Asymmetric Catalytic Epoxidation of Terminal Enones for the Synthesis of Triazole Antifungal Agents

Article abstract of DOI:10.1021/acs.orglett.1c02588

An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good enantioselectivities by employing a chiral N,N′-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It enabled the facile transformation for optically active isavuconazole, efinaconazole, and other potential antifungal agents.

Full text of DOI:10.1021/acs.orglett.1c02588

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Letter
Asymmetric Catalytic Epoxidation of Terminal Enones for the
Synthesis of Triazole Antifungal Agents
Qianwen He, Dong Zhang, Fengcai Zhang, Xiaohua Liu,* and Xiaoming Feng*
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ABSTRACT: An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide
intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good
enantioselectivities by employing a chiral N,N′-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It
enabled the facile transformation for optically active isavuconazole, efinaconazole, and other potential antifungal agents.
he discovery and construction of antifungal azoles is one
of the most interesting targets for medicinal and synthetic
contains a triazole ring linked to a difluorophenyl group
through a two-carbon chain and a hydroxyl group with vicinal
stereogenic centers (red structure).3 This key structural motif
could be obtained via ring opening of trisubstituted epoxide by
means of suitable nucleophiles.4 Concise and efficient
construction of such epoxides with consecutive chiral carbon
centers is in high demand, but represents a formidable task.3−6
Various endeavors toward the preparation of optically active
epoxide have been reported. Most of the initial strategies
involve using D- or L-lactic acid as a chiral pool,5 while only a
few examples concerning asymmetric catalytic routes have
been reported to date (Scheme 1, paths a−c).6 In 1995,
Bennett and co-workers utilized Sharpless’ epoxidation
reaction of uneasily available (Z)-alkene to provide the key
epoxide with 76% ee (path a).7 In 2014, Shibasaki’s group
demonstrated the construction of the key epoxide from
catalytic asymmetric cyanosilylation of ketone (path b).8
Later, Zhang and co-workers disclosed asymmetric allylic
substitution of vinylethylene carbonates with water utilizing a
chiral palladium complex to provide a precursor for the
epoxide (path c).9 Despite these impressive advances, there
still leaves room for further development in terms of synthetic
route, the use of safe, cheap, and high atom-efficient reagents,
and mild reaction conditions.
T
chemists.1 The third generation of triazole antifungal agents,
such as isavuconazole, efinaconazole, albaconazole, and others
(Scheme 1), have advanced properties related to safety, proper
pharmacokinetics, and activity spectrum.2 According to their
structure−activity relationship study, the pharmacophore
Scheme 1. Representative Structures of Antifungal Triazoles
and Their Catalytic Enantioselective Synthesis
Received: August 3, 2021
https://doi.org/10.1021/acs.orglett.1c02588
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Catalytic enantioselective epoxidations of olefins are power-
ful methods widely used in synthesis.10 Various important
substrate classes have been accomplished in the synthesis of
chiral epoxides using a wide range of chiral catalysts and
oxidants.10,11 The epoxidation reaction of readily available
vinyl ketones (path d) provides an alternative access to the key
epoxides for further elaboration in target-oriented synthesis.
Previously, the trial of epoxidation of 1,2-diphenylpropenone
using immobilized PLL yielded moderate enantioselectivity.12
List and co-workers identified an asymmetric catalytic
epoxidation of α-branched, α,β-unsaturated aldehydes via the
synergistic combination of a cinchona-based amine and a chiral
phosphoric acid.13 Cinchona thioureas catalyzing terminal
epoxide synthesis worked well with tert-butyl hydroperoxide
and α-benzoyl-N-phenylacrylamides in Lattanzi’s work.14
Nevertheless, the direct and highly efficient catalytic
asymmetric epoxidation of α-aryl or alkyl substituted terminal
enones by the use of aqueous hydrogen peroxide is still lacking.
