthyl Polymers to the Asymmetric Synthesis of Chiral Secondary Alcohols

Article abstract of DOI:10.1021/jo990992v

A 1,1′-binaphthyl-based polymeric chiral catalyst with the most general enantioselectivity for the alkylzinc addition to a broad range of aldehydes has been obtained. This polymer can be easily recovered, and the recycled polymer shows the same catalytic properties as the original polymer. A highly enantioselective catalytic diphenylzinc addition to aldehydes has also been achieved by using the chiral binaphthyl monomer and polymer catalysts. Particularly, the excellent enantioselectivity observed for the addition of diphenylzinc to aromatic aldehydes allows the preparation of optically active diaryl carbinols that are synthetically useful but difficult to access by asymmetric catalysis. A novel asymmetric reduction of ketones catalyzed by the mono- and polybinaphthyl zinc complexes has been discovered. Our work on the asymmetric organozinc addition to aldehydes and the asymmetric reduction of ketones catalyzed by the zinc complexes of chiral binaphthyl monomer (R)-12 and polybinaphthyl (R)-43 has not only provided new methods to prepare optically active secondary alcohols but also demonstrated that incorporation of an enantioselective monomeric catalyst into a rigid and sterically regular polymer structure could almost completely preserve the catalytic properties of the monomeric catalyst. This strategy may find general application in converting existing highly enantioselective monomer catalysts into polymer catalysts of similar enantioselectivity provided that the catalytically active species of the monomer catalysts contain only the monomeric units rather than the aggregates of the monomers. By using this strategy, it is possible to overcome the drawbacks associated with the traditional approach to preparing polymeric chiral catalysts where the microenvironments of the catalytic sites in the polymers are often significantly altered from those in the monomeric catalysts due to the flexible and sterically irregular polymer chains.

Full text of DOI:10.1021/jo990992v

7940
J . Org. Chem. 1999, 64, 7940-7956
F r om High ly En a n tioselective Mon om er ic Ca ta lysts to High ly
En a n tioselective P olym er ic Ca ta lysts: Ap p lica tion of Rigid a n d
Ster ica lly Regu la r Ch ir a l Bin a p h th yl P olym er s to th e Asym m etr ic
Syn th esis of Ch ir a l Secon d a r y Alcoh ols
Wei-Sheng Huang, Qiao-Sheng Hu, and Lin Pu*
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received J une 22, 1999
A 1,1′-binaphthyl-based polymeric chiral catalyst with the most general enantioselectivity for the
alkylzinc addition to a broad range of aldehydes has been obtained. This polymer can be easily
recovered, and the recycled polymer shows the same catalytic properties as the original polymer.
A highly enantioselective catalytic diphenylzinc addition to aldehydes has also been achieved by
using the chiral binaphthyl monomer and polymer catalysts. Particularly, the excellent enantio-
selectivity observed for the addition of diphenylzinc to aromatic aldehydes allows the preparation
of optically active diaryl carbinols that are synthetically useful but difficult to access by asymmetric
catalysis. A novel asymmetric reduction of ketones catalyzed by the mono- and polybinaphthyl
zinc complexes has been discovered. Our work on the asymmetric organozinc addition to aldehydes
and the asymmetric reduction of ketones catalyzed by the zinc complexes of chiral binaphthyl
monomer (R)-12 and polybinaphthyl (R)-43 has not only provided new methods to prepare optically
active secondary alcohols but also demonstrated that incorporation of an enantioselective monomeric
catalyst into a rigid and sterically regular polymer structure could almost completely preserve the
catalytic properties of the monomeric catalyst. This strategy may find general application in
converting existing highly enantioselective monomer catalysts into polymer catalysts of similar
enantioselectivity provided that the catalytically active species of the monomer catalysts contain
only the monomeric units rather than the aggregates of the monomers. By using this strategy, it
is possible to overcome the drawbacks associated with the traditional approach to preparing
polymeric chiral catalysts where the microenvironments of the catalytic sites in the polymers are
often significantly altered from those in the monomeric catalysts due to the flexible and sterically
irregular polymer chains.
In tr od u ction
filtration,4,5 and homogeneous polymer catalysts can be
separated by either membrane filtration or precipitation
with a poorer solvent followed by filtration.6 The tradi-
tional approach to constructing polymer-supported chiral
catalysts involves the development of a highly enantio-
selective monomeric catalyst and then the attachment
of this monomeric catalyst to a flexible and sterically
irregular polymer backbone. Although a few enantiose-
lective polymer catalysts have been obtained in this way,
a significant drop of enantioselectivity is often observed
when a monomeric chiral catalyst is attached to a
polymer support due to the changes in the microenvi-
ronment of the catalytic sites.4-6
Extensive activities in the field of asymmetric catalysis
have led to the discovery of many highly enantioselective
catalysts.1-3 A number of these catalysts have been
applied to pharmaceutical and agricultural industries for
the asymmetric synthesis of chiral organic molecules.
Since it is often quite expensive to prepare the optically
active catalysts, their easy recovery and reuse are highly
desirable. Because of the significant size difference
between polymers and small molecules, using polymer-
based catalysts greatly simplifies both the recycle of the
catalysts and purification of the products.4-6 Heteroge-
neous polymer catalysts can be separated by simple
Recently, we have used optically active binaphthyl
molecules to build novel main-chain chiral conjugated
polymers7-9 and have studied their application in asym-
metric catalysis.10-13 Polymers (S)-1,7d (R)-2,7b (R)-3,11 and
(1) Ojima, I. Ed. Catalytic Asymmetric Synthesis; VCH: New York,
1993.
(2) (a) Stinson, S. C. Chem. Eng. News 1994, 72(38), 38. (b) Stinson,
S. C. Chem. Eng. News 1997, 75(42), 38. (c) Stinson, S. C. Chem. Eng.
News 1998, 76(38), 83.
(3) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn
Wiley & Sons: New York, 1994.
(4) (a) Blossey, E. C.; Ford, W. T. In Comprehensive Polymer Science.
The Synthesis, Characterization, Reactions and Applications of Poly-
mers; Allen, G., Bevington, J . C., Eds.; Pergamon Press: New York,
1989; Vol. 6, p 81. (b) Pittman, C. U., J r. In Comprehensive Organo-
metallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.;
Pergamon Press: Oxford, 1983; Vol. 8, p 553.
(5) Itsuno, S. In Polymeric Materials Encyclopedia; Synthesis,
Properties and Applications; Salamone, J . C., Ed.; CRC Press: Boca
Raton, FL, 1996; Vol. 10, p 8078.
(7) (a) Hu, Q.-S.; Vitharana, D.; Liu, G.; J ain, V.; Wagaman, M. W.;
Zhang, L.; Lee, T. R.; Pu, L. Macromolecules 1996, 29, 1082. (b) Hu,
Q.-S.; Vitharana, D.; Liu, G.; J ain, V.; Pu, L. Macromolecules 1996,
29, 5075. (c) Ma, L.; Hu, Q.-S.; Musick, K.; Vitharana, D.; Wu, C.;
Kwan, C. M. S.; Pu, L. Macromolecules 1996, 29, 5083. (d) Cheng, H.;
Ma, L.; Hu, Q.-S.; Zheng, X.-F.; Anderson, J .; Pu, L. Tetrahedron:
Asymmetry 1996, 7, 3083. (e) Ma, L.; Hu, Q.-S.; Vitharana, D.; Wu,
C.; Kwan, C. M. S.; Pu, L. Macromolecules 1997, 30, 204. (f) Musick,
K. Y.; Hu, Q.-S.; Pu, L. Macromolecules 1998, 31, 2933. (g) Ma, L.;
Hu, Q.-S.; Pu, L. Tetrahedron: Asymmetry 1996, 7, 3103.
(8) Pu, L. In Electrical and Optical Polymer Systems: Fundamentals,
Methods, and Applications; Wise, D. L., Wnek, G. E., Trantolo, D. J .,
Cooper, T. M., Gresser, J . D., Eds.; Marcel Dekker Inc: New York,
1998, Chapter 24.
(6) (a) Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489. (b)
Bergbreiter, D. E. Chemtech 1987, 686.
10.1021/jo990992v CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7941
F igu r e 1. Examples of chiral binaphthyl polymers.
(R)-412 as shown in Figure 1 are examples of the optically
active polybinaphthyls prepared in our laboratory.
Through a systematic screening of the chiral binaphthyl
polymers, we have found that polymer (R)-4 exhibits very
good enantioselectivity for the reaction of diethylzinc with
certain aldehydes to give optically active secondary
alcohols.12 It represents a new generation of enantiose-
lective polymeric chiral catalysts that contain a rigid and
sterically regular polymer chain.
In the reactions catalyzed by (R)-4, up to 93% ee was
observed for the diethylzinc addition to para-substituted
benzaldehydes. However, less than 60% ee was observed
for the reaction of ortho-substituted benzaldehydes.12b
The enantioselectivity of (R)-4 for aliphatic aldehydes is
also limited. To improve the catalytic properties of (R)-
4, we have studied its monomeric model compound.
Based on the model compound study, we have designed
a new binaphthyl polymer and discovered that both the
monomeric model compound and the new polymer have
very high enantioselectivity for the reaction of diethylzinc
with a broad range of aldehydes.14a,b Using these new
chiral ligands, we have further achieved the first highly
enantioselective diphenylzinc addition to aldehydes.14c
Particularly, the excellent enantioselectivity observed for
the addition of diphenylzinc to aromatic aldehydes allows
the preparation of optically active diaryl carbinols that
are synthetically useful but difficult to obtain by asym-
metric catalysis.15
Besides the asymmetric organozinc addition to alde-
hydes, the asymmetric reduction of prochiral ketones is
also a very important method to synthesize chiral sec-
ondary alcohols.16,17 We have used the mono- and poly-
binaphthyl-based chiral zinc complexes to catalyze the
asymmetric reduction of ketones with catecholborane.
Our work on the organozinc addition to aldehydes and
the reduction of ketones with the binaphthyl-based
(14) The preliminary results were communicated: (a) Huang, W.-
S.; Hu, Q.-S.; Pu, L. J . Org. Chem. 1998, 63, 1364. (b) Hu, Q.-S.; Huang,
W.-S.; Pu, L. J . Org. Chem. 1998, 63, 2798. (c) Huang, W.-S.; Pu, L. J .
Org. Chem. 1999, 64, 4222.
(15) (a) Toda, F.; Tanaka, K.; Koshiro, K. Tetrahedron: Asymmetry
1991, 2, 873. (b) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1996, 37,
4837. (c) Botta, M.; Summa, V.; Corelli, F.; Pietro, G. D.; Lombardi, P.
Tetrahedron: Asymmetry 1996, 7, 1263. (d) Stanchev, S.; Rakovska,
R.; Berova, N.; Snatzke, G. Tetrahedron: Asymmetry 1995, 6, 183.
(16) For chiral boron-based Lewis acid-catalyzed asymmetric reduc-
tion of ketones, see: (a) Singh, V. K. Synthesis 1992, 605. (b) Deloux,
L.; Srebnik, M. Chem. Rev. 1993, 93, 763.
(17) For chiral titanium-based Lewis acid-catalyzed asymmetric
reduction of ketones, see: (a) Almqvist, F.; Torstensson, L.; Gud-
mundsson, A.; Frejd, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 376.
(b) Giffels, G.; Dreisbach, C.; Kragl, U.; Weigerding, M.; Waldmann,
H.; Wandrey, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 2005.
(9) For a review of chiral conjugated polymers, see: Pu, L. Acta
Polymerica 1997, 48, 116.
(10) Pu, L. Chem. Rev. 1998, 98, 2405.
(11) (a) Hu, Q.-S.; Zheng, X.-F.; Pu, L. J . Org. Chem. 1996, 61, 5200.
(b) Hu, Q.-S.; Vitharana, D.; Zheng, X.-F.; Wu, C.; Kwan, C. M. S.; Pu,
L. J . Org. Chem. 1996, 61, 8370.
(12) (a) Huang, W.-S.; Hu, Q.-S.; Zheng, X.-F.; Anderson, J .; Pu, L.
J . Am. Chem. Soc. 1997, 119, 4313. (b) Hu, Q.-S.; Huang, W.-S.;
Vitharana, D.; Zheng, X.-F.; Pu, L. J . Am. Chem. Soc. 1997, 119, 12454.
(13) (a) J ohannsen, M.; J ørgensen, K. A.; Zheng, X.-F.; Hu, Q.-S.;
Pu, L. J . Org. Chem. 1999, 64, 299. (b) Simonsen, K. B.; J orgensen, K.
A.; Hu, Q.-S.; Pu, L. J . Chem. Soc., Chem. Commun. 1999, 811.

