Asymmetric dihydroxylation of olefins using cinchona alkaloids on highly ordered inorganic supports

Article abstract of DOI:10.1021/ol010096h

(matrix presented) A modified cinchona alkaloid was grafted onto a mesoporous molecular sieve and onto amorphous silica gel. These heterogeneous ligands were employed in the asymmetric dihydroxylation of olefins under Sharpless conditions. The supported ligands yielded equivalent enantioselectivity compared with that of the homogeneous system and were easily recovered and reused.

Full text of DOI:10.1021/ol010096h

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2325-2328
Asymmetric Dihydroxylation of Olefins
Using Cinchona Alkaloids on Highly
Ordered Inorganic Supports
Irina Motorina and Cathleen M. Crudden*
Department of Chemistry, UniVersity of New Brunswick, P.O. Box 45222,
Fredericton, New Brunswick E3B 6E2, Canada
cruddenc@unb.ca
Received May 14, 2001
ABSTRACT
A modified cinchona alkaloid was grafted onto a mesoporous molecular sieve and onto amorphous silica gel. These heterogeneous ligands
were employed in the asymmetric dihydroxylation of olefins under Sharpless conditions. The supported ligands yielded equivalent
enantioselectivity compared with that of the homogeneous system and were easily recovered and reused.
Despite the variety of transformations that can be effected
with transition metal complexes modified by chiral ligands,
the use of these complexes in organic synthesis remains
relatively limited. This is primarily because of the limited
scope of many catalytic reactions and the sacrificial way the
chiral ligands are treated. Since chiral ligands are often more
expensive than the metals themselves, this can be a deterrent
to the large scale application of asymmetric catalysis.
The asymmetric dihydroxylation (AD) of alkenes is a rare
example of a reaction that has a wide and well-defined
scope.1 The generality of the AD reaction has prompted
several research groups to investigate the preparation of
supported versions of the cinchona alkaloid based chiral
ligands2 including the most generally effective ligand,
DHQD2PHAL (1, Figure 1). Alkaloids such as 1 and its
derivatives have been incorporated into various insoluble3,4
or soluble organic polymers5,6 and onto inorganic supports
such as silica gel.7 Cinchona alkaloids immobilized on
soluble poly(ethylene glycol) polymers described by Janda5
(1) Jacobsen, E. N.; Marko, I.; Mungall, S.; Schroeder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968. Sharpless, K. B.; Amberg, W.;
Beller, M.; Chen, H.; Hartung, J.; Kawanami, Yl; Lubben, D.; Manoury,
E.; Ogino, Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56, 4585. Kolb,
H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94,
2483.
(2) For reviews, see: Bolm, C.; Gerlach, A. Eur. J. Org. Chem. 1956,
21, 1. Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217.
(3) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 3003. Pini,
D.; Petri, A.; Nardi, A.; Rosini, C.; Salvadori, P. Tetrahedron Lett. 1991,
32, 5175. Lohray, B. B.; Thomas, A.; Chittari, P.; Ahuja, J. R.; Dhal, P. K.
Tetrahedron Lett. 1992, 33, 5453. Pini, D.; Petri, A.; Salvadori, P.
Tetrahedron: Asymmetry 1993, 4, 2351. Pini, D.; Petri, A.; Salvadori, P.
Tetrahedron 1994, 50, 11321. Lohray, B. B.; Nandanan, E.; Bhushan, V.
Tetrahedron Lett. 1994, 35, 6559. Petri, A.; Pini, D.; Salvadori, P.
Tetrahedron Lett. 1995, 36, 1549. Song, C. E.; Roh, E. J.; Lee, S.-G.; Kim,
I. O. Tetrahedron: Asymmetry 1995, 6, 2687. Petri, A.; Pini, D.; Rapaccini,
S.; Salvadori, P. Chirality 1995, 7, 580. Herrmann, W. A.; Kratzer, R. M.;
Blumel, J.; Friedrich, H. B.; Fischer, R, W.; Apperley, D. C.; Mink, J.;
Berkesi, O. J. Mol. Catal. A: Chem. 1997, 120, 197.
(4) Salvadori, P.; Pini, D.; Petri, A. J. Am. Chem. Soc. 1997, 119, 6929.
Petri, A.; Pini, D.; Rapaccini, S.; Salvadori, P. Chirality 1999, 11, 745.
(5) Han, H.; Janda, K. D. J. Am. Chem. Soc. 1996, 118, 7632. Han, H.;
Janda, K. D. Tetrahedron Lett. 1997, 38, 1527. Han, H.; Janda, K. D. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1731. Toy, P. H.; Janda, K. D. Acc. Chem.
Res. 2000, 33, 546.
(6) Bolm, C.; Maischak, A.; Gerlach, A. Chem. Commun. 1997, 2357.
Bolm, C.; Gerlach, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 741.
(7) Lohray, B. B.; Nandanan, E.; Bhushan, V. Tetrahedron: Asymmetry
1996, 7, 2805. Song, C. E.; Yang, J. W.; Ha, H.-J. Tetrahedron: Asymmetry
1997, 8, 841.
Figure 1. DHQD2PHAL.
10.1021/ol010096h CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/26/2001

