Site- And enantiodifferentiating C(sp3)-H oxidation enables asymmetric access to structurally and stereochemically diverse saturated cyclic ethers

Article abstract of DOI:10.1021/jacs.0c09636

A manganese-catalyzed site- and enantiodifferentiating oxidation of C(sp3)-H bonds in saturated cyclic ethers has been described. The mild and practical method is applicable to a range of tetrahydrofurans, tetrahydropyrans, and medium-sized cyclic ethers with multiple stereocenters and diverse substituent patterns in high efficiency with extremely efficient site- and enantiodiscrimination. Late-stage application in complex biological active molecules was further demonstrated. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity. The ability to employ ether substrates as the limiting reagent, together with a broad substrate scope, and a high level of chiral recognition, represent a valuable demonstration of the utility of asymmetric C(sp3)-H oxidation in complex molecule synthesis.

Full text of DOI:10.1021/jacs.0c09636

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Article
Site- and Enantiodifferentiating C(sp3)−H Oxidation Enables
Asymmetric Access to Structurally and Stereochemically Diverse
Saturated Cyclic Ethers
Shutao Sun,# Yiying Yang,# Ran Zhao, Dongju Zhang,* and Lei Liu*
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ABSTRACT: A manganese-catalyzed site- and enantiodifferenti-
ating oxidation of C(sp3)−H bonds in saturated cyclic ethers has
been described. The mild and practical method is applicable to a
range of tetrahydrofurans, tetrahydropyrans, and medium-sized
cyclic ethers with multiple stereocenters and diverse substituent
patterns in high efficiency with extremely efficient site- and
enantiodiscrimination. Late-stage application in complex biological
active molecules was further demonstrated. Mechanistic studies by
combined experiments and computations elucidated the reaction
mechanism and origins of stereoselectivity. The ability to employ
ether substrates as the limiting reagent, together with a broad
substrate scope, and a high level of chiral recognition, represent a
valuable demonstration of the utility of asymmetric C(sp3)−H
oxidation in complex molecule synthesis.
Scheme 1. Overview of Catalytic Enantioselective C−H
INTRODUCTION
■
Oxidation by Nonenzymatic Means
C(sp3)−H bonds are ubiquitous in organic molecules.
Enzymatic site- and enantioselective oxidation of C(sp3)−H
bonds is a fundamental transformation in biological systems.1
Nonenzymatic site- and enantioselective oxidation of aliphatic
C−H bonds with a general scope, with predictable selectivities,
and in preparatively useful yields would represent a paradigm
shift in the standard logic of organic synthesis, but has
remained a highly challenging area.2 Since the pioneering work
by Groves in asymmetric hydroxylation of ethylbenzene, only a
few examples of enantioselective oxidation of benzylic C−H
bonds have been disclosed, which typically suffer from
moderate enantioselectivity, low substrate conversion, and
narrow substrate scope (Scheme 1A).3 A chiral desymmetriza-
tion strategy was adopted for the reaction design, which
promoted the synthetic utility of enantioselective aliphatic C−
H oxidation (Scheme 1B).4 On the other hand, kinetic
resolution (KR) of racemic starting material is a powerful and
practical strategy to access optically active targets, especially in
cases where other methods are not possible.5−7 Integrating the
KR strategy into reaction design would advance the develop-
ment of enantioselective C−H oxidation. However, KR
reaction through site- and enantioselective C−H oxidation
remained elusive.8
spread occurrence, combined with the limitations associated
with the traditional multistep approaches relying on
enantiopure alcohols, have stimulated considerable interest in
Received: September 8, 2020
Structurally and stereochemically diverse saturated cyclic
ethers, such as tetrahydrofurans (THFs) and tetrahydropyrans
(THPs), are core units within a multitude of biologically active
natural products and synthetic pharmaceuticals.9 Their wide-
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a
the development of efficient catalytic asymmetric methods.
