Modeling rieske dioxygenases: The first example of iron-catalyzed asymmetric cis-dihydroxylation of olefins [3]

Full text of DOI:10.1021/ja015601k

6722
J. Am. Chem. Soc. 2001, 123, 6722-6723
Modeling Rieske Dioxygenases: The First Example
of Iron-Catalyzed Asymmetric cis-Dihydroxylation
of Olefins
Miquel Costas, Adrianne K. Tipton, Kui Chen,
Du-Hwan Jo, and Lawrence Que, Jr.*
Department of Chemistry and
Center for Metals in Biocatalysis
Figure 1. Tetradentate ligands used in this study.
UniVersity of Minnesota, 207 Pleasant Street SE
Minneapolis, Minnesota 55455
substituents dramatically alters the course of olefin oxidation and
strongly favors the cis-dihydroxylation pathway. These data
indicate that the catalytic activity associated with TPA iron
complexes can be also extended to a new class of complexes.
Encouraged by these findings we synthesized [Fe(BPMCN)-
(CF3SO3)2] (3) and [Fe(6-Me2-BPMCN)(CF3SO3)2] (4), the
analogous complexes with the chiral trans-cyclohexane-1,2-
diamine backbone. The oxidation of trans-2-heptene demonstrates
that 1R,2R-3 can carry out enantioselective olefin oxidation (Table
1); however the ee’s are modest, 29% for cis-diol and 12% for
epoxide. More promising are the results for the same reaction
catalyzed by 1S,2S-4, which affords the cis-diol with an ee of
79% and racemic epoxide. The use of the 1R,2R enantiomer
affords the same ee values but with the opposite configuration
for the major diol product. Therefore, catalytic reactions performed
by 4 emphasize the important role the 6-methyl substituents play.
Not only does the fraction of cis-diol increase significantly, ee’s
for the cis-dihydroxylation of trans-olefins as high as 82% at 30
°C (Table 1) and 88% at 50 °C are obtained, values which
approach those reported for the osmium-catalyzed reactions.8 Not
surprisingly, the major cis-diol products obtained in the oxidation
of trans-2-heptene by 1R,2R-3 and 1R,2R-4 have the same
chirality. Therefore, the configuration of the 1,2-cyclohexanedi-
amine moiety determines the chirality of the product.
ReceiVed January 29, 2001
ReVised Manuscript ReceiVed May 29, 2001
Rieske dioxygenases are bacterial enzymes that catalyze the
O2-dependent enantioselective cis-dihydroxylation of arene and
olefin double bonds.1 These enzymes utilize a mononuclear non-
heme iron center coordinated to a 2-histidine-1-carboxylate facial
triad motif that leaves at least two labile sites available for
catalysis.2,3 To date, the role of the metal center in the enzyme
mechanism is not well established, but the recent report of a
synthetic iron complex that can catalyze cis-dihydroxylation of
olefins with H2O2 demonstrates a key role for the mononuclear
iron active site.4 We have thus embarked on an effort to develop
synthetic catalysts that model this chemistry as a potential “green”
alternative to traditional heavy metal reagents such as OsO4 and
RuO4-, which are effective but less desirable due to their toxicity.
We have extended this chemistry by replacing the tripodal
tetradentate ligand with a linear tetradentate ligand based on a
chiral diamine backbone (Figure 1).5 In this report, we demonstrate
the first enantioselective olefin cis-dihydroxylations catalyzed by
an iron complex.
The use of ligands based on an ethylenediamine backbone is
an established strategy for chiral induction in metal-catalyzed
oxidations.6 We thus first explored the ability of the BPMEN
ligand framework to form iron complexes capable of catalyzing
olefin cis-dihydroxylation. To this end, the complexes [Fe-
(BPMEN)(MeCN)2](ClO4)2 (1)7 and the 6-methyl substituted [Fe-
(6-Me2-BPMEN)(CF3SO3)2] (2) were tested as catalysts. In the
reaction catalyzed by 1, addition via syringe pump of 10
equivalents of H2O2 to a 0.7 mM solution of the complex in
acetonitrile with 0.7 M in cyclooctene afforded cyclooctene oxide
and the cis-diol in respective yields of 75 and 9% relative to H2O2
(Table 1). Thus, 1 is an excellent catalyst for olefin epoxidation.
