Catalytic Asymmetric Cyclopropanation Using Bridged Dirhodium Tetraprolinates on Solid Support

Article abstract of DOI:10.1021/ol025758x

(Matrix Presented) Dirhodium tetraprolinates in highly cross-linked macroporous polystyrene resins are very effective catalysts for asymmetric cyclopropanation using methyl aryldiazoaceates.

Full text of DOI:10.1021/ol025758x

ORGANIC
LETTERS
2002
Vol. 4, No. 12
1989-1992
Catalytic Asymmetric Cyclopropanation
Using Bridged Dirhodium
Tetraprolinates on Solid Support
Tadamichi Nagashima and Huw M. L. Davies*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received February 21, 2002 (Revised Manuscript Received May 9, 2002)
ABSTRACT
Dirhodium tetraprolinates in highly cross-linked macroporous polystyrene resins are very effective catalysts for asymmetric cyclopropanation
using methyl aryldiazoaceates.
Polymer-supported reagents and catalysts are useful tools in
synthesis because, in principle, they can be readily separated
from the product and then recycled.1 In recent years there
has been considerable interest in the development of solid-
supported catalysts for asymmetric cyclopropanation.2 The
vast majority of these are copper-based catalysts, although
therehasbeenonereportonchiraldirhodiumtetracarboxamidates.2g
Major challenges with these systems include obtaining yields
comparable to those of the homogeneous reactions and
avoiding degradation in enantioselectivity with recycled
catalyst. Considering that the dirhodium tetracarboxylates are
the most generally useful catalysts for carbenoid transforma-
tions,3 the development of solid-supported chiral catalysts
of this class would be particularly worthwhile. The successful
accomplishment of this goal using an unusual immobilization
strategy is the basis of this paper.
Various chiral dirhodium carboxylates have been devel-
oped as homogeneous catalysts for carbenoid transforma-
tions.3 N-(Arylsulfonyl)prolinate dirhodium complexes such
as Rh2(S-TBSP)4 (1) and Rh2(S-DOSP)4 (2) are especially
effective for the asymmetric cyclopropanations of aryl- and
styryldiazoacetates.4 Recently, a conformationally restricted
catalyst, Rh2(S-biTISP)2 (3), was developed,5 which was
found to give high ee’s in cyclopropanation reactions and
in some C-H insertion reactions.4a Because of the broad
utility of these catalysts and the high price of rhodium, the
successful immobilization of these catalysts would be very
desirable.
(1) For reviews, see: (a) Clapham, B.; Reger, T. S.; Janda, K. D.
Tetrahedron 2001, 57, 4637. (b) Sherrington, D. C. J. Polym. Sci. Part A:
Polym. Chem. 2001, 39, 2364. (c) Flynn, D. L.; Devraj, R. V.; Parlow, J.
J. In Solid-Phase Organic Synthesis; Burgess, K., Ed.; Wiley-Interscience:
New York, 2000; pp 149-194.
(2) (a) Burguete, M. I.; Fraile, J. M.; Verdugo, E. G.; Luis, S. V.;
Mayoral, J. A. Org. Lett. 2000, 2, 3905. (b) Burguete, M. I.; Fraile, J. M.;
Garcia, J. I.; Garcia-Verdugo, E.; Herrerias, C. I.; Luis, S. V.; Mayoral, J.
A. J. Org. Chem. 2001, 66, 8893. (c) Glos, M.; Reiser, O. Org. Lett. 2000,
2, 2045. (d) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo,
M. J. Org. Chem. 2001, 113, 2587. (e) Orlandi, S.; Mandoli, A.; Pini, D.;
Salvadori, P. Angew. Chem. 2001, 113, 2587. (f) Rechavi, D.; Lemaire, M.
Org. Lett. 2001, 3, 2493. (g) Doyle, M. P.; Eismont, M. Y.; Bergbreiter, D.
E.; Gray, H. N. J. Org. Chem. 1992, 57, 6103.
Immobilization of a dirhodium tetracarboxylate has been
achieved by using a ligand exchange between Rh2(OAc)4
(3) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New
York, 1998.
(4) (a) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. (b) Davies, H.
M. L. Aldrichimica Acta 1997, 30, 105.
(5) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287.
10.1021/ol025758x CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/22/2002

