Oxidative Kinetic Resolution of Cyclic Benzylic Ethers

Article abstract of DOI:10.1002/anie.202009594

A manganese-catalyzed oxidative kinetic resolution of cyclic benzylic ethers through asymmetric C(sp³)?H oxidation is reported. The practical approach is applicable to a wide range of 1,3-dihydroisobenzofurans bearing diverse functional groups and substituent patterns at the α position with extremely efficient enantiodiscrimination. The generality of the strategy was further demonstrated by efficient oxidative kinetic resolution of another type of five-membered cyclic benzylic ether, 2,3-dihydrobenzofurans, and six-membered 6H-benzo[c]chromenes. Direct late-stage oxidative kinetic resolution of bioactive molecules that are otherwise difficult to access was further explored.

Full text of DOI:10.1002/anie.202009594

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How to cite:
International Edition: doi.org/10.1002/anie.202009594
German Edition: doi.org/10.1002/ange.202009594
Asymmetric Catalysis
Oxidative Kinetic Resolution of Cyclic Benzylic Ethers
Shutao Sun, Yingang Ma, Ziqiang Liu, and Lei Liu*
Abstract: A manganese-catalyzed oxidative kinetic resolution
bond adjacent to ether oxygen has never been disclosed to
date.[9]
Compared with alcohols and amines, cyclic benzylic ethers
3
À
of cyclic benzylic ethers through asymmetric C(sp ) H
oxidation is reported. The practical approach is applicable to
a wide range of 1,3-dihydroisobenzofurans bearing diverse
functional groups and substituent patterns at the a position
with extremely efficient enantiodiscrimination. The generality
of the strategy was further demonstrated by efficient oxidative
kinetic resolution of another type of five-membered cyclic
benzylic ether, 2,3-dihydrobenzofurans, and six-membered
6H-benzo[c]chromenes. Direct late-stage oxidative kinetic
resolution of bioactive molecules that are otherwise difficult
to access was further explored.
lack a strong interaction site with catalyst, which is typically
indispensable in asymmetric catalysis to engage both desired
reactivity and selectivity by directing substrate to an ideal
location in the transition state. Accordingly, chiral discrim-
ination of two ether enantiomers of the racemate would be
particularly difficult to achieve. We envisioned that the key to
success in OKR of benzylic ethers lies in discovering a chiral
catalyst with rigid scaffold whose specificity and catalytic
power come from the inflexible fit of the right enantiomer
onto the preformed catalyst surface. As part of our ongoing
interest in developing practical synthetic methods through
A
symmetric oxidation is a powerful and efficient strategy to
access valuable optically pure compounds.[1] Significant
progress has been made in asymmetric oxidation of reactive
functional groups such as alkenes and sulfides. However,
enantioselective oxidation of much less reactive aliphatic
sustainable asymmetric C H oxidation strategy,
we now
[8b]
À
report a manganese-catalyzed OKR of cyclic benzylic ethers.
a-Substituted 1,3-dihydroisobenzofurans are present in
a number of bioactive molecules.[10] Surprisingly, few asym-
metric synthetic methods have been established.[11] Therefore,
OKR of ether rac-1a was initially used as the reference
reaction with PhIO as the oxo-transfer agent to search for
a suitable chiral catalyst (Table 1). Chiral Mn(salen) C1
exhibited oxidation catalysis reactivity, though poor enantio-
selectivity was obtained (entry 1). We envisioned that prop-
erly introducing an axial chirality at C3(3’) sites of the basal
salen ligand would enhance the ability of Mn(salen) catalyst
in differentiating the two enantiomers. Delightedly, promising
chiral discrimination was observed when Mn(salen) C2–C5
bearing binaphthyl groups of axial chirality were employed,
and the Ra,S Mn(salen) C4 proved to be optimal (entries 2–
5).[3c] Further fine-tuning the binaphthyl moiety identified C9
to be the superior catalyst (entries 6–10). Temperature and
addition manner of oxidant were found to be crucial to
achieving an extremely high chiral recognition, and when
PhIO (0.6 equiv) was added as six equal portions in 30 min
intervals at À408C, (R)-1a was isolated in 49% yield with
98% ee (Krel = 152.9; entries 11–14).
À
C H bonds by nonenzymatic means has remained a daunting
challenge.[2] Only a few examples of nonenzymatic asymmet-
À
ric C H oxidation have been reported, which typically suffer
from moderate enantiocontrol, low substrate conversion, and
narrow substrate scope.[3,4] Developing an efficient catalytic
À
asymmetric C H oxidation with practical value for synthesis
would be highly desirable.
