Direct Access to β-Trifluoromethyl-β-hydroxy Thioesters by Biomimetic Organocatalytic Enantioselective Aldol Reaction

Article abstract of DOI:10.1021/acs.orglett.9b01469

A broadly applicable biomimetic enantioselective decarboxylative catalytic aldol reaction of trifluoromethyl ketones with malonic acid half-thioesters (MAHTs) is described. Utilizing cinchona-based thioureas as highly efficient polyketide synthase-mimic c

Full text of DOI:10.1021/acs.orglett.9b01469

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Access to β‑Trifluoromethyl-β-hydroxy Thioesters by
Biomimetic Organocatalytic Enantioselective Aldol Reaction
Jin Hyun Park,† Jae Hun Sim,† and Choong Eui Song*
Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea
S
* Supporting Information
ABSTRACT: A broadly applicable biomimetic enantioselec-
tive decarboxylative catalytic aldol reaction of trifluoromethyl
ketones with malonic acid half-thioesters (MAHTs) is
described. Utilizing cinchona-based thioureas as highly
efficient polyketide synthase-mimic catalysts, chiral tertiary
aldols, β-trifluoromethyl-β-hydroxy thioesters, were obtained in up to 99% yield and 95% ee. Facile transformation of the
thioester moiety of the aldol adducts showcases the synthetic utility of this biomimetic aldol protocol to deliver a range of chiral
trifluoromethylated tertiary aldol pharmacophores.
hiral secondary and tertiary β-hydroxy ester units are
outstanding challenge for expansion of the pharmaceutical
library with potentially interesting bioactivities (Figure 1a).
Some of antiparasitic isoxazoline drugs (e.g., fluralaner and
afoxolaner5) possessing synthetic equivalents of chiral β-CF3-β-
hydroxy esters are already available on the market (Figure 1b).
In principle, chiral β-trifluoromethyl β-hydroxy esters can be
directly accessed by a catalytic asymmetric aldol reaction of
trifluoromethyl ketones as aldol acceptors with ester enolate
derivatives as aldol donors. Surprisingly, the direct catalytic
enantioselective aldol reaction engaging trifluoromethyl
ketones with simple ester enolate equivalents is little explored
since simple esters without electron-withdrawing α-substitu-
ents are regarded as challenging aldol donor precursors in
terms of reluctant enolization.6 To the best of our knowledge,
the direct aldol reaction of trifluoromethyl ketones with
enolates possessing the oxidation state of carboxylic acid
derivatives have so far not been realized.7
C
encountered in various natural products and biologically
and pharmaceutically relevant compounds (Figure 1).1,2
By contrast, Nature freely uses the enzymatic decarbox-
ylative activation of malonic acid half-thioesters (MAHTs) to
generate simple ester enolates or their equivalents in the
biosynthesis of polyketides and fatty acids.8 Inspired by
Nature, recently, we successfully utilized MAHTs as ester
enolate equivalents in the organocatalytic decarboxylative aldol
reactions of MAHTs with aldehydes to obtain enantio-
enriched β-hydroxy thioesters.9 Thus, we presumed that
interconnecting MAHTs and trifluoromethyl ketones via
biomimetic aldol reactions would allow for facile access to a
tertiary β-hydroxy ester units with CF3-group. Systematic and
cooperative hydrogen-bonding catalysis mimicking the action
of polyketide synthases might be crucial for the deprotonation/
stabilization of MAHTs and orientation of trifluoromethyl
ketones for high facial selectivity (Figure 2).
Figure 1. (a) Representative examples of acetate aldol containing
therapeutic and natural compounds; gray-colored circles represent the
positions for the selective incorporation of CF3-group via aldol
chemistry. (b) Commercially available antiparasitic isoxazoline drugs
bearing synthetic equivalents of chiral β-CF3-β-hydroxy ester.