Scheme 2
and a solid-supported dicarboxylic acid, resulting in an active
hydroformylation catalyst.4a,6 Such an approach for a chiral
catalyst would be problematic because it would alter the
chiral environment around the catalyst. To immobilize chiral
dirhodium teracarboxylate catalysts without resorting to
ligand modification, we decided to study the use of polymer-
supported pyridines (Scheme 1). Axial coordination of
Scheme 1
Rh2(S-biTISP)2 was immobilized on the resin 7. The loading
of the rhodium complex was estimated by the increase of
the weight of the resin. The loading of Rh2(S-TBSP)4 in 7
was 0.18 mmol/g, and that of Rh2(S-biTISP)2 was 0.17 mmol/
g.
A standard cyclopropanation was used to evaluate the
catalytic activity of “7-Rh2(S-TBSP)4” and “7-Rh2(S-
biTISP)2”. Dropwise addition of methyl phenyldiazoacetate
to a solution of styrene (2 equiv) with the resin (0.5 mol %
of dirhodium catalyst) in toluene as solvent resulted in
efficient cyclopropanation. The rate of the reaction was found
to depend on the rate of stirring, and so all reactions were
run with approximately the same stirring rate. The end-point
of the reaction was judged by the cessation of the evolution
of nitrogen gas. The resin was rinsed with toluene (five times)
and dried before reuse in the next cycle.
dirhodium tetracarboxylates to basic sites is well-known.7
Thus the dirhodium complex could coordinate to the
polymer-supported pyridine to form 4, and the other rhodium
center in 4 could react with diazo compounds to form the
corresponding carbenoid 5.
The cyclopropanation with 7-Rh2(S-TBSP)4 gave the
cyclopropanation product in good yield (92-89%) and
diastereoselectivity (>94% de); however, the enantiomeric
excess (ee) dropped steadily from 82% to 70% over four
cycles (Table 1). The high diastereoselectivity is character-
istic of aryldiazoacetate cyclopropanations.9 A similar drop
in enantioselectivity has been observed in solution-phase
cyclopropanation with Rh2(S-DOSP)4 when using low cata-
lyst loading (<0.1 mol %).10 This indicates that the prolinate
catalysts are undergoing slow degradation under the reaction
conditions. This would also explain why there is a drop in
enantioselectivity using recycled catalyst. In contrast, 7-Rh2-
(S-biTISP)2 appears to be a very robust catalyst as the yield
(87-91%) and the enantioselectivity (85-88% ee) remains
steady over 15 cycles. The only change is the reaction time,
which increases by a factor of 6 over the 15 cycles. As is
ArgoPore resin was chosen for this study because it is a
highly cross-linked macroporous polystyrene and can be used
with a variety of solvents. To prevent possible steric
interaction between the ligands in the dirhodium complex
and the polymer backbone, a benzyl group was used as a
spacer between the pyridinyl group and the polystyrene. The
hydroxy group in ArgoPore-Wang resin (hydroxyl loading
) 0.65 mmol/g)8 was converted to the bromide 6 with PPh3
and CBr4, and 6 was reacted with the sodium alkoxide of
4-pyridinylmethanol to give 7 (Scheme 2). To immobilize
Rh2(S-TBSP)4, the pyridine resin 7 was gently stirred with
Rh2(S-TBSP)4 in dichloromethane. The color of the resin
changed from pale brown to purple, indicating the coordina-
tion of the pyridine to the rhodium metal. After the filtration
of the solvent, the resin was washed with dichloromethane
(nine times), and was dried under vacuum. In a similar way,
(6) Nowotny, M.; Maschmeyer, T.; Johnson, B. F. G.; Lahuerta, P.;
Thomas, J. M.; Davies, J. E. Angew. Chem., Int. Ed. 2001, 40, 955.
(7) Cotton, F. A.; Walton, R. A. Multiple Bonds between Metal Atoms,
2nd ed.; Clarendon Press: Oxford, U.K., 1993.
(9) (a) Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett.
1996, 37, 4133. (b) Doyle, M. P.; Zhou, Q.-L.; Charnsangavej, C.; Longoria,
M. A.; McKervey, M. A.; Garcia, C. F. Tetrahedron Lett. 1996, 37, 4129.
(10) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897.
(8) Available from Argonaut Technologies (www.argotech.com).
1990
Org. Lett., Vol. 4, No. 12, 2002

