Iron-catalyzed asymmetric olefin cis-dihydroxylation with 97% enantiomeric excess

Article abstract of DOI:10.1002/anie.200705061

Big cis-ster: The use of an (R,R)-bipyrrolidine backbone with two α-methylpyridine pendant arms affords a tetradentate N₄ ligand that coordinates an iron center with cis-α topology (see picture; Fe purple, C gray, N blue, O red, S yellow, F green). This complex catalyzes the reaction between H₂O₂ and cis-2-heptene to afford a cis-diol product in very high enantioselectivity. (Figure Presented)

Full text of DOI:10.1002/anie.200705061

Angewandte
Chemie
DOI: 10.1002/anie.200705061
Asymmetric Catalysis
Iron-Catalyzed Asymmetric Olefin cis-Dihydroxylation with 97%
Enantiomeric Excess**
Ken Suzuki, Paul D. Oldenburg, and Lawrence Que, Jr.*
The rising number of pharmaceuticals with chiral
centers[1] has heightened the necessity to discover
catalysts that provide asymmetric induction into
the products of their respective reactions.[2] In
addition, stringent constraints on trace impurities
allowed in the marketed pharmaceutical products
make the use of catalysts composed of physiolog-
ically benign metal centers increasingly attractive.
The cis-dihydroxylation of olefins has become an
important chemical reaction in the design of
pharmaceuticals[3] and natural product synthesis[4]
because this reaction is both stereospecific and,
through the use of the Sharpless asymmetric
dihydroxylation (AD) mixes, enantiospecific.[5]
A
potential disadvantage of the Sharpless procedure
is the extraordinary toxicity associated with the
osmium metal in the AD mixes.
In contrast, nature has evolved an important
Figure 1. Optically active ligands (chiral centers indicated by *) and their corre-
class of nonheme iron enzymes, called the Rieske sponding iron complexes (in which the ligand coordinates in either a cis-a or cis-b
topology) capable of promoting asymmetric olefin cis-dihydroxylation.
dioxygenases, that perform a novel, asymmetric
[6]
=
cis-dihydroxylation of arene C C bonds. Such
enzymes can be used as biocatalysts,[7] but they are
effective for only a narrow range of substrates, limiting their
applicability. The catalytically relevant mononuclear iron
center in the Rieske dioxygenases is coordinated by the 2-His-
1-carboxylate facial triad,[8] a common structural motif among
nonheme iron enzymes,[9] which leaves cis-oriented available
coordination sites on the iron octahedron for the activation of
dioxygen. Inspired by these enzymes, researchers have
developed the first examples of biomimetic complexes
involving iron[10] or manganese[11] that catalyze olefin cis-
dihydroxylation using H2O2 as oxidant. Two of these com-
plexes (4 and 5 in Figure 1) incorporate the optically active
trans-1,2-diaminocyclohexane backbone into the ligand
framework and exhibit asymmetric cis-dihydroxylation of
cis-2-heptene with ee values of 29 and 79%.[10c] With the goal
of achieving greater ee values, the trans-1,2-diaminocyclohex-
ane unit was replaced by bipyrrolidine to give the tetradentate
ligands (R,R)-BPBP, (R,R)-BQBP, and (R,R)-6-Me2-BPBP
(Figure 1). Herein, we compare the asymmetric cis-dihydrox-
ylation abilities of three iron complexes and find the 6-Me2-
BPBP complexcapable of achieving up to 97% enantiomeric
excess of the cis-diol product from two cis-disubstituted
olefins. These ee values are comparable to those obtained
with the osmium-based AD mixes.
The ligands (R,R)-BPBP, (R,R)-BQBP, and (R,R)-6-Me2-
BPBP (Figure 1) were obtained by following literature
procedures,[12] and corresponding iron(II) complexes were
obtained by the reactions of equimolar amounts of ligand and
FeII(OTf)2·2NCMe[13] in CH2Cl2 under a N2 atmosphere
(OTf = trifluoromethanesulfonate). Overnight stirring and
subsequent solvent removal gave light brown powders,
which were recrystallized from CH2Cl2/ether to afford pale
yellow crystals, formulated as [FeII(BPBP)(OTf)2] (1), [FeII-
(BQBP)(OTf)(EtOH)](OTf) (2), and [FeII(6-Me2-BPBP)-
(OTf)2] (3). These crystals were suitable for X-ray crystallo-
graphic analysis,[14] and the structures of the three complexes
are shown in Figure 2.[15]
[*] Dr. P. D. Oldenburg, Prof. Dr. L. Que, Jr.
