Catalytic Enantioselective Methylene C(sp3)-H Hydroxylation Using a Chiral Manganese Complex/Carboxylic Acid System

Article abstract of DOI:10.1021/acs.orglett.0c03585

Achieving direct C-H hydroxylation in a highly diastereo- and enantioselective manner is still a challenging goal. This reaction is mainly hindered by the potential for overoxidation of the generated alcohols as well as low stereoselectivity. Herein, we present an enantioselective benzylic C-H hydroxylation catalyzed by a manganese complex, H2O2, and a carboxylic acid in 2,2,2-trifluoroethanol. The benzylic alcohols were successfully furnished in excellent diastereoselectivities (up to >95:5) and enantioselectivities (up to 95% ee). As a highlight of this work, high diastereoselectivity of C-H hydroxylation could be achieved by tuning the amount of carboxylic acid additive.

Full text of DOI:10.1021/acs.orglett.0c03585

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Letter
Catalytic Enantioselective Methylene C(sp3)−H Hydroxylation Using
a Chiral Manganese Complex/Carboxylic Acid System
Qiangsheng Sun and Wei Sun*
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ABSTRACT: Achieving direct C−H hydroxylation in a highly
diastereo- and enantioselective manner is still a challenging goal.
This reaction is mainly hindered by the potential for overoxidation
of the generated alcohols as well as low stereoselectivity. Herein,
we present an enantioselective benzylic C−H hydroxylation
catalyzed by a manganese complex, H2O2, and a carboxylic acid
in 2,2,2-trifluoroethanol. The benzylic alcohols were successfully
furnished in excellent diastereoselectivities (up to >95:5) and
enantioselectivities (up to 95% ee). As a highlight of this work, high diastereoselectivity of C−H hydroxylation could be achieved by
tuning the amount of carboxylic acid additive.
nantioselective installation of a hydroxyl group on an
organic molecule represents a direct yet challenging
the past decades. Previous studies have focused on chiral iron,7
manganese,8 and ruthenium9 porphyrin complexes as well as
chiral manganese salen complexes.10 Among these methods,
the only example of benzylic C−H asymmetric hydroxylation
was accomplished by Bach and co-workers with up to 99% ee
by means of hydrogen bonding between the 3,4-dihydroqui-
nolone substrates and the Mn porphyrin catalyst. However, an
approximately 19% yield of the overoxidation product could be
isolated (Scheme 2a).11 Therefore, more effective catalytic
systems for enantioselective methylene C(sp3)−H hydrox-
ylation are required.
E
synthetic technique that has attracted considerable attention
in the field of C−H functionalization.1 In this regard, the
challenges of this stereocenter-generating transformation lie
not only in discriminating between enantiotopic and
diastereotopic C(sp3)−H bonds on the methylene groups
(Scheme 1; for achiral compound A, the hydroxylation of
Scheme 1. Stereochemistry of Enantioselective
Hydroxylation of Prochiral Compound A
In recent years, bioinspired non-heme Fe and Mn complexes
have demonstrated great potential for enantioselective
oxidations using H2O2 as the terminal oxidant.12−14 Regarding
the enantioselective oxidation of C−H bonds, the groups of
Costas15 and Bryliakov16 have reported manganese complexes
with chiral tetradentate aminopyridine ligands, in particular,
the PDP (PDP = N,N′-bis(2-pyridylmethyl)-2,2′-bipyrroli-
dine) structural core. Very recently, Costas and co-workers
reported the first example of a Mn-catalyzed C−H oxidation
directed by carboxylic acids that can avoid overoxidation to
yield γ-lactones in high enantioselectivity (Scheme 2b).17 Soon
after, Bryliakov and co-workers transferred ethylbenzenes into
the corresponding alcohols in 38% yield with 97% ee (Scheme
2c).18 However, the ratio of products between alcohol and
ketone (A/K, Scheme 2c) was only 0.90. We recently reported
stereotopic Ha, Hb, Hc, and Hd generates four different
stereoisomers) but also in the difficulty in preventing further
oxidation of the resulting chiral secondary alcohol.2 As we
know, metal enzymes (e.g., cytochrome P450) have been
recognized as effective catalysts for chemo- and enantiose-
lective introduction of an oxygen moiety in specific molecules
via metal-oxo-promoted C−H oxidation.2−5 As a result, the
development of small-molecule catalysts to realize the
functionality of enzymes is of great significance.6
Received: October 27, 2020
Along these lines, many catalytic systems have been
developed to facilitate this challenging transformation over
https://dx.doi.org/10.1021/acs.orglett.0c03585
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Scheme 2. Direct Enantioselective C(sp3)−H Hydroxylation
Often Uses Bioinspired Catalyst Systems
oxidant in the TFE. A variety of manganese catalysts were
screened at 0 °C (Table 1, entries 1−5).
