Decarboxylative Organocatalyzed Addition Reactions of
Fluoroacetate Surrogates for the Synthesis of Fluorinated Oxindoles
Dominik Zetschok, Lukas Heieck, and Helma Wennemers*
Cite This: Org. Lett. 2021, 23, 1753−1757 Read Online
ACCESS Metrics & More Article Recommendations *sı Supporting Information
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.
Fluorinated small molecules have found widespread use in
medicinal chemistry as the introduction of fluorine can
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
blocks for further derivatization, for example, into a fluorinated
analog of atorvastatin, a blockbuster antihypercholesterolaemia
drug.3
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
Figure 1. (A) F-MAHTs as fluoroacetate surrogates and the addition Published: February 16, 2021
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.
pubs.acs.org/OrgLett Letter
© 2021 American Chemical Society 1753

https://dx.doi.org/10.1021/acs.orglett.1c00172

Org. Lett. 2021, 23, 1753−1757
Downloaded via UNIV OF CONNECTICUT on May 15, 2021 at 14:14:15 (UTC).
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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
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
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).
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.
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).
Table 1. Addition of a F-MAHT and a F-MTM to N￾Methylisatin
entry cat. solventa additiveb convc drd eee
1 A THF 91 1.1:1 −64
2 B THF >98 1.3:1 −30
3 C THF >98 1.2:1 14
4 D THF >98 1.5:1 −82
5 D CH2Cl2 12 1.1:1 −82
6 D toluene 8 1.4:1 −82
7 D acetone >98 1.4:1 −90
8 E acetone >98 1.5:1 92
9 F acetone >98 1.6:1 73
10 E acetone DMAP 83 1.8:1 31
11 E acetone PhCO2H 75 1.5:1 89
12 E acetone Et3N >98 1.3:1 57
N-Methylisatin 25 mM, F-MAHT 37.5 mM. b
0.5 equiv. c
Conversion
as estimated by 1
H NMR spectroscopy using 1,3,5-trimethoxybenzene
as internal standard. d
dr as determined by 1
H NMR spectroscopy. e
as determined by chiral stationary-phase HPLC and/or SFC.
Organic Letters pubs.acs.org/OrgLett Letter

https://dx.doi.org/10.1021/acs.orglett.1c00172

Org. Lett. 2021, 23, 1753−1757
1754
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
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.
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
Scheme 1. Scope of the F-MAHT Addition to Isatins
Scheme 2. Derivatization of the Thioester Moietya
Conditions: (a) K2CO3 (3.0 equiv), MeOH, rt, 2 h; (b) BnNH2 (3.0
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.
Scheme 3. Synthesis of Fluorinated (S)-YK-4-279
Organic Letters pubs.acs.org/OrgLett Letter

https://dx.doi.org/10.1021/acs.orglett.1c00172

Org. Lett. 2021, 23, 1753−1757
1755
moiety provides a platform for fruitful follow up chemistry and
allowed the concise synthesis of a fluorinated analogue of (S)-
YK-4-279. The results highlight the versatility and utility of F￾MAHTs as fluoroacetate surrogates in decarboxylative addition
reactions.
■ ASSOCIATED CONTENT
*sı Supporting Information
The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.1c00172.

