Planar-chiral pyridine N-oxides, a new family of asymmetric catalysts: Exploiting an η5-C5Ar5 ligand to achieve high enantioselectivity [12]

Full text of DOI:10.1021/ja003573k

J. Am. Chem. Soc. 2001, 123, 353-354
353
Planar-Chiral Pyridine N-Oxides, a New Family of
Asymmetric Catalysts: Exploiting an η5-C5Ar5
Ligand to Achieve High Enantioselectivity1
Beata Tao, Michael M.-C. Lo, and Gregory C. Fu*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed October 3, 2000
We have recently described a number of applications of planar-
chiral heterocycles in asymmetric catalysis, both as enantiose-
lective nucleophilic catalysts (e.g., 1)2 and as chiral ligands for
transition metals (e.g., 2).3 In each case, nitrogen or phosphorus
atoms served as nucleophilic/ligating sites.
3a and 3b as our initial targets. As illustrated in Figure 1, these
complexes are easily accessible.6 Thus, one-pot treatment of FeCl2
with C5R5Li, followed by pyrindinyl anion, affords ferrocenes
4a and 4b. Oxidation with dimethyldioxirane then furnishes the
desired pyridine N-oxides 3a and 3b, the enantiomers of which
are readily resolved by chiral HPLC. We have determined the
absolute configuration of (-)-3b by X-ray crystallography (Figure
2).
As a test for our design, we chose to examine the effectiveness
of this new family of planar-chiral catalysts in the desymmetriza-
tion of meso epoxides with chlorosilanes,7 a reaction first studied
by Denmark with a chiral phosphoramide catalyst.8 We discovered
that, although (-)-3a efficiently catalyzes the ring-opening of cis-
stilbene oxide by SiCl4, the product is formed in very modest
enantiomeric excess (11% ee; Table 1, entry 1). Use of more steri-
cally hindered (-)-3b provides somewhat higher selectivity (25%
ee at room temperature; entry 2), which can be further enhanced
by lowering the reaction temperature to -78 °C (60% ee; entry
3).9
Examination of the crystal structure of 3b furnishes a clue to
the origin of the moderate stereoselection that we observe:
because the oxygen, not the nitrogen, of the catalyst is the
nucleophilic site, the Fe(η5-C5Ph5) group may not be sufficiently
large to provide an effective chiral environment (Figure 2).
Inspection of the structure further suggests that substitution in
the meta position might be the best approach to extending the
reach of the metal fragment. Fortunately, a method recently
reported by Miura and Dyker provides ready access to the
necessary cyclopentadiene derivative (eq 2).10
Catalysts in which oxygen is the nucleophilic site effect a
number of useful transformations.4 For example, pyridine N-oxides
catalyze the rearrangement of thiones, as well as the allylation
of aldehydes.5 In view of the utility of planar-chiral pyridine de-
rivatives such as 1, it occurred to us that the corresponding pyr-
idine N-oxides (3) might also prove to be effective asymmetric
catalysts. In this report, we describe the synthesis and structural
characterization of several planar-chiral pyridine N-oxides, and
we apply this new family of complexes to the catalytic enanti-
oselective desymmetrization of meso epoxides (eq 1).
In contrast to catalysts in which the pyridine nitrogen serves
as the nucleophilic site (e.g., 1), we anticipated that, for pyridine
N-oxide catalysts, an electron-donating 4-dialkylamino group
should not be critical for reactivity. We therefore chose complexes
(1) Dedicated to Professor K. Barry Sharpless on the occasion of his 60th
birthday.
(2) Kinetic resolution of alcohols: Bellemin-Laponnaz, S.; Tweddell, J.;
Ruble, J. C.; Breitling, F. M.; Fu, G. C. Chem. Commun. 2000, 1009-1010,
and references therein. (b) Ring-opening/dynamic kinetic resolution of
azlactones: Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154-
3155. (c) Rearrangement of O-acylated azlactones: Ruble, J. C.; Fu, G. C. J.
Am. Chem. Soc. 1998, 120, 11532-11533. (d) Addition of alcohols to
ketenes: Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
2637-2638.
(3) Amino alcohol-catalyzed addition of organozinc reagents to alde-
hydes: Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444-445.
(b) Rhodium-catalyzed hydrogenation of dehydroamino acids: Qiao, S.; Fu,
G. C. J. Org. Chem. 1998, 63, 4168-4169. (c) Copper-catalyzed cyclopro-
panation of olefins: Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
10270-10271.
