A New Approach to Highly Enantioselective Polymeric Chiral Catalysts

Full text of DOI:10.1021/jo980004a

2
798
J . Org. Chem. 1998, 63, 2798-2799
A New Ap p r oa ch to High ly En a n tioselective
P olym er ic Ch ir a l Ca ta lysts
for the reaction of ortho-, meta-, or para-substituted ben-
zaldehydes, linear or branched aliphatic aldehdyes, and aryl-
or alkyl-substituted R,â-unsaturated aldehydes. We at-
tribute the large enantioselectivity difference between (R)-1
and (R)-2 to their structural differences. In (R)-1, the two
Qiao-Sheng Hu, Wei-Sheng Huang, and Lin Pu*
Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22901
Received J anuary 6, 1998
Asymmetric catalysis is one of the most important meth-
ods to prepare optically active organic molecules.1,2 With
the growing demand for optically pure drugs, the demand
for recoverable and reusable chiral catalysts is also growing
because of the expense of the optically active reagents. To
facilitate the recovery of the catalysts, monomeric chiral
compounds have been anchored to polymer supports to
generate either heterogeneous catalysts or soluble macro-
alkoxy oxygens on a phenylene spacer can serve as a dual
ligand for both adjacent binaphthyl units. This makes the
electronic and steric environment of the catalytic sites in
molecular catalysts.3,4 The differences of the solubility and
the size between the polymers and the small molecules allow
the chiral catalysts to be separated conveniently from the
reaction system. Using polymeric catalysts also makes it
possible to carry out the reactions in flow reactors or flow
membrane reactors for continuous production. Although a
few good polymeric chiral catalysts have been obtained, this
(R)-1 different from that of (R)-2. On the basis of this
analysis, we have designed a new rigid and sterically regular
polymeric chiral catalyst in which the steric and electronic
environment of the monomeric catalyst is mostly preserved.
This strategy has produced the most general polymeric chiral
catalyst for the enantioselective reaction of aldehydes with
diethylzinc. Herein, this result is reported and the potential
application of this strategy is discussed.
strategy often leads to a significant drop of enantioselectivity
after a good monomeric catalyst is attached to a polymer.3,4
In the traditional polymeric chiral catalysts, the polymer
supports such as polystyrene normally have a flexible and
sterically irregular achiral structure that produces a mi-
croenvironment at the catalytic sites very different from that
of the monomeric catalysts. This should be responsible for
the observed reduced enantioselectivity in many cases. In
addition, because of the flexible and sterically irregular
structure, one cannot systematically modify the microenvi-
ronment of the catalytic sites in these polymers to achieve
the desired catalytic properties.
8
9
From the Suzuki coupling of (R)-3 with 4 followed by
hydrolysis, chiral polymer (R)-5 is obtained in 90% yield
(
Scheme 1). This polymer has very good solubility in THF,
toluene, and chloroform. Gel permeation chromatography
GPC) analysis of (R)-5 relative to polystyrene standards
(
shows its molecular weight is Mw ) 25 800 (PDI ) 1.8). The
specific optical rotation of this chiral polymer is [R]D ) -92.9
1
13
(
c ) 1.01, CH2Cl2). (R)-5 gives well-resolved H and
C
NMR spectra that are consistent with a well-defined polymer
structure. Because the 3,3′-phenylene dialkoxy groups can
only serve as ligands for one binaphthyl unit in (R)-5, the
steric and electronic environment of the monomeric catalyst
We have carried out a program to use rigid and sterically
regular polybinaphthols to develop a new generation of
5
,6
polymeric chiral catalysts for asymmetric catalysis.
Previ-
(R)-2 is mostly preserved in the polymer due to the rigidity
ously, we have reported the use of polymer (R)-1 for the
asymmetric reaction of aldehydes with diethylzinc.5 This
polymer can catalyze the reaction of diethylzinc with alde-
hydes to give chiral alcohols in over 90% ee for certain
substrates. However, the general applicability of (R)-1 was
limited because of its lower enantioselectivity for the reac-
tions of ortho-substituted benzaldehdyes and aliphatic al-
dehydes.
of the polymer structure.
When (R)-5 is used to catalyze the reaction of aldehydes
with diethylzinc, this polymer indeed shows the expected
high enantioselectivity for a very broad range of aldehydes.
Table 1 summarizes the results for the use of (R)-5. All of
the reactions are carried out in the presence of 5 mol % of
(R)-5 in toluene solution at 0 °C unless indicated otherwise.
The configuration of the alcohol products is R as determined
by comparing their optical rotation values and HPLC or GC
To gain further insight into the catalysis carried out by
7
(
R)-1, we have synthesized (R)-2 as the monomeric model
data with the literature results.7
,11
The results obtained
compound of (R)-1. We find that (R)-2 is an extremely
5
from the reactions catalyzed by (R)-1 are also included in
Table 1 for comparison. As shown in Table 1, (R)-5 exhibits
greatly enhanced enantioselectivity over (R)-1, especially for
aliphatic aldehydes and ortho-substituted benzaldehydes.
This polymer can be easily recovered by precipitation with
methanol, and the recovered (R)-5 shows the same enanti-
general catalyst for the asymmetric reaction of diethylzinc
with a broad range of aldehydes.7 It shows 91->99% ee’s
(
(
(
1) Stinson, S. C. Chem. Eng. News 1997, 75, 26.
2) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York, 1993.
3) Itsuno, S. In Polymeric Materials Encyclopedia; Synthesis, Properties
and Applications; Salamone, J . C., Ed.; CRC Press: Boca Raton, FL, 1996;
Vol. 10, p 8078.
