Site- and Enantioselective C?H Oxygenation Catalyzed by a Chiral Manganese Porphyrin Complex with a Remote Binding Site

Article abstract of DOI:10.1002/anie.201712340

A chiral manganese porphyrin complex with a two-point hydrogen-bonding site was prepared and probed in catalytic C?H oxygenation reactions of 3,4-dihydroquinolones. The desired oxygenation occurred with perfect site selectivity at the C4 methylene group and with high enantioselectivity in favor of the respective 4S-configured secondary alcohols (12 examples, 29–97 % conversion, 19–68 % yield, 87–99 % ee). Mechanistic studies support the hypothesis that the reaction proceeds through a rate- and selectivity-determining attack of the reactive manganese oxo complex at the hydrogen-bound substrate and an oxygen transfer by a rebound mechanism.

Full text of DOI:10.1002/anie.201712340

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Accepted Article
Title: Site- and Enantioselective C-H Oxygenation Catalyzed by a
Chiral Manganese Porphyrin Complex with a Remote Binding
Site
Authors: Finn Burg, Maxime Gicquel, Stefan Breitenlechner, Alexander
Pöthig, and Thorsten Bach
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712340
Angew. Chem. 10.1002/ange.201712340
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10.1002/anie.201712340
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Site- and Enantioselective C–H Oxygenation Catalyzed by a Chiral
Manganese Porphyrin Complex with a Remote Binding Site
Finn Burg,# Maxime Gicquel,# Stefan Breitenlechner, Alexander Pöthig and Thorsten Bach*
Abstract: A chiral manganese porphyrin complex with a two-point
hydrogen bonding site was prepared and probed in catalytic CH
oxygenation reactions of 3,4-dihydroquinolones. The desired
oxygenation occurred with perfect site-selectivity at the C4
methylene group and with high enantioselectivity in favor of the
respective (4S)-configured secondary alcohols (12 examples, 29-
97% conversion, 19-67% yield, 87-99% ee). Mechanistic studies
support a rate and selectivity determining attack of the reactive
manganese oxo complex at the hydrogen-bound substrate and an
oxygen transfer by a rebound mechanism.
and their limited availability due to loss of material in the
ruthenium incorporation step made us consider other metal
complexes for selective oxygenation reactions.
Inspired by the work of Groves and co-workers on C-H activation
reactions by manganese porphyrin complexes[11] we strived for
the synthesis of a porphyrin complex[12] that would be attached
to an octahydro-1H-4,7-methanoisoindol-1-one hydrogen
bonding motif. Gratifyingly, we found the Sonogashira cross-
coupling reaction of alkyne 1[10a] with zinc porphyrin complex 2 to
proceed smoothly and without extensive hydro-de-bromination
(Scheme 1). Upon acidic (TFA = trifluoroacetic acid) removal[13]
of the zinc atom the enantiomerically pure porphyrin 3 was
obtained and fully characterized. The insertion of manganese
into the porphyrin core was performed as previously described[14]
The direct oxygenation of methylene compounds to secondary
alcohols[1] poses a significant challenge to the imagination and
creativity of synthetic organic chemists. Several selectivity
issues need to be addressed: Further oxidation of the alcohol
should be avoided (chemoselectivity), the reaction should occur
at a specific site (site-selectivity), and most importantly, a single
enantiomer should be formed (enantioselectivity). Along these
lines, there have been numerous efforts to find enantioselective
oxygenation methods in which a transition metal catalyst
mediates the oxygenation of prochiral methylene compounds by
a stoichiometric oxidant. Common transition metals employed in
these catalysts include ruthenium,[2,3] iron,[4,5] and manganese[6,7]
and the chirality is typically provided by a chiral ligand. Some
prominent examples for benzylic oxygenation reactions include
the use of a chiral ruthenium porphyrin complex (up to 76% ee
at 36% conversion), of a chiral iron porphyrin complex (up to
72% ee at 47% yield based on oxidant), and a chiral manganese
salen complex (up to 87% ee at 13% yield). It is evident from
these data that there is a need to develop new methods to
process a prochiral methylene compound in a more selective
fashion.