7942 J . Org. Chem., Vol. 64, No. 21, 1999
Sch em e 1. Syn th esis of a Mon obin a p h th yl Mod el Com p ou n d (R)-12
Huang et al.
monomers and polymers demonstrates that it is possible
to preserve the high enantioselectivity of a monomeric
catalyst in a polymer by using the rigid and sterically
regular polymers. Herein, our detailed studies on the
development of novel enantioselective polymeric catalysts
for the asymmetric synthesis of chiral secondary alcohols
are reported.
Treatment of (R)-1,1′-bi-2-naphthol [(R)-6] with sodium
hydride and then with chloromethyl methyl ether gave
(R)-7.19 Reaction of (R)-7 with n-butyllithium followed by
the addition of iodine gave (R)-8.20 Compound 9 was
synthesized by bromination and alkylation of 1,4-dihy-
droquinone.21 One of the bromine atoms of 9 was removed
to form 10 by using 1 equiv of n-butyllithium. This
compound was then converted into a monoboronic acid
molecule 11 by reaction with n-butyllithium and trieth-
ylborate.21 The Suzuki coupling22 of (R)-8 with 11 followed
by hydrolysis generated (R)-12 as the monomeric model
compound of polymer (R)-4. The specific optical rotation
of (R)-12 was [R]D ) 95.0 (c ) 0.962, THF). The optical
purity of this compound was found to be over 99% as
determined by HPLC-Chiracel-OD column.23
Resu lts a n d Discu ssion
1. Syn th esis a n d Stu d y of th e Mon om er ic Mod el
Com p ou n d s of P olybin a p h th yl (R)-4. We have at-
tempted to modify the catalytic properties of (R)-4 by
preparing polymer (R)-5 that contains sterically bulkier
isopropyl groups.18 However, this polymer showed both
(R)-12 was used to catalyze the reaction of benzalde-
hyde with diethylzinc in toluene at 0 °C.24 In the presence
of 5 mol % of (R)-12, the chiral alcohol product (R)-1-
phenyl-1-propanol was obtained with over 99% ee (Scheme
2). When 0.5 mol % of (R)-12 was used, the high
enantioselectivity was maintained, but the reaction
became much slower. The generality of this catalyst for
a broad range of aldehydes was examined, and the results
are summarized in Table 1. As shown in Table 1, (R)-12
has high enantioselectivity for a great number of sub-
strates including para-, ortho-, or meta-substituted aro-
matic aldehydes, linear or branched aliphatic aldehydes,
slightly lower catalytic activity and enantioselectivity
than (R)-4. (R)-5 catalyzed the diethylzinc addition to
benzaldehyde with 89% ee and to cyclohexanecarboxal-
dehyde with 79% ee. This indicates that it could be
difficult to further improve the catalytic properties of
(R)-4 by varying the size of the R groups on the alkoxy-
phenylene linkers alone.
To gain more understanding on the catalysis carried
out by the binaphthyl polymers and to achieve more
general enantioselectivity, we have synthesized (R)-12
as the monomeric model compound of (R)-4 (Scheme 1).
(19) Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett. 1995,
1113.
(20) Cox, P. J .; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 17,
2253.
(21) Huber, J .; Scherf, U. Macromol. Rapid Commun. 1994, 15, 897.
(22) Selected references on the Suzuki coupling: (a) Miyaura, N.;
Yanagi, T.; Suzuki, A. Synth. Comm. 1981, 11, 513. (b) Wallow, T. I.;
Novak, B. M. J . Am. Chem. Soc. 1991, 113, 7411. (c) Suzuki, A. Acc.
Chem. Res. 1982, 15, 178.
(23) Conditions: hexane/2-propanol ) 97:3 at 0.5 mL/min. tS ) 12.88
min and tR ) 14.45 min. Or hexane/2-propanol ) 9:1 at 1.0 mL/min.
tS ) 4.8 min and tR ) 5.12 min.
(24) For reviews on asymmetric alkylzinc additions to aldehydes,
see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
(18) Lin, Z.-M.; Hu, Q.-S.; Pu, L. Polym. Prepr. 1998, 39(1), 235.

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7943
Ta ble 1. Rea ction of Ald eh yd es w ith Dia lk ylzin cs
by column chromatography on silica gel and showed no
change in both structure and activity.
Ca ta lyzed by (R)-12
dialkyl- time isolated
Figure 2 lists the catalysts that are currently known
to give good results for the asymmetric reaction of
aldehydes with diethylzinc.25-43 Their enantioselectivities
are compared with those of (R)-12 in Table 2. As shown
in Table 2, most of the catalysts are good for aromatic
aldehydes, but fewer are good for aliphatic aldehydes.
Although the addition to R,â-unsaturated aldehydes is
particularly useful since the resulting chiral allylic
alcohols are very versatile precursors to many important
organic compounds, it is very rare to find a good catalyst
for the reaction of alkyl-substituted R,â-unsaturated
aldehydes.
Among all of the previously reported catalysts, the
combination of 29a and 29b represents the best catalyst
system because of their generality.40 However, 29a does
not show good enantioselectivity for several ortho-
substituted aromatic aldehydes (ee ) 62-70%). In ad-
dition, a stoichiometric amount of Ti(OiPr)4 is required
most of the time when 29a or 29b is used. Recently,
Perica`s and co-workers have reported a highly enantio-
selective catalyst 33 for the diethylzinc addition,43 but it
requires an R-substituent for the R,â-unsaturated alde-
hyde substrates. With a catalytic amount of (R)-12,
excellent enantioselectivities are observed across the
entire spectrum of the listed aldehydes. Particularly, its
high enantioselectivity for various alkyl- and aryl-
substituted R,â-unsaturated aldehydes is most remark-
able.
aldehyde
zinc
(h) yield (%) ee (%) config
benzaldehyde
Et2Zn
4
4
6
4
4
6
4
8
6
5
6
40
24
45
40
95
91
92
96
97
95
93
90
92
94
90
89
86
91
90
99a
98b
97c
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
p-methylbenzaldehyde Et2Zn
p-anisaldehyde Et2Zn
p-chlorobenzaldehyde Et2Zn
m-chlorobenzaldehyde Et2Zn
>99a
98d
99a
m-anisaldehyde
o-fluorobenzaldehyde
o-anisaldehyde
1-naphthaldehyde
2-naphthaldehyde
2-furaldehyde
hexanal
heptanal
nonanal
cyclohexanecarbox-
aldehyde
isovaleraldehyde
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
94b
94b
>99a
99a
91d
98d
98d
98d
98d
Et2Zn
30
24
27
73
91
86
98e
92a
98d
R
R
R
trans-cinnamaldehyde Et2Zn
R-methyl-trans-
cinnamaldehyde
crotonaldehyde
3-methyl-2-butenal
trans-2-methyl-
2-butenal
2-butylacrolein
phenylpropargyl
aldehyde
Et2Zn
Et2Zn
Et2Zn
Et2Zn
18
40
18
66
62
64
91b,f
93b,f,g
97b
R
R
R
Et2Zn
Et2Zn
18
15
90
90
98d
R
R
93a,h
benzaldehyde
2-naphthaldehyde
octanal
Me2Zni
Me2Zni
96
96
90
86
62
90a
92a
88d
R
R
R
Me2Zni 165
a
b
Determined by HPLC-Chiracel OD column. Determined by
chiral GC (â-Dex capillary column). c Determined by HPLC-
In previous work, we found that when an ethylated
1,1′-bi-2-naphthol molecule (R)-34 was used to catalyze
the reaction of benzaldehyde with diethylzinc under the
same conditions as in the use of (R)-12, only 72%
conversion of benzaldehyde was observed in 24 h to give
(R)-1-phenyl-1-propanol with 57% ee.12 A dimeric complex
(R)-35 was produced from the reaction of (R)-34 with 1
equiv of diethylzinc, and it remained mostly intact even
when excess diethylzinc was added (Scheme 3). We have
d
Chiracel AD column. Determined by analyzing the acetate
derivative of the product on the GC-â-Dex capillary column.
e Determined by analyzing the benzoate derivative of the product
on the GC-â-Dex capillary column. f Et2O was used as the solvent.
The reaction was carried out at -40 °C, and 0.3 equiv of catalyst
was used. 0.2 equiv of catalyst was used. The reaction was
g
h
carried out in THF at -10 °C, and the aldehyde was distilled before
use. 2 equiv of Me2Zn was used.
i
Sch em e 2. Asym m etr ic Ad d ition of Dieth ylzin c to
Ben za ld eh yd e Ca ta lyzed by (R)-12
(28) Watanabe, M.; Araki, S.; Butsugan, Y.; Uemura, M. J . Org.
Chem. 1991, 56, 2218.
(29) J oshi, N. N.; Srebnik, M.; Brown, H. C. Tetrahedron Lett. 1989,
30, 5551.
(30) Ishizaki, M.; Fujita, K.-i.; Shimamoto, M.; Hoshino, O. Tetra-
hedron: Asymmetry 1994, 5, 411.
(31) (a) Kitajima, H.; Ito, K.; Katsuki, T. Chem. Lett. 1996, 343. (b)
Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. J pn. 1997,
70, 207.
(32) J in, M.-J .; Ahn, S.-J .; Lee, K.-S. Tetrahedron Lett. 1996, 37,
8767.
(33) Kang, J .; Lee, J . W.; Kim, J . I. J . Chem. Soc., Chem. Commun.
1994, 2009.
(34) Kang, J .; Kim, D. S.; Kim, J . I. Synlett 1994, 842.
(35) Prasad, K. R. K.; J oshi, N. N. J . Org. Chem. 1997, 62, 3770.
(36) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahedron
1991, 47, 8251.
(37) Wirth, T.; Kulicke, K. J .; Fragale, G. Helv. Chim. Acta 1996,
79, 1957.
(38) Rijnberg, E.; Hovestad, N. J .; Kleij, A. W.; J astrzebski, J . T. B.
H.; Boersma, J .; J anssen, M. D.; Spek, A. L.; van Koten, G. Organo-
metallics 1997, 16, 2847.
(39) (a) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett.
1989, 30, 1657. (b) Takahashi, H.; Kawakita, T.; Yoshioka, M.;
Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095.
(40) (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991,
30, 99. (b) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M.
Tetrahedron 1994, 50, 4363.
(41) Nugent, W. A. J . Chem. Soc., Chem. Commun. 1999, 1369.
(42) (a) Qiu, J .; Guo, C.; Zhang, X. J . Org. Chem. 1997, 62, 2665.
(b) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651.
(43) Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J .-F. J . Org. Chem. 1998,
63, 7078.
and aryl- or alkyl-substituted R,â-unsaturated aldehydes.
(R)-12 also shows high enantioselectivity for the addition
of dimethylzinc to aldehydes. As observed before, the
reaction of dimethylzinc is much slower than that of
diethylzinc.25 All the reactions were carried out in toluene
solution at 0 °C using 5 mol % of (R)-12 and 2 equiv of
diethylzinc unless otherwise indicated. The racemic
alcohol products were also prepared, and their HPLC or
GC data were compared with those of the optically active
alcohol products in order to determine the ee. The
absolute configuration of all the products was found to
be R by comparing their optical rotation values or GC
data with the literature results.24-43 (R)-12 was recovered
(25) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem.
Soc. 1986, 108, 6071.
(26) (a) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J . Am. Chem.
Soc. 1987, 109, 7111. (b) Soai, K.; Niwa, S. Chem. Lett. 1989, 481.
(27) (a) Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. J . Chem.
Soc., Chem. Commun. 1987, 1690. (b) Soai, K.; Yokoyama, S.; Ha-
yasaka, T. J . Org. Chem. 1991, 56, 4264.