In sharp contrast, 2 under the same conditions afforded epoxide
and cis-diol in respective yields of 15 and 64%. Thus, as observed
earlier in the Fe(TPA) catalysts,4 the introduction of the 6-methyl
Table 1. Oxidation of Olefins with H2O2 Catalyzed by 1-4a
cat
substrate/eq H2O2
epox(de)b
diol(de)b
eec
1
2
cyclooctene/10
cyclooctene/10
7.5(100)
1.5(100)
5.8(100)
5.4(100)
3.5(100)
5.4(100)
4.5(56)
4.8(26)
1.3
0.9(100)
6.4(94)
0.7(100)
0.3(100) 29(2)
5.8(79)
11.2(89)
7.8(82)
5.5(85)
8.1
9.0
10.1
1R,2R-3 cyclooctene/10
trans-2-heptene/10
1S,2S-4
cyclooctene/10
cyclooctene/20
cis-2-heptene/20
cis-3-heptene/20
1-octene/20
vinylcyclohexane/20
tert-butyl
9(2)
3(2)
60(2)
48(2)
23(2)
2.5
0.5
(1) (a) Gibson, D. T.; Subramanian, V. Microbial Degradation of Organic
Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; pp 181-
251. (b) Wende, P.; Bernhardt, F.-H.; Pfleger, K. Eur. J. Biochem. 1989, 181,
189-197. (c) Lee, K.; Gibson, D. T. J. Bacteriol. 1996, 178, 3353-3356. (d)
Beil, S.; Happe, B.; Timmis, K. N.; Pieper, D. H. Eur. J. Biochem. 1997,
247, 190-199. (e) Lange, C. C.; Wackett, L. P. J. Bacteriol. 1997, 179, 3858-
3865. (f) Wolfe, M. D.; Perales, J. V.; Gibson, D. T.; Lipscomb, J. D. J. Biol.
Chem. 2001, 276, 1945-1953.
acrylate/20
trans-2-heptene/20
trans-2-octene/20
trans-2-heptene/20
2.4(100)
2.3(100)
2.1(100)
7.5(100) 79(2)
7.5(100) 82(5)
8.2(100) 76(2)
1R,2R-4
a Reaction conditions: 0.7 mM catalyst and 700 mM olefin in 3
mL of CH3CN at 30 °C under air to which 10-20 equiv of H2O2 (from
50% aqueous H2O2) in MeCN is added via syringe pump over 30 min.
Results are given as mmol product/mmol of catalyst and are the average
of 2-3 runs. b de ) diastereomeric excess. c ee of the predominant diol
isomer. Determined by GC with a Hewlett-Packard Chiral-Permethy-
lated â-Cyclodextrin column.
(2) Kauppi, B.; Lee, K.; Carredano, E.; Parales, R. E.; Gibson, D. T.;
Eklund, H.; Ramaswamy, S. Structure 1998, 6, 571-586.
(3) (a) Hegg, E. L.; Que, L., Jr. Eur. J. Biochem. 1997, 250, 625-629. (b)
Que, L., Jr. Nat. Struct. Biol. 2000, 7, 182-184.
(4) Chen, K.; Que, L., Jr. Angew. Chem., Int. Ed. 1999, 38, 2227-2229.
(5) Abbreviations used. TPA; tris(2-pyridylmethyl)amine, 6-Me3-TPA; tris-
(6-methyl-2-pyridylmethyl)amine, 6-Me2-BPMCN; N,N′-bis-(6-methyl-2-
pyridylmethyl)-N,N′-dimethyl-1,2-cyclohexanediamine, BPMCN; N,N′-bis-(2-
pyridylmethyl)-N,N′-dimethyl-1,2-cyclohexanediamine, BPMEN; N,N′-bis-(2-
pyridylmethyl)-N,N′-dimethyl-1,2-ethylenediamine, 6-Me2-BPMEN; N,N′-bis-
(6-methyl-2-pyridylmethyl)-N,N′-dimethyl-1,2-ethylenediamine.
(6) (a) Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley-VCH: New York, 1993; pp 159-202. (b) Katsuki, T. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
287-325.
The crystal structures of 3 and 4 may help us understand the
differences in the degree of asymmetric induction. Both 3 and 4
have high-spin iron(II) centers, as indicated by Fe-N bond
(8) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547. (b) Bergstad, K.; Jonsson, S. Y.; Ba¨ckvall, J.-E. J.
Am. Chem. Soc. 1999, 121, 10424-10425. (c) Do¨bler, C.; Mehltretter, G.
M.; Sundermeier, U.; Beller, M. J. Am. Chem. Soc. 2000, 122, 10289-10297.
(7) Chen, K.; Que, L., Jr. Chem. Commun. 1999, 1375-1376.
10.1021/ja015601k CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/13/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 27, 2001 6723
out this novel transformation;10 therefore, efforts to characterize
such reactive intermediates are underway.
