Fluorous l -Carbidopa Precursors: Highly Enantioselective Synthesis and Computational Prediction of Bioactivity

Article abstract of DOI:10.1021/acs.joc.7b02685

New fluorous enantiopure (S)-α-aminated β-keto esters were prepared through a highly enantioselective electrophilic α-amination step in the presence of europium triflate and (R,R)-phenyl-pybox. These compounds are precursors of fluorinated analogues of l-

Full text of DOI:10.1021/acs.joc.7b02685

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Article
Fluorous L-Carbidopa Precursors: Highly Enantioselective
Synthesis and Computational Prediction of Bioactivity
Albert Granados, Anna Del Olmo López, Francesca
Peccati, Thierry Billard, Mariona Sodupe, and Adelina Vallribera
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02685 • Publication Date (Web): 04 Dec 2017
Downloaded from http://pubs.acs.org on December 5, 2017
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Fluorous LꢀCarbidopa Precursors: Highly Enantioselective Synthesis
and Computational Prediction of Bioactivity
Albert Granados,† Anna del Olmo, Francesca Peccati,† Thierry Billard,‡ Mariona
Sodupe†,* and Adelina Vallribera†,*
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Department of Chemistry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona
(Spain).
†Centro de Innovación en Química Avanzada (ORFEOꢀCINQA).
‡Institute of Chemistry and Biochemistry (ICBMSꢀUMR CNRS 5246), Université Claude BernardꢀLyon
1, 43 Bd du 11 novembre 1918, Bat. Raulin, 69622 Villeurbanne Cedex (France)
*Eꢀmails: adelina.vallribera@uab.cat, mariona.sodupe@uab.cat
Abstract. New fluorous enantiopure (S)ꢀαꢀaminated βꢀketo esters were prepared through a
highly enantioselective electrophilic αꢀamination step in the presence of europium triflate and
(R,R)ꢀphenylꢀpybox. These compounds are precursors of fluorinated analogues of LꢀCarbidopa,
which is known to inhibit DOPA decarboxylase (DDC), a key protein in Parkinson’s disease.
Fluorination provides better stability for biological applications, which could possibly lead to
better DDC inhibitors than LꢀCarbidopa itself. Induced fit docking computational simulations
performed on the newly structures interacting with DDC highlight that for an efficient binding
at the DDC site at least one hydroxyl substituent must be present at the aromatic ring of the Lꢀ
Carbidopa analogues, and point out that the presence of fluorine can further concur to fix the
position of the ligand in the active site.
Boc
N
N
Boc
O
O
O
O
R
R
Eu(OTf)3/L*
ACN, MS 4Å
O
O
NBoc
MeO
MeO
NHBoc
F
F
enantioselective amination
O
O
OH.H2O
NH
MeO
HO
L* = (R,R)-phenyl-pybox
NH2
F
F
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Parkinson’s disease is a chronic and progressive neurological disorder whose origin is linked
to the degeneration of dopamineꢀproducing cells in the brain.1 DOPA decarboxylase (DDC),
which is abundant in the nervous system and kidney, is responsible for the synthesis of
dopamine via decarboxylation of LꢀDOPA. Dopamine itself is not able to cross the bloodꢀbrain
barrier and thus cannot be used as a drug in the treatment of Parkinson’s disease. Moreover,
when administered LꢀDOPA is rapidly converted to dopamine in the blood stream and only a
small percentage will reach the nervous system. By adding DDC inhibitors, the most common
among which is LꢀCarbidopa, greater amounts of LꢀDOPA reach the brain, with a substantial
increase of dopamine in nerve cells.2 At the same time, dopamine side effects related to a high
concentration in the blood stream are diminished. The inhibitor is covalently linked to DDC by
forming a hydrazone derivative of the cofactor.3
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Since the preparation of fludrocortisone, one of the earliest synthetic fluorinated drugs,4
fluorine substitution in medicinal compounds is commonly used to improve metabolic stability,
bioavailability and proteinꢀligand interactions.5 The incorporation of a fluorine atom(s) or
fluorinated group(s) often provides molecules with quite unique properties. It is estimated that
30% of the leading 30 blockbuster drugs by sales contains fluorine.6 This element is generally
incorporated into the organic drug during the optimization studies. Almost every new drug
discovery and development program explores fluorineꢀcontaining drug candidates.