7944 J . Org. Chem., Vol. 64, No. 21, 1999
Huang et al.
F igu r e 2. Currently known good catalysts for the enantioselective diethylzinc addition to aldehydes.
Ta ble 2. Com p a r ison of th e En a n tioselectivity of th e Ch ir a l Ca ta lysts in th e Rea ction of Va r iou s Typ es of Ald eh yd es
w ith Dieth ylzin ca
a
b
For the ee’s: E ) excellent, g90%. V ) very good, 85-89%. G ) good, 80-84%. M ) moderate, 60-79%. P ) poor, <60%. X ) Me,
F, Cl, Br, or OMe. c R1 ) H, alkyl, or aryl. R2 ) alkyl.
also studied the reaction of (R)-12 with 2 equiv of
diethylzinc in toluene-d8. The resulting complex gave
complicated 1H NMR signals, indicating the possible
existence of isomeric structures. Cryoscopic analysis of
the molecular weight of the complex in cyclohexane44
suggests the formation of a monobinaphthyl dizinc
complex. (R)-36 is thus proposed as a possible structure
for the zinc complex generated from the reaction of (R)-
12 with 2 equiv of diethylzinc. The calculated molecular
weight for (R)-36 is 1026 and the value obtained by the
cryoscopic analysis is 1099. The restricted rotation of the
(44) Shoemaker, D. P.; Garland, C. W.; Nibler, J . W. Experiments
in Physical Chemistry; 3rd ed.; The McGraw-Hill: New York, 1996; p
179.

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7945
Sch em e 4. Syn th esis of a Mon obin a p h th yl
Com p ou n d (R)-38
F igu r e 3. The correlation of the ee of the product to the ee of
the monomeric catalyst for the diethylzinc addition to benzal-
dehyde.
observed. This indicates that the ethyl groups bonded to
the zinc centers in (R)-36 cannot migrate to the aldehyde
substrate. Thus, the reaction of an aldehyde with dieth-
ylzinc may take place by transferring an ethyl group of
the excess diethylzinc, probably coordinated to the oxy-
gens of (R)-36, to the re face of the aldehyde to generate
the corresponding R alcohol. Whether there are coopera-
tive effects between the two zinc atoms in (R)-36 remains
undetermined.
Sch em e 3. Rea ction of (R)-34 w ith Dieth ylzin c
Another monomeric model compound (R)-38, in which
one of the alkoxy groups on each 3,3′-phenyl substituent
of (R)-12 was replaced with a methyl group, was also
synthesized (Scheme 4). The Suzuki coupling of (R)-8
with a monoboronic acid molecule 3746 followed by
hydrolysis generated (R)-38. The specific optical rotation
of (R)-38 was [R]D ) 139.7 (c ) 1.01, CH2Cl2). Its 3,3′-
phenyl substituents are less electron rich than those of
(R)-12, and the methoxy groups are less basic. (R)-38
catalyzed the diethylzinc addition to benzaldehyde with
98% ee at room temperature. Thus, the stereoselectivity
of (R)-38 is very similar to that of (R)-12.
With the discovery of the highly general enantioselec-
tivity of (R)-12 for the asymmetric dialkylzinc addition
to aldehydes, we took on a more challenging tasksthe
catalytic asymmetric diphenylzinc addition to aldehydes.
Although extensive research has been carried out for the
asymmetric alkylzinc addition to aldehydes, little study
has been done on the asymmetric arylzinc addition to
aldehydes. Only recently was the first enantioselective
catalytic addition of diphenylzinc to aldehydes reported
by Fu and co-workers.47,48 In their work, a planar-chiral
ligand 39 was used for the reaction of diphenylzinc with
p-chlorobenzaldehyde (40) (Scheme 5).47 This has pro-
duced a chiral diaryl alcohol 41 with 57% ee.
In the reaction of diethylzinc with aldehydes, the
addition of chiral ligands not only controls the stereose-
lectivity but also activates diethylzinc, since diethylzinc
itself does not show appreciable reaction with any alde-
hydes in the absence of a catalyst. However, the uncata-
lyzed diphenylzinc addition can become competitive even
with the catalyzed reaction, which makes it more difficult
3,3′-dialkoxyphenyl substituents around the aryl-aryl
single bond in (R)-36 can lead to three diastereomers. In
addition, a zinc center can also bridge the two 2,2′-
oxygens. In the structure of the dimeric complex (R)-35,
the zinc atoms are four-coordinate but in (R)-36 they are
only three-coordinate. The greatly enhanced catalytic
activity of (R)-12 over (R)-34 may therefore be explained
by the tendency of (R)-36 to remain a monobinaphthyl
structure, which leads to its coordinatively more unsat-
urated zinc centers and higher Lewis acidity.
We have studied the reaction of diethylzinc with
benzaldehyde catalyzed by (R)-12 with different enan-
tiomeric purities, and the results are displayed in Figure
3. Unlike the nonlinear effects observed by Noyori et al.
in the amino alcohol-based catalysts,45 the ee of the
alcohol product is linear with the ee of catalyst (R)-12.
We also found that the ee of the alcohol product was
independent of the concentration of (R)-12. These results
further support the assumption that the catalytically
active species in the reaction catalyzed by (R)-12 contains
only one binaphthyl unit.
(46) Maruoka, K.; Murase, N.; Yamamoto, H. J . Org. Chem. 1993,
58, 8, 2938.
(47) (a) Dosa, P. I.; Ruble, J . C.; Fu, G. C. J . Org. Chem. 1997, 62,
444. (b) An asymmetric reaction of diphenylzinc with ketones was
reported: Dosa, P. I.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 445.
(48) (a) An in situ generated phenylzinc reagent was added to aryl
aldehydes in the presence of a stoichiometric amount of a chiral
ligand: Soai, K.; Kawase, Y.; Oshio, A. J . Chem. Soc., Perkin Trans. 1
1991, 1613. (b) An enantioselective catalytic diphenylzinc addition was
reported shortly after our preliminary communication:14c Bolm, C.;
Mun˜iz, K. J . Chem. Soc., Chem. Commun. 1999, 1295.
When benzaldehyde was treated with 2 equiv of
diethylzinc and 1 equiv of (R)-12, no reaction was
(45) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J . Am. Chem.
Soc. 1989, 111, 4028.

7946 J . Org. Chem., Vol. 64, No. 21, 1999
Huang et al.
Sch em e 5. Asym m etr ic Dip h en ylzin c-Ald eh yd e
Ad d ition
The reaction of organozinc reagents with aromatic
aldehydes is normally much faster than with aliphatic
aldehydes as shown in Table 1. Therefore, the catalytic
asymmetric diphenylzinc addition to aromatic aldehydes
is expected to be even more challenging than its addition
to aliphatic aldehydes because of the faster uncatalyzed
background reaction. Entry 3 in section a of Table 3
shows that the diphenylzinc addition to p-anisaldehyde
can be completed at 0 °C even in the absence of a catalyst.
We have explored the reaction conditions by carefully
varying the reaction temperatures, solvents, amount of
catalyst (R)-12, and concentrations of the aldehydes and
by using additives such as diethylzinc and methanol.
Through this study, we have achieved excellent enantio-
selectivity for the addition of diphenylzinc to various
aromatic aldehydes and cinnamaldehyde (Table 3, entries
4-29).
to develop an enantioselective catalyst for the diphenyl-
zinc addition.
Our study shows that the enantioselectivity of the
diphenylzinc addition to aldehydes are influenced by the
following factors: (1) increased enantioselectivity is
generally observed when chiral ligand (R)-12 is pre-
treated with diethylzinc (e.g., Table 3, entries 4-6). Thus,
the reaction of diethylzinc with (R)-12 generates a better
chiral zinc catalyst than the reaction of diphenylzinc with
(R)-12. (2) The enantioselectivity is dramatically in-
creased by reducing the concentration of the reaction
system (e.g., Table 3, entries 13-15). This indicates that
the uncatalyzed background reaction may become less
competitive at low concentration. (3) In the case of
cinnamaldehyde, the use of methanol as the additive
greatly improves the enantioselectivity (Table 3, entries
26 and 29). In this reaction, the structure of the catalyst
formed from the reaction of (R)-12 with diethylzinc may
be modified when treated with methanol. Previously, Fu
and co-worker also observed the enhancement of enan-
tioselectivity with the addition of methanol in their study
of organozinc additions.47b In entries 26 and 29 of Table
3, higher temperature in methylene chloride solution led
to higher ee. A better catalyst might have been produced
at higher temperature for the reaction of diphenylzinc
with trans-cinnamaldehye. Entries 27 and 28 of Table 3
are two attempts to improve the enantioselectivity of the
diphenylzinc addition to trans-cinnamaldehyde by using
an in situ generated optically active 1-phenyl-1-propyl-
oxyzinc complex as the additive, since the addition of
methanol in entry 26 significantly increased the enan-
tioselectivity of the reaction. The in situ generated
1-phenyl-1-propyloxyzinc had an R configuration for
entry 27 and an S configuration for entry 28. These two
experiments were designed to avoid the “mismatch” of
the chirality of the ligand with that of the in situ
generated chiral alcohol additive. However, neither entry
27 nor entry 28 showed enhanced enantioselectivity.
Instead, a significant reduction in enantioselectivity over
the use of methanol additive was observed. Thus, the
sterically more hindered (R)- or (S)-1-phenyl-1-propyloxy-
zinc additive in these experiments might have generated
We have used (R)-12 to carry out the asymmetric
diphenylzinc addition to aldehydes, and the results are
summarized in Table 3. In the presence of 5 mol % of
(R)-12, the addition of diphenylzinc to propionaldehyde
gave (S)-1-phenyl-1-propanol with 86% ee at 0 °C (Table
3, section a, entry 1). This is the first example of a highly
enantioselective catalytic diphenylzinc addition to alde-
hydes. The S configuration of the chiral alcohol product
indicates that the phenyl addition occurs at the re face
of the aldehyde. This is the same as the diethylzinc
addition catalyzed by (R)-12, which, however, produces
(R)-1-phenyl-1-propanol when reacted with benzalde-
hyde. Therefore, (R)-12 can catalyze the formation of both
the R and S enantiomers of 1-phenyl-1-propanol by either
reacting diethylzinc with benzaldehyde or diphenylzinc
with propionaldehyde.
The high enantioselectivity observed for the diphenyl-
zinc addition to the aliphatic aldehyde encouraged us to
launch a major effort to investigate the diphenylzinc
addition to aromatic aldehydes for the asymmetric syn-
thesis of chiral diaryl carbinols. Chiral diaryl carbinols
are useful for making a number of biologically active
compounds but are difficult to produce by asymmetric
catalysis.15 Preparation of secondary alcohols is normally
completed by either addition of organometallic reagents
to aldehydes or reduction of ketones. A chiral diaryl-
carbinol is difficult to form with high enantioselectivity
from the asymmetric reduction of ketones because a
prochiral diaryl ketone often contains two sterically and
electronically very similar aryl groups. Nevertheless,
using chiral oxazaborolidines as the catalysts, Corey and
co-workers have accomplished a highly enantioselective
reduction of ketones containing two sterically and/or
electronically very different aryl groups.15b,49 On the other
hand, because of the large differences between an aryl
group and a hydrogen atom in an aryl aldehyde, addition
of organometallic aryl reagents to such a prochiral
aldehyde in the presence of a chiral catalysts should have
large chiral bias toward the two prochiral faces and
should be more suitable for the asymmetric synthesis of
chiral diarylcarbinols. It is a surprise to notice that very
few reports on the catalytic enantioselective addition of
organometallic aryl reagents to aryl aldehydes have
appeared,47,50,51 even though a large number of highly
enantioselective alkyl additions have been documented.24
(51) For the enantioselective reaction of stoichiometric or excess
chiral organometallic aryl compounds with aryl aldehydes, see: (a)
Seebach, D.; Beck, A. K.; Roggo, S.; Wonnacott, A. Chem. Ber. 1985,
118, 3673. (b) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura,
M. Pure Appl. Chem. 1988, 60, 1597. (c) Tomioka, K.; Nakajima, M.;
Koga, K. Chem. Lett. 1987, 65. (d) Kaino, M.; Ishihara, K.; Yamamoto,
H. Bull. Chem. Soc. J pn. 1989, 62, 3736. (e) Wang, J .-T.; Fan, X.; Feng,
X.; Qian, Y.-M. Synthesis 1989, 291. (f) Nakajima, M.; Tomioka, K.;
Koga, K. Tetrahedron 1993, 49, 9751.
(49) (a) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1995, 36, 9153.
(b) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1996, 37, 5675.
(50) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7947
Ta ble 3. Asym m etr ic Dip h en ylzin c Ad d ition to Ald eh yd es Ca ta lyzed by th e Mon om er (R)-12
a
Determined by HPLC-Chiracel-OD column. b Determined by analyzing the acetate derivative of the alcohol product by HPLC-Chiralcel-
OD column. c Determined by comparing the optical rotation with the literature data.
a less active catalyst and allowed the uncatalyzed reac-
tion to become more competitive.
monomer ligand can be maintained in the resulting
polymer structure. However, even though polymer (R)-4
contains (R)-12 as its structural units, the enantioselec-
tivity of the polymer is much more limited. (R)-42 (Chart
1) is proposed as the catalytically active species for the
diethylzinc addition to aldehydes in the presence of (R)-
4. In (R)-42, the two alkoxy oxygens on a phenylene
spacer serve as a dual ligand to coordinate to the zinc
atoms in the two adjacent binaphthyl units. Because of
this interference between the neighboring units, the
electronic and steric environments of the catalytic sites
in (R)-42 should be different from those of (R)-36, causing
2. Con ver tin g th e High ly En a n tioselective Mon o-
bin a p h th yl Ca ta lyst to a High ly En a n tioselective
P olym er ic Ca ta lyst for th e Or ga n ozin c Ad d ition . As
described in the last section, the catalytically active
species generated from the reaction of (R)-12 with dieth-
ylzinc in the alkyl addition to aldehydes is likely to be
monomeric rather than the aggregate of the zinc complex.
Therefore, it would be possible to convert this monomeric
catalyst into a highly enantioselective polymeric catalyst
if both the steric and electronic environments of the