However, each catalytic asymmetric system is typically
applicable for a single class of THF or THP skeleton bearing
a single stereogenic center.10−12 We envisioned that late-stage
site- and enantiodifferentiating oxidation of C(sp3)−H bonds
adjacent to ether oxygens in racemic targets would provide a
reliable and straightforward approach to asymmetric access
structurally and stereochemically diverse saturated cyclic ethers
(Scheme 1C).13
Table 1. Reaction Condition Optimization
Take cis- or trans-α,α′-disubstituted saturated cyclic ethers
bearing two stereogenic centers, for example, two main
challenges hamper the reaction design (Scheme 1C). First,
site-selective discrimination of chemically similar C(sp3)−H
bonds with subtle electronic and steric differences adjacent to
ether oxygen would be a significant challenge. Second, the
saturated ether skeleton lacks an effective interaction site with
a catalyst to direct substrates to an ideal location in the
transition state, and chiral discrimination of two enantiomers
would be difficult to attain. Identifying a chiral catalyst with a
confined active site buried within a highly sterically demanding
chiral environment would facilitate the reaction. Herein, we
disclosed a manganese-catalyzed late-stage site- and enantio-
differentiating oxidation of C(sp3)−H bonds enabling
asymmetric access to structurally and stereochemically diverse
saturated cyclic ethers (Scheme 1C).
RESULTS AND DISCUSSION
■
Initially, enantiodifferentiating oxidation of α-aryl-substituted
THF 1a was selected as the model reaction for optimization
(Table 1). When PhIO was used as an oxidant, simple chiral
Mn(salen) C1 exhibited oxidation catalysis reactivity, though
poor chiral recognition was observed (entry 1, Table 1).
Introducing an extra chirality into the salen framework might
enhance the enantiodiscrimination ability of the catalyst by
tuning the chiral environment around the active site.3b Indeed,
enhanced chiral discrimination was observed for catalysts C2−
C5 containing an axial chirality at C3(3′) sites of the basal
salen ligand, and the (Ra,S) Mn(salen) complex C5 containing
a 1,2-diphenyl-1,2-ethanediamine moiety was found to be
optimal (entries 2−5, Table 1). Replacing the 2″-phenyl group
on the C3 substituent with other moieties provided inferior
results (see the Supporting Information for details). Further
fine-tuning substituents on 1,2-ethanediamine revealed that
electronic and steric properties of aryl groups was crucial to the
enantiodiscrimination ability, and C9 bearing PMP moieties
was identified to be superior (entries 6−12, Table 1). Notably,
excellent site selectivity at the tertiary C−H bond (blue color)
with greater electron-rich character over less sterically hindered
secondary C−H bond (red color) was observed. Increasing the
loading of PhIO to 0.8 equiv gave a better selectivity factor
(entry 13, Table 1). Employing other solvents and oxidants to
replace respective CH2Cl2 and PhIO afforded inferior results
(entries 14−17, Table 1).
a
Reaction conditions: to rac-1a (0.1 mmol) and the catalyst (5 mol
%) in CH2Cl2 (1.0 mL) at −40 °C was added PhIO (0.06 mmol) as
six portions in 30 min intervals for 3 h, unless otherwise noted.
b
Conversion was calculated from the yield of recovered 1a.
c
Determined by HPLC analysis on a chiral stationary phase.
d
Selectivity (s) values were calculated through the equation s =
ln[(1 − C)(1 − ee)]/ln[(1 − C)(1 + ee)], where C is the conversion.
e
0.8 equiv of PhIO added as eight portions in 30 min intervals for 4 h.
f
g
h
CH3CN as solvent. Chlorobenzene as solvent. NaClO as oxidant.
TBHP (5.5 M in decane) as oxidant.
