Hydrogen-bond-mediated enantio- and regioselectivity in a Ru-catalyzed epoxidation reaction

Article abstract of DOI:10.1021/ja107601k

A chiral epoxidation catalyst based on a tricyclic octahydro-1H-4,7- methanoisoindol-1-one scaffold, in which a hydrogen bonding site and the catalytically active ruthenium center are spatially separated, was synthesized. It was shown that epoxidation reactions in such a supramolecular catalyst occur with high enantio- and regioselectivity because the hydrogen bonds expose the substrate to the ruthenium porphyrin complex with a clear conformational preference. The epoxidation of 3-vinylquinolone proceeded in up to 95% ee (71% yield).

Full text of DOI:10.1021/ja107601k

Published on Web 10/26/2010
Hydrogen-Bond-Mediated Enantio- and Regioselectivity in a Ru-Catalyzed
Epoxidation Reaction
Philipp Fackler,† Carola Berthold,† Felix Voss, and Thorsten Bach*
Lehrstuhl fu¨r Organische Chemie I and Catalysis Research Center (CRC), Technische UniVersita¨t Mu¨nchen,
Lichtenbergstr. 4, 85747 Garching, Germany
Received August 31, 2010; E-mail: thorsten.bach@ch.tum.de
proximity of the ligand-bound metal appeared to prevent the substrate
Abstract: A chiral epoxidation catalyst based on a tricyclic
from binding to the δ-lactam in motif II. The two entities are oriented
octahydro-1H-4,7-methanoisoindol-1-one scaffold, in which a
almost parallel at a relatively short distance (ca. 400 pm). Inspired by
hydrogen bonding site and the catalytically active ruthenium
the pioneering work of Deslongchamps and co-workers,9 we inves-
center are spatially separated, was synthesized. It was shown
tigated hydrogen-bonding scaffold III, which can be connected to a
that epoxidation reactions in such a supramolecular catalyst occur
transition metal via an appropriate ligand and provides a reasonable
with high enantio- and regioselectivity because the hydrogen
open space for a substrate in the presence of a ligand-bound metal
bonds expose the substrate to the ruthenium porphyrin complex
because of its V-shaped structure. In addition, it offers the significant
with a clear conformational preference. The epoxidation of
advantage of easy synthetic accessibility (Scheme 1).
3-vinylquinolone proceeded in up to 95% ee (71% yield).
Scheme 1. Preparation of Chiral Ruthenium Porphyrin Complex 4
from Substrate 1
Nature has mastered the use of hydrogen bonds to selectively
process substrates in enzyme-catalyzed reactions. Along with other
noncovalent interactions, hydrogen bonds can serve to display a
substrate for regio- and stereoselective transformations in the active
site of an enzyme. Model systems to mimic this mode of action have
attracted significant scientific interest and continue to be developed.1
With regard to oxidation chemistry, extensive attention has been paid
to the development of mimics of cytochrome P 450,2 an enzyme that
plays a pivotal role in biological oxidation chemistry.3 Through the
combination of a noncovalent binding site with a catalytically oxidative
metal, selective oxidation reactions have become possible.4 While
hydrogen bonds have frequently been used for substrate activation in
organocatalysis,5 the use of a remote hydrogen-bonding motif6,7 for
directing the enantioselective approach of a transition-metal catalyst
has not yet been investigated. We have now found that highly enantio-
and regioselective oxidation reactions are feasible with a ruthenium
porphyrin complex that is fused to a stereodirecting lactam unit, and
we report on our results in preliminary form.