Other studies provide further mechanistic insight. In osmium-
catalyzed asymmetric cis-dihydroxylation, lowering the reaction
temperature results in an increase in enantioselectivity.11 Contrary
to this expectation, ee values for the 4-catalyzed oxidation of
trans-2-heptene decrease upon lowering the temperature (e.g.,
40% at 0 °C); however, raising the temperature has the opposite
effect, and ee values reach a maximum of 88% at 50 °C. This
behavior suggests that there may be more than one active species
present in solution capable of effecting asymmetric cis-dihy-
droxylation, perhaps corresponding to intermediates with different
BPMCN conformations. Increasing the temperature would thus
favor in this case population of the more enantioselective isomer.
The relative order in asymmetric induction with respect to the
olefin parallels that observed in the osmium-catalyzed reaction.8a
Accordingly trans di-substituted olefins yield the best results,
followed by terminal olefins with ee values of 23-60% and then
cis di-substituted olefins with ee values around 3-9%. Thus,
similar steric considerations may apply to both reactions,12
suggesting that the active species responsible for the cis-
dihydroxylation in Os and Fe are structurally related. The analogue
to the (cis-dioxo)osmium(VIII) moiety in this iron chemistry has
been proposed to be either an η2-hydroperoxo iron(III) species
or its valence tautomer, a cis-iron(V)-oxo(hydroxo) species.4
In conclusion, we have found the first iron catalyst capable of
performing enantioselective cis-dihydroxylation of olefins. Al-
though the requirement for a large excess of substrate severely
limits its current utility as a synthetic method, it does establish a
precedent for using iron catalysts for such reactions and will
hopefully stimulate the future development of biomimetic iron
catalysts that could replace the more toxic and expensive
traditional oxidants used for cis-dihydroxylation.
Figure 2. ORTEP plots for 3 (top) and 4 (bottom) showing 50% thermal
ellipsoids. Hydrogen atoms are omitted for clarity. Selected bond distances
(Å) for 3: Fe-N1 ) 2.237(2), Fe-N2 ) 2.220(2), Fe-N3 ) 2.151(2),
Fe-N4 ) 2.162(2), Fe-O1 ) 2.131(2), Fe-O4 ) 2.159(2). For 4: Fe-
N1 ) 2.203(4), Fe-N2 ) 2.239(3), Fe-N3 ) 2.274(3), Fe-N4 ) 2.191-
(4), Fe-O1 ) 2.084(3), Fe-O4 ) 2.190(3).
Acknowledgment. This work was supported by the National Institutes
of Health (GM-33162) and Degussa Corporation. M.C. wishes to thank
the Fundacio La Caixa for a fellowship. D.-H.J. is grateful to the Korean
Science and Engineering Foundation (KOSEF) for a postdoctoral fel-
lowship. We thank Dr. Victor Young and Dr. Maren Pink of the
University of Minnesota X-ray Crystallographic Laboratory for determin-
ing the crystal structures of 3 and 4.
distances that range from 2.151 to 2.274 Å. The structure of
1S,2S-4 reveals that the ligand adopts a cis-â topology around
the iron center with the two pyridine rings cis to each other (Figure
2) and the two N-Me groups in a syn conformation. In contrast,
the parent bpmcn ligand in 1R,2R-3 adopts the cis-R topology,
where the two pyridine groups coordinate trans to each other and
the two N-Me groups are oriented anti to each other. Thus, the
difference in topologies may rationalize the different degrees of
asymmetric induction. It should be noted that the cis-R topology
found in 3 is structurally closely related to other C2-symmetric
complexes which make effective asymmetric catalysts.9 However
it appears that the cis-â structure may be superior in inducing
chirality, at least with respect to cis-dihydroxylation. A caveat to
be made at this point is that we cannot ascertain whether these
different conformations are maintained in the structures of the
reactive peroxo species that undoubtedly must be formed to carry
Supporting Information Available: X-ray crystallographic files for
3 and 4 in CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA015601K
(10) Transient FeIII hydroperoxo (Kim, C.; Chen, K.; Kim, J.; Que, L., Jr.
J. Am. Chem. Soc. 1997, 119, 5964-5965) or alkylperoxo species (Zang, Y.;
Kim, J.; Dong, Y.; Wilkinson, E. C.; Appelman, E. H.; Que, L., Jr. J. Am.
Chem. Soc. 1997, 119, 4197-4205) have been characterized upon reaction
t
of the related Fe(TPA) complexes with H2O2 or BuOOH, respectively.
(11) Sharpless, K. B.; Åmberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768-2771.
(9) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York,
1993. (b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1-45. (c) Alt, H. G.; Samuel, E. Chem. Soc. ReV. 1998, 27, 323-
329.
(12) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968-1970.