A factor limiting the clinical use of many pharmaceuticals is their excessively rapid metabolic
degradation. The key to many of these degradation processes is oxidative metabolism by the
cytochrome P450 family. The strategic incorporation of fluorine(s) into metabolism site(s) has
been widely used to prevent this deactivation.7 Cytohrome P450 oxidation is easier for electronꢀ
rich π systems such as aromatic moieties. Introduction of a fluorine substituent avoids oxidation
of the CarꢀF site and can also induce electronic effects on its neighbors, decreasing the pKa value
and the Lewis basicity and retarding its oxidation. For instance, it can increase the acidity of an
alcohol group, which in turn will promote a better binding to the enzyme binding site.8
In the present study fluorine(s) or fluorineꢀcontaining groups are incorporated into the
synthetic precursors of LꢀCarbidopa, which could be transformed to fluorous LꢀCarbidopa
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derivatives by previously described chemistry. We envisioned different fluorination positions
(Figure 1) as a tool to block undesired metabolic pathways. We were also concerned about
whether the presence of hydroxylic groups on the aromatic moiety is essential for binding to
DDC and thus for yielding the desired biologic activity. Therefore, some of the fluorous Lꢀ
Carbidopa analogues will be computationally studied to assess how fluorination can tune their
affinity for the DDC target. Further biochemistry binding experiments of these compounds with
DDC, which are not the objective of this manuscript, could confirm the theoretical hypothesis.
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Figure 1. LꢀCarbidopa formula indicating the positions where fluorine atoms or groups will be introduced.
We have previously described a straightforward methodology for the synthesis of Lꢀ
Carbidopa (seven steps, 50% overall yield and 98% ee) through a key enantioselective αꢀ
amination step,9 which will be used in this work to synthesize enantiopure fluorous LꢀCarbidopa
precursors.
We first selected a series of fluorous commercially available acetophenones 1 to prepare the
corresponding βꢀketo esters 2. Using dimethylcarbonate and 2 equiv of NaH as a base, the
desired products 2a,10 2b,11 2c11 and 2dꢀe were obtained in excellent yields (92ꢀ97%, Scheme 1
and Table 1). However, for 4ꢀfluoro acetophenones A (Scheme 1, R = F) possessing an electron
withdrawing group in orto to the CarꢀF, as F and –OCF3,12 we observed a partial SNAr reaction
on the Carꢀ F to form CarꢀOMe in the same conditions. Indeed, the nucleophilic additionꢀ
elimination reaction of the sodium enolate of 1 with dimethylcarbonate involves methoxide as a
leaving group which partially reacts as nucleophile at the CarꢀF, producing the introduction of
the OMe substituent. Thus, mixtures of 4ꢀfluoro (2i and 2h) and 4ꢀmethoxy (2f13 and 2c) βꢀ
ketoesters were obtained (Scheme 1). Additionally, for CarꢀF possessing electron withdrawing
groups in both orto positions, as for example for the 3,4,5ꢀtrifluoroacetophenone, A(1k), the
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SNAr reaction of methoxide at the CarꢀF is synthetically useful to selectively obtain the
substitution product 2g (85% yield, Scheme 1, Table 1). The solution to avoid fluoride loss was
found in using methyl 1Hꢀimidazoleꢀ1ꢀcarboxylate in the presence of 1.5 equiv of NaH. The
corresponding βꢀketo esters 2h, 2j and 2k were afforded in yields between 80ꢀ96% (Scheme 1,
Table 1).
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Scheme 1. Different methodologies used in the preparation of βꢀketo esters 2.
Our previous experience suggested that a βꢀketo ester substrate bearing an OR group bulkier
than methoxy might be necessary to achieve efficient enantioinduction, and secondary 3ꢀpentyl
group fulfills these requirements.14 Therefore transesterification of 2aꢀk with 3ꢀpentanol was
accomplished using catalytic amounts of ZnO in refluxing toluene rendering 3aꢀk in excellent
yields (80ꢀ99% yield, Scheme 2, Table 1).15 Subsequent alkylation under classical conditions
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using methyl iodide and potassium carbonate in anhydrous acetone afforded the αꢀmethyl βꢀ
keto esters 4aꢀk (52ꢀ96% yield, Scheme 2, Table 1).
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O
O
O
O
R2
R
R2
R
O
HO
OMe
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ZnO, toluene
3a-k
2a-k
R1
R1
O
O
Eu(OTf)3
L*
R2
R
O
O
O
NBoc
MeI
K2CO3, acetone
R2
O
CH3CN
r.t.
NHBoc
R1
R
4a-k
5a-k
R1
O
O
N
N
N
Ph
Ph
L* = R,R-phenyl-pybox
Scheme 2. Synthesis of fluorous (S)ꢀαꢀaminated βꢀketo esters 5aꢀk.
