Decarboxylative Organocatalyzed Addition Reactions of Fluoroacetate Surrogates for the Synthesis of Fluorinated Oxindoles

Article abstract of DOI:10.1021/acs.orglett.1c00172

Fluorinated malonic acid half thioesters (F-MAHTs) were used as thioester enolate equivalents in organocatalyzed addition reactions to isatins. The products from a range of different N-protected and nonprotected isatins were obtained under mild reaction conditions in high yields and enantioselectivities. The unique reactivity of the thioester moiety enabled diverse derivatization and allowed for the straightforward access to a fluorinated analogue of the anticancer agent (S)-YK-4-279, a therapeutically active compound against Ewing's sarcoma.

Full text of DOI:10.1021/acs.orglett.1c00172

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Letter
Decarboxylative Organocatalyzed Addition Reactions of
Fluoroacetate Surrogates for the Synthesis of Fluorinated Oxindoles
Dominik Zetschok, Lukas Heieck, and Helma Wennemers*
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ABSTRACT: Fluorinated malonic acid half thioesters (F-
MAHTs) were used as thioester enolate equivalents in organo-
catalyzed addition reactions to isatins. The products from a range
of different N-protected and nonprotected isatins were obtained
under mild reaction conditions in high yields and enantioselectiv-
ities. The unique reactivity of the thioester moiety enabled diverse
derivatization and allowed for the straightforward access to a
fluorinated analogue of the anticancer agent (S)-YK-4-279, a therapeutically active compound against Ewing’s sarcoma.
luorinated small molecules have found widespread use in
medicinal chemistry as the introduction of fluorine can
blocks for further derivatization, for example, into a fluorinated
analog of atorvastatin, a blockbuster antihypercholesterolaemia
drug.3
F
lead to an improved activity, metabolic stability, and
lipophilicity of therapeutically active compounds.1,2 Our
group recently introduced fluorinated malonic acid half
thioesters (F-MAHTs) as fluoroacetate surrogates for stereo-
selective organocatalyzed aldol reactions and their protected
derivatives, monothiomalonates (F-MTMs), for Mannich and
Michael additions.3−5 These reagents are thioester enolate
equivalents (Figure 1A) and allow for the stereoselective
introduction of fluorine at sp3-hybridized carbon centers.3−5
The decarboxylative aldol addition of F-MAHTs to aldehydes
yielded α-fluoro-β-hydroxy thioesters as versatile building
Oxindoles are widespread among natural products and
pharmaceutically active compounds (Figure 1B).6 Fluorinated
derivatives have therefore attracted much attention.7 Most
procedures for the fluorination of oxindoles are, however,
limited to the inner oxindole core.8 Fluorination of the
oxindole side chain is desirable as it can lead to metabolically
more stable derivatives and more rigid structures due to the
fluorine gauche effect (Figure 1B).1,2 To date, protocols for the
preparation of fluorinated 3-hydroxy-3-substituted oxindoles
are limited to the installation of a ketone moiety in the side
chain.9−11 There is therefore a need for more versatile methods
that allow for the incorporation of fluorine into the side chain
of the oxindole scaffold and provide access to different
functional moieties.
We anticipated fluorinated thioester−enolate equivalents as
effective building blocks for the preparation of fluorinated
oxindoles (Figure 1A, right). Further, the thioester should
provide a platform for derivatization12,13 and, thus, be useful
for the preparation of, for example, fluorinated oxindoles of
therapeutic relevance.
Herein, we report the enantioselective, organocatalyzed
addition of F-MAHTs to isatins. We show that the obtained
fluorinated oxindole-thioesters can be converted into multiple
different derivatives in good yields. The methodology also
provided access to a fluorinated analogue of (S)-YK-4-279, a
Received: January 18, 2021
Published: February 16, 2021
Figure 1. (A) F-MAHTs as fluoroacetate surrogates and the addition
reaction to aldehydes and isatins, respectively. (B) Examples of
oxindole natural products or pharmaceutically active compounds. The
arrows mark positions for selective fluorination via fluoroacetate
chemistry.
https://dx.doi.org/10.1021/acs.orglett.1c00172
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1753−1757
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Letter
therapeutically active compound against the rare bone cancer
Ewing’s sarcoma.14
We started our investigations by allowing F-MAHT 1 and F-
MTM 2 to react with N-methylisatin in THF in the presence
of an epi-quinidine−urea organocatalyst (Cat A) that had been
optimal for related reactions (Table 1, top).3 The reaction with
the addition reaction of 1 to N-methyl isatin with the highest
conversion (quant.) and enantioselectivity (82% ee, Table 1,
entry 4). Subsequently we tested modifications of catalyst D
and performed a screening of the reaction parameters,
including the solvent, stoichiometry, additives, and temper-
ature.18 These studies revealed that epi-cinchonidine−
sulfonamide catalyst E19,20 is optimal for catalyzing the
addition of F-MAHT to N-methylisatin. In acetone at 10 °C,
4a was obtained in 98% yield, 1.5:1 dr, and 92% ee (Table 1
entry 8).
