Immobilization of asymmetric multifunctional catalysts on an insoluble polymer

Article abstract of DOI:10.1016/S0040-4039(00)01486-6

Polymer-supported linked-BINOL was synthesized to immobilize asymmetric catalysts with two BINOL units. The advantage of the polymer-supported linked-BINOL over randomly polymer-supported BINOL was confirmed by asymmetric Michael reaction. A novel polymer

Full text of DOI:10.1016/S0040-4039(00)01486-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8473–8478
Immobilization of asymmetric multifunctional catalysts on
an insoluble polymer
Shigeki Matsunaga, Takashi Ohshima and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 16 August 2000; revised 30 August 2000; accepted 1 September 2000
Abstract
Polymer-supported linked-BINOL was synthesized to immobilize asymmetric catalysts with two
BINOL units. The advantage of the polymer-supported linked-BINOL over randomly polymer-supported
BINOL was confirmed by asymmetric Michael reaction. A novel polymer-supported LaꢀZn-linked-
BINOL complex afforded the Michael adduct in good yield and moderate ee. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: asymmetric catalyst; asymmetric synthesis; solid-phase synthesis; Michael reaction; linked-BINOL.
Polymer-supported catalysts have various advantages over homogeneous catalysts in asym-
metric synthesis, such as easy separation, reusability, stability and less toxicity of immobilized
species. Numerous efforts have been devoted to develop polymer-supported asymmetric cata-
1
lysts and several successful examples have been published so far. However, no efficient method
has been reported to immobilize asymmetric catalysts consisting of two or more chiral ligands
per center metal. On the other hand, various highly efficient chiral catalysts constructed from
Figure 1.
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01486-6

8474
2
two chiral ligands, including our heterobimetallic multifunctional catalysts (Fig. 1, 1 and 2), are
3
known in homogeneous asymmetric synthesis. Therefore, the development of efficient methods
to immobilize these catalysts is well desired. The main difficulty in achieving immobilization is
summarized as follows. The classical random attachment of ligands onto a polymer often results
in poor yield and/or ee of the products. The formation of desirable 1:2 (metal:ligand) species,
essential for high enantiomeric induction, is partially prevented due to diluted distribution of the
ligands on the polymer. If undesired 1:1 (metal:ligand) species catalyze the target reaction in
lower selectivity, the ee of the product should become much lower than that obtained by the
4
homogeneous counterpart. To prepare this type of polymer-supported catalyst successfully,
control of the relative spatial relationships between the ligands on the polymer seems to be
necessary, which is by no means an easy task.
Recently, we have succeeded in developing a novel linked-BINOL 3 (Fig. 1), which bears an
5a
asymmetric environment similar to that constructed by two BINOLs around a center metal.
We envisioned that the use of one linked-BINOL instead of two BINOLs makes a standard
anchoring approach possible and facilitates the immobilization of asymmetric catalysts which
require two BINOL units for high enantiomeric induction. In this paper we wish to report our
efforts toward this direction—synthesis of polymer-supported linked-BINOL and evaluation of
its asymmetric environment by asymmetric Michael reaction catalyzed by an La-linked-BINOL
5
b
complex.
6
On the basis of precedent reports concerning polymer-supported binaphthyl ligands, we
designed linked-BINOL 13 possessing a spacer at the 6,6%-position to avoid adverse effects of the
Scheme 1. Synthesis of polymer-supported linked-BINOL 13. Reagents and conditions: (a) CH OCH Cl, i-Pr NEt,
3
2
2
CH Cl , rt, 90%; (b) CH ꢁCHCH CH MgBr, PdCl dppf (4 mol%), THF, 50°C; (c) 9-BBN, THF, rt; (d) aq. NaOH,
2
2
2
2
2
2
3
0% H O , rt; (e) TBSCl, imidazole, DMF, rt, 71% (four steps); (f) t-BuLi, THF, −78°C; then DMF, 68%; (g)
2 2
+
−
NaBH , THF, CH OH, 0°C; (h) NaH, THF, DMF; 10, rt, 57% (two steps); (i) Bu N F , THF, rt; (j) PCC, MS 4
4
3
4
A, CH Cl , rt, 69% (two steps); (k) LHMDS, THF, rt; (l) 11 (0.25 mol equiv.), THF, −10°C to rt; (m) acetaldehyde
,
2 2
(
capping); (n) TsOH·H O, CH Cl , CH OH, 40°C
2 2 2 3