Table 1. Diastereoselective and Enantioselective Benzylic
a
C−H Oxidation Catalyzed by a Manganese Complex
b
c
d
entry
catalyst
T (°C)
yield (%)
ee (%)
dr
1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
1
1
1
1
1
1
1
1
1
0
0
0
0
0
−20
−30
−40
−40
−40
−40
−40
−40
−40
40
46
21
17
49
46
46
75
78
78
78
77
43
30
75
70
66
−78
−74
89
90
92
92
93
2.0:1
1.6:1
1:1.2
1:1.5
1.5:1
3.2:1
3.2:1
4.9:1
e
5.7:1
f
>95:5
>95:5
>95:5
>95:5
6.7:1
g
93
82
86
80
h
i
13
14
j
a
Conditions: 0.2 mmol of substrate 1a, 0.1 mmol of H2O2 in 0.5 mL
of solvent (TFE/DCM = 5:1), 1.0 mol % of catalyst, additive 2.0
equiv in 0.5 mL of solvent (catalyst, acid, and oxidant were
b
portionwise added in twice). Determined by 1H NMR of the
crude products using 0.1 mmol of trimethoxylbenzene as the internal
c
reference based on H2O2. Determined by HPLC on chiral stationary.
d
e
Determined by 1H NMR of the crude products. 4.0 equiv of
a manganese/H2O2 catalytic system that catalyzes asymmetric
oxidation of benzylic methylene C−H bonds of spirocyclic
compounds to ketones with high enantioselectivity.19 Regard-
less of the remarkable progress during the past few years,
highly chemo- and enantioselective C−H hydroxylation
remains one of the most challenging tasks in the field of C−
H functionalization. On the other hand, fluorinated alcohols
such as 2,2,2-trifluoroethanol (TFE) have emerged as solvents
of choice for oxidation reactions because of their mild acidity,
high polarity, and strong hydrogen-bond donation,20−22
thereby inhibiting further oxidation of the resulting secondary
alcohols.20,21a Prompted by these achievements, we anticipated
that direct enantioselective C−H hydroxylation could be
possible with the TFE as the reaction medium when using an
appropriate catalyst.
Herein, we report the enantioselective hydroxylation of
benzylic methylene C−H bonds catalyzed by manganese
complexes of N4 ligands, using aqueous H2O2 as the terminal
oxidant and TFE as the solvent, providing alcohols as the only
products with high enantioselectivities (Scheme 2d, up to 95%
ee). More importantly, this method also allows excellent
diastereoselectivity depending on the amount of the carboxylic
acid additive.
f
g
h
DMBA. 6.0 equiv of DMBA. 8.0 equiv of DMBA. 6.0 equiv of
AcOH. 6.0 equiv of EHA. MeCN was used as the solvent, and 6.0
equiv of DMBA was used as the additive.
i
j
Taking into account the diastereo- and enantioselectivity,
catalyst 1 (S-PEB-Mn)23 gave the best outcome (Table 1,
entry 1). To further improve the yield, diastereoselectivity, and
enantioselectivity of the oxidation, this reaction was then
investigated at lower temperatures (Table 1, entries 6−8). It
was found that the reaction gave better yield (75% yield) and
enantioselectivity (Table 1, entries 8, 92% ee) at −40 °C,
although the diastereoselectivity was unsatisfactory (4.9:1 dr).
Notably, the diastereoselectivity of alcohol 2a could be
improved by adding more 2,2-dimethylbutanoic acid
(DMBA), and 6 equiv of additive proved to be the best
choice (>95:5 dr, Table 1, entry 10).19,24 Several acids
commonly used in these oxidative methods, such as acetic acid
(AcOH) and 2-ethylhexanoic acid (EHA),25 were also
investigated under the standard reaction conditions. However,
no further improvement was observed (Table 1, entries 12 and
13). The enantioselective hydroxylation of 1a was also tested
in MeCN, which was usually used in an oxidation reaction, and
the decreased result showed the effect of medium in the
reaction (Table 1, entry 14).
Initially, an indan-based substrate 1a, possessing enantio-
topic and diastereotopic hydrogen atoms, was chosen as the
model substrate. We attempted to identify an appropriate N4
manganese catalyst for enantioselective benzylic C−H
hydroxylation using 30% aqueous hydrogen peroxide as the
With the optimal reaction conditions in hand (Table 1, entry
10), we examined the substrate scope of this diastereo- and
enantioselective benzylic C−H oxidation (Scheme 3).