7948 J . Org. Chem., Vol. 64, No. 21, 1999
Huang et al.
Ch a r t 1
Ch a r t 2
Sch em e 6. Syn th esis of th e Rigid a n d Ster ica lly
Sch em e 7. Syn th esis of th e p-Tr ip h en ylen e
Dibor on ic Acid Lin k er 44
Regu la r Ch ir a l P olym er (R)-43
the observed different enantioselectivity. On the basis of
this analysis, we designed a new rigid and sterically
regular polymeric chiral catalyst (R)-43 (Chart 2) for the
asymmetric reaction of aldehydes with organozincs.
Because the binaphthyl units in (R)-43 are separated by
long and rigid linkers, the interference between the
catalytic sites in the polymer should be minimum, and
the steric and electronic environments of the monomeric
catalyst (R)-12 should be mostly preserved. We therefore
expect (R)-43 to have the same catalytic properties as
(R)-12.
1
well-resolved H and 13C NMR spectra consistent with a
structurally well-defined polymer chain. Figure 4 is the
1H NMR spectrum of the polymer in CDCl3.
The diboronic acid linker 44 was obtained from 9
(Scheme 7).21 Treatment of 9 with 1 equiv of n-BuLi
followed by reaction with triethylborate and hydrolysis
gave 45. Because the Suzuki coupling of aryl iodide
generally proceeds much faster than aryl bromide,22 46
was obtained from the reaction of 45 with 1,4-diiodoben-
zene, which was then converted to diboronic acid 44.
When polymer (R)-43 was used to catalyze the reaction
of aldehydes with diethylzinc, we were very pleased to
find that this polymer showed the expected high enan-
tioselectivity for a broad range of aldehydes. Table 4
summarizes the results for the use of (R)-43. All the
reactions were carried out in the presence of 5 mol %
(based on the repeating unit in the polymer) of (R)-43
and 2 equiv of diethylzinc in toluene solution at 0 °C
unless indicated otherwise. As shown in Table 4, (R)-43
(R)-43 was obtained in 90% yield from the Suzuki
coupling of (R)-8 with 44 followed by hydrolysis (Scheme
6). The coupling was carried out with a slight excess of
44. After the completion of the polymerization, 4-tert-
butylbromobenzene was added to cap the polymer chain
by consuming the boronic acid end groups. The resulting
polymer (R)-43 has very good solubility in THF, toluene,
methylene chloride, and chloroform. Gel permeation
chromatography (GPC) analysis of (R)-43 showed its
molecular weight as Mw ) 25 800 and Mn ) 14 300
(PDI ) 1.8). The specific optical rotation of this chiral
polymer was [R]D ) -92.9 (c ) 1.01, CH2Cl2). (R)-43 gave

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7949
F igu r e 4. 1H NMR spectrum of polymer (R)-43.
exhibits greatly enhanced enantioselectivity over (R)-4,12
especially for the reaction of aliphatic aldehydes. This
polymer was easily recovered by precipitation with
methanol after workup, and the recovered (R)-43 showed
the same enantioselectivity as the original polymer.
Previously, the best polymer-supported amino-alcohol
catalyst for the reaction of aliphatic aldehydes gave only
69% ee.53 Cross-linked polystyrene-supported chiral
R,R,R′,R′-tetraphenyl-1,3-dioxolane-4,5-dimethanoltita-
nium(IV) catalysts carried out a diethylzinc addition to
heptyl aldehyde with 92% ee (75% yield) and to cyclo-
hexanecarboxaldehyde with 86% ee (57% yield), but these
reactions required the use of a stoichiometric amount of
Ti(OCHMe2)4 versus the aldehydes.54 Therefore, (R)-43
is the best polymeric catalyst yet obtained for the
asymmetric reaction of aldehydes with diethylzinc. This
polymer also showed excellent enantioselectivity for the
addition of dimethylzinc to aldehydes. Since the dimeth-
ylzinc addition was a very slow reaction, more of the
polymer ligand was used.
The reaction of (R)-43 with diethylzinc in toluene-d8
was studied. We found that although (R)-43 was soluble
in toluene, it formed an insoluble gel after treatment with
2 equiv of diethylzinc. This gel was probably produced
from the cross-link of a proposed polybinaphthyl zinc
complex (R)-47 (Chart 3), formed from the reaction of (R)-
43 with 2 equiv of diethylzinc, through a very small
amount of interchain coordination of the oxygen atoms
to the zinc centers. The 1H NMR spectrum of the reaction
mixture showed the release of ethane accompanied with
a complete disappearance of the polymer signal. Further
addition of diethylzinc converted the gel into a homoge-
neous solution because excess diethylzinc might have
saturated the coordination ability of the oxygen atoms
in each polymer chain so that the interchain Zn-O-Zn
cross-link was cleaved. Due to the broadness of the NMR
signals, no structural information on (R)-47 could be
deduced. The behavior of (R)-43 when reacted with
diethylzinc is very similar to what was observed in the
reaction of (R)-4 with diethylzinc.12b
We have used polymer (R)-43 to catalyze the diphen-
ylzinc addition to propionaldehyde and p-anisaldehyde
and the results are summarized in Table 5. To achieve
high enantioselectivity, 0.2-0.4 equiv (based on the
repeat unit) of the polymer was needed. In the presence
of 0.2 equiv of the polymer, diphenylzinc reacted with
propionaldehyde at 0 °C with 85% ee. For the reaction
with the aromatic aldehyde, slow mixing of the reactants
with the catalyst was required (Table 5, entries 3 and
4). In these experiments, two solutions were prepared,
one containing (R)-43, diethylzinc, and diphenylzinc in
toluene and another containing the aldehyde in toluene.
Both of the solutions were simultaneously added into a
flask containing toluene at -30 °C over 20 h via a syringe
pump. After the addition, the reaction mixture was
stirred further at -30 °C. Up to 92% ee was observed
when the double slow addition technique was applied.
In these reactions, the polymer was pretreated with
excess diethylzinc. Since the diphenylzinc addition was
much faster than the diethylzinc addition, no product
from the reaction of diethylzinc was observed even
though the amount of diethylzinc was 2-3 times more
than diphenylzinc during the reaction. The excess dieth-
ylzinc was added in order to dissolve the gel formed from
the reaction of (R)-43 with 2 equiv [versus the binaphthyl
unit of (R)-43] of diethylzinc.
(52) Wu, B.; Mosher, H. S. J . Org. Chem. 1986, 51, 1904.
(53) Soai, K.; Watanabe, M. Tetrahedron: Asymmetry 1991, 2, 97.
(54) Seebach, D.; Marti, R. E.; Hintermann, T. Helv. Chim. Acta
1996, 79, 1710.

7950 J . Org. Chem., Vol. 64, No. 21, 1999
Ta ble 4. Rea ction of Ald eh yd es w ith Dia lk ylzin cs in th e P r esen ce of P olym er (R)-43
Huang et al.
a
b
Determined by HPLC-Chiracel OD column. Determined by chiral GC (â-Dex capillary column). c Determined by analyzing the acetate
d
derivative of the product on the GC-â-Dex capillary column. Determined by analyzing the propionate derivative of the product on the
GC-â-Dex capillary column. e Determined by analyzing the Mosher’s ester of the product on the GC-â-Dex capillary column. f The solvent
g
was a 1:1 mixture of toluene/diethyl ether. 3 equiv of Me2Zn and 0.2 equiv of polymer were used.
Ch a r t 3
To account for the observed differences between the
catalytic properties of the polymer and those of the
monomer, the following explanation is proposed. Since
the catalytic sites in (R)-43 are almost identical to the
structure of monomer (R)-12, in principle, the polymer
should have the same stereoselectivity as the monomer.
This is true if there is no competition from the uncata-
lyzed reaction as we have demonstrated for the dialkyl-
zinc addition. However, in the diphenylzinc addition, the
rate difference between the catalyzed and the uncata-
lyzed reactions is small. Because of the mobility differ-
ences between the polymer and the monomer, there may
be less collision between the substrate and the catalytic
sites in the polymer which will make the uncatalyzed