Department of Chemistry and Center for Metals in Biocatalysis
University of Minnesota
207 Pleasant St. SE, Minneapolis, MN 55455 (USA)
Fax: (+1)612-624-7029
E-mail: que@chem.umn.edu
Dr. K. Suzuki
Research & Development Division
Takasago International Corporation
1-4-11 Nishi-yawata, Hiratsuka, Kanagawa 254-0073 (Japan)
[**] This work was supported by the US Department of Energy (DOE DE-
FG02-03ER15455) and the Takasago Corporation. We would like to
acknowledge Dr. Victor G. Young, Jr., and the X-Ray Crystallographic
Laboratory of the University of Minnesota for solving the structures
of complexes 1–3.
In all three structures, the BPBP ligands coordinate the
iron center in a cis-a topology, in which equivalent available
coordination sites (occupied by triflate or ethanol in the solid
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Oxidation of olefins with H2O2 catalyzed by iron complexes.[a]
Epoxide
TON[b]
cis-Diol
% ee[d] Diol/
Epox.
Cat. Substrate
TON[b]
[% de][c]
[% de][c]
1
1
1
2
2
2
3
3
3
3
3
3
3
3
3
trans-2-heptene
1-octene
tert-butyl acrylate
trans-2-heptene
1-octene
5.1(1) [98] 1.1(4) [90]
38(3)
11(1)
1:4.6
2.6(3)
3.0(1)
1.7(1)
0.1(1)
1:1.5
1:30
4:1
0.9(2) [90] 3.6(2) [99]
78(3)
29(4)
23(1) >27:1
97(1)
11(1)
96(1)
Figure 2. ORTEP plots for [FeII(BPBP)(OTf)2] (1), [FeII(BQBP)(OTf)-
0.5(1)
4.6(3)
2.7(4)
9:1
(EtOH)](OTf) (2), and [FeII(6-Me2-BPBP)(OTf)2] (3) showing 50%
tert-butyl acrylate <0.1
probability ellipsoids. Hydrogen atoms and noncoordinating solvent
trans-2-heptene
cis-2-heptene
trans-4-octene
cyclooctene
1-octene
0.2(1) [67] 5.2(2) [99]
0.6(1) [95] 3.4(1) [95]
0.3(1) [80] 3.9(2) [93]
0.7(1) [94] 4.0(5)
26:1
5.7:1
13:1
5.7:1
64:1
À
molecules have been omitted for clarity. Average Fe N bond lengths
[Š]: for 1, 2.197; for 2, 2.230; and for 3, 2.234. C gray, O red, S yellow,
F green.
0.1(1)
<0.1
<0.1
6.4(3)
6.5(2)
4.9(1)
76(1)
styrene
allyl chloride
15(2) >65:1
70(1) >49:1
68(1) >40:1
78(4) >75:1
state) are trans to the amine donors derived from the
tert-butyl acrylate <0.1
ethyl trans-croto- <0.1
nate
dimethyl fuma-
rate
4.0(1)
7.5(5) [99]
À
bipyrrolidine backbone. The Fe Npyrrolidine bond lengths for
À
all three complexes are similar, but the average Fe Npyridine/
bond length increases from 2.192 Š for 1 to 2.272 and
quinoline
3
<0.1
5.3(5) [99]
23(2) >53:1
2.264 Š for 2 and 3, respectively, as a result of a-substitution.
These distances are indicative of high-spin iron centers.
The structures of 1–3 can also be compared with those of
two other iron complexes with chiral diamine ligands that
promote asymmetric olefin cis-dihydroxylation with H2O2,
namely a-[FeII{(1R,2R)-BPMCN}(OTf)2] (4) and [FeII-
{(1S,2S)-6-Me2-BPMCN}(OTf)2] (5).[10c] Interestingly, all
ligands in the BPBP series adopt a cis-a topology upon
complexformation. In contrast, the BPMCN ligand forms
both cis-a and cis-b iron(II) complexes,[10b] whereas 6-Me2-
BPMCN adopts a cis-b ligand topology in 5.[10c] It is clear from
an examination of the structures in Figure 2 that the cis-a
topology in 1–3 is determined by the constraints of the
bipyrrolidine moiety.