Table 1. Addition of a F-MAHT and a F-MTM to N-
Methylisatin
Regardless of the conditions, the diastereoselectivity of the
addition remained poor. This finding is likely due to
decarboxylation of the F-MAHT after C−C bond forma-
tion15−17 without substrate or catalyst control. Neither basic or
acidic additives nor catalyst optimization improved the
diastereoselectivity of the reaction.18 However, the obtained
diastereoisomers could be separated by column chromatog-
raphy, thus enabling the isolation of both diastereoisomers.
Next, we evaluated the scope of the F-MAHT addition to
isatins (Scheme 1). At first, we examined differently
substituted N-methylisatins and observed that both electron-
rich and electron-poor isatins reacted efficiently to yield 3-
hydroxyoxindoles in good to excellent yields (78−98%) and
enantioselectivities (87−93% ee, 4c, 4d, 4f−h). Whereas
previous synthetic protocols for the synthesis of monofluori-
nated 3-hydroxyoxindoles10 did not tolerate substituents at C4,
F-MAHT 1 reacted readily with 4-substituted isatins in good
yields and excellent enantioselectivities (4i, 4j, 4l−n). Even the
isatin with a sterically demanding bromine substituent reacted,
and addition product 4l was isolated in 79% yield and 96% ee.
The poorest reactivity was observed for the bulky biphenyl
derivative 4m that was still isolated in 35% yield and 99% ee.
In addition, 3-hydroxyoxindoles with substituents at each of
the other positions and/or more than one substituent were
readily obtained (4n, 4q−v). We also probed derivatives with
different substituents at the isatin N and found that methyl and
benzyl protection afforded products with high yields and
stereoselectivities (4n and 4p). Boc-protected isatins did not
yield the desired product, which was probably due to
competitive hydrogen bonding with the catalyst and/or the
increased steric hindrance. Remarkably, reactions with
unprotected isatin derivatives provided the addition products
(4b, 4e, 4k, 4o) in comparable yields and enantioselectivity as
observed for the N-alkylated analogues (4a, 4d, 4j, 4n). These
findings show that isatins with a broad range of substituents
and substitution patterns and even unprotected isatins react
readily to enantioenriched fluorinated 3-hydroxyoxindoles
under the optimized reaction conditions.
a
b
c
d
e
entry
cat.
solvent
additive
conv
dr
ee
1
2
3
4
5
6
7
8
A
B
C
D
D
D
D
E
F
E
E
E
THF
THF
THF
THF
91
>98
>98
>98
12
1.1:1
1.3:1
1.2:1
1.5:1
1.1:1
1.4:1
1.4:1
1.5:1
1.6:1
1.8:1
1.5:1
−64
−30
14
−82
−82
−82
−90
92
73
31
89
57
CH2Cl2
toluene
acetone
acetone
acetone
acetone
acetone
acetone
8
>98
>98
>98
83
75
>98
9
10
11
12
DMAP
PhCO2H
Et3N
1.3:1
a
b
c
N-Methylisatin 25 mM, F-MAHT 37.5 mM. 0.5 equiv. Conversion
as estimated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene
d
e
as internal standard. dr as determined by 1H NMR spectroscopy. ee
as determined by chiral stationary-phase HPLC and/or SFC.
Single crystals of 4p revealed the absolute and relative
configuration of the fluorinated 3-hydroxyoxindole (Scheme
1).21 Within the crystal structure, the relative orientation of the
vicinal F and OH groups is gauche and that of the F and
thioester groups is anti. This finding suggests that the
conformation of the 3-hydroxyoxindoles is controlled by a
gauche effect.
Next, we explored the synthetic versatility of the thioester
moiety. The transformation of 4a into oxoester 5 and amide 6
by the addition of an alcohol or amine, respectively, afforded
the desired products in quantitative yields (Scheme 2, top).