Currently, the incorporation of fluorine atom(s) into druglike
molecules has attracted a great deal of interest in drug
discovery, since it can improve the pharmacological properties
of a bioactive molecule by altering its lipophilicity, metabolic
stability, and bioavailability compared to the nonfluorinated
parent compound.3 In particular, the trifluoromethyl group
(−CF3) is frequently used as a bioisostere to improve both
pharmacodynamics and pharmacokinetics of the molecule by
replacing a chloride or a methyl group.4
Herein we report a broadly applicable organocatalytic
enantioselective decarboxylative aldol reaction of MAHTs
In this regard, the enantioselective incorporation of CF3 unit
into bioactive chiral β-hydroxy ester derivatives would be one
Received: April 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01469
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tion of aromatic moiety in cinchonidine-based catalysts did not
improve the catalytic outcomes. The incorporation of an urea
moiety instead of a thiourea was also not beneficial in terms of
enantioselectivity and reactivity (87% ee using CD-TU vs 76%
ee using CD-U). Thus, further optimization studies were
conducted with CD-TU as the optimal catalyst. Lowering
reaction temperatures resulted in increased enantioselectivity
(87% ee at rt; 90% ee at 0 °C, entry 1; 92% ee at −20 °C, entry
3). The enantioselectivity could be further increased (91% ee
at 0 °C, entry 2; 95% ee at −20 °C, entry 4) by employing the
para-fluorophenyl substituted MAHT (2b) (see the Support-
ing Information for further MAHT screening results).
However, only 50% conversion after 96 h was observed at
−20 °C (entry 4). Even with higher catalyst loading (30 mol
%), the reaction proceeded very slowly (entry 5). To our
delight, however, a significant increase in yield without any
erosion of the enantioselectivity was achieved simply by adding
THF as a cosolvent (entry 6 and 7). Further solvent screening
did not improve the catalytic outcome (see the Supporting
Information for further solvent screening results). Thus, the
reaction condition of entry 7 (using 2b, MTBE/THF (1:1 v/
v)) proved to be optimal in terms of both chemical yield and
enantioselectivity.
Under the optimized reaction conditions (entry 7 of Table
1), a variety of trifluoromethyl ketones 1a−1u were subjected
to this protocol. As shown from the results summarized in
Scheme 2, most of the trifluoromethylated tertiary aldols (3)
were obtained in high yields and enantioselectivity. Regardless
of the electronic and steric nature of the aromatic substituent,
high enantioselectivity (up to 95% ee) was achieved. In
addition to aryl trifluoromethyl ketones 1a−1q, heteroar-
omatic trifluoromethyl ketones were also smoothly converted
into the desired products 3r−3s with good enantioselectivity.
Aliphatic trifluoromethyl ketone 1t was tolerated and yielded
the desired aldol products 3t, however, only with moderate
enantioselectivity. Notably, the reaction also worked well with
ketone with CF2CF3 group to give the corresponding tertiary
aldol 3u in good enantioselectivity. In addition, the absolute
configuration of 3a and 3d was determined to be (S) by
comparison with the sign of optical rotation of the trans-
esterification products 4a and 4d reported in the literature
(Scheme 3).11
Figure 2. Reaction mechanism of the polyketide synthase catalyzed
malonyl-CoA addition to a thioester (left) and a plausible working
model of an organocatalyzed aldol reaction of MAHT and
trifluoromethyl ketones (right).
with a variety of trifluoromethyl ketones using cinchona-based
thioureas as highly efficient polyketide synthase-mimic
catalysts. The resulting enantio-enriched trifluoromethyl-
substituted β-hydroxy thioesters were easily converted into a
range of chiral trifluoromethylated tertiary aldol pharmaco-
phores, highlighting the synthetic utility of the present
biomimetic aldol protocol.