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7951
Ta ble 5. Asym m etr ic Dip h en ylzin c Ad d ition to Ald eh yd es Ca ta lyzed by th e P olym er (R)-43
a
b
Determined by HPLC-Chiracel-OD column. Determined by comparing the optical rotation with the literature data. c Slow mixing of
the catalyst, reagent, and substrate via a syringe pump.
Sch em e 8. Red u ction of Acetop h en on e w ith
Ca ltech olbor a n e in th e P r esen ce of a Ch ir a l
P olybin a p h th yl-Zin c Com p lex
reaction, the enantioselectivity of polymer (R)-43 is
almost the same as that of monomer (R)-12. This further
demonstrates that the steric and electronic environments
around the catalytic sites of (R)-43 are indeed almost
identical to those in (R)-12.
Table 6 summarizes the results obtained from the use
of monomer (R)-12 and polymers (S)-4 and (R)-43 in the
asymmetric reduction of a variety of prochiral ketones.
As a polymer-catalyzed asymmetric reaction, the enan-
tioselectivity of the zinc complex of (R)-43 for the reduc-
tion of the methyl aryl/vinyl ketones listed in Table 6 is
considered to be quite good (Table 6, entries 10-15).
However, when the methyl group of these substrates was
changed to other substituents, the enantioselectivity was
significantly reduced (Table 6, entries 16-18). When
dimethylzinc was used in place of diethylzinc, the ee was
slightly lower (Table 6, entry 7). Using BH3‚SMe2 as the
reducing agent in place of catecholborane gave very low
ee (Table 6, entry 8). Entry 9 of Table 6 shows that more
than 2 equiv of diethylzinc versus the ligand caused a
dramatic decrease of the ee of the product. This indicates
that both the free and ligand-bound diethylzinc are able
to catalyze the reduction of ketones with catecholborane.
Polymer (R)-43 was readily recovered by addition of
methanol to the product mixture. After the polymer was
recycled three times, it still showed 78% ee and 86% yield
for the reduction of acetophenone. The specific optical
reaction even more competitive. Therefore, more of the
polymer and lower concentration of the substrate are
needed to suppress the competing uncatalyzed diphen-
ylzinc addition in order to maintain the high enantiose-
lectivity.
3. Asym m etr ic Red u ction of P r och ir a l Keton es
Ca ta lyzed by th e Ch ir a l Bin a p h th yl Mon om er a n d
P olym er Ca ta lysts. Asymmetric reduction of ketones
is another important method for the synthesis of optically
active secondary alcohols.16,17 We have studied the use
of the zinc complexes generated from the reaction of
diethylzinc with the monobinaphthyl and polybinaphthyl
ligands for the asymmetric reduction of prochiral ketones.
Scheme 8 shows the reaction of acetophenone with
catecholborane in the presence of (S)-412b and diethylzinc.
The molecular weight of (S)-4 was Mw ) 10 000 and
Mn ) 4600 (PDI ) 2.2) as determined by GPC. The
specific optical rotation of this polymer was [R]D ) -14.2
(c ) 1.01, CH2Cl2). (S)-4 is soluble in common organic
solvents such as THF, methylene chloride, chloroform,
and toluene. When 5 mol % (based on the repeating unit
of the polymer) of (S)-4 and 10 mol % of diethylzinc were
used, acetophenone was reduced to 1-phenylethanol by
catecholborane in 77% yield and 54% ee at room tem-
perature in toluene. When the reaction temperature was
decreased to -30 °C, the ee of the product was raised to
67%. Lower ee’s were observed when the reaction was
carried out in other solvents such as methylene chloride,
THF, and diethyl ether.
We have examined the use of the monobinaphthyl
model compound (R)-12 for this reaction. In the presence
of 5 mol % of (R)-12 and 10 mol % of diethylzinc,
acetophenone was reduced to 1-phenylethanol in 87%
yield and 81% ee at -30 °C in toluene. As expected, the
absolute configuration of the product was S, opposite to
that obtained in the presence of (S)-4. Similar to what
was observed in the diethylzinc addition to aldehydes,
the enantioselectivity of polymer (S)-4 was significantly
lower than that of monomer (R)-12, probably due to the
interference of the adjacent binaphthyl units in (S)-4. The
long linker polymer (R)-43 was thus used for the asym-
metric reduction of acetophenone. Under the same condi-
tions as in the use of (R)-12, (S)-1-phenylethanol was
obtained with 80% ee in the presence of (R)-43. In this
rotation of this three-time-recycled polymer was [R]D
)
-90.6 (c ) 0.9, CH2Cl2), very similar to that of the
1
original polymer. The H NMR spectrum of the recycled
polymer was also very close to that of the original
polymer. This demonstrates that there are almost no
structural and functional changes for the polymer after
repeated usage.
Su m m a r y
In summary, we have developed the most general
polymeric catalyst for the highly enantioselective dialkyl-
zinc addition to aldehydes. A catalytic asymmetric di-
phenylzinc addition to aldehydes by using the binaphthyl
monomer and polymer catalysts has also been achieved
with excellent enantioselectivity. This allows the prepa-
ration of the synthetically useful chiral diaryl carbinols
that are difficult to access by asymmetric catalysis. We
have further discovered that the mono- and polybinaph-
thyl zinc complexes can catalyze the asymmetric reduc-
tion of ketones with catecholborane.
Our work on both the asymmetric organozinc addition
to aldehydes and the asymmetric reduction of ketones
catalyzed by the zinc complexes of monomer (R)-12 and
polymer (R)-43 has not only provided new methods for
the synthesis of optically active secondary alcohols, but

7952 J . Org. Chem., Vol. 64, No. 21, 1999
Ta ble 6. Th e Asym m etr ic Red u ction of Keton es in th e P r esen ce of (S)-4, (R)-12, a n d (R)-43
Huang et al.
a
b
Determined on an GC (â-Dex capillary column). Determined by HPLC-Chiracel OD column. c The reactions were carried out at -30
°C in the presence of 5 mol % chiral ligand and 10 mol % Et2Zn using catecholborane as the reducing agent unless otherwise specified.
The reaction was performed at rt. e 5 mol % Me2Zn was used in place of Et2Zn. f BH3‚SMe2 was the reducing agent. 0.2 equiv of Et2Zn
d
g
was used.
also demonstrated that incorporation of an enantioselec-
tive monomeric catalyst into a rigid and sterically regular
polymer structure could largely preserve the catalytic
properties of the monomeric catalyst. This strategy may
be generally applicable in converting existing highly
enantioselective monomer catalysts into polymer cata-
lysts of similar enantioselectivity provided that the
catalytically active species in the monomer catalysts are
monomeric rather than the monomer aggregates. By
using this strategy, it is possible to overcome the draw-
backs associated with the traditional approach to prepar-
ing polymeric catalysts where the microenvironment of
the catalytic sites in the polymers are often significantly
altered from those in the monomeric catalysts due to the
flexible and sterically irregular polymer chains. The
diphenylzinc addition study also reveals that the kinetics
of a polymer in catalysis could be different from that of
its monomeric version as a result of the large size
differences. When there are competitive uncatalyzed
background reactions, more of the polymer may be
needed. In some cases, it may also require the modifica-
tion of the polymer structure. One should be able to
accomplish this since the use of the rigid and sterically
regular polymers can not only maintain the steric and
electronic environments of the monomeric catalysts but
also allow a systematic modification of the catalytic sites
in the polymer to achieve the desired catalytic property.
Exp er im en ta l Section
Gen er a l Da ta . All the solvents were dried according to the
standard methods prior to use. Aldehydes, ketones and cat-
echolborane (1 M, THF) were purchased from Aldrich and used
directly. Et2Zn, Me2Zn, and Ph2Zn were purchased from Strem.
Molecular weights of the polymers were measured with gel
permeation chromatography (GPC) by using THF eluent and
polystyrene standards.
P r ep a r a tion a n d Ch a r a cter iza tion of 2,5-Dih exyloxy-
p h en ylbor on ic Acid , 11. (a ) P r ep a r a tion of 1,4-Dih exyl-
oxy-2-br om oben zen e, 10. Under N2, to a solution of 1,4-
dihexyloxy-2,5-dibromobenzene 9 (25.92 g, 59.45 mmol) in THF
(150 mL) was added n-BuLi (23.8 mL, 2.5 M in hexanes) at
-78 °C over 30 min. After the addition, the reaction mixture
was stirred at -78 °C for 1 h and was then quenched with
aqueous NH4Cl at -78 °C. Usual workup gave 10 as a pale
yellow liquid (97% yield). (b) P r ep a r a tion of 11. To a solution
of 10 (10.71 g, 30 mmol) in THF (100 mL) was added n-BuLi
(12 mL, 2.5 M in hexanes) at -78 °C over 10 min. After the
addition, the reaction mixture was stirred at -78 °C for 30
min and was then cannulated into a solution of triethylborate
(3 equiv, 15 mL) in THF (80 mL) at -78 °C. The mixture was
stirred at -78 °C for 2 h and then at room temperature
overnight. Hydrolysis of the resulting product solution with 2