and compound
4
showed spectroscopic and analytical
properties that matched data of known manganese porphyrin
complexes.[15]
A potential way to achieve this goal is the development of
catalysts that exhibit a distinct binding mode for a given
substrate[8,9] and thus display superior site- and enantio-
selectivity in the oxygenation protocol. In previous work we have
developed chiral ruthenium porphyrin complexes which display a
chiral hydrogen bonding entity and which proved to be efficient
catalysts for enantioselective epoxidation and enantiotopos-
selective oxygenation reactions.[10] However, their propensity to
promote the further oxidation of secondary alcohols to ketones
Scheme 1. Preparation of MnIII catalyst 4 by Sonogashira cross-coupling at
ZnII porphyrin 2 and subsequent metal-metal exchange.
Oxygenation reactions were attempted with 3,3-disubstituted
3,4-dihydroquinolones which represent a class of heterocyclic
compounds with significant biological activity.[16] We envisioned
that a late-stage modification of this compound class would lead
to secondary alcohols which have yet not been available in
enantiomerically pure form.[17] Iodosobenzene was used as the
stoichiometric oxidant in dichloromethane solution (Table 1).
Substrate 5a[16b] showed a remarkable enantioselectivity even at
ambient temperature (entry 1). A temperature decrease led to
an improved enantioselectivity for product 6a but induced
simultaneously the formation of ketone 7a (entries 2,3). A good
compromise in terms of reactivity vs. selectivity was found at a
temperature of 0 °C at which the ratio of oxidant and catalyst
was varied (entries 4-7). While there was little improvement in
yield, the experiment with slightly superstoichiometric quantities
of oxidant (entry 7) revealed that the enantioselectivity remained
high, even at low ketone formation. A substrate concentration of
10 mM (entry 9) was identified as optimal within the probed
concentration range (entries 8-10).
[*]
M.Sc. Finn Burg,# Dr. Maxime Gicquel,# Dr. Stefan Breitenlechner,
Dr. Alexander Pöthig and Prof. Dr. Thorsten Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching, Germany
Fax: +49 (0)89 289 13315
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
[#]
F.B. and M.G. contributed equally to this work.
Supporting information and the ORICD identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org./10.1002/....
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10.1002/anie.201712340
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Table 1. Optimization of the Mn-Catalyzed Enantioselective Oxygenation of
Substrate 5a.
position C7 (5j-5l) exhibited
a
reduced reactivity and
conversions were lower (29-57%) than for the more electron rich
substrates. Even for less reactive substrates, the fidelity of the
catalyst remained high. Compounds 5i and 5k turned out to be
processed with a comparably low enantioselectivity (87% ee)
while the 7-chloro- and the 7-trifluoromethylsulfonyloxy-
substituted quinolones 5j and 5l gave the respective products
with 94% and 97% ee.
T
5a
6a
7a
ee[d]
entry
c (mM)[a]
mol%[b]
eq.[c]
(°C)
(%)
(%)
(%)
(%)
Table 2. Influence of Substituents X and R on the Catalytic Enantioselective
Oxygenation of 3,4-Dihydroquinolones 5[a]
1
2
20
20
20
20
20
20
20
40
10
5
2
2
2
1
2
2
2
2
2
2
2.0
2.0
2.0
2.0
3.0
1.5
1.2
2.0
2.0
2.0
25
0
32
6
52
59
44
52
33
60
53
60
68
38
11
15
19
21
31
13
7
97
98
99
99
99
98
97
97
99
92
3
–20
0
9
4
5
5
0
–
6
0
19
36
6
7
0
8
0
13
19
21
9
0
8
10
0
19
[a] The reaction was performed under indicated conditions and was initiated by
addition of the catalyst to the pre-cooled reaction mixture. All yields refer to
isolated material. [b] Loading of catalyst 4 in mol%. [c] Amount of oxidant
(PhIO) in equivalents relative to 5a. [d] Enantiomeric excess (ee) of secondary
alcohol 6a as determined by chiral HPLC analysis.