The scope of site- and enantiodifferentiating oxidation of
THFs bearing one stereogenic center was explored (Scheme
2). OKR of α-phenyl-substituted rac-1a proceeded with
excellent site selectivity at a tertiary C−H bond with greater
electron-rich character over less sterically hindered secondary
C−H bonds, and remaining (S)-1a was isolated in 49% yield
with 94% ee (s = 70) (Scheme 2A).14 Selectivities were not
impaired for reaction on a 1.0 mmol scale. The asymmetric
oxidation reaction was not sensitive to the electronic
substituent effect on the α-arene substituents, as demonstrated
i
by effective access to optically pure 1b−1g with good
selectivity factors (23−70). α-Alkynyl-substituted THFs were
also competent candidates for the protocol, as illustrated by
effective resolution of respective rac-1h−1n (Scheme 2B).14
The method exhibited good compatibility toward THFs with
diverse substituent patterns (Scheme 2C). Installing a germinal
dimethyl group to any position of the THF skeleton (1o, 1t,
B
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a
Scheme 2. Scope of THFs Bearing One Stereogenic Center
Scheme 3. Scope of THPs and Other Medium-Sized
Saturated Cyclic Ethers Bearing One Stereogenic Center
a
a
The s value calculation is based on isolated yields of recovered 3 on a
b
0.1 mmol scale, unless otherwise noted. Reaction with catalyst C9 (5
mol %) and PhIO (0.08 mmol) in CH2Cl2 at −40 °C. Reaction with
1.0 mmol rac-3a. PMP = 4-MeOC6H4.
c
a
The s value calculation is based on isolated yields of recovered 1 on a
b
0.1 mmol scale, unless otherwise noted. Reaction with 1.0 mmol rac-
1. Reaction with catalyst C3 (5 mol %) and PhIO (0.12 mmol) in
c
CH3CN at 0 °C. PMP = 4-MeOC6H4.
bond, furnishing (2R,5S)-5a in 43% yield with 96% ee together
with oxidized secondary alcohol (S)-6a in 50% yield with 78%
ee (s = 32) (Scheme 4A). cis-2,5-disubstituted THF rac-5b was
also well-tolerated with the same site selectivity. The reaction
was not sensitive to the length of alkyl side chains, as
demonstrated by effective asymmetric oxidation of rac-5c−5e
with good selectivity factors of 35−44.14 2,5-Disubstituted
THFs bearing commonly encountered functional groups in the
side chain, including terminal alkynes (5f and 5g), benzoate
(5h), silyl ether (5i), azide (5j), halide (5k), and amine (5l),
were well-tolerated for further manipulation. Importantly,
preferential oxidation at a benzylic tertiary C−H bond was
observed when multiple activated, more sterically accessible
C−H bonds, such as propargyl (5f, 5g), α-oxy (5h, 5i), and α-
amino (5j, 5l) ones, were present. THFs bearing two
stereocenters with other substituent patterns were next
evaluated. Both trans-2,4-disubstituted 5m and cis-2,4-disub-
stituted 5n proved to be viable substrates (Scheme 4B). trans-
2,2,5-Trisubstituted THFs 5o and 5q together with cis-2,2,5-
trisubstituted 5p, 5r, and 5s containing quaternary stereo-
centers were also competent components with a high level of
chiral recognition (Scheme 4C).15 Similarly, cis-2,6-disubsti-
tuted THPs 5t, 5v, and 5w together with trans-2,6-
and 1u) did not impair the levels of site- and enantiodiffer-
entiation. Spirocyclic 1p−1s bearing different ring sizes and
functionalities were well-tolerated.
The generality of the strategy for asymmetric access to
structurally diverse saturated cyclic ether skeletons was then
investigated (Scheme 3). THPs bearing a range of aryl and
alkynyl substituents at the α-position were compatible with the
protocol, with corresponding enantiopure 3a−3l isolated in
good yields with 91−96% ee (Scheme 3A).14 Asymmetric
synthesis of medium-sized, saturated cyclic ethers has been a
daunting challenge (Scheme 3B). Delightedly, seven-mem-
bered oxepane 3m, eight-membered oxocane 3n, and nine-
membered oxonane 3o proved to be competent substrates with
good selectivity factors, albeit obviously decreased selectivity
for 10-membered 3p.
The success in site- and enantiodifferentiating oxidation of
substrates with one stereocenter encouraged us to further
explore the compatibility of racemic ethers bearing two
stereocenters (Scheme 4). Oxidation of trans-2,5-disubstituted
THF rac-5a proceeded with excellent site selectivity at the
more electron-rich tertiary C5−H bond over the tertiary C2−H
C
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Scheme 4. Scope of THFs and THPs Bearing Multiple
Stereocenters
Scheme 5. Late-Stage Enantiodifferentiating Oxidation of
Complex Bioactive Molecules and a Gram-Scale Reaction
a b
,
a
a
rac-8, 10, or 12 (0.1 mmol) and C9 (5 mol %) in CH2Cl2 (1.0 mL)
at −40 °C was added PhIO (0.1 mmol) as ten portions in 30 min
intervals for 5 h, unless otherwise noted.
monophosphate-activated protein kinase (AMPK) activator for
treatment and prevention of AMPK-mediated disorders
(Scheme 5A).16 N-Methyl-protected (S)-8 was facilely
obtained in 43% yield with 88% ee through our protocol.