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7953
N HCl at room temperature for 2 h followed by usual workup
and column chromatography on silica gel (hexanes/EtOAc )
5/1) gave 11 as a pure white solid in 68% yield: mp 85-87
°C; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J ) 3.4 Hz, 1H),
6.95 (dd, J ) 8.8, 3.0 Hz, 1H), 6.82 (d, J ) 8.8 Hz, 1H), 6.53
(s, 1H), 6.44 (s, 1H), 4.01 (t, J ) 6.6 Hz, 2H), 3.93 (t, J ) 6.6
Hz, 2H), 1.82 (m, 2H), 1.75 (m, 2H), 1.33-1.45 (m, 12H), 0.90
(t, J ) 6.8 Hz, 3H), 0.89 (t, J ) 6.8 Hz, 3H); 13C NMR (100.5
MHz, CDCl3) δ 158.28, 153.32, 121.34, 119.41, 112.19, 69.07,
68.67, 31.69, 31.58, 29.45, 29.38, 25.80, 25.78, 22.71, 22.62,
14.15, 14.08; FT-IR (cm-1) 3462 (m), 2936 (s), 2864 (m). Anal.
Calcd for C18H31BO4: C, 67.08; H, 9.63. Found: C, 67.37; H,
9.75.
(160 mg, 1 mmol) was added, and the resulting mixture was
stirred at 0 °C for 80 h. Quenching the reaction with 1 N HCl
followed by usual workup gave (R)-1-(2′-naphthyl)ethanol as
a colorless liquid in 86% yield (148 mg). Analysis by HPLC-
Chiracel-OD column showed an ee of 92%.
Con d ition s for th e An a lysis of th e Ch ir a l Secon d a r y
Alcoh ol P r od u cts fr om th e Dia lk ylzin c Ad d ition s. Chiral
Capillary GC: Supelco â- Dex 120 column 30 m × 0.25 mm
(i.d.), 0.25 µm film. Carrier gas: He (1.05 mL/min). Detector:
FID, 280 °C. Injector: 220 °C.
Chiral HPLC: Chiracel OD or Chiracel AD column, 254 nm
UV detector. The solvents used were hexane/2-propanol ) 9/1
at 1.0 mL/min unless indicated otherwise.
P r ep a r a tion a n d Ch a r a cter iza tion of (R)-3,3′-Bis(2′′,4′′-
d ih exyloxyp h en yl)-1,1′-bin a p h th ol, (R)-12. (a ) P r ep a r a -
t ion of (R)-2,2′-Bis(m et h oxym et h oxy)-3,3′-b is(2′′,4′′-d i-
h exyloxyp h en yl)-1,1′-bin a p h th yl, A. Under N2, to a solution
of (R)-8 (2.63 g, 4.21 mmol) and 11 (4.07 g, 12.63 mmol) in
THF (50 mL) were added Pd(PPh3)4 (250 mg) and K2CO3
(aqueous 2 M, 20 mL, degassed with N2) sequentially. The
reaction mixture was heated at reflux for 22 h and then
quenched with brine at room temperature. Usual workup
followed by column chromatography on silica gel (hexanes/
EtOAc ) 10/1) gave A as a colorless oil in 88% yield: 1H NMR
(270 MHz, CDCl3) δ 7.88 (s, 2H), 7.83 (d, J ) 8.0 Hz, 2H),
7.33-7.41 (m, 4H), 7.24-7.29 (m, 2H), 7.03 (d, J ) 2.7 Hz,
2H), 6.88 (s, 2H), 6.86 (d, J ) 2.7 Hz, 2H), 4.46 (d, J ) 5.6 Hz,
2H), 4.41 (d, J ) 5.6 Hz, 2H), 3.94 (t, J ) 6.5 Hz, 4H), 3.89 (t,
J ) 6.9 Hz, 4H), 2.35 (s, 6H), 1.77 (m, 4H), 1.64 (m, 4H), 1.45
(m, 4H), 1.16-1.35 (m, 20H), 0.89 (t, J ) 6.9 Hz, 6H), 0.77 (t,
J ) 6.9 Hz, 6H). (b) P r ep a r a tion of (R)-12. To a solution of
A (3.0 g) in a mixed solvent (10 mL of CH2Cl2 and 30 mL of
EtOH) was added concentrated HCl (5 mL). The reaction
mixture was heated at reflux under N2 for 16 h. The volatile
component was removed under reduced pressure, and the
residue was purified by column chromatography on silica gel
(hexanes/EtOAc ) 10/1) to give (R)-12 as a colorless oil in 85%
yield: [R]D ) 95.0 (c ) 0.962, THF); 1H NMR (270 MHz, CDCl3)
δ 7.96 (s, 2H), 7.91 (d, J ) 8.0 Hz, 2H), 7.25-7.38 (m, 6H),
7.12 (d, J ) 2.5 Hz, 2H), 6.96 (s, 2H), 6.94 (d, J ) 2.7 Hz, 2H),
6.32 (s, 2H), 3.99 (t, J ) 6.5 Hz, 4H), 3.92 (t, J ) 6.7 Hz, 4H),
1.81 (m, 4H), 1.63 (m, 4H), 1.49 (m, 4H), 1.33-1.40 (m, 8H),
1.21-1.28 (m, 4H), 1.11-1.26 (m, 8H), 0.93 (t, J ) 6.9 Hz, 6H),
0.76 (t, J ) 6.9 Hz, 6H); 13C NMR (100.5 MHz, CDCl3) δ 154.10,
150.36, 149.95, 133.75, 131.02, 129.27, 129.17, 129.11, 128.26,
126.55, 124.97, 123.72, 118.52, 116.67, 115.16, 114.94, 70.75,
68.76, 31.72, 31.52, 29.47, 29.34, 25.86, 25.56, 22.74, 22.51,
14.18, 14.05; FT-IR (cm-1) 3530 (m), 2930 (s), 2870 (s); MS
(DIP) m/z 839 (M + H+). Anal. Calcd for C56H70O6: C, 80.19;
H, 8.35. Found: C, 79.89; H, 8.80.
A Typ ica l Exp er im en ta l P r oced u r e for th e Dieth yl-
zin c Ad d ition to Ald eh yd es Ca ta lyzed by Mon om er (R)-
12. Under nitrogen, to a Schlenk flask containing toluene (10
mL, dried, and degassed with N2) were added (R)-12 (42 mg,
0.05 mmol) and Et2Zn (0.21 mL, 2.0 mmol) at room temper-
ature. After the colorless solution was stirred for ca. 15 min,
the flask was cooled to 0 °C, and benzaldehyde (0.1 mL, 1.0
mmol) was added dropwise. The solution turned yellow, which
then faded in 4 h, indicating the completion of the reaction.
HCl (1 N) was added to quench the reaction at 0 °C, and the
aqueous layer was extracted with the diethyl ether. The
combined organic layer was washed with brine until pH ) 7
and then dried over anhydrous Na2SO4. HPLC analysis of the
crude product on a Chiracel-OD column (eluent: 2-propanol/
hexane ) 1/9 at 1 mL/min) showed an ee of >99%. The crude
product was purified by column chromatography on silica gel
with EtOAc/hexanes (1:5) to give (R)-1-phenyl-1-propanol as
a colorless liquid (129 mg, 95%). HPLC analysis showed the
same ee as that of the crude product.
The racemic alcohol products were obtained by either
addition of Et2Zn to aldehydes in the presence of 2-pyridyl-
carbinol catalyst or addition of EtMgBr or MeMgBr to alde-
hydes. The retention times of the racemic alcohol products
under the given conditions are listed below.
1-P h en yl-1-p r op a n ol: tR ) 7.45 min, tS ) 8.80 min (HPLC
OD column).
1-(p-Meth ylp h en yl)-1-p r op a n ol: tR ) 32.18 min, tS
34.11 min (GC, 100 to 150 °C, 1 °C/min).
)
1-(p-Meth oxyp h en yl)-1-p r op a n ol: tR ) 8.70 min, tS ) 9.48
min (HPLC AD column).
1-(p-Ch lor op h en yl)-1-p r op a n ol: tR ) 6.25 min, tS ) 7.20
min (HPLC OD column).
1-(m -Ch lor op h en yl)-1-p r op a n ol. The ee was measured by
analyzing its acetate with GC. tR ) 17.46 min, tS ) 16.79 min
(135 to 160 °C at 1 °C/min).
1-(m -Meth oxyp h en yl)-1-p r op a n ol: tR ) 10.00 min, tS
10.73 min (HPLC OD column).
)
1-(o-F lu or op h en yl)-1-p r op a n ol: tR ) 26.74 min, tS ) 28.02
min (GC, 100 to 140 °C at 1 °C/min).
1-(o-Meth oxyp h en yl)-1-p r op a n ol: tR ) 45.73 min, tS
44.05 min (GC, 100 to 150 °C at 1 °C/min).
)
1-(r-Na p h th yl)-1-p r op a n ol: tR ) 16.08 min, tS ) 8.83 min
(HPLC OD column).
1-(â-Na p h th yl)-1-p r op a n ol: tR ) 11.87 min, tS ) 10.40 min
(HPLC OD column).
1-(2′-F u r yl)-1-p r op a n ol. The ee was measured by analyz-
ing its acetate with GC. tR ) 22.23 min, tS ) 21.31 min (80 to
120 °C at 1 °C/min).
3-Octa n ol. The ee was measured by analyzing its acetate
with GC. tR ) 32.03 min, tS ) 30.75 min (60 to 100 °C at
1 °C/min).
3-Non a n ol. The ee was measured by analyzing its acetate
with GC. tR ) 33.54 min, tS ) 32.43 min (70 to 110 °C at
1 °C/min).
3-Un d eca n ol. The ee was measured by analyzing its
acetate with GC. tR ) 28.82 min, tS ) 28.07 min (100 to
140 °C at 1 °C/min).
1-Cycloh exyl-1-p r op a n ol. The ee was measured by ana-
lyzing its acetate with GC. tR ) 21.00 min, tS ) 20.34 min
(100 to 130 °C at 1 °C/min).
5-Meth yl-3-h exa n ol. The ee was measured by analyzing
its benzoate with GC. tR ) 48.87 min, tS ) 47.71 min (110 to
135 °C at 0.4 °C/min).
(E)-1-P h en yl-1-p en ten -3-ol: tR ) 9.08 min, ) 13.40 min
(HPLC OD column).
(E)-1-P h en yl-2-m eth yl-1-p en ten -3-ol. The ee was mea-
sured by analyzing its acetate with GC. tR ) 33.17 min, tS
32.26 min (140 °C).
)
(E)-4-Hexen -3-ol: tR ) 20.42 min, tS ) 22.09 min (GC,
60 °C).
5-Meth yl-4-h exen -3-ol: tR ) 11.06 min, tS ) 13.88 min (GC,
85 °C).
(E )-4-Meth yl-4-h exen -3-ol: tR ) 22.46 min, tS ) 26.64 min
(GC, 75 °C).
2-(n -Bu tyl)-1-p en ten -3-ol. The ee was measured by ana-
lyzing its acetate with GC. tR ) 23.04 min, tS ) 22.13 min
(90 °C).
1-P h en yl-1-p en tyn -3-ol: tR ) 7.27 min, tS ) 15.40 min
(HPLC OD column).
A Typ ica l Exp er im en ta l P r oced u r e for th e Dim eth -
ylzin c Ad d ition to Ald eh yd es Ca ta lyzed by Mon om er
(R)-12. To a Schlenk flask were added toluene (10 mL, dried,
and degassed with N2), (R)-12 (42 mg, 0.05 mmol), and Me2Zn
(0.14 mL, 2 mmol). The mixture was stirred at room temper-
ature for 15 min and then cooled to 0 °C. 2-Naphthaldehyde
1-P h en yleth a n ol: tR ) 7.23 min, tS ) 8.08 min (HPLC OD
column).