Table 1. Yields of reactions indicated in Scheme 1.
R2
R
R1
Yield Yield
Yield
4-k
2a-k
3a-k
H
H
H
H
H
CF3
H
H
F
92%
(2a)
85%
(3a)
85%
(4a)
OCF3
OCH3
93%
(2b)
85%
(3b)
81%
(4b)
92%
(2c)
95%
(2d)
89%
(3c)
92%
(3d)
89%
(4c)
90%
(4d)
OCH3 CF3
OCH3 OCH3 97%
(2e)a
99%
(3e)a
95%
(3f)
96%
(4e)a
81%
(4f)
H
F
OCH3 OCF3
45%
(2f)b
OCH3
F
85%
(2g)
85%
(3g)
89%
(4g)
H
H
F
F
F
96%
(2h)
80%
(3h)
92%
(4h)
OCF3
38%
(2i)b
92%
(3i)
86%
(4i)
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H
F
F
F
CF3
F
80%
(2j)
88%
(3j)
88%
(4j)
84%
(2k)
82%
(3k)
89%
(4k)
6
a Previously prepared, see ref. 9;b Reaction of 3ꢀtrifluoromethoxyꢀ4ꢀfluorobenzophenone with dimethylcarbonate and
NaH as base gave 45% of 2f and 38% of 2i.
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Substrates 4aꢀk underwent enantioselective electrophilic αꢀamination in S configuration with
diꢀtertꢀbutyl azodicarboxylate16 using a Eu(OTf)3/L* mixture as a catalyst. A solution of
Eu(OTf)3 (0.017 mmol) and (R,R)ꢀphenylꢀpybox (0.023 mmol) in dry acetonitrile (1.5 mL) was
stirred overnight in the presence of 4Å molecular sieves under argon atmosphere at room
temperature. Then, the βꢀketo ester (0.184 mmol) and the electrophile (0.298 mmol) were
sequentially added. We have previously reported that in those cases the best choice for the
pybox ligand was (R,R)ꢀdiphenylpybox,14b however using fluorous substrates, the simpler and
commercially available (R,R)ꢀphenylꢀpybox employed at room temperature gave excellent
chemical yields (70ꢀ87%) and excellent ee’s (90ꢀ100%). The presence of the phenyl substituents
in the pybox ligand is essential for a good enantioselection, probably due to π stacking
interactions between the aromatic moiety of the substrate 4 (Scheme 3) and the aromatic ring of
the phenylpybox (using (R,R)ꢀisopropylpybox only a moderate 63% was obtained in the same
conditions for 5e). In addition, the enantiomeric excesses were much greater (90ꢀ99%) with
electron withdrawing groups as substituents in the aromatic positions (5aꢀd, fꢀk in Figure 2)
than those obtained for the aromatic electronic rich derivatives (80% ee for 5e in Figure 2) in
the same conditions.
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O
O
O
O
O
O
4
5
6
7
8
9
O-R
O-R
O-R
N-Boc
N-Boc
N-Boc
F3CO
F3C
NH-Boc
NH-Boc
H3CO
5b
5a
NH-Boc
5c
F
98% ee
77% yield
96% ee
76% yield
92% ee
74% yield
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O
O
O
O
O
O
O-R
O-R
O-R
N-Boc
N-Boc
N-Boc
H3CO
H3CO
NH-Boc
H3CO
NH-Boc
NH-Boc
5f
5d
5e
OCF3
CF3
OCH3
90% ee
75% yield
80% ee
81% yield
94% ee
87% yield
O
O
O
O
O
O
F
O-R
O-R
O-R
N-Boc
N-Boc
N-Boc
H3CO
F
F
NH-Boc
NH-Boc
NH-Boc
5g
5h
5i
F
F
OCF3
92% ee
76% yield
>99% ee
82% yield
94% ee
70% yield
O
O
O
O
F
F
O-R
N-Boc
O-R
N-Boc
5j
5k
F
NH-Boc
NH-Boc
CF3
F
93% ee
75% yield
90% ee
74% yield
Figure 2. Structures, yields and ee’s of the αꢀamination step (Scheme 2) for compounds 5.