Inspired by our previous success in chiral N,N′-dioxide-metal
complex catalysis15,16 and interest in synthesis of azoles
antifungal agents, we explored these catalysts for the
asymmetric catalytic epoxidations of α-branched enones and
accomplished concise syntheses of a series of azole antifungal
agents as well.
desired product 2a in 17% yield with 64% ee. Next, the effect
of solvent was investigated. To our delight, when using ethanol
as the solvent, the yield increased to 64% while a higher ee
value was obtained (Table 1, entry 4). Encouraged by the
result, alcohol solvents were screened carefully (Table 1,
entries 5 and 6). Gratifyingly, isopropanol was the best solvent
candidate which can afford the desired product in 87% yield
with 90% ee (Table 1, entry 6). Upon lowering the catalyst
loading to 5 mol %, the enantioselectivity was maintained in
spite of a lower yield (Table 1, entries 6 and 7). Subsequently,
the structure of the chiral N,N′-dioxide ligands was evaluated.
Variation of the chiral backbones suggested that the (S)-
pipecolic acid-derived L-PiPr2 gave better results, especially
the yield, than the L-proline-derived L-PrPr2 and the L-
ramipril-derived L-RaPr2 (Table 1, entries 7−9). Also, steric
hindrance on the phenyl ring of the ligand had an obvious
effect. A moderate steric hindrance on the amide moiety led to
an increase of yield and ee value (Table 1, entry 10 vs entry 7).
Finally, a higher yield with excellent ee was afforded when
ligand L-PiEt2Me was used (Table 1, entry 11). Other
conditions such as temperature and other metal salts were also
surveyed, but no superior results were obtained (see SI for
details).
With the optimized reaction conditions in hand, the
substrate scope was then screened (Table 2). First, various
α-aryl-substituted vinyl ketones derivatives were examined.
When R2 was set as the methyl group, electron-withdrawing
groups on the aromatic groups gave the corresponding α,β-
epoxyketones 2b−2f in good yields and great enantioselectiv-
In the initial study, 3-phenylbut-3-en-2-one (1a) was
selected as the model substrate to optimize the reaction
conditions. Aqueous hydrogen peroxide was selected as the
oxidant because of its advantage of cheapness, high atom
efficiency, and generation of water as the sole byproduct. First,
different metal salts complexed with N,N′-dioxide L-PiPr2
were examined in MeOH at 30 °C (Table 1, entries 1−3).
Sc(OTf)3 performed better than other metal salts, giving the
a
Table 2. Substrate Scope
a
Table 1. Optimization of Reaction Conditions
b
c
Entry
Metal salt
Ligand
Solvent
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
Sc(OTf)3
La(OTf)3
Eu(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PrPr2
L-RaPr2
L-PiEt2
L-PiEt2Me
MeOH
MeOH
MeOH
EtOH
n-BuOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
17
6
trace
64
24
87
74
trace
17
84
64
42
12
85
73
90
90
84
80
95
95
d
d
d
d
d
11
90
a
a
Unless otherwise noted, all reactions were carried out with 1a (0.1
Unless otherwise noted, all reactions were carried out with L-
mmol), metal salt/ligand (1:1, 10 mol %), 35% aq. H2O2 (0.3 mmol)
PiEt2Me/Sc(OTf)3 (1:1, 5 mol %), 1 (0.2 mmol), and 35% aq. H2O2
(0.6 mmol) in i-PrOH (1.0 mL) at 30 °C. Isolated yield. The ee value
b
in solvent (1.0 mL) at 30 °C for 45 h. Isolated yield of 2a.
c
d
b
Determined by HPLC on a chiral stationary phase. With 1a (0.2
was determined by HPLC on a chiral stationary phase. Purification
c
d
mmol), metal salt/ligand (1:1, 5 mol %), 35% aq. H2O2 (0.6 mmol)
in i-PrOH (1.0 mL) at 30 °C for 24 h.
via flash filtration with a thin silica gel. On a 0.1 mmol scale. In
DME with L-PiMe2Br/Sc(OTf)3 (1:1, 5 mol %).