8475
spacer on the asymmetric environment. Compound 13 has a sufficiently long (C ) and flexible
8
spacer so that the ligand part would be positioned far away from the polymer backbone. It
should be mentioned that the spacer part does not contain an ester or amide functionality,
which often interacts strongly with Lewis acidic center metals to affect the asymmetric
environment in undesirable manner. The synthetic route towards 13 is shown in Scheme 1.
Starting from 6,6%-Br-BINOL 6, 11 was prepared in ten steps. The aldehyde 11 was attached to
7
resin 12, which was prepared from Merrifield resin following the literature procedure, by a
Wittig reaction. After checking complete consumption of 11 by TLC analysis, excess acetalde-
hyde was added to quench the remaining ylide. Following the removal of the MOM group by
treatment of the resin with a catalytic amount of TsOH·H O in CH Cl at 40°C, the polymer-
2
2
2
supported linked-BINOL 13 was obtained (loading 0.24 mmol/g based on mass balance).
To evaluate the utility of polymer-supported linked-BINOL 13, we investigated the Michael
reaction of 15 with 14 catalyzed by an La-linked-BINOL complex. The polymer-supported
La-linked-BINOL complex 17 was prepared in a similar manner to the homogeneous La-linked-
5
b,8
BINOL complex 5.
Although the chemical yield was relatively low (45%), moderate ee was
achieved (66%) using 17 (Table 1, entry 2). The advantage of the polymer-supported linked-
BINOL over randomly polymer-supported BINOL is apparent, when comparing this result
(
66% ee) with that obtained using the catalyst prepared from 2 equiv. of polymer-supported
BINOL (27% ee, Ref. 4). To improve the reactivity and selectivity, we tried using DME as
solvent instead of THF. In the homogeneous case, La-linked-BINOL complex 5 afforded the
best results when using DME instead of THF (4°C, 72 h, yield 98%, >99% ee, Ref. 5b).
Unfortunately, the reactivity of 17 in DME became very low: the Michael product 16 was
obtained only in 56% yield despite the use of 50 mol% catalyst, although a better ee (78%) was
Table 1
Catalytic asymmetric Michael reaction promoted by La-linked-BINOL complexes
O
O
COOBn
COOBn
15
(R,R)-La-catalyst
conditions
+
COOBn
COOBn
14
16
a
Entry
Cat. (mol%)
Solvent
Temp. (°C)
Time (h)
Yield (%)
Ee (%)
b
1
5 (10)
17 (20)
17 (50)
18 (20)
THF
THF
DME
THF
0
45
72
87
45
53
45
56
72
85
66
78
66
2
3
4
rt
rt
rt
a
5
: homogeneous La-linked-BINOL; 17: polymer-supported La-linked-BINOL; 18: polymer-supported LaꢀZn-
linked-BINOL.
b
The result was reported in Ref. 5b.
O
O
O
O
O
O
La
M
O
M = H: catalyst 17, M = ZnEt: catalyst 18