For the synthesis of alkyne 2 (Scheme 1), the Diels-Alder product
of 6,6-dimethylfulvene and maleic anhydride10 was converted into
imide 1. Straightforward separation and functional-group operations
delivered alkyne 2 and its enantiomer ent-2 (not depicted in Scheme
1) in an overall yield of 27%. The absolute configuration of compound
2 was established by a reported procedure.11 Alkyne 2 can be coupled
to a variety of potential ligands by Sonogashira cross-coupling
Figure 1. Hydrogen bonds as directing devices in transition-metal-catalyzed
reactions (M ) metal center; gray shaded region ) ligand).
reactions.12 On the basis of the well-documented oxidation properties
of metalloporphyrins,13,14 the porphyrin-based transition-metal complex
3 (Mes ) 2,4,6-trimethylphenyl),15,16 which does not carry an element
The ability of hydrogen bonds to display the enantiotopic face of a
of chirality for itself, was chosen for the coupling. Chiral ruthenium
porphyrin complexes have previously been employed in enantiose-
lective epoxidations of alkenes.17 In the present case, however, the
element of chirality in catalyst 4 is spatially remote from the ruthenium
center and acts exclusively by hydrogen bonding.
substrate to a transition-metal catalyst was probed in the present study
by combining a hydrogen-bonding motif with a catalytically active
metal center. In such a catalyst, the hydrogen bonds provide the
orientation of a given substrate with respect to a ligand-bound metal
center, as schematically depicted by I in Figure 1. The known 1,5,7-
trimethyl-3-azabicyclo[3.3.1]nonan-2-one scaffold8 (II in Figure 1) was
considered to be less suited for the desired approach because the spatial
The epoxidation of 3-vinylquinolone (5a) was established as a
test reaction and conducted in the presence of ruthenium catalyst 4
(Scheme 2, Table 1). 2,6-Dichloropyridine-N-oxide was employed
as the stoichiometric oxidant.18 With as little as 1 mol % catalyst
† These authors contributed equally.
9
10.1021/ja107601k  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 15911–15913 15911

C O M M U N I C A T I O N S
Scheme 2. Enantioselective Oxidation of Olefin 5a to Epoxide 6a
by Chiral Catalyst 4 and Unselective Oxidation of Olefin 5b (cf.
Table 1 and the Text)
At 50 °C, the reaction went to completion within 4 h (entry 9). Again,
however, the lower enantioselectivity in comparison with entry 4 was
undesirable.
In order to visualize the outcome of the reaction, we conducted
a semiempirical calculation of the presumed intermediate ruthenium
complex21 generated from precursor 4 by decarbonylation and
oxidation (see the Supporting Information). Complexation of
substrate 5a in silico delivered a model for the oxygen transfer in
which the internal carbon atom of the double bond is perfectly
positioned to receive the oxygen atom (Figure 2). On the basis of
the outcome of the configuration determination (see above), the
double bond of substrate 5a must be s-cis oriented, as shown.
Table 1. Enantioselective Epoxidation Reactions Catalyzed by
Complex 4 (cf. Schemes 1 and 2)
entrya substrate c (mM)
solvent
Θ (°C) product yield (%)b ee (%)c
1
2
3
4
5a
5a
5a
5a
5b
5a
5a
5a
5a
20
20
20
20
20
20
20
100
20
CH2Cl2
toluene
PhCF3
benzene
benzene
benzene
benzene
benzene
benzene
25
25
25
25
25
25
25
25
50
6a
6a
6a
6a
6b
6a
ent-6a
6a
6a
54
60
53
71
55
68
71
78
86
85
91
94
95
e5
14
95
92
89
5
6d
7e
8
9
a The reactions were carried out on a 29 µmol scale in the given
solvent at the given temperature Θ and substrate concentration c using
2,6-dichloropyridine-N-oxide (32 µmol) as a stoichiometric oxidant and
1 mol % catalyst 4 (see the Supporting Information). b Yield of isolated
product. c The enantiomeric excess (ee) was determined by chiral HPLC
(Chiralpak AS-H). d The N-methylated derivative of catalyst 4 was used
in this experiment. e The enantiomer ent-4 of catalyst 4 was used in this
experiment.
Figure 2. Coordination of substrate 5a to the dioxoruthenium complex
derived from catalyst 4, visualized by a semiempirical calculation and a
chemical structure.
