The first highly enantioselective catalytic diphenylzinc additions to aldehydes: Synthesis of chiral diarylcarbinols by asymmetric catalysis

Full text of DOI:10.1021/jo990402t

4222
J . Org. Chem. 1999, 64, 4222-4223
prochiral faces of a diaryl ketone should be small. Neverthe-
less, Corey and co-workers have shown that ketones con-
taining two sterically and/or electronically very different aryl
groups can be reduced with high enantioselectivity when
using chiral oxazaborolidines as the catalysts.6b,7 Unlike the
reduction of diaryl ketones, the addition of organometallic
aryl reagents to aryl aldehydes should be more suitable for
asymmetric induction because of the large steric and elec-
tronic differences between the aryl group and the hydrogen
atom in an aromatic aldehyde. However, very few reports
on the catalytic enantioselective addition of organometallic
aryl reagents to aryl aldehydes have appeared.4,8,9
Recently, we have shown that chiral binaphthyl ligand
(R)-2 catalyzes the addition of diethylzinc to a large number
of aldehydes, including o-, m-, or p-substituted benzaldehyde,
linear or branched aliphatic aldehydes, and alkyl- or aryl-
substituted R,â-unsaturated aldehydes, with very high
enantioselectivity.10 The excellent catalytic properties of
(R)-2 have prompted us to explore its application to the
asymmetric diarylzinc addition to aldehydes. We find that
(R)-2 is also highly enantioselective for this reaction. Par-
ticularly, its high enantioselectivity for the catalytic addition
of diphenylzinc to aromatic aldehydes allows the synthesis
of chiral diarylcarbinols that are generally difficult to access.
Herein, these results are reported.
We have first investigated the reaction of propionaldehyde
with diphenylzinc in the presence of (R)-2. The reaction is
conducted at 0 °C in a toluene solution in the presence of
10 mol % of (R)-2 which produces (S)-1-phenylpropanol in
87% ee. This is the first example of a catalytic diphenylzinc
addition to aldehydes with high enantioselectivity. The S
configuration of the product indicates that the phenyl
addition occurs at the re face of the aldehyde, the same as
the diethylzinc addition catalyzed by (R)-2.10 This suggests
that the catalytic diphenylzinc addition should be mecha-
nistically similar to the diethylzinc addition. In the case of
the diethylzinc addition to benzaldehyde in the presence of
(R)-2, the R product is obtained. Thus, both the R and S
enantiomers of 1-phenylpropanol can be obtained by carrying
out either diethylzinc addition to benzaldehyde or diphen-
ylzinc addition to propionaldehyde in the presence of (R)-2.
Encouraged by the result obtained for the diphenylzinc
addition to the aliphatic aldehyde, we have studied the
diphenylzinc addition to aromatic aldehydes for the synthe-
sis of chiral diarylcarbinols. The results are summarized in
Table 1. The reaction of organozinc reagents with aromatic
aldehydes is normally much faster than with aliphatic
aldehydes.2,3,10 Therefore, the catalytic asymmetric diphen-
ylzinc addition to aromatic aldehydes is expected to be even
more challenging than its addition to aliphatic aldehydes
because of the more competitive uncatalyzed background
reaction. Entry 2 in Table 1 shows that at 0 °C the
diphenylzinc addition to p-anisaldehyde can proceed even
without a catalyst. Because of the competitive background
reaction, a low ee was observed when a 5 mol % of (R)-2
was used (entry 3). When a larger amount of (R)-2 is
pretreated with diethylzinc, the resulting chiral zinc complex
Th e F ir st High ly En a n tioselective Ca ta lytic
Dip h en ylzin c Ad d ition s to Ald eh yd es:
Syn th esis of Ch ir a l Dia r ylca r bin ols by
Asym m etr ic Ca ta lysis
Wei-Sheng Huang and Lin Pu*
Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22901
Received March 5, 1999
Since the early reports on catalytic enantioselective di-
ethylzinc additions,1 the asymmetric reaction of aldehydes
with dialkylzinc reagents has been studied very exten-
sively.2,3 A number of excellent catalysts have been discov-
ered and have found many applications in the synthesis of
optically active secondary alcohols. However, compared to
the work on dialkylzinc additions, very little work has been
carried out on asymmetric diarylzinc additions to alde-
hydes.4,5 In 1997, Fu and co-workers reported the first
enantioselective catalytic addition of diphenylzinc to alde-
hydes by using a catalyst based on planar-chiral ligand 1.4a
In the presence of a catalytic amount of 1, the addition of
diphenylzinc to p-chlorobenzaldehyde has generated p-
chlorophenylphenylcarbinol but with only 57% ee. Unlike
the diethylzinc addition to aldehydes which is extremely slow
in the absence of a catalyst, the uncatalyzed diphenylzinc
addition can even be competitive with the catalyzed reaction
(vide infra). This makes the development of an enantiose-
lective catalyst for the diphenylzinc addition much more
challenging.
In our laboratory, we are interested in the synthesis of
chiral diarylcarbinols by using the asymmetric diarylzinc
addition to aromatic aldehydes because chiral diaryl-
carbinols are synthetically useful intermediates but are
difficult to obtain by asymmetric catalysis.6 Secondary
alcohols are generally prepared by either reduction of
ketones or addition of organometallic reagents to aldehydes.
Because of the similar electronic and steric properties
between the two aryl groups in a prochiral diaryl ketone, it
is inherently more difficult to obtain chiral diarylcarbinols
with high enantiomeric purity through asymmetric reduc-
tion. That is, the chiral bias of a catalyst toward the two
(1) (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823. (b) Kitamura,
M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem. Soc. 1986, 108, 6071.
(2) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(3) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49.
(4) (a) Dosa, P. I.; Ruble, J . C.; Fu, G. C. J . Org. Chem. 1997, 62, 444. (b)
An enantioselective diphenylzinc addition to ketones has been reported:
Dosa, P.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 445.
(7) (a) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1995, 36, 9153. (b)
Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1996, 37, 5675.
(8) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.
(5) 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. The highest
observed ee was 82%.
(6) (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.
(9) 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 1991, 49, 9751.
(10) Huang, W.-S.; Hu, Q.-S.; Pu, L. J . Org. Chem. 1998, 63, 1364.
10.1021/jo990402t CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/15/1999