B
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the present C−H oxidative transformation, giving excellent
diastereoselectivities and enantioselectivities (Scheme 3, 1h−
1k). It should be noted that enantioselective C−H oxidation
only occurs at the indan methylene site, even though substrates
bear multiple benzylic C−H bonds (Scheme 3, 1i and 1k). In
the case of substrate 1l, which possessed significant steric
hindrance, the conversion of the C−H oxidation was very low
and no product could be isolated. Then, indan substrates with
electron-withdrawing groups were tested under the standard
conditions (Scheme 3, 1m and 1n). The corresponding
benzylic alcohols were obtained successfully with good yields
and excellent enantioselectivities, but the diastereoselectivities
were decreased. Furthermore, six-membered spirocyclic
ketones were smoothly oxidized to benzylic alcohols with
excellent enantioselectivities and diastereoselectivities (Scheme
3, 1o−1q). This stands in contrast to our previous work, where
these substrates were rapidly transformed into diketones. Also,
a substrate without phenyl adjacent to the carbonyl group, 2-
acetylindan, was examined under the standard condition
(Scheme 3, 1t). It was found that the reaction gave 2t with
lower yield (30%) and stereoselectivity (10:1 dr, 58% ee). We
subsequently determined the relative configuration of these
alcohol products by the COSY and NOESY spectra of product
2c. It was shown that the hydroxyl group was cis to the acyl
group.
Scheme 3. Asymmetric Synthesis of Benzylic Alcohols by
the C−H Oxidation
a
To demonstrate the effectiveness and practicability of our
catalytic hydroxylation method, a gram-scale synthesis using
our system was performed (Scheme 4). When 5 mmol of 1a
was subjected to the direct hydroxylation transformation, the
desired β-hydroxy ketone product 2a was obtained in 68%
yield, >95:5 dr, and 92% ee.
Scheme 4. Gram-Scale Synthesis for the Preparation of 2a
a
All reactions were performed on 0.4 mmol scale with 0.2 mmol of
H2O2 in 1.0 mL of solvent (TFE/DCM = 5:1), 1.0 mol % of catalyst,
6.0 equiv of DMBA in 1.0 mL of solvent (catalyst 1, acid, and oxidant
were all added in portionwise twice; for details, see the Supporting
Information). Isolated yields and dr ratios were determined by the
crude products, and ee was determined by HPLC on a chiral
stationary phase.
Based on both experimental and DFT evidence from similar
catalytic systems, the reaction intermediate is likely a Mn(V)-
oxo species bearing a carboxylate moiety.25−27 This species can
readily oxidize unactivated C−H bonds28 as well as the
resulting alcohols.29 To evaluate the effect of the carbonyl
group on the selectivity of C−H oxidation, the reduced
substrates 1r and 1s were investigated under the standard
oxidative conditions. Even though substrate 1r contained
multiple benzylic C−H bonds, the reaction conditions failed to
convert 1r into the alcohol product with low conversion.
Similarly, the oxidation of 1s, which contains a secondary
alcohol moiety, did not occur, further implying that the present
oxidative system does not oxidize the resulting alcohol product
(Scheme 5). On the basis of the observed results, it appears
that intermolecular hydrogen bonding between the Mn(V)-
oxo species, TFE, and the carbonyl-containing substrate seems
to direct the oxidative hydroxylation (Figure 1).
Variously functionalized indan-based substrates were explored.
In general, the desired chiral alcohols were exclusively
produced with good to excellent diastereo- and enantiose-
lectivities. The halo substituents on the para-position of the
benzene ring had an obvious effect on the reaction stereo-
selectivity. Substrate 1b, bearing a 4-bromo group, gave
benzylic alcohol 2b in 56% yield, 94% ee, and 12:1 dr, whereas
the fluorinated substrate 1d was transformed in lower
enantioselectivity. This oxidation was compatible with
substrates bearing electron-donating groups. All substrates
with the MeO group were converted successfully in good
yields and excellent diastereoselectivities (Scheme 3, 1e−1g).
Substrate 1f, substituted with a MeO group at the meta-site,
gave excellent results (92% ee), whereas ortho-MeO (1e) and
para-MeO (1g) substituted substrates only delivered moderate
to good enantioselectivities. Additionally, substrates containing
different alkyl groups on the benzene ring were also suitable for
In conclusion, we have developed a direct, diastereo- and
enantioselective C−H hydroxylation of the indan skeleton
bearing a carbonyl group. Catalyzed by an S-PEB-Mn(OTf)2
complex, benzylic alcohols were successfully assembled as the
only product with high enantioselectivities (up to 95% ee) in
TFE. By tuning the amount of additive DMBA, high
C
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Notes
Scheme 5. Controlled Experiments with Respect to
Substrates without a Carbonyl Group
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by National Natural
Science Foundation of China (21773273, 21802153,
21902166), the Dalian National Laboratory for Clean Energy
(DNL) Cooperation Fund, CAS (Grant No. DNL201904),
Key Research Program of Frontier Sciences, CAS (QYZDJ-
SSW-SLH051), and Natural Science Foundation of Jiangsu
Province (BK20170420).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03585.
Experimental procedures, characterization data, and
spectra of new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
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Wei Sun − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; orcid.org/0000-0003-
4448-2390; Email: wsun@licp.cas.cn
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Qiangsheng Sun − State Key Laboratory for Oxo Synthesis
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