For our initial studies, the addition of MAHT (2a) and
2,2,2-trifluoroacetophenone (1a) in methyl tert-butyl ether
(MTBE) at room temperature was chosen as a model reaction
(Scheme 1). Acid−base bifunctional cinchona alkaloid
abc
Scheme 1. Catalyst Screening
Thioesters are ubiquitous not only in many biosynthetic
reactions (e.g., in the biosynthesis of fatty acids, polyketides
and nonribosomal peptides)12 but also in many functional
group manipulations and C−C bond forming reactions, since
they are more reactive toward nucleophiles than analogous
oxyesters due to smaller orbital overlap between the sulfur as
well as the higher acidity of α-proton.13,14a Thus, to illustrate
the synthetic utility of our aldol protocol, diverse trans-
formation of the thioester moiety of enantio-enriched CF3-
containing tertiary aldols 3 were performed. Products (4a and
4d) of direct transesterification were successfully obtained
without any erosion of ee values.11 The β-hydroxy amides, 5a,
5j, and 5r, key building blocks in the synthesis of
trifluoromethylated analogues of antidepressant drugs, such
as (R)-fluoxetine, (R)-tomoxetine, and (R)-duloxetine, were
also accessed by direct amidation.9,14 The CF3-analogue 6i of
antidepressant drug fenpentadiol15 was also simply obtained
from 3i, using Grignard reaction. Furthermore, the ketones 7j
and 7o, key intermediates in the synthesis of the antiparasitic
isoxazoline drugs such as fluralaner and afoxolaner,5b
respectively, were accessed from 3j and 3o, using Liebe-
a
Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv, 0.3 mmol),
catalyst (10 mol %, 0.02 mmol), MTBE (anhydrous, 0.1 M, 2.0 mL),
b
rt, 24 h. The conversion was determined by 19F NMR integration.
c
The % ee values were determined by HPLC analysis using a chiral
stationary phase.
derivatives are known to promote addition reactions of
MAHTs,9,10 and we therefore examined their catalytic
performance in this model reaction. As shown in Scheme 1,
the catalyst screening revealed thiourea-type catalysts (QN-TU
and CD-TU) and showed promising catalytic results, whereas
all the others (QN, QN-SA, QN-N-SQA, QN-SQA, and CD-
SQA) gave inferior catalytic results (see the Supporting
Information for further catalyst screening results). Notably,
the absence of a methoxy group at the 6′-position of the
quinoline moiety in the thiourea catalysts provoked a dramatic
change in enantioselectivity (77% ee using QN-TU vs 87% ee
using CD-TU). These results prompted us to further
investigate cinchonidine thiourea type catalysts in detail, to
improve activity and enantioselectivity. However, a modifica-
B
DOI: 10.1021/acs.orglett.9b01469
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Condition Optimization
b
c
entry
cat (mol %)
MAHT
solvent
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE/THF 9:1
MTBE/THF 5:5
temp (°C)
time (h)
conv (%)
ee (%)
1
2
3
4
5
6
7
10
10
20
20
30
30
30
2a
2b
2a
2b
2b
2b
2b
0
0
48
48
96
96
205
96
95
50
74
50
82
82
87
90
91
92
95
95
95
95
−20
−20
−20
−20
−20
96
a
b
Reaction conditions: 1a (0.1 mmol), 2 (3 equiv, 0.3 mmol), CD-TU, solvent (anhydrous, 0.1 M, 1.0 mL). The conversion was determined by 19
F
c
NMR integration. The % ee values were determined by HPLC analysis using a chiral stationary phase.