Communications
J . Org. Chem., Vol. 64, No. 12, 1999 4223
Ta ble 1. Asym m etr ic Dip h en ylzin c Ad d ition s to Ald eh yd es Ca ta lyzed by (R)-2
Sch em e 1. Asym m etr ic Ad d ition of Dip h en ylzin c to
rt for 15 min, Ph2Zn (55 mg, 0.25 mmol) was added. Stirring
was continued for another 15 min, and then p-chloroben-
zaldehyde (35 mg, 0.25 mmol) was added. The reaction
mixture was stirred at rt for 10 h and quenched with 1 N
HCl. Usual workup gave (R)-R-phenyl-4-chlorobenzyl alcohol
in 86% yield (47 mg). The alcohol product was converted to
its acetate and was analyzed by HPLC on a Chiracel-OD
column without purification. The ee of the ester was found
to be 94%.
p-An isa ld eh yd e Ca ta lyzed by (R)-2
We have further found that polymer (R)-3,12 a rigid and
sterically regular polymer containing (R)-2 as the chiral
ligand units, can also carry out the diphenylzinc addition
to aldehydes in a preliminary study. For example, the
reaction of diphenylzinc with propionaldehyde in the pres-
ence of 20 mol % (based on the binaphthyl repeating units)
of (R)-3 produces (S)-1-phenylpropanol with 85% ee and 82%
yield. Both the reaction condition and result are similar to
catalyzes the reaction of diphenylzinc with p-anisaldehyde
to generate (R)-p-methoxyphenylphenylcarbinol with 93% ee
and 84% yield at -30 °C in toluene (entry 5) (Scheme 1).
Through variation of the solvents, reaction temperatures,
concentrations of the aldehydes, and amount of the catalyst
(R)-2, and with the use of additives such as diethylzinc and
methanol, excellent enantioselectivity for the addition of
diphenylzinc to various aromatic aldehydes and an R,â-
unsaturated aldehyde has been achieved. The factors that
influence the enantioselectivity of these reactions are sum-
marized below: (1) Pretreatment of the chiral ligand (R)-2
with diethylzinc generally increases the enantioselectivity.
This indicates that the zinc complex generated from the
reaction of diethylzinc with (R)-2 is a better catalyst than
that generated from the reaction of diphenylzinc with (R)-
2. (2) Reducing the concentration of the substrates leads to
dramatically increased enantioselectivity (entries 6 and 7).
This is probably because the uncatalyzed reaction is sup-
pressed at lower concentration. (3) In the case of the R,â-
unsaturated aldehyde, addition of methanol might have
modified the structure of the catalyst formed from the
reaction of (R)-2 with diethylzinc, leading to a much im-
proved enantioselectivity (entries 10 and 11). The use of
alcohol additives to enhance the enantioselectivity of an
organozinc addition was reported by Fu.4b It is interesting
to notice that higher temperature in methylene chloride
solution actually leads to higher ee for the reaction of
diphenylzinc with trans-cinnamaldehyde (entry 11). A more
active catalyst may be produced at higher temperature for
this reaction.
those when the monomer catalyst (R)-2 is used. The polymer
(R)-3 can be easily recovered with almost quantitative yield
by simple precipitation with methanol after workup. The
convenient recyclability of the polymer makes the new
asymmetric catalytic diphenylzinc addition very practical.
Ack n ow led gm en t. Partial support for this work from
the donors of the Petroleum Research Fund, administered
by the American Chemical Society, the National Science
Foundation (DMR-9796210), the US Air Force (F49620-
96-1-0360), and the J effress Memorial Trust is gratefully
acknowledged. We also thank Dr. Qiao-Sheng Hu for his
preparation of the polymer (R)-3.
As an example, the experimental procedure for the di-
phenylzinc addition to p-chlorobenzaldehyde catalyzed by
(R)-2 is given here. To a Schlenk flask were added diethyl
ether (50 mL, dried, and degassed with N2), (R)-2 (42 mg,
0.05 mmol), and Et2Zn (10 µL, 0.1 mmol). After stirring at
Su p p or tin g In for m a tion Ava ila ble: Detailed experimental
procedures for the catalytic asymmetric reactions and for the
determination of the ee’s of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) Wu, B.; Mosher, H. S. J . Org. Chem. 1986, 51, 1904.
(12) Hu, Q.-S.; Huang, W.-S.; Pu, L. J . Org. Chem. 1998, 63, 2798.
J O990402T