products were consistently obtained (entries 2-5). The
styryldiazoacetate (entry 6) was also effective, but the
reaction was slower than that of the aryldiazoacetates.
One of the attractive features of recoverable catalysts is
that they can be useful for the preparation of compound
libraries. To determine further this potential, a series of
cyclopropanations was carried out using recycled catalyst
(Table 3). The yields and the ee’s are comparable to those
Table 1. Asymmetric Cyclopropanation of Styrene Using a
Polymer Supported Catalyst
7-Rh2 (S-TBSP)4
7-Rh2 (S-biTISP)2
Table 3. Asymmetric Cyclopropanation of Styrenes with
Various Aryl- and Styryldiazoacetates Using Recycled Catalyst
time
yield
(%)
ee
time
yield
(%)
ee
cycle
(min)
(%)
cycle
(min)
(%)
1
2
3
4
10
17
14
14
92
91
89
89
82
78
73
70
1
2
3
4
10
15
18
23
26
36
60
92
91
91
90
90
87
89
85
86
87
87
88
88
well-established with the corresponding homogeneous cata-
lysts,9,10 7-Rh2(S-TBSP)4 gave the (S,S)-cyclopropane,
whereas 7-Rh2(S-biTISP)2 gave the (R,R)-cyclopropane.
The observation that the bridged prolinate catalyst Rh2-
(S-biTISP)2 is much more effective at maintaining high
enantioselectivity compared to the unbridged catalyst may
have a major impact on the future design of robust chiral
dirhodium catalysts. To further evaluate the catalytic activity
of 7-Rh2(S-biTISP)2, the reactions of several diazo com-
pounds using lower equivalents of the catalyst were exam-
ined. As shown in Table 2, the reaction with methyl
obtained with the fresh catalyst (see Table 2). With 0.5 mol
% of the catalyst, all of the reactions were completed within
30 min. Furthermore, from the 1H NMR spectra of the crude
mixture, there was no cross-contamination between succes-
sive cyclopropanations. This would indicate that the product
is efficiently washed from the polymer support between
cycles even though the catalyst is retained.
Table 2. Asymmetric Cyclopropanation of Styrene with Aryl-
and Vinyldiazoacetates
In some regards, the success of this chemistry is surprising
because donor groups such as pyridine tend to deactivate
dirhodium tetracarboxylates.7 Therefore, control experiments
were carried out to determine why 7-Rh2(S-biTISP)2 was
able to function as such an efficient catalyst. To study the
effect of pyridine, both Rh2(S-TBSP)4 and Rh2(S-biTISP)2
were mixed with 1.5 equiv of 4-alkyl-pyridine 8 (Scheme
3). The cyclopropanation of styrene with phenyldiazoacetate
using these catalysts was conducted in toluene. With Rh2-
(S-TBSP)4 coordinated to 8 the reaction was complete in 10
min but the yield was only 43%. Rh2(S-biTISP)2 coordinated
to 8 showed very little catalytic activity. Even after 12 h the
yield of cyclopropanation was only 18%, and many unidenti-
1
fied side products were observed by H NMR of the crude
mixture. In both cases, however, the enantioselectivity
remained high. These results suggest that coordination of
pyridine to Rh2(S-biTISP)2 greatly decreases its catalytic
activity, and that in the 7-Rh2(S-biTISP)2 catalyst, the
“active” catalyst is not Rh2(S-biTISP)2 coordinated to the
pyridine.
phenyldiazoacetate (entry 1) was similarly achieved (88%
yield, 88% ee) with 0.04 mol % of 7-Rh2(S-biTISP)2, but
the reaction took 3 h to reach completion. With the other
aryldiazoacetates (entries 2-5), when 0.1 mol % of the
catalyst was used, high yields and enantioselectivities of the
To further determine the importance of the pyridine group
a second control experiment was undertaken. The analogous
Org. Lett., Vol. 4, No. 12, 2002
1991