(4) (a) Blossey, E. C.; Ford, W. T. In Comprehensive Polymer Science.
(8) Selected references on the Suzuki coupling: (a) Miyaura, N.; Yanagi,
T.; Suzuki, A. Synth. Commun. 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. (d) Huber, J .; Scherf, U. Macromol. Rapid Commun. 1994, 15, 897.
(9) (a) Cox, P. J .; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 17,
2253. (b) Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett. 1995, 1113.
(c) Hu, Q.-S.; Vitharana, D.; Pu, L. Tetrahedron: Asymmetry 1995, 6, 2123.
(10) (a) Itsuno, S.; Sakurai, Y.; Ito, K.; Maruyama, T.; Nakahama, S.;
Fr e´ chet, J . M. J . J . Org. Chem. 1990, 55, 304. (b) Itsuno, S.; Fr e´ chet, J . M.
J . J . Org. Chem. 1987, 52, 4140.
The Synthesis, Characterization, Reactions and Applications of Polymers;
Allen, G., Bevington, J . C., Eds.; Pergamon Press: New York, 1989; Vol. 6,
p 81. (b) Pittman, C. U., J r. In Comprehensive Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: Oxford,
1
983; Vol. 8, p 553.
5) (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.
(6) (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.
(11) For reviews on the asymmetric reaction of aldehydes with dieth-
ylzinc, see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
(7) Huang, W.-S.; Hu, Q.-S.; Pu, L. J . Org. Chem. 1998, 63, 1364.
S0022-3263(98)00004-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/07/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2799
Sch em e 1. Syn th esis of th e Rigid a n d Ster ica lly Regu la r Ch ir a l P olym er (R)-5
Ta ble 1. Rea ction of Ald eh yd es w ith Dieth ylzin c in th e
P r esen ce of Ch ir a l P olybin a p h th yls
ylzinc with heptyl aldehyde in 92% ee (75% yield) and with
cyclohexanecarboxaldehyde in 86% ee (57% yield), but these
reactions require the use of a stoichiometric amount of Ti-
(
OCHMe2)4 versus the aldehydes.13 Therefore, (R)-5 is the
best polymeric catalyst yet reported for the asymmetric
reaction of aldehydes with diethylzinc.
A typical procedure for the use of (R)-5 is described below.
Under nitrogen, to a solution of (R)-5 (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 added. The resulting mixture was stirred for 5
h, and the reaction was monitored by TLC. A 100%
conversion of benzaldehyde was observed, and 1 N HCl was
added to quench the reaction. The mixture was extracted
with Et2O, and the combined organic layer was washed with
brine, NaHCO3, and brine. After evaporation of the solvent,
the residue was redissolved in CH2Cl2 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 94% yield (128 mg)
and 98% ee.
Our earlier discovery of (R)-1 as an enantioselective
catalyst is achieved by systematically screening the use of
different polymers for the reaction.5 The design of (R)-5 and
the discovery of its high enantioselectivity demonstrate that
highly enantioselective polymeric catalysts can be obtained
by incorporating good monomeric catalysts into a rigid and
sterically regular polymer chain. This new approach may
have general applications in the design of enantioselective
polymer catalysts from the existing monomeric catalysts.
When a monomeric catalyst is introduced into a rigid and
sterically regular polymer chain rather than anchored to a
flexible and sterically irregular polymer chain as in the
traditional polymeric catalysts, the steric and electronic
properties of the monomeric catalyst should be mostly main-
tained because of the rigid and sterically regular polymer
structure. The catalytic activity and stereoselectivity of the
resulting polymeric catalyst should closely resemble that of
the monomer as long as the catalytically active species is
not the aggregate of the monomer. The rigidity and stereo-
regularity the polymer structure also allows a systematic
modification of the catalyst when necessary.
a
b
Determined by HPLC-Chiracel OD column. Determined by
c
chiral GC (â-Dex capillary column). Determined by analyzing the
acetate derivative of the product on the GC-â-Dex capillary
d
column. Determined by analyzing the propionate derivative of
e
the product on the GC-â-Dex capillary column. Determined by
analyzing the Mosher’s ester of the product on the GC-â-Dex
f
capillary column. The solvent was a 1:1 mixture of toluene/diethyl
g
ether. The recovered catalyst was used.
oselectivity as the original polymer. Although highly enan-
tioselective polymer-supported amino alcohol catalysts have
been developed for the reaction of a few benzaldehyde
derivatives with diethylzinc,10 the best results for the
Ack n ow led gm en t. This work was supported by North
Dakota State University and then by University of Vir-
ginia. Partial support from the National Science Founda-
tion (DMR-9529805) and the US Air Force (F49620-96-1-
0360) is gratefully acknowledged.
reaction of aliphatic aldehydes using these polymer catalysts
are only 69% ee.1
1,12
The cross-linked polystyrene-supported
chiral R,R,R′,R′-tetraphenyl-1,3-dioxolane-4,5-dimethanol-
titanium(IV) catalysts can carry out the reaction of dieth-
Su p p or tin g In for m a tion Ava ila ble: Detailed experimental
procedures and characterizations involving (R)-5 and
4 are
(
(
12) Soai, K.; Watanabe, M. Tetrahedron: Asymmetry 1991, 2, 97.
13) Seebach, D.; Marti, R. E.; Hintermann, T. Helv. Chim. Acta 1996,
provided (3 pages).
7
9, 1710.
J O980004A