4
trans-2-heptene
5.4 [99]
1.2 [99]
0.7
0.3 [99]
3.8 [99]
4.1
29
79
60
23
1:18
5[e] trans-2-heptene
5[e] 1-octene
3.2:1
5.9:1
17:1
5[e] tert-butyl acrylate
0.3
5.1
[a] Reaction conditions: A 70 mm solution of H2O2 (10 equiv) in CH3CN
was delivered by syringe pump over a period of 20 min to a degassed and
stirred solution of catalyst (0.7 mm) and substrate (0.35m) at ambient
temperature in air for 1 and 2 and under Ar atmosphere for 3. See the
Supporting Information for further details. [b] Catalyst turnover number,
TON=mmol product/mmol catalyst with standard deviation values
reported in parentheses. [c] Percent of diastereomeric excess (de).
[d] Percent of enantiomeric excess (ee) of the predominant diol isomer.
[e] Results are normalized to 10 equiv H2O2.
Table 1 compares the abilities of the five complexes as
catalysts for the asymmetric cis-dihydroxylation of olefins
with H2O2 as oxidant and reveals the outstanding perfor-
mance of 3. This catalyst is quite cis-diol-selective, affording a
diol/epoxide ratio of about 6 for cyclooctene oxidation and as
much as 60 or greater for the oxidation of 1-octene, styrene,
and crotonate. As can be seen in the trend for the 1–3 series
and illustrated previously for the BPMCN complexes,[10b,c] the
high selectivity for cis-diol undoubtedly arises from the
introduction of the a-methyl substituents on the two pyridine
ligands. As the steric bulk at that position increases, the
catalyst goes from being epoxide-selective, as in the case of 1,
to being cis-diol-selective in 2, and even more cis-diol-
selective in 3.
The asymmetric induction results obtained in 3-catalyzed
reactions are to date the best for an iron catalyst (Table 1) and
rival those obtained with the AD mixes.[5] The highest
ee values were obtained for electron-rich, trans-disubstituted
olefins, such as trans-2-heptene and trans-4-octene (97 and
96% ee, respectively). These values diminished with the
replacement of alkyl groups on the trans-disubstituted olefins
with electron-withdrawing groups, for example, ethyl trans-
crotonate (78%) and dimethyl fumarate (23%). Terminal
olefins, however, offered moderate to good ee values, for
example, 1-octene (76%), allyl chloride (70%), and tert-butyl
acrylate (68%).
The asymmetric induction provided by 3 is significantly
greater than for 5 (Table 1).[10c] The improvement most likely
arises from two factors: the more rigid bipyrrolidine back-
bone of 3 relative to the 1,2-diaminocyclohexane backbone of
5 and the cis-a ligand topology of 3 in contrast to the cis-b
topology of 5. From a comparison of 1–3, it is also clear that
the size of the pyridine a-substituent is important, as a
systematic increase in ee value is observed on going from H in
2
À
1 to an sp -hybridized C H group in 2 to a CH3 group in 3.
Complex 3 is thus the most effective iron-based asym-
metric olefin cis-dihydroxylation catalyst reported to date.
These results demonstrate for the first time that a synthetic
nonheme iron catalyst can approach the high enantioselec-
tivity found in cis-dihydroxylating enzymatic systems. How-
ever, more work needs to be done in improving reaction
conditions to overcome the requirement for limiting oxidant
in these reactions.
Experimental Section
1, 2, and 3: Under a nitrogen atmosphere, a solution of (R,R)-BPBP,
(R,R)-BQBP, or (R,R)-6-Me2-BPBP (96.7 mg, 0.3 mmol) in dichloro-
methane (2 mL) was added to a suspension of Fe(OTf)2·2NCMe[13]
(130.8 mg, 0.3 mmol) in dichloromethane (2 mL) at room temper-
ature with stirring. The mixture was stirred overnight and the solvent
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Chemie
removed in vacuo to give a light brown powder, which was recrystal-
lized from dichloromethane and ether to afford pale yellow crystals in
72% yield for 1, 60% yield for 2, and 75% yield for 3, which were
suitable for X-ray crystallographic analysis. Characterization data for
1: Anal. calcd (found) [%] for C22H26F6FeN4O6S2·H2O: C 38.05
(38.10), H 4.06 (4.15), N 8.07 (8.04), S, 9.23 (9.26). Characterization
data for 2: Anal. calcd (found) [%] for C30H30F6FeN4O6S2·H2O:
C 45.35 (45.41), H 4.06 (4.02), N 7.05 (6.95), S 8.07 (7.96). Charac-
terization data for 3: Anal. calcd (found) [%] for
C24H30F6FeN4O6S2·0.5CH2Cl2: C 39.40 (39.83), H 4.18 (4.38), N 7.50
(7.54), S 8.59 (8.64).