Optically pure a-substituted cyclic benzylic ethers are key
structural motifs spread across medicinally relevant natural
products and synthetic pharmaceuticals. Considerable advan-
ces have been made in their asymmetric synthesis through
manipulation of prefunctionalized olefins or acetals.[5] How-
ever, each method is typically suitable for specific ether
skeleton and a-functionality. Given the ready availability of
structurally diverse racemic cyclic benzylic ethers, oxidative
kinetic resolution (OKR) through enantioselective oxidation
3
À
of C(sp ) H bonds adjacent to ether oxygen would be an
attractive strategy to access optically pure ethers with diverse
skeletons and a-substituent patterns.[6] Existing KR studies
À
initiated by asymmetric C H oxidation predominantly
The scope of OKR of a-substituted 1,3-dihydroisobenzo-
furans was then investigated (Scheme 1). In general, sub-
strates bearing either electron-donating or electron-with-
drawing substituents around the 1,3-dihydroisobenzofuran
arene were tolerated, and respective 1a–1g were recovered in
good efficiency with 95–99% ee (Scheme 1A).[12a] Modifica-
tion of the geminal C1 disubstitution did not impair the
reactivity and enantioselectivity for 1h–1l. Notably, spirocy-
clic 1i–1k with different ring size and substituent pattern were
well compatible with oxidation process. Moreover, ether 1l
bearing two stereogenic centers at a positions was competent
component with good enantiodiscrimination. A modest ee
value was observed for 1m without a C3 substituent probably
focused on secondary alcohols and amines.[7,8] To our knowl-
À
edge, KR of ethers through asymmetric oxidation of C H
[*] S. Sun, Y. Ma, Z. Liu, Prof. Dr. L. Liu
School of Pharmaceutical Sciences, Shandong University
Jinan 250100 (P. R. China)
E-mail: leiliu@sdu.edu.cn
S. Sun, Prof. Dr. L. Liu
School of School of Chemistry and Chemical Engineering
Shandong University
Jinan 250100 (P. R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202009594.
À
owing to competitive oxidation of the C3 H bond. OKR of
ethers 1n–1t bearing a wide range of electronically varied
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Table 1: Optimization of the reaction conditions.[a]
Entry
Catalyst
Conv. [%][b]
ee [%][c]
Krel
1.3
2.7
2.7
11.7
10.5
2.3
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C9
C9
C9
C9
30
38
41
37
40
39
36
42
38
37
46
32
49
51
5
23
25
45
49
20
3
26
56
8
1.1
2.7
38.9
1.4
64.1
21.7
117.4
152.9
10
11[d]
12[e]
13[d,f]
14[d,g]
79
41
91
98
[a] Reaction conditions: rac-1a (0.1 mmol), catalyst (5 mol%), and PhIO
(0.06 mmol) in CH2Cl2 (1.0 mL) at À108C for 2 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] Reac-
tion at À408C. [e] Reaction at À608C. [f] PhIO was added in three
portions at 30 min intervals over 1.5 h. [g] PhIO was added in six
portions at 30 min intervals over 2.5 h. PMP=4-MeOC6H4.
Scheme 1. Scope of the reaction of 1,3-dihydroisobenzofurans. Yields
are for recovered 1. [a] Reaction with 0.5 mmol of rac-1. [b] Catalyst C3
(5 mol%) was used. [c] Catalyst C9 (5 mol%) was used. Bz=benzoyl,
TBS=tert-butyldimethylsilyl.
a-aryl groups proceeded smoothly. a-Alkynyl-substituted
ethers were also competent components, as demonstrated
by effective OKR of aryl acetylenes 1aa–1af and alkyl
acetylenes 1ag–1aj.[12b] Commonly encountered functionali-
ties were well tolerated as additional functional handles.
Notably, a-alkynyl-substituted 1,3-dihydroisobenzofurans
cannot be prepared with existing asymmetric methods. The
skeleton 1ak with an a-alkyl substituent was also tolerated.
To further demonstrate the generality in asymmetric
access to diverse cyclic benzylic ethers, OKR of 2,3-dihydro-
benzofurans, the other type of biologically important five-
membered skeleton, was next examined (Scheme 2). Ethers
3a–3c bearing electronically varied a-aryl moieties were
tolerated. No identifiable oxidized product was detected,
which might be ascribed to over-oxidation of phenol 4 by
PhIO. 2,3-Dihydrobenzofurans containing diverse a-alkyl
substituents were also competent candidates, as demon-
strated by isolating enantiopure 3d–3i with good selectivity
factors.
Besides five-membered cyclic benzylic ethers, the applic-
ability to six-membered cyclic benzylic ethers was then
studied (Scheme 3). In general, substituents on either arene
ring of 6H-benzo[c]chromene skeleton were well-tolerated,
and respective 5a–5m were resolved with excellent selectivity
factors (34.7–152.9).[12c] OKR of isochroman 5n proceeded
with a modest selectivity factor. Racemic 5o–5s containing
a range of electronically varied aryl and heteroaryl moieties at
a position participated in OKR process smoothly. a-Alkyl-
substituted 5t–5x were also well tolerated.
Perhaps the most striking advance of the strategy would
be direct late-stage OKR of bioactive molecules that are
otherwise difficult to access (Scheme 4). a-PMP-substituted
3H-spiro[isobenzofuran-1,4’-piperidine] 7 is a potential ther-
apeutic agent to central nervous system with marked anti-
2
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Scheme 2. Scope of the reaction of 2,3-dihydrobenzofurans. TMS=tri-
methylsilyl.