7954 J . Org. Chem., Vol. 64, No. 21, 1999
Huang et al.
1-(â-Na p h th yl)eth a n ol: tR ) 24.93 min, tS ) 23.82 min
(HPLC OD column, 0.5 mL/min).
2-Non a n ol. The ee was measured by analyzing its acetate
with GC. tR ) 18.00 min, tS ) 17.20 min (100 to 120 °C at
1 °C/min).
Diph en ylzin c Addition to tr a n s-Cin n am aldeh yde Cata-
lyzed by Mon om er (R)-12 w ith th e Ad d ition of Meth a n ol.
To a Schlenk flask were added methylene chloride (30 mL,
dried, and degassed with N2), (R)-12 (42 mg, 0.05 mmol), and
diethylzinc (20 µL, 0.2 mmol). After the mixture was stirred
at room temperature for 15 min, methanol (4 µL, 0.1 mmol)
was added. Stirring was continued at room temperature for
another 30 min, and diphenylzinc (55 mg, 0.25 mmol) was then
added. The resulting solution was heated at reflux to which
trans-cinnamaldehyde (31.5 µL, 0.25 mmol) was added. Re-
fluxing the reaction mixture for 10 h followed by quenching
with 1 N HCl at room temperature and usual workup gave
(S)-1,3-diphenyl-2-propen-1-ol in 94% yield (49 mg). Analysis
by HPLC-Chiracel-OD column showed an ee of 83%.
Th e Sp ecific Op tica l Rota tion s of th e Dip h en ylzin c
Ad d ition P r od u cts. 1-P h en yl-1-p r op a n ol: [R]D ) -40.82
(c ) 2.52, CHCl3), 86% ee, S.
(p-Meth oxyp h en yl)p h en ylm eth a n ol: [R]D ) +7.94 (c )
1.63, C6H6), 54% ee, R; [R]D ) +13.92 (c ) 1.86, C6H6), 93%
ee, R.
(p-Ch lor op h en yl)p h en ylm eth a n ol: [R]D ) -6.00 (c )
0.91, CHCl3), 41% ee, R; [R]D ) -7.68 (c ) 0.82, CHCl3), 50%
ee, R; [R]D) -13.86 (c ) 0.860, CHCl3), 94% ee, R.
(â-Na p h th yl)p h en ylm eth a n ol: [R]D ) +5.37 (c ) 0.87,
C6H6), 71% ee, R; [R]D) +6.22 (c ) 0.76, C6H6), 87% ee, R.
1,3-Dip h en yl-2-p r op en -1-ol: [R]D ) -12.33 (c ) 0.80, CH2-
Cl2), 46% ee, S; [R]D ) -29.1 (c ) 0.96, CH2Cl2), 83% ee, S.
Deter m in a tion of th e ee for th e Dip h en ylzin c Ad d i-
tion P r od u cts by Ch ir a l HP LC a n d GC. All ee’s were
determined by comparing the HPLC data of the chiral products
with those of the corresponding racemic alcohols. The latter
were obtained from the addition of PhMgBr to aldehydes.
Chiral HPLC: Chiracel OD column, hexanes/2-propanol as
eluent, 254 nm UV detector.
Cr yscop ic An a lysis of th e Molecu la r Weigh t of (R)-36.
Under N2, to a solution of (R)-12 (305 mg, 0.36 mmol) in
cyclohexane (7.4 mL) was added Et2Zn (73 µL, 0.72 mmol).
After 10 min at room temperature, the produced ethane was
removed by bubbling N2 through the solution for 5 min. The
resulting solution was used for the freezing point measure-
ment. The test tube containing the solution of (R)-36 under
N2 and a thermometer was placed into a beaker filled with
saturated NaCl aqueous solution. The beaker was then placed
into a -15 °C 2-propanol-dry ice solution. The temperature
change of the (R)-36 solution was recorded every 30 s. The
measured frozen point is 5.5 °C. According to ∆Tf ) kfm
(Tf° ) 6.7, kf ) 20.4), the measured molecular weight for
(R)-36 is 1099.
P r ep a r a tion a n d Ch a r a cter iza tion of (R)-3,3′-Bis(2′-
m eth oxy-5′-m eth ylp h en yl)-1,1′-bi-2-n a p h th ol, (R)-38. To
a mixture of (R)-8 (4.06 g, 6.5 mmol), compound 37 (3.00 g,
18.0 mmol), THF (25 mL), and K2CO3 (1 M, 35 mL) was added
Pd(PPh3)4 (125 mg). The reaction was complete after reflux
1
for 24 h as shown by H NMR spectroscopy. The mixture was
then extracted with EtOAc, and the combined organic layer
was washed with brine. Evaporation of the solvent gave a solid.
Hydrolysis of this solid (6 N HCl/THF, reflux for 12 h) followed
by flash chromatography (hexane/ethyl acetate ) 8:1) gave (R)-
38 as a white amorphous solid in 70% yield (2.40 g) for the
two-step reaction: [R]D ) +139.7 (c ) 1.01, CH2Cl2); UV-vis
λ
max (CH2Cl2, nm) 254, 290, 338; fluorescence λemi (CH2Cl2, nm)
1
(λexc 338 nm) 387; H NMR (CDCl3, 400 MHz) δ 2.39 (s, 6H),
3.80 (s, 6H), 5.86 (s, 2H), 6.93 (d, J ) 8.7 Hz, 2H), 7.21 (dd,
J ) 8.2, 1.5 Hz, 2H), 7.29-7.37 (m, 8H), 7.89 (d, J ) 8.2 Hz,
2H), 7.97 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 20.74, 56.39,
115.12, 115.58, 123.92, 125.04, 126.76, 127.16, 128.42, 128.88,
129.44, 130.00, 132.96, 133.60, 150.65, 154.76; FT-IR (KBr,
cm-1) 3522 (s), 3050 (w), 2924 (m), 2836 (w); MS (EI) (m/z)
527 (M + H+). Anal. Calcd for C36H30O4: C, 82.11; H, 5.74.
Found: C, 82.02; H, 5.88.
1-P h en yl-1-p r op a n ol: tR ) 22.30 min, tS ) 24.65 min
(HPLC, hexanes/2-propanol ) 97:3 at 0.5 mL/min).
(p -Met h oxyp h en yl)p h en ylm et h a n ol: tR ) 15.28 min,
tS ) 16.18 min (HPLC, hexanes/2-propanol ) 9:1 at 1.0 mL/
min).
(p-Ch lor op h en yl)p h en ylm eth a n ol. The ee was measured
by analyzing its acetate on HPLC: tR ) 45.05 min, tS ) 43.57
min (hexanes/2-propanol ) 99:1 at 0.2 mL/min).
Dip h en ylzin c Ad d ition to P r op ion a ld eh yd e Ca ta lyzed
by Mon om er (R)-12. To a Schlenk flask were added toluene
(5 mL, dried, and degassed with N2), (R)-12 (42 mg, 0.05
mmol), and Ph2Zn (132 mg, 0.6 mmol). The mixture was stirred
at room temperature for 15 min and then cooled to 0 °C.
Propionaldehyde (36 µL, 0.5 mmol) was added, and the
resulting mixture was stirred at 0 °C for 20 h. The reaction
was quenched with addition of 1 N HCl. Extraction of the
aqueous layer with diethyl ether followed by washing the
combined organic layer with brine and purifying on silica gel
column (eluent: EtOAc/hexanes ) 1:5) gave (S)-1-phenyl-1-
propanol as a colorless liquid in 90% yield (62 mg). Analysis
by HPLC-Chiracel OD column showed an ee of 87%.
Diph en ylzin c Addition to p-Ch lor oben zaldeh yde Cata-
lyzed by Mon om er (R)-12. To a Schlenk flask were added
diethyl ether (50 mL, dried, and degassed with N2), (R)-12 (42
mg, 0.05 mmol), and Et2Zn (10 µL, 0.1 mmol). After the
mixture was stirred at room temperature for 15 min, Ph2Zn
(55 mg, 0.25 mmol) was added. Stirring was continued for
another 15 min, and then p-chlorobenzaldehyde (35 mg, 0.25
mmol) was added. The reaction mixture was stirred at room
temperature for 10 h and quenched with 1 N HCl. Usual
workup gave (R)-(p-chlorophenyl)phenylmethanol in 86% yield
(47 mg). To a solution of the chiral alcohol (10 mg) in
methylene chloride (5 mL) were added acetic anhydride (1 mL),
Et3N (1 mL), and a catalytic amount of 4-(dimethylamino)-
pyridine. The mixture was stirred at room temperature for 4
h until TLC indicated the disappearance of the alcohol starting
material. The reaction mixture was taken into hexanes (30
mL) and washed with 1 N HCl, brine, aqueous NaHCO3, and
brine successively. Evaporation of the solvent gave (R)-(p-
chlorophenyl)phenylmethyl acetate, which was shown to be
pure by 1H NMR. Analysis by GC-chiral column showed an ee
of 94%.
(â-Na p h th yl)p h en ylm eth a n ol: tR ) 21.88 min, tS ) 18.68
min (HPLC, hexanes/2-propanol ) 9:1 at 1.0 mL/min).
1,3-Dip h en yl-2-p r op en -1-ol: tR ) 24.62 min, tS ) 18.98
min (HPLC, hexanes/2-propanol ) 9:1 at 1.0 mL/min).
P r ep a r a tion of 4-Br om o-2,5-d ih exyloxyp h en ylbor on ic
Acid 45. To a solution of 1,4-dibromo-2,5-dihexyloxybenzene
9 (8.80 g, 20 mmol) in THF (100 mL) was added n-BuLi (8.5
mL, 21.25 mmol, 2.5 M in hexanes) at -78 °C. The mixture
was stirred at this temperature for 4 h and was then cannu-
lated to a solution of B(OEt)3 (10 mL) in THF (30 mL) in 30
min at -78 °C. The mixture was allowed to warm to room
temporature slowly and stirred for 18 h. A solution of 1 N HCl
was then added, and the resulting mixture was extracted with
EtOAc. The combined organic layer was washed with brine,
saturated NaHCO3, and brine. Evaporation of the solvent gave
a solid that was washed with hexane. The solid was redissolved
in CH2Cl2/EtOAc (1:1) and filtered. Removal of the solvent gave
45 as a white solid in 81% yield (6.48 g): mp 99.5-103.5 °C;
UV-vis λmax (CH2Cl2, nm) 238, 312; 1H NMR (CDCl3, 400 MHz)
δ 0.92 (m, 6H), 1.34 (m, 8H), 1.48 (m, 4H), 1.82 (m, 4H), 4.02
(t, J ) 6.7 Hz, 2H), 4.03 (t, J ) 6.4 Hz, 2H), 6.19 (s, 2H), 7.11
(s, 1H), 7.37 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.18, 14.24,
22.72, 22.80, 25.84, 25.86, 29.38, 29.42, 31.64, 31.74, 69.55,
70.18, 116.63, 116.75, 118.54, 120.88, 150.25, 158.29; FT-IR
(KBr, cm-1) 3380 (s), 2940 (s), 2857 (m).
P r ep a r a tion a n d Ch a r a cter iza tion of p-Tr ip h en ylen e
Dibr om id e 46. To a mixture of 4-bromo-2,5-dihexyloxy-
phenylboronic acid 45 (17.0 g, 42.4 mmol), 1,4-diiodobenzene
(6.90 g, 21.0 mmol), THF (80 mL), and K2CO3 (1 M, 80 mL)
was added Pd(PPh3)4 (300 mg). After being refluxed for 12 h,
the reaction mixture was cooled to room temperature and
extracted with EtOAc. The combined organic layer was washed
with brine. Evaporation of the solvent gave a solid. Flash