The validity of the proposed model for hydrogen-bond-directed
epoxidation was further investigated by studying the regioselectivity
of the process. According to Figure 2, coordination by the hydrogen-
bonding site should locate only the vinylic double bond at C3 of a
quinolone in an ideal position for enantioselective epoxidation but not
other double bonds at the heterocyclic scaffold. Reactions at other
possible oxidation sites should consequently be disfavored and occur
less quickly. Diolefin 7 was prepared in order to verify this hypothesis
in an intramolecular competition experiment (Scheme 3). Oxidation
of this substrate in benzene in the presence of an achiral Ru complex
derived from bromide 3 and tert-butylacetylene by Sonogashira cross-
coupling (see the Supporting Information) delivered a mixture of the
two constitutionally isomeric racemic products 8 and 9 in a 62/38 ratio.
The reaction was sluggish, and it was incomplete even after a reaction
time of 40 h. In stark contrast to this observation, epoxidation of
diolefin 7 with catalyst 4a or its enantiomer ent-4a was complete after
only 12 h and delivered product 8 as the major isomer (8/9 ) 91/9,
71% yield). The enantioselectivity was high (88% ee) for the major
product isomer 8; the minor product 9 was formed in amounts that
4, a sufficiently fast epoxidation reaction could be initiated at
ambient temperature (25 °C) in a variety of solvents (entries 1-4).
Even in the relatively polar solvent CH2Cl2, a high enantiomeric
excess (ee) of 85% was recorded (entry 1), and the ee was further
improved in nonpolar solvents in the order toluene < trifluorotoluene
< benzene (entries 2-4). While conversion was complete in all
cases and no side products were detected in the crude reaction
mixture, facile epoxide ring opening/rearrangement may lead to a
loss of material upon purification by column chromatography.
Yields varied between 53 and 71% (entries 1-4) The absolute
configuration of product 6a was determined by the Mosher method19
upon reductive ring opening to a secondary alcohol (see the
Supporting Information).
Experiment to prove the directing ability of the remote hydrogen
bonds were performed with N-methylquinolone (5b) (entry 5) and the
N-methylated analogue of catalyst 4 (entry 6). In both cases, the
substrate-catalyst interaction was restricted to a single hydrogen bond,
and the reactions were expected to be significantly less enantioselective
than entry 4. Indeed, product 6b (entry 5) was obtained with e5% ee
and product 6a (entry 6) with 14% ee. Moreover, the reaction of
substrate 5b (entry 5) was slower than the reaction of substrate 5a.
The olefin was still present in detectable amounts after a reaction time
of 40 h, at which point the transformation 5a f 6a had in all instances
reached completion (entries 1-4). This observation suggests that
hydrogen bonding exerts not only a stereodirecting effect but also an
activating effect. As expected, the enantiomer of catalyst 4, catalyst
ent-4, delivered the same enantioselectivity as catalyst 4 under identical
conditions (entries 4 and 7) but with opposite face selection. An
increase in the substrate concentration20 led to an increase in yield,
but the enantioselectivity dropped slightly (entry 8). The reaction rate
increased when the oxidation was conducted at elevated temperature.
Scheme 3. Regio- and Enantioselective Epoxidation of Diolefin 7
to Product 8 (See the Text for Further Explanation)
9
15912 J. AM. CHEM. SOC. VOL. 132, NO. 45, 2010

C O M M U N I C A T I O N S
ˇ
(c) Smejkal, T.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 3946. (d) Lu,
Y.; Johnstone, T. C.; Arndtsen, B. A. J. Am. Chem. Soc. 2009, 131, 11284,
and references cited therein.
did not allow for its isolation in pure form or for the determination of
its enantiomeric excess.