Natural product (−)-centrolobine 9 isolated from the heart
wood of Centrolobium robustum possesses diverse biological
activities including anti-inflammatory, antibacterial, and
antileishmanial ones (Scheme 5B).17 Enantiodifferentiating
oxidation of cis-2,6-disubstituted THP rac-10 proceeded,
affording silyl-protected (−)-centrolobine in 47% yield with
87% ee. Natural product lariciresinol methyl ether 11 was
known to possess a variety of biological activities including
antitumor, antioxidant, analgesic, and anti-inflammatory
properties (Scheme 5C).18 Subjecting acyl-protected rac-12
to the asymmetric oxidation conditions providing optically
pure 12 in 44% yield with 87% ee. A gram-scale reaction
proceeded without obvious loss of efficiency and enantiose-
lectivity, as demonstrated by recovery of (S)-1a in 47% yield
with 94% ee (Scheme 5D).
a
The s value calculation is based on isolated yields of recovered 5 on a
In general, manganese-catalyzed C(sp3)−H oxidation
proceeds through an alkyl radical intermediate 13 for
subsequent oxygen rebound (Scheme 6A).19 Typically, there
are two plausible mechanisms for converting THF 1a to radical
13, which includes (1) one-step hydrogen atom transfer
(HAT) and (2) single-electron transfer (SET) followed by
proton transfer.19,20 Mechanistic studies were performed to get
a preliminary understanding of the reaction. A competition
deuterium kinetic isotope effect (KIE) study, using a mixture
of rac-1a and [D]-rac-1a, revealed a KIE of 2.9 (Scheme 6B).
The result suggested that the C−H bond cleavage might be
involved in the rate-determining step. Oxidation experiments
of THFs with various kinds of p-substituents (X) on α-aryl
b
0.1 mmol scale, unless otherwise noted. s values were calculated
through the equation s = ln[(1 − C)(1 − ee5)]/ln[(1 − C)(1 + ee5)],
where C is the conversion; C = ee5/(ee5 + ee6). Oxidized tertiary
alcohols 6q and 6r decomposed during purification; s value
calculation is based on isolated yields of recovered 6q and 6r. PMP
= 4-MeOC6H4.
b
disubstituted 5u bearing varied alkyl side chain lengths were
well-tolerated (Scheme 4D).
Perhaps the most remarkable advance of the protocol would
be direct late-stage site- and enantiodifferentiating oxidation of
complex bioactive molecules that are otherwise difficult to
access (Scheme 5). THF 7 was identified as adenosine
D
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Scheme 6. Mechanistic studies
Scheme 7. Computational Mechanistic Studies
moieties were conducted and the reaction rates were
dependent on the electronic effects of the substituents (see
the Supporting Information for details) (Scheme 6C).21 The
Hammett plot (log(kX/kH) versus σ) displayed linear
correlation with a ρ value of −0.627 (R2 = 0.99). Good
linearity suggests that the oxidation proceeds through a single
E
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mechanism.22 The quite small negative value of ρ together with
the poor correlation with σ+ (R2 = 0.87; see the Supporting
Information for details) indicate the absence of charge
separation in the transition state.23
demonstration of the utility of asymmetric C(sp3)−H
oxidation in complex molecule synthesis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09636.