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Received: November 1, 2007
Published online: January 31, 2008
[13] K. S. Hagen, Inorg. Chem. 2000, 39, 5867.
Keywords: asymmetric catalysis · dihydroxylation · iron ·
N ligands · oxidation
.
[14] Single-crystal structure and refinement data for 1:
C22H26F6FeN4O6S2, Mw = 676.44, monoclinic, space group P21,
a = 9.184(1), b = 28.648(3), c = 10.614(1) Š, b = 90.950(2)8, V=
2792.1(5) Š3, Z = 4, 1calcd = 1.609 MgmÀ3, MoKa radiation (l =
0.71073 Š, m = 0.774 mmÀ1), T= 173(2) K. A total of 12444
(Rint = 0.0435) independent reflections with 2q < 27.508 were
collected. The resulting parameters were refined to converge at
R1 = 0.0438 (I > 2q) for 739 parameters on 12444 independent
reflections (wR2 = 0.0971). Max./min. residual electron density
0.626/À0.487 eŠÀ3; GOF = 1.026. Single-crystal structure and
refinement data for 2: C33H38Cl2F6FeN4O7S2, Mw = 907.54,
monoclinic, space group P21, a = 9.497(1), b = 12.343(2), c =
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16.643(2) Š, b = 92.008(2)8, V= 1949.7(4) Š3, Z = 2, 1calcd
1.546 MgmÀ3, MoKa radiation (l = 0.71073 Š, m = 0.711 mmÀ1),
T= 173(2) K. total of 7722 (Rint = 0.0346) independent
=
A
reflections with 2q < 27.518 were collected. The resulting param-
eters were refined to converge at R1 = 0.0457 (I > 2q) for 510
parameters on 7722 independent reflections (wR2 = 0.1200).
Max./min. residual electron density 0.750/À0.599 eŠÀ3; GOF =
1.034. Single-crystal structure and refinement data for 3:
C25H32Cl2F6FeN4O6S2, Mw = 789.42, orthorhombic, space group
P212121, a = 12.618(1), b = 14.662(2), c = 17.678(2) Š, V=
3270.6(6) Š3, Z = 4, 1calcd = 1.603 MgmÀ3, MoKa radiation (l =
0.71073 Š, m = 0.832 mmÀ1), T= 173(2) K.
A total of 7510
(Rint = 0.0338) independent reflections with 2q < 27.528 were
collected. The resulting parameters were refined to converge at
R1 = 0.0297 (I > 2q) for 417 parameters on 7510 independent
reflections (wR2 = 0.0597). Max./min. residual electron density
0.426/À0.358 eŠÀ3; GOF = 1.061. Further experimental details
are provided in the Supporting Information. CCDC-657096 (1),
CCDC-657097 (2), and CCDC-657098 (3) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] While this paper was being reviewed, the crystal structure of
[FeII{(S,S)-BPBP}(NCCH3)2](SbF6)2, a complexclosely related
to 1, was reported (M. S. Chen, M. C. White, Science 2007, 318,
783). In this work, the authors reported that this complexreacted
with H2O2 in the presence of acetic acid to generate an oxidant
[10] a) K. Chen, M. Costas, J. Kim, A. K. Tipton, L. Que, Jr., J. Am.
Chem. Soc. 2002, 124, 3026; b) M. Costas, L. Que, Jr., Angew.
Chem. 2002, 114, 2283; Angew. Chem. Int. Ed. 2002, 41, 2179;
c) M. Costas, A. K. Tipton, K. Chen, D.-H. Jo, L. Que, Jr., J. Am.
Chem. Soc. 2001, 123, 6722; d) M. Klopstra, G. Roelfes, R. Hage,
R. M. Kellogg, B. L. Feringa, Eur. J. Inorg. Chem. 2004, 846;
e) P. D. Oldenburg, A. A. Shteinman, L. Que, Jr., J. Am. Chem.
À
capable of hydroxylation of tertiary C H bonds with predictable
selectivity, which is quite a remarkable achievement.
Angew. Chem. Int. Ed. 2008, 47, 1887 –1889
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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