8476
achieved (entry 3). With less catalyst loading, a further decrease in the chemical yield was
observed. The low reactivity is due to the property of DME against polystyrene beads. The
polymer was not swollen sufficiently in DME, and so the substrates did not interact well
with the catalyst on the polymer. After many trials, we were pleased to find that a novel
heterobimetallic LaꢀZn-linked-BINOL complex, prepared by adding 1.0 equiv. of Et Zn to
2
La-linked-BINOL, was effective for the present heterogeneous reaction. Polymer-supported
LaꢀZn-linked-BINOL 18 afforded 16 in good yield (72%) and moderate ee (66%) (entry 4).
In fact, the LaꢀZn-linked-BINOL complex also promoted the Michael reaction efficiently in
the homogeneous phase (Table 2). An Et-Zn moiety was used for the first time as a Brønsted
9
base in our heterobimetallic asymmetric catalysis. We believe that this finding opens up the
possibility of developing new types of asymmetric reactions by utilizing the mild and selective
reactivity of Zn species.
Table 2
a
Catalytic asymmetric Michael reaction promoted by homogeneous (R,R)-LaꢀZn-linked-BINOL complex 20
O
O
O
O
O
COOCH3
COOCH3
COOBn
COOBn
COOCH3
COOCH3
COOBn
COOBn
COOBn
COOBn
Time (h)
Yield (%)
Ee (%)
87
92
80
72
99
96
72
86
83
72
70
93
72
83
89
a
Conditions: enone (1 equiv.), malonate (1 equiv.), (R,R)-LaꢀZn-linked-BINOL 10 mol%, THF, 4°C. Ee’s were
determined by HPLC analysis, see Ref. 5b.
In summary, we have synthesized a new polymer-supported linked-BINOL. The advantage
of polymer-supported linked-BINOL over randomly polymer-supported BINOL was confi-
rmed by the catalytic asymmetric Michael reaction: a much higher ee (up to 78% vs 27%) of
the Michael adduct was achieved when polymer-supported linked-BINOL was used. It is
worth noting that moderate to good ees (up to 78%) were achieved for the first time with a
polymer-supported asymmetric catalyst which essentially needs two chiral ligand units. In
addition, a novel LaꢀZn-linked-BINOL complex—a new entry to heterobimetallic asymmetric
complexes—was developed during the investigation to improve the reactivity of the polymer-
supported La-linked-BINOL complex. We believe that the polymer-supported linked-BINOL
can be applied to various useful chiral catalysts with two BINOL units other than La
complexes. However, it is apparent that the present polymer-supported linked-BINOL is still
unsatisfactory, compared with its homogeneous analogue. Moreover, the recovery of the
10
metal complex itself has not yet been fully achieved, although the recovery and reuse of the
ligand was performed easily. Further optimizations of polymer-supported linked-BINOL, in
combination with its application to other Lewis acidic complexes, are now under investiga-
tion by our group.

8477
Acknowledgements
This work was supported by CREST and RFTF. S.M. thanks the JSPS Research Fellowships
for Young Scientists.
References
1
. Review: (a) Shuttleworth, S. J.; Allin, S. M.; Wilson, R. D.; Nasturica, D. Synthesis 2000, 1035. For a recent
representative of polymer-supported asymmetric Lewis acid catalysts, see: (b) Annis, D. A.; Jacobsen, E. N. J.
Am. Chem. Soc. 1999, 121, 4147; (c) Heckel, A.; Seebach, D. Angew. Chem., Int. Ed. 2000, 39, 163. See also, Refs.
6
d,e.
2
3
4
. Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236–1256.
. For asymmetric catalysts with two or more 1,1%-binaphthyl ligands, see: Pu, L. Chem. Rev. 1998, 98, 2405.
. Attempts to immobilize ALB 1, which consists of Al, Li, and two BINOLs, by the standard approach failed.
Polymer-supported ALB, prepared from AlMe (1 equiv.), BuLi (1 equiv.), and polymer-supported-BINOL 19 (2
3
equiv.) catalyzed the Michael reaction of 15 with 14 to give product 16 in only 18% yield and 27% ee, while
homogeneous ALB catalyzes the same reaction to give 16 in 99% ee (Ref. 2). In this case, other species than the
desirable ALB species, CH AlꢀBINOL and lithiumꢀBINOL, might coexist and so yield and ee became low. The
3
homogeneous CH AlꢀBINOL complex prepared from Al(CH ) (1 equiv.) and BINOL (1 equiv.) did not
3
3 3
promote the Michael reaction. On the other hand, the mono-lithium salt of BINOL prepared from BINOL (1
equiv.) and BuLi (1 equiv.) promoted the Michael reaction, but afforded product 16 in only 3% ee. Sasai et al.
reported similar results concerning polymer-supported ALB. They also reported a different strategy to tackle this
Polymer-supported ALB
O
+
1
) AlMe (1.0 mol eq), THF
3
OH
OH
Polymer-supported CH Al-BINOL
3
2) BuLi (1.0 mol eq)
+
Polymer-supported Li-BINOL
2.0 mol eq 19
difficult immobilization, see: Annual Meeting of the Pharmaceutical Society of Japan, March, 2000. Seebach et
al. reported similar phenomena in the Diels–Alder reaction catalyzed by polymer-supported Ti-TADDOLates, in
which the active species seemed to contain two or more TADDOLs. See: Seebach, D.; Marti, R. E.; Hintermann,
T. Helv. Chim. Acta 1996, 79, 1710. Although Sodeoka et al. reported a polymer-supported binuclear m-hydroxo
Pd complex, which promoted the asymmetric Mannich-type reaction in high ee, the active species in the reaction
was monomeric (1:1 complex) according to their precise mechanistic studies. See: Ref. 6c and references cited
therein.
5
6
. (a) The structure of GaꢀLi-linked-BINOL complex 4 was elucidated by X-ray analysis and compared with GaLB
2
: Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 2252. (b) La-linked-BINOL 5: Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506.
. For examples possessing the spacer at the 6-position, see: (a) Bayston, D. J.; Fraser, J. L.; Ashton, M. R.; Baxter,
A. D.; Polywka, M. E. C.; Moses, E. J. Org. Chem. 1998, 63, 3137. (b) Nozaki, K.; Itoi, Y.; Shibahara, F.;
Shirakawa, E.; Ohta, T.; Takaya, H.; Hiyama, T. J. Am. Chem. Soc. 1998, 120, 4051. (c) Fujii, A.; Sodeoka, M.
Tetrahedron Lett. 1999, 40, 8011. (d) Kobayashi, S.; Kusakabe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225. For
other recent examples at the 3,3%-position, see: (e) Yang, X.-W.; Sheng, J.-H.; Da, C.-S.; Wang, H.-S.; Su, W.;
Wang, R.; Chan, A. S. C. J. Org. Chem. 2000, 65, 295. For examples at the 2-position, see: (f) Uozumi, Y.;
Danjo, H.; Hayashi, T. Tetrahedron Lett. 1998, 39, 8303. Pu et al. reported excellent soluble BINOL and/or
BINAP polymers, see: (g) Huang, W.-S.; Hu, Q.-S.; Zheng, X.-F.; Anderson, J.; Pu, L. J. Am. Chem. Soc. 1997,
1
19, 4313. (h) Yu, H.-B.; Hu, Q.-S.; Pu, L. J. Am. Chem. Soc. 2000, 122, 6500 and references cited therein.