Experimental details, optimization of reaction conditions
and catalyst, as well as analytical data including NMR
spectra, HPLC chromatograms, and X-ray crystal
structure of 4m and 4p (PDF)
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 [email protected], 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: [email protected]
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.
■ REFERENCES
(1) For selected reviews, see: (a) Wang, J.; Sanchez-Roselló, M.; ́
Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok,
V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine￾Containing Drugs Introduced to the Market in the Last Decade
(2001−2011). Chem. Rev. 2014, 114, 2432−2506. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal
chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (c) O’Hagan, D.
Understanding organofluorine chemistry. An introduction to the C−F
bond. Chem. Soc. Rev. 2008, 37, 308−319. (d) Muller, K.; Faeh, C.;
Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition.
Science 2007, 317, 1881−1886.
(2) For a recent perspective, see: Müller, K. Organic Fluorine: The
Mighty Mite. Chimia 2019, 73, 417−419.
(3) Saadi, J.; Wennemers, H. Enantioselective aldol reactions with
masked fluoroacetates. Nat. Chem. 2016, 8, 276−280.
(4) Cosimi, E.; Engl, O. D.; Saadi, J.; Ebert, M.; Wennemers, H.
Stereoselective Organocatalyzed Synthesis of α-Fluorinated β-Amino
Thioesters and Their Application in Peptide Synthesis. Angew. Chem.,
Int. Ed. 2016, 55, 13127−13131.
(5) Cosimi, E.; Saadi, J.; Wennemers, H. Stereoselective synthesis of
α-fluoro-γ-nitro thioesters under organocatalytic conditions. Org. Lett.
2016, 18, 6014−6017.
(6) For selected reviews, see: (a) Cao, Z.; Zhou, F.; Zhou, J.
Development of Synthetic Methodologies via Catalytic Enantiose￾lective Synthesis of 3,3-Disubstituted Oxindoles. Acc. Chem. Res. 2018,
51, 1443−1454. (b) Kaur, M.; Singh, M.; Chadha, N.; Silakari, O.
Oxindole: A chemical prism carrying plethora of therapeutic benefits.
Eur. J. Med. Chem. 2016, 123, 858−894. (c) Figueiredo, G. S. M.;
Zardo, R. S.; Silva, B. V.; Violante, F. A.; Pinto, A. C.; Fernandes, P.
D. Convolutamydine A and synthetic analogues have antinociceptive
properties in mice. Pharmacol., Biochem. Behav. 2013, 103, 431−439.
(7) (a) Gribkoff, V. K.; Starrett, J. E.; Dworetzky, S. I.; Hewawasam,
P.; Boissard, C. G.; Cook, D. A.; Frantz, S. W.; Heman, K.; Hibbard, J.
R.; Huston, K.; Johnson, G.; Krishnan, B. S.; Kinney, G. G.;
Lombardo, L. A.; Meanwell, N. A.; Molinoff, P. B.; Myers, R. A.;
Moon, S. L.; Ortiz, A.; Pajor, L.; Pieschl, R. L.; Post-Munson, D. J.;
Signor, L. J.; Srinivas, N.; Taber, M. T.; Thalody, G.; Trojnacki, J. T.;