Furthermore, we were able to obtain the corresponding alcohol
7 by reduction with sodium borohydride and ketone 8 under
Liebeskind−Srogl conditions22 in good yields (Scheme 2,
bottom).
F-MTM did not yield the desired product 3, and only starting
material was recovered. Here, the reactants are most likely in
equilibrium with the addition product 3, but the equilibrium
lies on the side of the starting materials. In contrast, the
addition of F-MAHT 1 to isatin proceeded well and afforded
the product 4a with 91% yield and an encouraging 64% ee.
These results show that the decarboxylation of F-MAHT over
the course of the addition provides a strong driving force and is
key for the reaction to proceed.4,15−17
Variations of the hydrogen-bonding motif within the
cinchona alkaloid catalyst with urea, thiourea, squareamide
and sulfonamide moieties showed that sulfonamide D catalyzes
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Letter
Scheme 1. Scope of the F-MAHT Addition to Isatins
a
corresponding boronic acid did not enable the conversion of
thioester ent-4o. This significantly lower reactivity of ent-4o
compared to 4a is most likely due to the greater steric
congestion caused by the chlorine substituent, thereby
hindering the oxidative addition onto the palladium catalyst.
Reassuringly, careful addition of the corresponding Grignard
reagent to thioester ent-4o allowed for the preparation of
ketone 9 in 60% yield, albeit with an erosion of the
diasteroselectivity under the basic reaction conditions (Scheme
3). No evidence of overaddition of the Grignard reagent to the
formed ketone was observed.
Scheme 2. Derivatization of the Thioester Moiety
a
Conditions: (a) K2CO3 (3.0 equiv), MeOH, rt, 2 h; (b) BnNH2 (3.0
Scheme 3. Synthesis of Fluorinated (S)-YK-4-279
equiv), CH2Cl2, rt, 5 h; (c) NaBH4 (5.0 equiv), THF, 0 °C, 1 h; (d)
CuTC (1.6 equiv), PMPB(OH)2 (1.2 equiv), Pd2dba3 (5 mol %),
(furyl)3P (15 mol %), THF, 50 °C, 20 h.
Encouraged by these results, we explored the synthesis of a
fluorinated analogue of (S)-YK-4-279, a biologically active
compound against the rare bone cancer Ewing’s sarcoma.14 We
envisioned a concise access to the fluorinated target ketone 9
by addition of F-MAHT 1 to 4,7-dichloroisatin in the presence
of the pseudoenantiomer of catalyst E23 as the key step.
Indeed, the mirror-image addition product ent-4o was obtained
with the same high enantioselectivity (92% ee), and the
diastereoisomers (dr 1.8:1) were separated by column
chromatography.24 Somewhat surprisingly, Fukuyama cou-
pling13 with (4-methoxyphenyl)zinc bromide under different
conditions did not yield ketone 9, and only starting material
remained. In addition, Liebeskind−Srogl conditions with the
In summary, we have developed an efficient organocatalytic
method for the synthesis of fluorinated 3-hydroxyoxindoles
with excellent yields and enantioselectivities. The methodology
puts forth the first addition of F-MAHTs to ketones and
tolerates both protected and unprotected isatins with a diverse
set of substituents and substitution patterns. The thioester
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Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition.
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allowed the concise synthesis of a fluorinated analogue of (S)-
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MAHTs as fluoroacetate surrogates in decarboxylative addition
reactions.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00172.
■
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Accession Codes
CCDC 2049349 and 2056442 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 Author
■
Helma Wennemers − Laboratory of Organic Chemistry, D-
CHAB, ETH Zurich, CH-8093 Zurich, Switzerland;
orcid.org/0000-0002-3075-5741;
Email: helma.wennemers@org.chem.ethz.ch
Authors
Dominik Zetschok − Laboratory of Organic Chemistry, D-
CHAB, ETH Zurich, CH-8093 Zurich, Switzerland
Lukas Heieck − Laboratory of Organic Chemistry, D-CHAB,
ETH Zurich, CH-8093 Zurich, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00172
Author Contributions
D.Z. and L.H. conducted the experiments. D.Z. and H.W.
conceived and designed the project, analyzed the data, and
prepared this manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Swiss National Science
Foundation (grant 200020_169423). We thank Dr. Nils Trapp
and Michael Solar from the Small Molecule Crystallography
Center (SMoCC) of ETH Zurich for recording the X-ray
crystal structures.
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