B
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Scheme 2. Further Transformations of the Product and Stereoselective Synthesis of Efinaconazole, Isavuconazole, and Others
ities (82−87% yield, 89−94% ee). The meta-methyl aryl group
substituted epoxyketone 2g was achieved in 94% yield and
94% ee. However, more electron-rich groups such as para-
methyl and para-methoxyl aryl substituted products could not
be isolated because of decomposition of the epoxides during
purification (see Supporting Information (SI) for details). It
was found that the steric hindrance of the substituent at the
ortho-position had a significant influence on the reactivity and
enantioselectivity. Variation of the R1 unit using the 2-
chlorophenyl group provided the corresponding product 2j in
moderate yield and enantioselectivity (79% yield, 73% ee).
The products (2h and 2i) containing difluorophenyl groups,
key structures for antifungal agents, were provided in 81−86%
yield and 87−91% ee. Furthermore, the vinyl ketone bearing
the 2-naphthyl group could also perform well to yield the
desired product (2k) in excellent enantioselectivity. We were
pleased to find the R2 unit of vinyl ketones could be replaced
with ethyl, n-propyl, n-butyl, isopropyl, cyclohexyl, and aryl
groups, all of which were tolerated in the epoxidation reactions
to afford the desired products 2l−2s in satisfactory yields and
high level of enantioselectivities (67−84% yield, 94−99% ee).
Besides, alteration of R1 and R2 moieties using alkyl groups and
a phenyl or methyl group, respectively, proved efficient under
current reaction conditions. Moderate to good yields with
excellent ee values were obtained after a prolonged reaction
time (2t−2y, 49−93% yield, 84−97% ee). Moreover, exocyclic
enone was suitable for the current reaction, producing
exocyclic terminal epoxide 2z in 55% yield and 89% ee after
modulation of ligand and solvent. The absolute configuration
of the products 2k and 2q were determined to be (S) by X-ray
crystallographic analysis.
The utility of the present methodology was demonstrated by
stereoselective synthesis of the antifungal agents isavuconazole
and efinaconazole (Scheme 2). The epoxidation reaction of
vinyl ketone 1h with antipodal ligand ent-L-PiEt2Me furnished
ent-2h bearing functionalities in a suitable stereochemistry. To
avoid a laborious purification process, and based on previous
work about catalytic epoxide ring-opening reactions,17 we
carried out a one-pot sequential manifestation of asymmetric
epoxidation and ring-opening reaction to allow efficient access
to h-1. After extensive manipulations of the reaction conditions
(see SI for details), the pyrazole-embellished alcohol h-1 was
furnished in 70% yield with 88% ee upon treating with 1,2,4-
triazole, K2CO3, and 3 Å MS in MeCN at 70 °C. However,
attempted reduction of ketone h-1 with NaBH4 proved
unproductive, providing the undesired cis-diastereomer as a
major product. Gratifyingly, the reduction reaction conditions
were subsequently optimized by subjection of h-1 to LiBH4 in
the presence of CoCl2 at −78 °C, which gave the favorable
trans-diol h-2 in 16:1 dr (see SI for details). The diastereomers
were easily separable using silica gel column chromatography
to provide the requisite trans-diol h-2 as a single diastereomer
in 86% yield. Furthermore, the nearly enantiopure (R,R)-diol
h-2 could be afforded by recrystallization. Regioselective
mesylation of diol h-2 and subsequently ring-closure reaction
C
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proceeded smoothly to provide the key intermediate epoxide
h-3 in one pot.
With the significant epoxide h-3 in hand, we demonstrated
its further transformations for the synthesis of isavuconazole.
Successive ring-opening of epoxide with TMSCN in the
presence of TBAF gave h-4 in favor of the desired
diastereomer in a 5.6:1 ratio and excellent yield using
microwave irradiation at 70 °C (see SI for more details).
According to the literature procedure (Scheme 2),5c the nitrile
functionality of h-4 was transformed into a primary thioamide
using diethyl dithiophosphate to give h-5. The treatment of h-
5 with 2-bromo-4′-cyanoacetophenone furnished isavucona-
zole as a single diastereomer in 70% yield and 98% ee.