Wiener, H.; Yeleswaram, K.; Yeola, S. W. Targeting acute ischemic
stroke with a calcium-sensitive opener of maxi-K potassium channels.
Nat. Med. 2001, 7, 471−477. (b) Badillo, J. J.; Hanhan, N. V.; Franz,
A. K. Enantioselective synthesis of substituted oxindoles and
spirooxindoles with applications in drug discovery. Curr. Opin. Drug
Discovery Devel 2010, 13, 758−776. (c) Hewawasam, P.; Gribkoff, V.
K.; Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.; Martinez, E.;
Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram, K.;
Pajor, L. M.; Knipe, J.; Gao, Q.; Perrone, R.; Starrett, J. E. The
synthesis and characterization of BMS-204352 (MaxiPost) and related
3-fluorooxindoles as openers of maxi-K potassium channels. Bioorg.
Med. Chem. Lett. 2002, 12, 1023−1026.
(8) (a) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.;
Sodeoka, M. Catalytic enantioselective fluorination of oxindoles. J.
Am. Chem. Soc. 2005, 127, 10164−10165. (b) Ishimaru, T.; Shibata,
N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M.
Cinchona alkaloid catalyzed enantioselective fluorination of allyl
silanes, silyl enol ethers, and oxindoles. Angew. Chem., Int. Ed. 2008,
47, 4157−4161. (c) Tang, X.-J.; Thomoson, C. S.; Dolbier, W. R.
Photoredox-Catalyzed Tandem Radical Cyclization of N-Arylacryla￾mides: General Methods To Construct Fluorinated 3,3-Disubstituted
2-Oxindoles Using Fluoroalkylsulfonyl Chlorides. Org. Lett. 2014, 16,
4594−4597. (d) Bort, A.; Quesada, S.; Ramos-Torres, A.; Gargantilla,
M.; Priego, E. M.; Raynal, S.; Lepifre, F.; Gasalla, J. M.; Rodriguez￾Henche, N.; Castro, A.; Diaz-Laviada, I. Identification of a novel 2-
oxindole fluorinated derivative as in vivo antitumor agent for prostate
cancer acting via AMPK activation. Sci. Rep. 2018, 8, 4370.
(9) Saidalimu, I.; Fang, X.; He, X.; Liang, J.; Yang, X.; Wu, F. Highly
Enantioselective Construction of 3-Hydroxy Oxindoles through a
Decarboxylative Aldol Addition of Trifluoromethyl α-Fluorinated
gem-Diols to N-Benzyl Isatins. Angew. Chem., Int. Ed. 2013, 52,
5566−5570.
(10) Li, Y.-L.; Wang, X.-L.; Xiao, D.; Liu, M.-Y.; Du, Y.; Deng, J.
Organocatalytic Biomimetic Decarboxylative Aldol Reaction of
Fluorinated β-Keto Acids with Unprotected Isatins. Adv. Synth.
Catal. 2018, 360, 4147−4152.
(11) For other examples of difluorinated 3-hydroxyoxindoles, see:
(a) Liu, Y. L.; Zhou, J. Organocatalytic asymmetric synthesis of 3-
difluoroalkyl 3-hydroxyoxindoles. Chem. Commun. 2012, 48, 1919−
1921. (b) Yu, J.-S.; Liu, Y.-L.; Tang, J.; Wang, X.; Zhou, J. Highly
Efficient “On Water” Catalyst-Free Nucleophilic Addition Reactions
Organic Letters pubs.acs.org/OrgLett Letter