Scheme 4. Synthetic utility and gram-scale reaction study.
tetrabenazine activity (Scheme 4A).[10a] Under standard con-
ditions, rac-8 underwent OKR process smoothly, and (R)-8
was recovered in 48% yield with 95% ee (Krel = 56.4).
Corsifuran A (9) is isolated from the Mediterranean liverwort
Corsinia coriandrina, and exhibits promising antinociceptive
effect in mice (Scheme 4B).[13] OKR of rac-9 proceeded, and
remaining (S)-9 was isolated in 45% yield with 91% ee (Krel
=
21.2).[12c] A gram-scale reaction proceeded without obvious
loss of selectivity factor, as demonstrated by recovery of (R)-
5j in 47% yield with 97% ee (Scheme 4C).
Mechanistic studies were performed to get a preliminary
understanding of manganese-catalyzed OKR of cyclic ben-
zylic ethers (Scheme 5). The Hammett plot (log(kX/kH) versus
s) for competitive oxidation of 1o and respective 1a and 1p–
1s was shown in Scheme 5A.[14] The observed plot displayed
linear correlation with a 1 value of À0.288 (R2 = 0.98). Good
linearity suggests that oxidation proceeds through a single
mechanism.[15a,b] The quite small negative value of 1 together
with the poor correlation with s+ (R2 = 0.92, see the Support-
ing Information) indicate the absence of obvious charge
separation in the transition state.[15c,d,16] Radical clock experi-
ment was next performed (Scheme 5B). Subjecting cyclo-
propane 10 to asymmetric oxidation conditions provided
a mixture of hydroxylated 11 and spirocyclic ether 12. We
envisioned that both 11 and 12 should be generated from
carbon-centered radical 13. In general, there are two plausible
mechanisms for converting 10 to 13, which are 1) one-step
hydrogen atom transfer (HAT) and 2) single electron transfer
(SET) followed by proton transfer.[17] Competitive and
independent deuterium kinetic isotope effect (KIE) studies
of rac-1a and [D]-rac-1a revealed respective KIE of 1.3 and
1.0 (Schemes 5C and D).[18] These values suggested that the
À
C H bond cleavage should not be involved in the rate-
Scheme 3. OKR of a-substituted 6H-benzo[c]chromenes. [a] Reaction
with 0.5 mmol of rac-5a. [b] Catalyst C3 (5 mol%) was used. [c] Cata-
lyst C9 (5 mol%) was used.
determining step. Given that manganese-catalyzed HAT
typically exhibits a high KIE, the HAT pathway might be
excluded for this reaction.[17] Instead, it has been reported that
À
manganese-catalyzed C H oxidation with a KIE around 1.0
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furans, (S)-1 should be oxidized more preferentially than
(R)-1.
In summary, the first OKR of cyclic benzylic ethers has
been established. The practical manganese-catalyzed asym-
3
À
metric C(sp ) H oxidation is applicable to a range of five-
membered 1,3-dihydroisobenzofurans and 2,3-dihydrobenzo-
furans together with six-membered 6H-benzo[c]chromenes
bearing diverse a-substituent patterns with extremely effi-
cient enantiodiscrimination. The direct late-stage OKR of
bioactive molecules that are otherwise difficult to access was
further investigated. This strategically different approach
would unlock opportunities for topologically straightforward
synthetic planning for asymmetric access to diversely sub-
stituted cyclic benzylic ethers.
Acknowledgements
We gratefully acknowledge the National Science Foundation
of China (21722204 and 21971148).
Conflict of interest
The authors declare no conflict of interest.
À
Keywords: asymmetric C H oxidation · cyclic benzylic ethers ·
kinetic resolution · late-stage oxidation · synthetic methods
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À
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À
Finally, the rebound of incipient substrate radical 23 to 22
affords hemiacetal 2 and regenerates MnIII 18. Based on
the absolute configuration of recovered 1,3-dihydroisobenzo-
4
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Manuscript received: July 12, 2020
Version of record online: && &&, &&&&
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Communications
Asymmetric Catalysis
S. Sun, Y. Ma, Z. Liu,
L. Liu*
&&&& — &&&&
Oxidative Kinetic Resolution of Cyclic
Benzylic Ethers
A manganese-catalyzed kinetic resolution
bearing diverse a-substituents with
extremely efficient enantiodiscrimination
(see scheme). Late-stage oxidative kinetic
resolution of bioactive molecules that are
otherwise difficult to access was further
demonstrated.
3
À
through asymmetric C(sp ) H oxidation
was applied to a wide range of five-
membered 1,3-dihydroisobenzofurans
and 2,3-dihydrobenzofurans as well as
six-membered 6H-benzo[c]chromenes
6
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Angew. Chem. Int. Ed. 2020, 59, 1 – 6
These are not the final page numbers!