8478
7. Nicolaou, K. C.; Winssinger, N.; Vourloumis, D.; Ohshima, T.; Kim, S.; Pfefferkorn, J.; Xu, J.-Y.; Li, T. J. Am.
Chem. Soc. 1998, 120, 10814. The Wittig reaction was performed following the described procedure.
8. General Procedure: After the polymer-supported linked-BINOL (414 mg, ca. 0.1 mmol) was washed with
anhydrous THF (10 mL×2), it was swollen with THF (1.5 mL). La(O-i-Pr) (0.2 M in THF, 0.4 mL, 0.08 mmol)
3
was added and the mixture was shaken gently (300 rpm) at room temperature. After 12 h, THF was removed by
filtration and the resin was washed with THF (5 mL×2). THF (1.4 mL), dibenzyl malonate 15 (100 mL, 0.4 mmol)
and cyclohexenone 14 (40 mL, 0.41 mmol) were added successively and the mixture was shaken at room
temperature. After 72 h, the product in THF was collected by filtration, and the resin was washed with THF (10
mL×2). The combined organic layers were evaporated and the residue was purified by flash column chromatog-
raphy (SiO , hexane/acetone 8/1) to afford 16 (yield 45%, 66% ee). The recovered resin was treated with
2
TsOH·H O, washed with CH Cl , CH OH, and Et O, and then dried in vacuo. The recovered ligand on resin was
2
2
2
3
2
reused at least five times without loss of activity. In the case of LaꢀZn-linked-BINOL, Et Zn (1.0 M in hexane,
2
1
.0 equiv. to La-linked-BINOL complex) was added to La-linked-BINOL resin in THF before adding 15.
9. Heterobimetallic achiral catalysts containing Zn are known. For recent examples, see: Kamitani, J.; Kawahara,
R.; Yashiro, M.; Komiyama, M. Chem. Lett. 1998, 1047 and references cited therein.
1
0. We tried to reuse the recovered resin as catalyst without treating with TsOH·H O. However, the ee decreased to
2
4
0–50% in the second cycle.
.