a
ab
Scheme 2. Substrate Scope
Scheme 3. Synthetic Utility of the Aldol Products
a
Reaction conditions: (i) Mg, MeOH, rt, 2 h. (ii) RNH2, MeOH, rt,
12 h or MeNH(OMe)·HCl, AgOCOCF3, Et3N, DCM, rt, 72 h. (iii)
(a) TMSOTf, 2,6-Lutidine, DCM, rt, 18 h. (b) MeMgBr, DCM, rt, 18
h. (c) TBAF, THF, rt, 24 h. (iv) (a) TMSOTf, 2,6-Lutidine, DCM, rt,
18 h. (b) ArB(OH)2, CuTC, TFP, Pd2(dba)3, THF, reflux, 18 h. (c)
b
TetraEG, KF, rt, 6 h. Abbreviations: TMSOTf = trimethylsilyl
trifluoromethanesulfonate, TBAF = n-tetrabutylammonium fluoride,
CuTC = copper thiophene-2-carboxylate, TFP = tri(2-furyl)-
phosphine, Pd2(dba)3 = tris(dibenzylideneacetone) dipalladium,
c
d
TetraEG = tetraethylene glycol. 3ab (90% ee) was used. 3i (87%
ee) was used.
Finally, on the basis of in situ electrospray ionization mass
spectroscopy (ESI-MS) analysis of the reaction mixture (see
Supporting Information for details), it is proposed that
nucleophilic addition of MAHTs to trifluoromethyl ketones
precedes decarboxylation to complete the catalytic cycle by
releasing the desired aldol products. Other types of catalytic
aldol reactions using MAHTs have also been proposed to
occur via a similar reaction sequence.8b,9
In conclusion, we have developed a broadly applicable
enantioselective biomimetic aldol reaction of malonic acid half
thioesters as acetate enolate precursors with a variety of
trifluoromethyl ketones. Utilizing chiral cinchona-based
thioureas as efficient polyketide synthase-mimic catalysts, a
range of aromatic and nonaromatic trifluoromethyl ketones
were converted into the corresponding β-hydroxy esters in
good to excellent yields and enantioselectivities. The resulting
enantio-enriched trifluoromethyl-substituted β-hydroxy thio-
esters were easily converted into a range of chiral
a
Reaction conditions: 1a−u (0.3 mmol), 2b (3.0 equiv, 0.9 mmol),
CD-TU (30 mol %, 0.09 mmol), MTBE/THF = 1:1 (anhydrous, 0.1
b
M, 3.0 mL), −20 °C, 96 h. Cinchonine thiourea (CN-TU) was used.
c
Reaction was performed at rt.
skind-Srogl coupling.16 Notably, a recent report suggests that
fluralaner and afoxolaner can be utilized in the control of
vector-borne human diseases including malaria, zika fever, and
leishmaniasis.17
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trifluoromethylated tertiary aldol pharmacophores, facilitated
by the synthetic flexibility of the sulfur atom. Thus, the current
methodology will lead to various applications in the field of the
development of new pharmaceutical compounds with
improved therapeutic properties.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01469.
Experimental details and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s1673@skku.edu.
ORCID
Choong Eui Song: 0000-0001-9221-6789
Author Contributions
†J.H.P. and J.H.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(9) Bae, H. Y.; Sim, J. H.; Lee, J.-W.; List, B.; Song, C. E. Angew.
Chem., Int. Ed. 2013, 52, 12143−12147 and references therein. .
(10) For the selected recent examples: (a) Saadi, J.; Wennemers, H.
Nat. Chem. 2016, 8, 276−280. (b) Hara, N.; Nakamura, S.; Sano, M.;
Tamura, R.; Funahashi, Y.; Shibata, N. Chem. - Eur. J. 2012, 18,
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7284−7285. For the enantioselective decarboxylative aldol reactions
with malonic acid half-oxyesters (MAHOs): (e) March, T.; Murata,
A.; Kobayashi, Y.; Takemoto, Y. Synlett 2017, 28, 1295−1299.
(11) (a) Gautschi, M.; Seebach, D. Angew. Chem., Int. Ed. Engl.
We are grateful to the National Research Foundation of Korea
for the financial support of this work (NRF-
2017R1A2A1A05001214 and NRF-2019R1A4A2001440).
We also thank to Prof. H. Y. Bae (Ulsan National Institute
of Science and Technology) for carrying out preliminary work
(catalyst screening with QN-SQA) and Prof. J. W. Lee
(University of Copenhagen) for helpful discussions.
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