Scheme 1. Synthesis of Modified Cinchona Alkaloid 2
and by Bolm6 provide by far the best mimicry of the
homogeneous system.
are studying a newly developed class of silicates called
mesoporous molecular sieves13 for this purpose. Unlike
regular, amorphous silica gel, mesoporous molecular sieves
have well-defined nanometer-sized pores, with a very narrow
pore size distribution. The exact size of the pores and even
their shape can be tailored depending on how they are
prepared.14 We have employed hexagonal mesoporous mo-
lecular sieves of the SBA-15 type15 as supports for hetero-
geneous cinchona alkaloids. We find that these supported
ligands give extremely close agreement with the solution
phase dihydroxylation reaction in terms of rate and enantio-
selectivity.
Two different grafting techniques were examined for the
preparation of the supported alkaloids. Both routes begin with
compound 2, which was prepared as shown in Scheme 1.
Dichlorophthalazine (3) was reacted with dihydroquinidine
(4) under mild conditions to give the product of monosub-
stitution, 5. Treatment of 5 with quinidine (6) at 50 °C gave
compound 2.
Insoluble supports would be preferable for several rea-
sons: they are readily recovered; they have potential
applications in flow processes; and they do not require extra
solvent for precipitation. Insoluble organic polymers can be
effective supports as shown by Salvadori,4 but the polymer
needs to be carefully tuned and caution taken to ensure that
the chiral ligand is chemically bound to, and not merely
occluded in, the organic support.8 Inorganic supports such
as amorphous silica gel have been generally less effective
in the asymmetric dihydroxylation reaction.7 This reaction
is particularly challenging for supported ligands because the
reaction must be run in highly polar solvent (1:1 t-BuOH/
H2O) in order to obtain the highest enantioselectivities.1 Thus
significant tuning of either the polymer3,4 or the ligand9 has
been necessary to obtain high yields and enantioselectivities
in this medium. In many of the successful cases, a long
spacer is used to distance the chiral ligand from the
amorphous polymer.6
Our initial attempts at grafting this material onto the
surface followed the commonly employed method of adding
a functionalized thiol across the alkene under radical condi-
tions. Thus the molecular sieve was pretreated with 3-mer-
captopropyl trimethoxysilane and then reacted with 2 in the
presence of AIBN. Although this method did provide an
active catalyst for the AD reaction, the mesoporous structure
An alternative approach to distancing the chiral ligand
from the amorphous support is to use a support that puts the
catalyst in an ordered microenvironment.10 We11 and others12
(8) Sherrington et al. have shown that certain methods reported for the
synthesis of supported alkaloids do not lead to chemically bound alkaloid
but instead give alkaloid occluded in the insoluble polymer: Canali, L.;
Song, C. E.; Sherrington, D. C. Tetrahedron: Asymmetry 1998, 9, 1029.
Nandanan, E.; Sudalai, A.; Ravindranathan, T. Tetrahedron Lett. 1997, 38,
2577. Song, C. E.; Yang, J. W.; Ha. H. J.; Lee, S.-G. Tetrahedron:
Asymmetry 1996, 7, 645.
(9) Compare refs 7a and b where an alkaloid supported at one point
gives marginal enantioselectivities, whereas immobilizing the ligand at two
positions gives significantly better results.
(10) A highly ordered microenvironment can be achieved using polymers
composed entirely of the chiral ligand. For this innovative approach, see:
Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757 and references therein.
(11) Crudden, C. M.; Allen, D.; Mikoluk, M.; Sun, J. Chem. Commun.
in press.
(12) Brunel, D. Micro. Meso. Mater. 1999, 27, 329 and references therein.
Johnson, B. F. G.; Raynor, S. A.; Shephard, D. S.; Maschmeyer, T.; Thomas,
J. M.; Sankar, G.; Bromley, S.; Oldroyd, R.; Gladden, L.; Mantle, M. D.
Chem. Commun. 1999, 1167. Catalytic applications: Ying, J. Y.; Mehnert,
C. P.; Wong, M. S. Angew. Chem., Int. Ed. 1999, 38, 56.
(13) Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartulli, J. C.; Beck,
J. S. Nature 1992, 359, 710. Zhao, D.; Feng, J.; Huo, Q.; Melosh, N.;
Fredrickson, G. H.; Chmelka, B. F.; Stucky, G. D. Science 1998, 279, 548.
Zhao, D.; Huo, Q.; Feng, J.; Chmelka, B. F.; Stucky, G. D. J. Am. Chem.
Soc. 1998, 120, 6024.
(14) Melosh, N. A.; Davidson, P.; Chmelka, B. F. J. Am. Chem. Soc.
2000, 122, 823. Feng, P.; Bu, X.; Stucky, G. D.; Pine, D. J. J. Am. Chem.
Soc. 2000, 122, 994. Melosh, N. A.; Lipic, P.; Bates, F. S.; Wudl, F.; Stucky,
G. D.; Fredrickson, G. H.; Chmelka, B. F. Macromolecules 1999, 32, 4332.
Lu, Y.; Ganguli, R.; Drewien, C. A.; Anderson, M. T.; Brinker, C. J.; Gong,
W.; Guo, Y.; Soyez, H.; Dunn, B.; Huang, M. H.; Zink, J. I. Nature 1997,
389, 364, Bruinsma, P. J.; Kim, A. Y.; Liu, J.; Baskaran, S. Chem. Mater.
1997, 9, 2507. Lin, H. P.; Cheng, Y.-R.; Mou, C.-Y. Chem. Mater. 1998,
10, 3772.
(15) Hereafter referred to as SBA, prepared using the method described
in ref 13 (Stucky et al.).
2326
Org. Lett., Vol. 3, No. 15, 2001