Scheme 3
Table 4. Asymmetric Cyclopropanation of Styrene Using a
Polymer-Supported Catalyst Lacking a Pyridine Linker
9-Rh2 (S-TBSP)4
9-Rh2 (S-biTISP)2
time
yield
(%)
ee
time
yield
(%)
ee
cycle
(min)
(%)
cycle
(min)
(%)
1
3
5
21
19
15
92
91
90
85
83
81
1
3
5
24
37
57
85
84
83
82
84
84
phenyl-substituted resin 9 was prepared, and it also could
immobilize Rh2(S-TBSP)4 and Rh2(S-biTISP)2 (Scheme 4).
dirhodium complex. The immobilization of these catalysts
is most likely due to a microencapsulation effect,11 although
further studies are needed to determine all the controlling
factors. The high molecular weight catalysts remain trapped
on the highly cross-linked polymer and can be recycled 15
times, while the products are readily removed by solvent
washing.
Scheme 4
In summary, dirhodium tetraprolinates in highly cross-
linked macroporous polystyrene resins are very effective
catalysts in asymmetric cyclopropanation. Future studies are
needed to determine the key structural features that govern
this simple immobilization of the catalyst and if the approach
is applicable to other catalyst systems. A further significant
observation from this study is that the bridged prolinate
catalyst Rh2(S-biTISP)2 is much more effective at maintain-
ing high enantioselectivity than the unbridged catalyst. This
will have important ramifications for the design of dirhodium
catalysts capable of very high turnover numbers.
The resin 9 was treated with either Rh2(S-TBSP)4 or Rh2-
(S-biTISP)2 in toluene, and the resin was then washed with
toluene (five times). The resulting green-colored resins
contained 0.11 mmol/g of Rh2(S-TBSP)4 and 0.07 mmol/g
of Rh2(S-biTISP)2, respectively.
Acknowledgment. This work was supported by the
National Institutes of Health (CA85641) and the National
Science Foundation (CHE 0092490). Partial support of this
work by a Johnson & Johnson Focused Giving Grant is also
gratefully acknowledged. We thank Dr. David Hangauer for
helpful suggestions regarding the solid support.
With the phenyl-substituted resin catalysts, five cycles of
cyclopropanation of styrene with methyl phenyldiazoacetate
were tried. As shown in Table 4, the reaction with the phenyl
resin 9-Rh2(S-TBSP)4 gave the cyclopropanation product
in good yields (90-92%); however, the enantioselectivity
dropped slightly from 85% to 81% ee. The reaction with
the phenyl-resin 9-Rh2(S-biTISP)2 maintained the same level
of enantioselectivity over four cycles; however, longer
reaction times were required to complete the reaction.
Supporting Information Available: Experimental data
for the synthesis of the solid supported catalysts and for the
asymmetric cyclopropanation. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL025758X
(11) (a) Kobayashi, S.; Endo, M.; Nagayama, S. Org. Lett. 2001, 3, 2649.
(b) Kobayashi, S.; Endo, M.; Nagayama, S. J. Am. Chem. Soc. 1999, 121,
11229. (c) Nagayama, S.; Endo, M.; Kobayashi, S. J. Org. Chem. 1998,
63, 6094. (d) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1998, 120,
2985.
These control experiments suggest that the actual catalyst
in the pyridine-resin 7 is not the pyridine-coordinated
1992
Org. Lett., Vol. 4, No. 12, 2002