Asymmetric Synthesis of Chiral Secondary Alcohols
J . Org. Chem., Vol. 64, No. 21, 1999 7955
chromatography (hexane/ethyl acetate ) 20:1) and recrystal-
lization (hexane/EtOAc ) 100:1) gave 46 as a white crystalline
solid in 60.4% yield (10.0 g): mp 99.5-101.0 °C; UV-vis λmax
(CH2Cl2, nm) 232, 274, 324; 1H NMR (CDCl3, 400 MHz) δ 0.88
(t, J ) 7.0 Hz, 6H), 0.92 (t, J ) 7.0 Hz, 6H), 1.29 (m, 8H), 1.37
(m, 12H), 1.51 (m, 4H), 1.71 (m, 4H), 1.84 (m, 4H), 3.91 (t, 6.5
Hz, 4H), 4.02 (t, J ) 6.4 Hz, 4H), 6.96 (s, 2H), 7.18 (s, 2H),
7.57 (s, 4H); 13C NMR (CDCl3, 100 MHz) δ 14.21, 14.25, 22.77,
22.81, 25.88, 29.29, 29.46, 31.60, 31.74, 69.72, 70.44, 111.50,
116.57, 118.38, 129.15, 130.66, 150.03, 150.65; FT-IR (KBr,
cm-1) 2940 (s), 2870 (s). Anal. Calcd for C42H60Br2O4: C, 63.96;
H, 7.67. Found: C, 63.72; H, 7.54.
P r ep a r a tion a n d Ch a r a cter iza tion of p-Tr ip h en ylen e
Dibor on ic Acid 44. To a solution of the p-triphenylene
dibromide 46 (9.2 g, 11.7 mmol) in THF (120 mL) at -78 °C
was added n-BuLi(15 mL, 2.5 M in hexane, 37.5 mmol). The
mixture was stirred at this temperature for 2 h and was then
cannulated to a solution of B(OEt)3 (20 mL) in THF (50 mL).
The mixture was then warmed to room temperature and
stirred for another 22 h. HCl (1 N) was added. Filtration gave
a white solid. The solid was washed with H2O and EtOAc.
Recrystallization from DMSO (44 was soluble in hot DMSO,
but has very low solubility in DMSO at room temperature)
gave 44 as a white solid in 88% yield (7.4 g). Diboronic acid
44 was converted to its ester derivative by reaction with 2,2-
dimethyl-1,3-propandiol in refluxing benzene and then char-
acterized: mp 90.0-91.5 °C; IR (KBr, cm-1) 2953 (s), 2932 (s),
2870 (s); 1H NMR (CDCl3, 400 MHz) δ 0.90 (m, 12H), 1.07 (s,
12H), 1.29 (m, 8H), 1.36 (m, 12H), 1.50 (m, 4H), 1.70 (m, 4H),
1.79 (m, 4H), 3.81 (s, 8H), 3.96 (m, 8H), 6.93 (s, 2H), 7.25 (s,
2H), 7.61 (s, 4H); 13C NMR (CDCl3, 100 MHz) δ 14.23, 14.29,
22.14, 22.79, 22.91, 25.95, 25.97, 29.54, 29.75, 31.68, 31.87,
31.97, 69.53, 70.08, 72.61, 116.01, 120.20, 129.13, 133.73,
137.47, 150.26, 157.93; MS m/e (DIP) 855 (M + H+).
added. The resulting mixture was stirred for 5 h, and the
reaction was monitored by TLC. A 100% conversion of benz-
aldehyde was observed. Then, 1 N HCl was added to quench
the reaction. The mixture was extracted with diethyl ether,
and the combined organic layer was washed with brine,
NaHCO3, and brine. After evaporation of the solvent, the
residue was redissolved in methylene chloride and precipitated
with methanol. The polymer was recovered by filtration, and
the solution was concentrated under vacuum. The product was
purified by flash chromatography on silica gel to give (R)-1-
phenylpropanol as a colorless oil in 95% yield (120 mg). HPLC
analysis of the product on an Chiracel-OD column (eluent:
2-propanol/hexane ) 3:97) showed 98% ee. The recovered
polymer was redissolved in methylene chloride and filtered.
The solution was reprecipitated with methanol. After two more
dissolution and precipitation steps and vacuum-drying, (R)-
43 was obtained in over 95% yield.
Dip h en ylzin c Ad d ition to p-An isa ld eh yd e in th e P r es-
en ce of P olym er (R)-43. (A double slow addition technique
for the polymer-catalyzed diphenylzinc addition reaction was
applied). To a Schlenk flask containing toluene (15 mL, dried,
and degassed with N2) were added the polymer (R)-43 (92 mg,
0.1 mmol based on the repeating unit) and diethylzinc (20 µL,
0.2 mmol). After being stirred at room temperature for 20 min,
the reaction mixture turned to a gel. Diphenylzinc (55 mg, 0.25
mmol) was then added, and the above mixture became more
viscous. More diethylzinc (60 µL, 0.6 mmol) was added to
convert the viscous gel into a cloudy yellowish solution.
Another Schlenk flask containing toluene (15 mL) was charged
with p-anisaldehyde (35 mg, 0.25 mmol). Both the Zn-polymer
complex solution and the aldehyde solution were added from
two syringes simultaneously into a flask containing toluene
(20 mL) at -30 °C within 20 h via a syringe pump. After the
addition, stirring was continued for an additional 36 h at
-30 °C. Quenching the reaction with 1 N HCl followed by
usual workup gave (R)-(p-methoxyphenyl)phenylmethanol in
72% yield (39 mg). Analysis by HPLC-Chiracel-OD column
showed an ee of 92%.
Gen er a l P r oced u r e for th e Red u ction of Keton es w ith
Ca tech olbor a n e in th e P r esen ce of P olym er s (S)-4 a n d
(R)-43 or th e Mon om er (R)-12. To a Schlenk flask containing
toluene (10 mL, dried, and degassed with N2) was added
monomer (R)-12 (42 mg, 0.05 mmol), polymer (S)-4 (32 mg,
0.055 mmol, based on the repeating unit), or (R)-43 (50 mg,
0.055 mmol) and diethylzinc (10 µL, 0.1 mmol) under N2 at
room temperature. After the mixture was stirred at room
temperature for 20 min, acetophenone (0.12 mL, 1 mmol) was
added. The resulting mixture was then cooled to -30 °C, and
catecholborane (1.5 mmol, 1.5 mL, 1 M in THF) was added.
After being stirred at this temperature for 48 h, the reaction
was quenched with 1 N HCl and the aqueous layer was
extracted with diethyl ether. The combined organic layer was
washed with brine until pH ) 7 and then dried over anhydrous
Na2SO4. Concentration with rotary evaporator gave a yellow
oil. When monomer (R)-12 was used, purification by flash
column chromatography on silica gel with EtOAc/hexanes
(1:5) gave the product. When polymer (S)-4 or (R)-43 was used,
precipitation by addition of methanol to the yellow oil recov-
ered the polymer. The product was then purified by column
chromatography on silica gel.
P r ep a r a tion a n d Ch a r a cter iza tion of P olym er (R)-43.
To a mixture of (R)-8 (5.0 g, 8.0 mmol), 44 (6.20 g, 8.6 mmol),
THF (50 mL), and 1 M K2CO3 (50 mL) under nitrogen was
added Pd(PPh3)4 (60 mg). After the mixture was heated at
reflux for 36 h until the 1H NMR spectrum showed the
disappearance of the iodide end group signals, 4-tert-butyl-
bromobenzene (0.5 mL, 2.9 mmol) was added to the mixture
to cap the polymer chain by reacting with the boronic acid end
groups. The mixture was heated at reflux for another 5.5 h
and then cooled to room temperature. Ethyl acetate was added
to extract, and the combined organic layer was washed with
brine. Evaporation of the solvent gave a yellow residue that
was redissolved in methylene chloride and precipitated with
methanol. This procedure was repeated three times. After the
residue was dried under vacuum, a polymer was obtained as
a yellow solid in 94% yield (7.55 g): GPC Mw ) 24 000 and
Mn ) 12 200 (PDI ) 1.97); [R]D ) -140.98 (c ) 1.00, CH2Cl2).
Hydrolysis of this polymer in 6 N HCl/THF at reflux under
nitrogen for 17 h gave (R)-43 in 96% yield: [R]D ) -92.9 (c )
1.01, CH2Cl2); UV-vis λmax (CH2Cl2, nm) 234, 276, 338; GPC
(relative to polystyrene standard) Mw ) 25 800 and Mn
)
14 300 (PDI ) 1.80); 1H NMR (CDCl3, 400 MHz) δ 0.77 (t, J )
7.0 Hz, 6H), 0.89 (m, 6H), 1.17 (m, 8H), 1.32 (m, 20H), 1.46
(m, 4H), 1.68 (m, 4H), 1.79 (m, 4H), 4.01 (m, 8H), 6.49 (s, 2H),
7.14 (s, 2H), 7.23 (s, 2H), 7.31 (m, 2H), 7.38 (m, 4H), 7.72 (s,
4H), 7.96 (d, J ) 8.0 Hz, 2H), 8.05 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 14.16, 14.25, 22.63, 22.81, 25.69, 25.98, 29.47,
29.50, 31.64, 31.66, 69.62, 71.00, 116.84, 117.00, 117.57,
123.94, 125.14, 126.74, 128.01, 128.39, 129.17, 129.31, 129.42,
131.17, 131.47, 133.88, 137.09, 150.04, 150.52, 151.30; IR (KBr,
cm-1) 3528 (s), 3055 (w), 2928 (s), 2859 (s); CD (CH2Cl2) [θ]λ )
-8.72 × 104 (343 nm), 8.59 × 103 (305 nm), -2.66 × 103 (290
nm), 1.10 × 105 (258 nm), -1.87 × 105 (235 nm), and 4.63 ×
104 (221 nm). Anal. Calcd for (C62H72O6)n: C, 81.54; H, 7.95.
Found: C, 81.40; H, 8.00.
Th e Sp ecific Op tica l Rota tion s of th e Ch ir a l Alcoh ol
P r od u cts Obta in ed fr om Red u ction of Keton es. (S)-1-
P h en ylet h a n ol: [R]D ) -40.6 (c ) 2.04, CH2Cl2) [lit.55
[R]D ) -52.5 (c ) 2.27, CH2Cl2), S].
(S)-1-(p-Meth oxyp h en yl)eth a n ol: [R]D ) -40.6 (c ) 1.12,
CHCl3) [lit.56 [R]D ) 52.1 (c ) 1, CHCl3), 87% ee, R].
(S)-1-(p-Br om op h en yl)eth a n ol: [R]D ) -24.6 (c ) 1.26,
MeOH) [lit.57 [R]D ) 32.9 (c ) 1.39, MeOH), 99.3% ee, R].
A Typ ica l P r oced u r e for th e Rea ction of Dia lk ylzin cs
w ith Ald eh yd es in th e P r esen ce of P olym er (R)-43. Under
nitrogen, to a solution of (R)-43 (50 mg, 0.05 mmol) in toluene
(4 mL) was added diethylzinc (0.21 mL, 2.0 mmol) at room
temperature. After being stirred for 10 min, the solution was
cooled to 0 °C, and benzaldehyde (0.10 mL, 1.0 mmol) was
(55) Nagai, U.; ShiShido, T. Tetrahedron 1965, 21, 1701.
(56) J anssen, A. J . M.; Klunder, J . H.; Zwanenburg, B. Tetrahedron
1991, 47, 7645.
(57) Mathre, D. J .; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.;
Carroll, J . D.; Corley, E. G.; Grabowski, E. J . J . J . Org. Chem. 1993,
58, 2880.

7956 J . Org. Chem., Vol. 64, No. 21, 1999
Huang et al.
(S)-1-(o-Br om op h en yl)eth a n ol: [R]D ) -37.8 (c ) 1.06,
CHCl3) [lit.58 [R]D ) 54 (c ) 1, CHCl3), R].
1-P h en yleth a n ol: tR ) 20.02 min, tS ) 20.68 min (100 to
150 °C at 1 °C/min).
2-Meth yl-3-h ep ta n ol. The ee was determined by analyzing
its acetate derivative: tR ) 27.88 min, tS ) 27.46 min (60 to
100 °C at 1 °C/min).
The HPLC retention times of the R and S enantiomers:
1-(p-Meth oxyp h en yl)eth a n ol: tR ) 15.60 min, tS ) 16.60
min (method B).
1-(p-Br om op h en yl)eth a n ol: tR ) 7.53 min, tS ) 6.95 min
(method A).
1-(o-Br om op h en yl)eth a n ol: tR ) 6.65 min, tS ) 6.97 min
(method A).
1-(â-Na p h th yl)eth a n ol: tR ) 27.35 min, tS ) 26.03 min
(method B).
4-P h en yl-3-b u t en -2-ol: tR ) 22.01 min, tS ) 28.40 min
(method A).
2-Ch lor o-1-p h en yleth a n ol: tR ) 8.90 min, tS ) 9.52 min
(method A).
2-Meth yl-1-p h en yl-1-p r op a n ol: tR ) 5.97 min, tS ) 6.67
min (method A).
(S)-1-(â-Na p h th yl)eth a n ol: [R]D ) -24.8 (c ) 1.36, EtOH)
[lit.59 [R]D ) 41.3 (c ) 5.0, EtOH), R].
(S)-4-P h en yl-3-bu ten -2-ol: [R]D ) -30.2 (c ) 1.21, CHCl3)
[lit.60 [R]D ) -32.16 (c ) 5, CHCl3), 81% ee, S].
(R)-2-Ch lor o-1-p h en yleth a n ol: [R]D ) -4.87 (c ) 1.29,
cyclohexane) [lit.61 [R]D ) 49.6 (c ) 2.81, cyclohexane), 96.5%
ee, S].
(R)-2-Meth yl-1-p h en yl-1-p r op a n ol: [R]D ) 2.61 (c ) 0.31,
Et2O) [lit.62 [R]D ) 47.7 (c ) 1.0, Et2O), R].
(S)-2-Meth yl-3-h ep ta n ol: [R]D ) -8.86 (c ) 1.06, EtOH)
[lit.63 [R]D ) -15.5 (c ) 10, EtOH), 56% ee, S].
GC a n d HP LC An a lyses of th e Ch ir a l Alcoh ol P r od -
u cts fr om th e Asym m etr ic Red u ction of Keton es. Condi-
tions for the GC analysis: Chiral capillary GC. Supelco â-Dex
120 column 30 m × 0.25 mm (i.d.), 0.25 mm film. Carrier gas:
He (1.0 mL/min).
Conditions for the HPLC analysis: Chiracel OD column. 254
nm UV detector. Method A. Hexane/2-propanol ) 9:1 at 1.0
mL/min. Method B. 0.5 mL/min.
Ack n ow led gm en t. This work was supported by the
Department of Chemistry at North Dakota State Uni-
versity and then by the Department of Chemistry at the
University of Virginia. Partial support from the Na-
tional Science Foundation (DMR-9529805), the US Air
Force (F49620-96-1-0360), and J effress Memorial Trust
is gratefully acknowledged.
The GC retention times of the R and S enantiomers:
(58) Aldrich Catalog; Aldrich: Milwaukee, 1998-1999; p 257.
(59) Collyer, T. A.; Kenyon, J . J . Chem. Soc. 1940, 676.
(60) Brown, H. C.; Chandrasekharan, J .; Ramachandran, P. V. J .
Am. Chem. Soc. 1988, 110, 1539.
(61) Corey, E. J .; Shibata, S.; Bakshi, R. K. J . Org. Chem. 1988, 53,
2861.
(62) Niwa, S.; Soai, K. J . Chem. Soc., Perkin Trans. 1 1991, 2717.
(63) Mukaiyama, T.; Soai, K.; Kobayashi, S. Chem. Lett. 1978, 219.
J O990992V