Under optimized conditions (Table 1, entry 9), product 6a was
isolated in 68% yield and could be readily separated from
starting material 5a and ketone 7a. For best comparability, the
reactions of all other substrates 5 were performed under
identical conditions and they were all terminated after a reaction
time of 16 hours (Table 2). Yields refer to isolated material and
the conversion (conv.) was determined by re-isolation of starting
material. The main parameter to be studied was the influence of
the substitution pattern in positions C3 and C7 on the yield and
on the enantioselectivity. Benzyl ether 5b reacted similarly to
methyl ether 5a and delivered product 6b with 97% ee.
Modification of the geminal disubstitution at position C3[18] did
not reduce the reactivity of the three substrates 5c-5e (>80%
conversion). The ee of the products 6c-6e remained high but
turned out to be slightly more variable (88-97% ee). Alkyl
substitution in position C7 lowered the reactivity of the
substrates slightly (56-76% conversion) but the enantio-
selectivity remained extraordinary high (93-96% ee). Neither the
benzylic methyl group in substrate 5f nor the benzylic methylene
group in substrate 5g displayed any reactivity towards CH
oxygenation. Most remarkably, the potentially reactive, doubly
aryl-substituted methylene group in substrate 5h was not
touched by the oxygenation reagent which illustrates the
exquisite site-selectivity of the reaction. The parent compound 5i
and 3,4-dihydroquinolones with an electron withdrawing group in
Control experiments were performed to shine some light on the
mode of action of the catalyst (Scheme 2). In the first
experiment, racemic alcohol rac-6a was subjected to the
reaction conditions of the oxygenation reaction. Oxidation to
ketone 7a was observed but the kinetic resolution was not
extensive. At a conversion of 55%, an enantioselectivity of 53%
ee was recorded in favor of (S)-configured (vide infra) alcohol
6a. The relative rates of the two enantiomers (s factor) can be
calculated from these values to be kR/kS = 4.2.[19] In a second
control experiment the influence of the hydrogen bond donating
NH group was probed. N-methylated substrate 8 that lacks this
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hydrogen binding site reacted poorly under the standard
oxygenation conditions. Only 14% of alcohol 9 was obtained in
almost racemic form (5% ee).
geometric constrains allow for no other hydrogen atom being
attacked by the oxygenation reagent. In line with the rate law the
rate determining step is the oxygenation event which is likely to
occur by a rebound mechanism,[20] i.e. by a hydrogen atom
abstraction and a subsequent delivery of the hydroxyl group
from the manganese atom.
Figure 2. The complex 10 of substrates 5 with the active MnV catalyst enables
enantioselective oxygenation leading to the respective (4S)-configured alcohol
as proven by the crystal structure of product 6j (X = Cl).
Scheme 2. Control experiments performed with racemic alcohol rac-6a and
with the N-methylated dihydroquinolone substrate 8.
Although the low s factor obtained in the kinetic resolution
experiment (Scheme 2) indicated that the prime reason for the
observed enantioselectivity was the differentiation of the two
enantiotopic hydrogen atoms in the oxygenation event, the
enantiomeric excess was monitored over time (Figure 1). It was
found for the transformation 5a → 6a that the enantioselectivity
was already high (>95% ee) at low substrate conversion (<20%)
clearly supporting the hypothesis that the oxygenation reagent
was guided to a specific substrate position by the hydrogen
bonding interaction. Detailed kinetic studies employing an
internal standard (see the Supporting Information for details)
revealed that the reaction was first order in substrate
(concentration range c = 2.5-15 mM) and first order in catalyst (c
In our specific case, the reaction of substrate 5c provided
evidence for an oxygen rebound mechanism. The transient
cyclopropyl substituted radical 11 (Figure 3) in the above-
mentioned mechanistic scenario would be an intermediate which
is expected to open to the homobenzylic radical 12. Rate
constants for cyclopropyl methyl/but-3-enyl radical clocks[21] are
on the order of 108 s1 and the ring opening should therefore
compete with the hydroxyl transfer from the manganese atom. A
homobenzylic alcohol 13 was expected as the by-product which
was indeed isolated in 5% yield from the reaction 5c → 6c
(Table 2). This finding supports the intermediacy of a transient
radical in the oxygenation reaction. The fact that the cleavage of
the CH bond was rate determining was further substantiated by
kinetic isotope effect (KIE) studies. Experiments were performed
with substrates d2-5a and 5a (c = 10 mM, 2 mol% 4) and the
individual reactions were followed by GLC analysis (internal
standard). The KIE obtained from the individual reaction rate
constants was kH/kD = 3.0 ± 0.2 which matched previous values
observed for oxygenation reactions catalyzed by manganese
porphyrin complexes.[22]
=
0.1-0.3 mM). The oxidant loading was found to be
inconsequential for the rate law (zero order).