The last set of experiments demonstrates that the combination
of hydrogen bonding and oxidation catalysis enables both a regio-
and enantioselective approach to chiral epoxides. As in biological
systems, the substrate is presented to the metal in the catalytically
active site by hydrogen bonds. This principle should be applicable
to other enantioselective reactions and may be further exploited in
organic synthesis.
(7) For artificial metalloenzymes that act by tethering a transition metal to a
host protein via hydrogen bonds, see: (a) Letondor, C.; Humbert, N.; Ward,
T. R. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 4683. (b) Pordea, A.; Creus,
M.; Panek, J.; Duboc, C.; Mathis, D.; Novic, M.; Ward, T. R. J. Am. Chem.
Soc. 2008, 130, 8085, and references cited therein.
(8) (a) Bach, T.; Bergmann, H.; Harms, K. Angew. Chem., Int. Ed. 2000, 39,
2302. (b) Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem.
Soc. 2002, 124, 7982. (c) Bauer, A.; Westka¨mper, F.; Grimme, S.; Bach,
T. Nature 2005, 436, 1139. (d) Mu¨ller, C.; Bauer, A.; Bach, T. Angew.
Chem., Int. Ed. 2009, 48, 6640.
(9) (a) Lonergan, G. D.; Riego, J.; Deslongchamps, G. Tetrahedron Lett. 1996,
37, 6109. (b) Lonergan, D. G.; Halse, J.; Deslongchamps, G. Tetrahedron
Lett. 1998, 39, 6865. (c) Lonergan, D. G.; Deslongchamps, G. Tetrahedron
1998, 54, 14041.
Acknowledgment. This project was supported by the Deutsche
Forschungsgemeinschaft (Ba 1372-10), the Universita¨t Bayern e.V.
(Predoctoral Scholarship to C.B.), and the TUM Graduate School.
We thank Wacker-Chemie (Munich) and Umicore (Hanau) for the
donation of chemicals and Dr. S. Huber (TU Mu¨nchen) for
conducting the semiempirical calculations.
(10) Corwin, L. R.; McDaniel, D. M.; Bushby, R. J.; Berson, J. A. J. Am. Chem.
Soc. 1980, 102, 276.
(11) Bauer, A.; Bach, T. Tetrahedron: Asymmetry 2004, 15, 3799.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467. (b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 2006;
pp 203-227. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(13) (a) Groves, J. T.; Myers, R. S. J. Am. Chem. Soc. 1983, 105, 5791. (b)
Mansuy, D.; Battioni, P.; Renaud, J.-P.; Guerin, P. J. Chem. Soc., Chem.
Commun. 1985, 155. (c) Naruta, Y.; Tani, F.; Maruyama, K. Chem. Lett.
1989, 1269. (d) O’Malley, S.; Kodadek, T. J. J. Am. Chem. Soc. 1989,
111, 9116. (e) Collman, J. P.; Zhang, X.; Hembre, R. T.; Brauman, J. I.
J. Am. Chem. Soc. 1990, 112, 5356. (f) Halterman, R. L.; Jan, S.-T. J.
Org. Chem. 1991, 56, 5253. (g) Konishi, K.; Oda, K.-i.; Nishida, K.; Aida,
T.; Inoue, S. J. Am. Chem. Soc. 1992, 114, 1313.
Supporting Information Available: Synthetic procedures for the
preparation of all new compounds; analytical data, including HPLC
traces, proving the ee of 6a and 8; NMR spectra for new compounds,
including 1, 2, 6a, 7, and 8; and further information on the computa-
tional data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) For reviews, see: (a) Che, C.-M.; Huang, J.-S. Chem. Commun. 2009, 3996.
(b) Rose, E.; Andrioletti, B.; Zrig, S.; Quelquejeu-Ethe`ve, M. Chem. Soc.
ReV. 2005, 34, 573. (c) Meunier, B. Chem. ReV. 1992, 92, 1411.
(15) Liddell, P. A.; Gervaldo, M.; Bridgewater, J. W.; Keirstead, A. E.; Lin, S.;
Moore, T. A.; Moore, A. L.; Gust, D. Chem. Mater. 2008, 20, 135.