of the silicate was not retained. Hydrosilylation16 proved to
be a better option. Treatment of 2 with HSi(OEt)3 in the
presence of H2PtCl6 (eq 1) provided 7, which was grafted
onto hexagonally ordered SBA17 at room temperature by
condensation of the siloxane with surface hydroxyl groups
to give 8-SBA (eq 2).
of 7 with silica gel yielded 8-SiO2 with a loading of 0.09
mmol/g. The catalytic activity and the enantioselectivity of
this material were compared with the homogeneous system
and the ordered ligand 8-SBA.19 The results for the dihy-
droxylation of methyl cinnamate are compiled in Table 1.
Table 1. Activity of Heterogeneous and Homogeneous Ligands
in the Asymmetric Dihydroxylation of Methyl Cinnamatea
ligand
loading
conversion
DHQD2PHAL
8-SBA
8-SiO2
0.1%
0.1%
0.1%
44%
54%
46%
a Reaction conditions: 3 mmol of K3Fe(CN)6 and 3 mmol of K2CO3
were dissolved in 5 mL of H2O, and the inorganic-supported ligand was
added (0.01 mmol). K2OsO4‚2H2O (0.01 mmol) and 5 mL of t-BuOH were
added. After cooling to 0 °C in an ice bath, the substrate (1 mmol) was
added with stirring in one portion. The mixture was stirred for 14 h at 0 °C
and then allowed to warm to room temperature for ca. 4 h. An extractive
workup was performed, and the crude material was analyzed by 1H NMR.
As shown in Figure 2, after grafting the alkaloid via a
silicon tether, the silicate is still highly ordered, with an
average pore size18 of 72 Å, decreased slightly from 78 Å
in the unfunctionalized SBA. The surface area was deter-
mined to be 761 m2/g, also decreased from the original 975
m2/g. These decreases are consistent with the low loading
of the catalyst, which is 0.13 mmol/g as determined by
elemental analysis.
To compare the reactivities of the various catalysts, the
dihydroxylation of methyl cinnamate was performed at 0.1%
loading of both ligand and Os (usual conditions call for 2%
ligand and 1% Os)1. As can be seen from Table 1, the
amorphous silica gel supported dihydroxylation ligand 8-SiO2
gives approximately the same yield as the homogeneous
system, while 8-SBA was marginally superior.
The enantioselectivity of the AD was also assessed using
various ligands and substrates, at a 1% loading. The results
are presented in Table 2. As can be seen, the cinchona
alkaloid supported on mesoporous, ordered SBA-type silica
gives virtually perfect agreement with the homogeneous
catalyst in terms of enantioselectivity. This is quite remark-
able considering how closely the chiral ligand is tethered to
the support and the fact that optimization of the ligand was
not attempted. All of these results were obtained using a 1:1
ratio of ligand to Os, which is more efficient than the
homogeneous procedure that employs an excess of ligand.
The cinchona alkaloid supported on amorphous silica gel
gives lower enantioselectivies for all the substrates we have
tried, although the differences between it and the ordered
SBA support are not large.
Figure 2. TEM of supported cinchona alkaloid 8-SBA.
Finally, we assessed the reusability of the supported ligand.
The insoluble ligand can be recovered and reused several
times. The enantioselectivity remains within 3% of the initial
run, and yields are (5% (isolated). Although the ligand is
recovered unchanged from the reaction and can be used
multiple times, the Os is not retained on the surface and must
be added prior to reuse of the ligand.20
To evaluate the effect of the ordered structure, compound
7 was grafted onto regular amorphous silica gel with an
average pore size of 100 Å. The main differences between
this support and SBA are that the pores are not uniform in
size or shape, there is no long range order, and the surface
area is approximately half that of SBA (436 m2/g). Reaction
Although we cannot rule out the possibility that a small
amount of the alkaloid is removed from the support and is
(16) Pirkle, W. H.; Pochapsky, T. C.; Mahler, G. S.; Corey, D. E.; Reno,
D. S.; Alessi, D. M. J. Org. Chem. 1986, 51, 4991 and ref 11.
(17) See Supporting Information for the precise method used to synthesize
the molecular sieve.
(18) The pore size is determined from analysis of the TEM and analysis
of nitrogen adsorption isotherms.
(19) Note that for the heterogeneous ligands, the amount of catalyst used
(1:1 with the ligand) is normalized based on the % loading of the alkaloid
on the support.
Org. Lett., Vol. 3, No. 15, 2001
2327