Furthermore, we also examined the transformation to
efinaconazole and other potential biological activity species.
The synthesis of 2,4-difluoroarylated intermediate epoxide i-3
was easily performed by the procedure similar to that described
in the preparation of h-3. Next, epoxide i-3 was subjected to a
ring-opening reaction with 4-methylenepiperidine by micro-
wave irradiation at 120 °C, affording efinaconazole in 84%
yield and 97% ee. Similarly, the potential bioactive species i-5
and i-6 could be provided by a ring-opening reaction of
epoxide i-3 with 1-(2-(4-fluorophenoxy)ethyl)piperazine and
2-(3,4-dimethoxyphenyl)-N-methylethan-1-amine separately
(Scheme 2). Moreover, after a nucleophilic ring-opening
reaction of the epoxide with sodium azide, catalytic hydro-
genation under a hydrogen atmosphere gave the vicinal amino
alcohol i-7 with maintained enantioselectivity, the key
intermediate for the synthesis of albaconazole18 and YC-
071.19 As a result, these antifungal agents shown in Scheme 1
could be available through the new asymmetric synthetic route.
In addition, other transformations of the ketone unit of h-1
analogs might provide a new chance for synthesis of more
substituted derivatives.
The enantioselectivity-determining step in epoxidation of
terminal enones differs from β-substituted enones,20 where the
second cyclization step determines the ee value rather than the
first oxa-addition step. In order to achieve high enantiose-
lectivity, the limitation of rotation of the intermediate before
cyclization is important. Based on the previous study15 and the
absolute configuration of the products, a working mode was
proposed to elucidate the activation manner and enantiocon-
trol. The chiral N,N′-dioxide L-PiEt2Me, carbonyl group of the
enone, and alcohol or H2O coordinate to the scandium(III),
forming an octahedral complex. As shown in Figure 1, the
complexation of one enone molecule might adopt two
conformers, and the fashion b, where the α-substitution
toward the upward amide unit of the ligand, is proposed to be
unfavorable due to this steric hindrance. The oxa-addition
performs via the transition state TS1, and the hydrogen-net
between hydrogen peroxide and solvent molecule, in
connection with the coordination of oxygens to the metal
centra inhibits the rotation of C−C bond between the α- and
β-position. Then, the cyclization occurs preferably from the α-
Re face via the transition state TS2, and the O−O bond breaks
in the assistance of the metal ion and hydrogen bond, yielding
the (S)-2k as the major product. From the favorable transition
state, both acyl substitution and α-substitution of enone locate
at the open area of the chiral catalyst, and the reaction could
tolerate a wide range of terminal enones.
Figure 1. Proposed working mode.
the key intermediate epoxides in moderate overall yield in
three steps from α-substituted vinyl ketones. The chiral N,N′-
dioxide/Sc(OTf)3 catalytic system benefited the asymmetric
epoxidation process efficiently, providing a wide range of α,α-
disubstituted epoxides in good yields with high enantiose-
lectivities. This strategy provided a highly efficient and
enantioselective route for synthesis of efinaconazole, isavuco-
nazole, and other potential antifungal agents.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02588.
Experimental procedures, full spectroscopic data for all
new compounds, and copies of H, 13C{1H}, NMR and
1
HPLC spectra (PDF)
Accession Codes
CCDC 2060412, 2060723, and 2081873 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Xiaohua Liu − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0001-9555-0555; Email: liuxh@ scu.edu.cn
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478; Email: xmfeng@scu.edu.cn
In conclusion, we have developed an efficient catalytic
asymmetric epoxidation reaction of α-substituted vinyl ketones
with hydrogen peroxide. The reaction allowed to get access to
D
https://doi.org/10.1021/acs.orglett.1c02588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Authors
pubs.acs.org/OrgLett
Letter
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Qianwen He − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Dong Zhang − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Fengcai Zhang − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02588
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the National Natural Science Foundation of
China (Nos. U19A2014 and 21890723) for financial support.
Thanks Dr. Yuqiao Zhou at Sichuan University for X-ray single
crystal analysis.
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