(16) For functionalization of porphyrins, see: Senge, M. O.; Shaker, Y. M.;
Pintea, M.; Ryppa, C.; Hatscher, S. S.; Ryan, A.; Sergeeva, Y. Eur. J.
Org. Chem. 2010, 237.
References
(1) van Leeuwen, P. W. N. P. Supramolecular Catalysis; Wiley-VCH:
Weinheim, Germany, 2008.
(2) (a) Mansuy, D. Pure Appl. Chem. 1987, 59, 759. (b) Mansuy, D. Pure
Appl. Chem. 1994, 66, 737. (c) Feiters, M. C.; Rowan, A. E.; Nolte, R. J. M.
Chem. Soc. ReV. 2000, 29, 375. (d) Meunier, B. Biomimetic Oxidations
Catalyzed by Transition Metal Complexes; Imperial College Press: London,
2000. (e) Groves, J. T. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 3569.
(3) Ortiz de Montellano, P. R. Cytochrome P450: Structure, Mechanism, and
Biochemistry, 3rd ed.; Kluwer: New York, 2005.
(17) For a review of ruthenium porphyrin complexes, see: Simmoneaux, G.;
Le Maux, P. Coord. Chem. ReV. 2002, 228, 43.
(18) Higuchi, T.; Ohtake, H.; Hirobe, M. Tetrahedron Lett. 1989, 30, 6545.
(19) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b) Hoye,
T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451.
(4) (a) Breslow, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 119, 4535.
(b) Yang, J.; Breslow, R. Angew. Chem., Int. Ed. 2000, 39, 2692. (c) Fang,
Z.; Breslow, R. Org. Lett. 2006, 8, 251. (d) Das, S.; Incarvito, C. D.;
Crabtree, R. H.; Brudvig, G. W. Science 2006, 312, 1941. (e) Das, S.;
Brudvig, G. W.; Crabtree, R. H. J. Am. Chem. Soc. 2008, 130, 1628. (f)
Lee, S. J.; Cho, S.-H.; Mulfort, K. L.; Tiede, D. M.; Hupp, J. T.; Nguyen,
S. T. J. Am. Chem. Soc. 2008, 130, 16828. (g) Hull, J. F.; Sauer, E. L. O.;
Incarvito, C. D.; Faller, J. W.; Brudvig, G. W.; Crabtree, R. H. Inorg. Chem.
2009, 48, 488.
(5) For a review, see: Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 1520.
(6) For recent studies of the directing effect of hydrogen bonds in transition-
metal-catalyzed reactions, see: (a) Jo´nsson, S.; Odille, F. G. J.; Norrby,
P.-O.; Wa¨rnmark, K. Chem. Commun. 2005, 549. (b) Jo´nsson, S.; Odille,
F. G. J.; Norrby, P.-O.; Wa¨rnmark, K. Org. Biomol. Chem. 2006, 4, 1927.
(20) Substrate dimerization is expected to occur in competition with substrate
association to the catalyst. The dimerization constant of substrate 5a at
room temperature in toluene can be estimated as Kdim ≈ 900 M-1 on the
basis of earlier measurements (see: Selig, P.; Bach, T. J. Org. Chem. 2006,
71, 5662–5673). Further association studies have not yet been undertaken.
(21) For the depicted model, a dioxoRu(VI) intermediate was assumed. Recent
studies have suggested oxoRu(V) species as key intermediates in oxygen-
ation and epoxidation processes (see: Wang, C.; Shalyaev, K. V.; Bonchio,
M.; Carofiglio, T.; Groves, J. T. Inorg. Chem. 2006, 45, 4769). In this
case, the second axial substituent would be a ligand but not an oxygen
atom. The conclusions drawn from the model remain the same, however.
JA107601K
9
J. AM. CHEM. SOC. VOL. 132, NO. 45, 2010 15913