https://dx.doi.org/10.1021/acs.orglett.1c00172

Org. Lett. 2021, 23, 1753−1757
1756
Using Difluoroenoxysilanes: Dramatic Fluorine Effects. Angew. Chem.
2014, 126, 9666−9670.
(12) (a) Engl, O. D.; Fritz, S. P.; Wennemers, H. Stereoselective
organocatalytic synthesis of oxindoles with adjacent tetrasubstituted
stereocenters. Angew. Chem., Int. Ed. 2015, 54, 8193−8197.
(b) Clerici, P.; Wennemers, H. Mono thiomalonates as thioester
enolate equivalentsenantioselective 1,4-addition reactions to nitro￾olefins under mild conditions. Org. Biomol. Chem. 2012, 10, 110−113.
(13) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Lin, S.-C.; Li,
L.; Fukuyama, T. Facile palladium-mediated conversion of ethanethiol
esters to aldehydes and ketones. J. Braz. Chem. Soc. 1998, 9, 381−387.
(b) Miyazaki, T.; Han-ya, X.; Tokuyama, H.; Fukuyama, T. New
odorless protocols for the synthesis of aldehydes and ketones from
thiol esters. Synlett 2004, 477−480.
(14) (a) Erkizan, H. V.; Kong, Y.; Merchant, M.; Schlottmann, S.;
Barber-Rotenberg, J. S.; Yuan, L.; Abaan, O. D.; Chou, T.;
Dakshanamurthy, S.; Brown, M. L.; Ü
ren, A.; Toretsky, J. A. A
small molecule blocking oncogenic protein EWS-FLI1 interaction
with RNA helicase A inhibits growth of Ewing’s sarcoma. Nat. Med.
2009, 15, 750−756. (b) Barber-Rotenberg, J. S.; Selvanathan, S. P.;
Kong, Y.; Erkizan, H. V.; Snyder, T. M.; Hong, S. P.; Kobs, C. L.;
South, N. L.; Summer, S.; Monroe, P. J.; Chruszcz, M.; Dobrev, V.;
Tosso, P. N.; Scher, L. J.; Minor, W.; Brown, M. L.; Metallo, S. J.;
ren, A.; Toretsky, J. A Single Enantiomer of YK-4−279
Demonstrates Specificity in Targeting the Oncogene EWS-FLI1.
Oncotarget 2012, 3, 172−182.
(15) Note that previous studies showed that reactions with malonic
acid half thioesters proceed via C−C bond formation followed by
decarboxylation.16,17
(16) Lubkoll, J.; Wennemers, H. Mimicry of Polyketide Synthases
Enantioselective 1,4-Addition Reactions of Malonic Acid Half￾Thioesters to Nitroolefins. Angew. Chem., Int. Ed. 2007, 46, 6841−
6844.
(17) Blaquiere, N.; Shore, D. G.; Rousseaux, S.; Fagnou, K.
Decarboxylative Ketone Aldol Reactions: Development and Mecha￾nistic Evaluation under Metal-Free Conditions. J. Org. Chem. 2009,
74, 6190−6198.
(18) For details on the optimization of the reaction conditions, see
Tables S1−S3.
(19) (a) Zhang, Z.; Schreiner, P. R. (Thio)urea organocatalysis
What can be learnt from anion recognition? Chem. Soc. Rev. 2009, 38,
1187−1198. (b) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.;
Hausmann, H.; Guenther, S.; Schreiner, P. R. Hydrogen-Bonding
Thiourea Organocatalysts: The Privileged 3,5-Bis(trifluoromethyl)
phenyl Group. Eur. J. Org. Chem. 2012, 2012, 5919−5927.
(20) Corti, V.; Camarero Gonzalez, P.; Febvay, J.; Caruana, L.;
Mazzanti, A.; Fochi, M.; Bernardi, L. Organocatalytic Asymmetric
Sulfa-Michael Addition of 2-Aminothiophenols to Chalcones: First
Enantioselective Access to 2,3,4,5-Tetrahydro-1,5-benzothiazepines.
Eur. J. Org. Chem. 2017, 2017, 49−52.
(21) The stereochemical outcome of the addition reaction is in
agreement with a transition-state geometry in which the F-MAHT
coordinates to the sulfonamide and the phenyl thioester moiety of the
F-MAHT is oriented away from the 3,5-di(trifluoromethyl)phenyl
group of the catalyst. For a depiction of a plausible transition-state
model, see, for example: (a) Bahlinger, A.; Fritz, S. P.; Wennemers, H.
Stereoselective Organocatalyzed Synthesis of a-Fluorinated β-Amino
Thioesters and Their Application in Peptide Synthesis. Angew. Chem.,
Int. Ed. 2014, 53, 8779−8783. (b) Arakawa, Y.; Fritz, S. P.;
Wennemers, H. Organocatalytic Stereoselective Synthesis of Acyclic
γ-Nitrothioesters with All-Carbon Quaternary Stereogenic Centers. J.
Org. Chem. 2014, 79, 3937−3945.
(22) Liebeskind, L. S.; Srogl, J. Thiol ester−boronic acid coupling. A
mechanistically unprecedented and general ketone synthesis. J. Am.
Chem. Soc. 2000, 122, 11260−11261.
(23) The pseudoenantiomer of Cat E, epi-cinchonine−sulfonamide,
was derived from cinchonine.
(24) Note that the separation of the diastereoisomers by column
chromatography was tested with selected examples and was feasible YK-4-279
for all of these spot checks.
Organic Letters pubs.acs.org/OrgLett Letter

https://dx.doi.org/10.1021/acs.orglett.1c00172

Org. Lett. 2021, 23, 1753−1757
1757