■
According to the absolute configuration of recovered α-
substituted THF 1a, ether (R)-1a was oxidized more
preferentially than (S)-1a. Accordingly, density functional
theory (DFT) calculations on chiral oxoMn(V) C13 mediated
oxidation of (R)-1a were conducted to distinguish the
forementioned two processes (Scheme 6; see the Supporting
Information for details).24 The calculated lowest-barrier Gibbs
energy profiles of singlet, triplet, and quintuplet spin states for
respective SET and HAT pathways merit further comment
sı
Experimental procedures, absolute configuration deter-
mination, experimental and computational mechanistic
studies, and spectra data (PDF)
X-ray crystallographic data for 5p (CCDC 1945290)
(CIF)
3
4
(Scheme 7A). First, the SET pathway from C13 to C15
needs to overcome a barrier of 12.9 kcal/mol and is
endothermic by 12.0 kcal/mol, while the HAT process from
AUTHOR INFORMATION
Corresponding Authors
■
5
3IM1(R) to IM2 occurs with a barrier of 5.5 kcal/mol and is
Lei Liu − School of Chemistry and Chemical Engineering and
School of Pharmaceutical Sciences, Shandong University, Jinan
250100, China; orcid.org/0000-0002-0839-373X;
Email: leiliu@sdu.edu.cn
strongly exothermic by 58.1 kcal/mol. Thus, the HAT pathway
is believed to be both thermodynamically and kinetically more
favorable than the SET one. Second, the singlet energy surface
of the HAT pathway has a much higher energy than triplet and
quintuplet ones. Third, a triplet−quintuplet intersystem
crossing is observed to make the reaction proceed on the
lowest energy surface, which involves a rate- and stereo-
Dongju Zhang − School of Chemistry and Chemical
Engineering, Shandong University, Jinan 250100, China;
orcid.org/0000-0002-6117-4958; Email: zhangdj@
sdu.edu.cn
3
selectivity-determining HAT step via TS1(R) followed by a
barrier-free oxygen rebound step via 5TS2.25 Fourth, the HAT
process has an “early” transition state with a small degree of
Authors
Shutao Sun − School of Chemistry and Chemical Engineering
and School of Pharmaceutical Sciences, Shandong University,
Jinan 250100, China
Yiying Yang − School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, China
Ran Zhao − School of Pharmaceutical Sciences, Shandong
University, Jinan 250012, China
3
C−H cleavage in TS1(R), which has a rather short C−H
distance compared to that in (R)-1a (1.16 versus 1.10 Å), and
a long H−O distance compared with that in 5IM2 (1.67 versus
0.97 Å; see Figure S6 in the Supporting Information) (Scheme
7B). We next probed the origin of enantioselectivity by
analyzing the free energy profiles of the chiral oxoMn(V) C13-
mediated HAT process for (R)-1a and (S)-1a, respectively
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09636
3
(Scheme 7B). The HAT step for (R)-1a via TS1(R) was 3.0
3
kcal/mol more favorable than that for (S)-1a via TS1(S),
which is consistent with experimentally observed stereo-
selectivity. The noncovalent interaction (NCI) analyses for
these two enantiocontrolling transition states reveal that the
π···π interaction between the N-(3-naphthylmethylene) moiety
Author Contributions
#S.S. and Y.Y. contributed equally to this work.
Notes
The authors declare no competing financial interest.
3
of C13 and phenyl group of 1a in TS1(R) is much stronger
than that in 3TS1(S) (Scheme 7C and Figure S7 in the
Supporting Information). There was an additional π···π
interaction between the phenyl ring of (R)-1a and the phenyl
ACKNOWLEDGMENTS
Financial support was provided by the National Science
Foundation of China (21722204, 21971148).
■
3
moiety on binaphthalene of C13 in TS1(R). These NCI
differences might induce the preference for oxidation of (R)-1a
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CONCLUSION
■
In summary, a manganese-catalyzed site- and enantiodifferen-
tiating oxidation of C(sp3)−H bonds in saturated cyclic ethers
has been described. The mild and practical method is
applicable to a wide range of THFs, THPs, and medium-
sized cyclic ethers with multiple stereocenters and diverse
substituent patterns in high efficiency with extremely efficient
site- and enantiodiscrimination. Direct late-stage site- and
enantiodifferentiating oxidation of biological active molecules
that are otherwise difficult to access was further demonstrated.
Mechanistic studies by combined experiments and computa-
tions elucidated the reaction mechanism and origins of
stereoselectivity. The ability to employ ether substrates as
the limiting reagent, together with a broad substrate scope, and
a high level of chiral recognition, represent a valuable
F
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