(4) For some examples of catalytic enantioselective processes, see: (a)
Phosphoramide-catalyzed aldol reactions: Denmark, S. E.; Stavenger, R. A.
Acc. Chem. Res. 2000, 33, 432-440. (b) Overview of several X3PdO-based
reactions: Buono, G.; Chiodi, O.; Wills, M. Synlett 1999, 377-388. (c)
Formamide-catalyzed allenylations of aldehydes: Iseki, K.; Kuroki, Y.;
Kobayashi, Y. Tetrahedron: Asymmetry 1998, 9, 2889-2894. (d) Phosphora-
mide-catalyzed allylations of aldehydes: Denmark, S. E.; Coe, D. M.; Pratt,
N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161-6163.
(5) We are aware of only four reports of asymmetric catalysis using a chiral
pyridine N-oxide: (a) Rearrangement of thiones: Diana, M. B.; Marchetti,
M.; Melloni, G. Tetrahedron: Asymmetry 1995, 6, 1175-1179. (b) Allylation
of aldehydes: Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-i. J. Am.
Chem. Soc. 1998, 120, 6419-6420. (c) Reduction of ketones and addition of
ZnEt2 to aldehydes: Derdau, V.; Lachat, S.; Hupe, E.; Ko¨nig, W. A.; Dix, I.;
Jones, P. G. Eur. J. Inorg. Chem. 1999, 1001-1007. (d) Saito, M.; Nakajima,
M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 2000, 1851-1852.
Planar-chiral pyridine N-oxide 3c can then be synthesized
according to the general route described above (Figure 1; X-ray
structure: Figure 3). It is evident from the crystal structures that,
compared to the parent η5-C5Ph5 ligand of 3b, the meta-substituted
(6) These reactions have not been optimized.
(7) For a review of catalytic asymmetric ring-openings of epoxides, see:
Jacobsen, E. N.; Wu, M. H. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Chapter
35.
(8) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. J. Org.
Chem. 1998, 63, 2428-2429. (b) After our work was completed, Buono
reported an effective phosphonamide catalyst: Brunel, J. M.; Legrannd, O.;
Reymond, S.; Buono, G. Angew. Chem., Int. Ed. 2000, 39, 2554-2557.
(9) We have found that, in the presence of (i-Pr)2NEt, we obtain higher
enantioselectivities and more reproducible results. We believe that, in the
absence of (i-Pr)2NEt, HCl that is produced through adventitious hydrolysis
of SiCl4 reacts directly with the epoxide to form the chlorohydrin in a
nonstereoselective process. In a control reaction, we have determined that no
ring-opening occurs upon treatment of an epoxide with SiCl4 and (i-Pr)2NEt
(no pyridine N-oxide) at room temperature.
(10) Miura, M.; Pivsa-Art, S.; Dyker, G.; Heiermann, J.; Satoh, T.; Nomura,
M. Chem. Commun. 1998, 1889-1890.
10.1021/ja003573k CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/15/2000

354 J. Am. Chem. Soc., Vol. 123, No. 2, 2001
Communications to the Editor
Table 2. Catalytic Enantioselective Desymmetrization of Meso
Epoxides
entry
R
yield (%)
ee (%)
Figure 1. Synthesis of planar-chiral pyridine N-oxides.
1
2
3
4
5
6
Ph
88
97
94
93
84
91
94
91
93
98
94
50
4-FC6H4
4-CH3C6H4
4-CF3C6H4
2-naphthyl
CH2OBn
All data are the average of two runs.
Under these conditions (5% catalyst 3c), a number of epoxides
are desymmetrized in very good yield and high stereoselection
(Table 2).12 The enantiomeric excess of the chlorohydrin is
modestly sensitive to electronic effects (entries 1-4), with the
highest selectivity observed in the case of an electron-poor
aromatic group (entry 4). The ring-opening proceeds in good ee
with a naphthyl substituent (entry 5), but modest ee with an alkyl
group (entry 6). At the end of these reactions, catalyst 3c can be
recovered nearly quantitatively (>90%).13
Figure 2. X-ray crystal structure of (-)-3b‚MeOH (for clarity, the MeOH
is omitted).