10.0
8.0
100
80
60
40
20
0
6.0
c / mM
ee / %
4.0
2.0
0.0
0
30 60 90 120 150 180 210 240 270
t / min
Figure 3. Structures of radicals 11 and 12, and of quinolones 13 and d2-5a.
Figure 1. Rate and ee profile for the enantioselective oxygenation of substrate
5a to product 6a under standard reaction conditions (cf. Table 2).
A bent transition state has been suggested to account for the
relative low KIEs obtained for oxygenation catalyzed by
manganese porphyrin complexes.[22a] Preliminary DFT
calculations[23] support a reaction via a MnV oxo triplet inter-
mediate and a bent transition state but it seems warranted to
perform a CAS analysis to get a more reliable picture.
The mechanistic picture that evolves from the experimental data
includes a reactive MnV oxo species the active site of which is
directed by hydrogen bonding to a specific CH bond (Figure 2).
The absolute configuration which was determined for product 6j
by anomalous X-ray diffraction is in line with a preferred attack
at the pro-S hydrogen atom attached to carbon atom C4. The
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Chem. Soc. Rev. 2014, 43, 1660–1733; d) S. Carboni, C. Gennari, L.
Pignatoro, U. Piarulli, Dalton Trans. 2011, 40, 4355–4373.
In summary, we have shown that a hydrogen bonding ligand
serves as a key element in controlling the selectivity of a
manganese porphyrin catalyzed CH oxygenation reaction. 3,3-
Disubstituted 3,4-dihydroquinolones reacted exclusively and with
high enantioselectivity at position C4 of the heterocyclic
skeleton. Evidence was collected that the reaction occurs via an
oxygen transfer from a manganese oxo complex by a rebound
mechanism. It appears as if the hydrogen bonding event lowers
the activation barrier for attack at a specific CH bond and it is
likely that this mode of action will apply also to related reactions.
More importantly, it seems possible to address distinct CH
positions in a given substrate by spatially adjusting the position
of the catalytic entity relative to the hydrogen bonding substrate.
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[10] a) P. Fackler, C. Berthold, F. Voss, T. Bach, J. Am. Chem. Soc. 2010,
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Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(grant Ba 1372-17) is gratefully acknowledged. O. Ackermann
and J. Kudermann are acknowledged for their help with the
HPLC and GLC analyses.
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Keywords: enantioselectivity • hydrogen bonds • manganese •
oxygenation • porphyrinoids
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Entry for the Table of Contents (Please choose one layout)
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Look into my active site, small: A
chiral manganese porphyrin complex
catalyzes the oxygenation of 3,4-
dihydroquinolones to the respective 4-
hydroxy compounds (12 examples,
87-99% ee). The enantio- and site-
selectivity is enforced by hydrogen
bonding to the catalyst: Methylene
groups at C3 or at C7 are not
attacked.
F. Burg, M. Gicquel, S. Breitenlechner,
A. Pöthig, T. Bach*
Page No. – Page No.
Site- and Enantioselective C–H
Oxygenation Catalyzed by a Chiral
Manganese Porphyrin Complex with a
Remote Binding Site
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