unlikely if the active catalyst was composed of a small
percentage of leached alkaloid. The reusability of the
supported ligand is also good evidence that it is the
heterogeneous ligand that is responsible for the catalysis.
In conclusion, we have demonstrated that mesoporous
molecular sieves are valuable supports for the preparation
of recoverable cinchona alkaloids. Supporting the alkaloids
on structured silicates of the SBA-15 type gave enantio-
selectivities identical or nearly identical to those observed
in the homogeneous case. No optimization of the tether or
support was carried out. Supporting the same ligand on
amorphous silica gel gave slightly lower enantioselectivities.
Table 2. Enantioselectivity of the AD Reaction Using
Supported and Homogeneous Ligandsa
isolated
yield
enantio-
selectivity (ee)b
ligand
DHQD2PHAL
8-SBA
DHQD2PHAL
8-SBA
R
Ph
Ph
99%
97%
d
>99%c
>99%
97%c
98%
94%
99%
98%
96%
96%f
CO2Et
CO2Me
CO2Me
67%
72%
83%
98%
85%
95%
73%
85%
8-SiO2
Acknowledgment. We thank Dr. Robert Young, Merck
& Company, the Natural Sciences and Engineering Research
Council of Canada, the Canada Foundation for Innovation,
and the Atlantic Canadian Opportunities Agency for generous
funding of this research.
DHQD2PHAL-PEG-OMee Me
8-SBA
8-SiO2
DHQD2PHAL
8-SBA
8-SiO2
Me
Me
H
H
H
92%
87%
Supporting Information Available: 1H NMR spectra
used to determine the enantiomeric excess of the product
diols and experimental details for the preparation of the
mesoporous materials. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Experimental conditions are as listed in Table 1, with the exception
that flash chromatography was performed after the extraction and that 1%
catalyst and 1% ligand loading were employed in the heterogeneous cases
(2% ligand in homogeneous). b Enantioselectivity determined by preparation
of bis Mosher’s esters (see Supporting Information) and confirmed by optical
rotation of the unreacted diols. c Sharpless, K. B.; Amberg, W.; Beller, M.;
Chen, H.; Hartung, J.; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino,
Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56, 4585. d Yield not provided
in original reference. e Han, H.; Janda, K. D. Tetrahedron Lett. 1997, 38,
1527. f Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579.
OL010096H
(20) The best method for recovery of Os involves the preparation of
microencapsulated Os: Kobayashi, S.; Endo, M.; Nagayama, S. J. Am.
Chem. Soc. 1999, 121, 11229. Note that although this method is extremely
valuable for the recovery of osmium, it involves the use of a homogeneous
chiral ligand.
(21) Note that the isolated yields (unoptimized) are sometimes lower
for the supported alkaloid than those reported for the homogeneous ligand
(see Table 2). This is a less accurate comparison because some of the diol
may be lost upon chromatography.
responsible for the catalysis, this is unlikely for two reasons.
When the supported ligand is compared with the homoge-
neous DHQD2PHAL ligand at very low loadings (0.1%,
Table 1), an increased yield is obtained.21 This would be
2328
Org. Lett., Vol. 3, No. 15, 2001