Table 1. Desymmetrization of cis-Stilbene Oxide Catalyzed by
Planar-Chiral Pyridine N-Oxides
In summary, we have designed and synthesized a new family
of chiral catalysts, planar-chiral pyridine N-oxides, and we have
applied them to the catalytic, highly enantioselective ring-opening
of meso epoxides. In the course of these studies, we have provided
the first demonstration that appropriate incorporation of substit-
uents on a C5Ar5 ring can serve as a powerful means for tuning
catalyst enantioselectivity. In view of the widespread use of
cyclopentadienylmetal complexes, particularly ferrocene deriva-
tives,14 in asymmetric catalysis, we anticipate that this strategy
will prove to be broadly applicable. Ongoing studies are directed
at providing support for this hypothesis and at developing
additional applications of planar-chiral pyridine N-oxides as
enantioselective catalysts.
entry
catalyst
temperature
ee (%)
1
2
3
4
5
3a
3b
3b
3c
3c
rt
rt
11
25
60
68
92
-78 °C
rt
-78 °C
Acknowledgment. We thank Dr. Jack Liang for furnishing C5Ar5H
(Ar ) 3,5-Me2C6H3) and the Seeberger and Danheiser groups for sharing
chemicals and equipment. Support has been provided by Bristol-Myers
Squibb, Merck, the National Institutes of Health (National Institute of
General Medical Sciences, R01-GM57034), Novartis, and Pfizer.
Supporting Information Available: Experimental procedures, com-
pound characterization data, and X-ray crystallographic data (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Figure 3. X-ray crystal structure of (+)-3c‚TsOH (for clarity, the TsOH
is omitted).
JA003573K
(12) General experimental (Table 2, entry 1): A solution of catalyst (+)-
3c (11.6 mg, 0.015 mmol) in CH2Cl2 (1.0 mL), cis-stilbene oxide (58.9 mg,
0.30 mmol) in CH2Cl2 (1.0 mL), (i-Pr)2NEt (60 µL, 0.34 mmol), and CH2Cl2
(4.0 mL) were added in turn to a Schlenk tube. The Schlenk tube was closed
and then cooled to -80 °C. SiCl4 (1.0 M solution in CH2Cl2; 0.36 mL, 0.36
mmol) was added by syringe to the reaction mixture over 5-10 min. After
24 h at ∼-85 °C, the reaction was quenched by the addition of a solution of
saturated KF/1M KH2PO4 (1:1). The resulting mixture was extracted with
EtOAc, and the organic layer was dried (Na2SO4), filtered, and concentrated.
Purification by silica gel chromatography (10% Et2O in hexanes) afforded
60.8 mg (87%) of (S,S)-2-chloro-1,2-diphenylethan-1-ol. GC analysis (Chiral-
dex G-TA) showed 94% ee.
(13) We have begun to explore the mechanism of this catalytic enantiose-
lective ring-opening process. Some of our preliminary observations include:
(1) a positive nonlinear correlation between the ee of the catalyst and the ee
of the chlorohydrin; (2) a rate that is zero-order in SiCl4 and zero-order in
(i-Pr)2NEt; (3) 1H and 29Si NMR evidence (-70 °C) for an interaction between
SiCl4 and the catalyst, but not between SiCl4 and either the epoxide or (i-
Pr)2NEt.
η5-C5Ar5 ligand of 3c more effectively occupies the space beneath
the plane of the pyridine N-oxide (Figure 2 vs Figure 3).
Gratifyingly, this increased steric demand does indeed lead to
increased enantioselectivity in the catalytic desymmetrization of
meso epoxides with SiCl4. Thus, whereas the parent complex (3b)
furnishes 25% ee in the room-temperature ring-opening of cis-
stilbene oxide (Table 1, entry 2), the more bulky derivative (3c)
affords 68% enantiomeric excess (entry 4). Simply by decreasing
the reaction temperature to -78 °C, we can now obtain the
chlorohydrin with excellent stereoselection (92%, entry 5).
A lower catalyst loading can be employed without compromis-
ing enantioselectivity (Table 2, entry 1 vs Table 1, entry 5).11
(11) We have found that, even with a catalyst loading as low as 1%, we
can obtain chlorohydrin in >90% ee for the reaction of cis-stilbene oxide.
With chiral phosphonamides, Buono has reported a significant decrease in
enantioselectivity at catalyst loadings less than 10% (ref 8b).
(14) Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH: New York, 1995.
(b) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377-
2407.