The mechanism of this type of reaction has been proposed previously.14a,17 There is enough
evidence in the literature to propose the formation of the intermediate corresponding to the
coordination of pybox ligand, βꢀketo ester and azo reactive to the europium atom in the
disposition shown in Figure 3. One of the phenyl ring on the oxazoline unit can attain a
conformation to present a suitable distance so as to provide stabilizing π interactions. This is
possible when the rightꢀside phenyl is parallel to the aryl ring of 4. In this pausible intermediate
(Figure 3) the bulkiness of the ester in 4 is also responsible of the coordination of the ketoester
with this functional group ortogonal to the leftꢀside phenyl. The CꢀN formation step is the
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chiralꢀdetermining step. Formation of a sixꢀmembererd ring transition state has been proposed
by other authors.17
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Figure 3. Schematic representation of a plausible intermediate of the enantioselective αꢀ
amination reaction
Precursors 5 (except non fluorous 5e) could be easily converted to fluorous LꢀCarbidopa
analogues following a chemistry well established and previously published by our group.9
Other fluorous derivatives were also prepared. Monofluorination of βꢀketo esters 2e and 3e
with Selectfluor®18 in acetonitrile gave compounds 6e and 7e with excellent 95% yield in both
cases. The amination step was carried out using diꢀtertꢀbutyl azodicarboxylate, Eu(OTf)3 and
commercially available (R,R)ꢀphenylꢀpybox at room temperature, obtaining 11e in a high yield
and excellent 93% ee (Scheme 3). Other fluorinated groups, such as –SCF3,19 could also be
introduced in the intercarbonylic position, although they are too bulky for the following
amination process. The introduction of –CF3 was discarded since in the amination conditions
HF will be lost. Thus, we thought to intercalate at least one methylene group. However,
commercially available IꢀCH2CF3 and IꢀCH2CH2CF3 underwent acid elimination in the
alkylation step basic conditions. Using trifluoroiodobutane (Scheme 3) a 96% yield of 10e was
obtained and the enantioselective amination step was accomplished with a 99% of ee (78%
yield).
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O
O
O
O
Selectfluor
CH3CN
Eu(OTf)3
L*
OR
O
O
O
F
N-Boc
CH3CN
F
95%
MeO
MeO
MeO
OR
NH-Boc
R = CH3, 6e
11e
OMe
OMe
OMe
R = CH(CH2CH3)2, 7e
O
LDA
TsN(Me)SCF3
MeO
2e
78% yield
93 % ee
OMe
R = CH3, 2e
R = CH(CH2CH3)2, 3e
O
65%
OR
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SCF3
R = CH3, 8e
R = CH(CH2CH3)2, 9e
I-CH2CH2CH2CF3
acetone
O
O
N
N
96%
N
O
O
Ph
Ph
O
O
L* = R,R-phenyl-pybox
Eu(OTf)3
O
O
L*
N-Boc
12e
MeO
MeO
CH3CN
NH-Boc
OMe
OMe
CF3
CF3
78% yield
99% ee
10e
Selectfluor
:
TsN(Me)SCF3:
O
S
SCF3
Me
Cl
2BF4
N
-
N
N
O
F
Scheme 3. Introduction of fluorine and fluorous groups in the intercarbonylic position and
subsequent αꢀamination step.
The assignment of the absolute configuration of compounds 5 and 12e as S was based on the
comparison of the circular dichroism (CD) (all compounds show a positive Cotton Effect), and
the position of the major peak on the chiral HPLC spectrum with previously described
analogues prepared in our laboratories.9,14c In the case of 11e, due to the presence of F in the
intercarbonylic chiral carbon, the asymmetric induction is obtained in the same sense although
the resulting product is the (R) enantiomer.
Additionally, induced fit docking simulations were performed to assess how fluorination of
the LꢀCarbidopa scaffold can modify its affinity for the DDC receptor. To do so, some of the
fluorinated analogues of LꢀCarbidopa (Figure 5) were tested using the PELE suite20,21 (see SI for
further details), which provides an efficient tool for the prediction of binding poses of
ligand/receptor complexes. The LꢀCarbidopa/DDC complex was derived from the structure
reported in PDB file 1JS3. DDC is a dimer, with two equivalent binding sites for Carbidopa,
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which, as already mentioned, forms a hydrazone intermediate with the pyridoxal 5'ꢀphosphate
(PLP) cofactor. The docking method was first tested on this complex, by cleaving the
CarbidopaꢀPLP covalent bond and submitting an unconstrained binding site search simulation
for the same LꢀCarbidopa on the receptor. Satisfactorily, the ligand is docked in the
crystallographic binding site with the correct conformation, with the aldehyde group of PLP
correctly oriented to start the reaction with the hydrazine group of LꢀCarbidopa (Figure 4a).
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Correct orientation
"Upside down"
OH
F3C
O
NH NH2
L
i
n
k
a
g
e
OH
OH
H2NNH
O
O
H
HO
O
H
O
P
O
OH
O
P
L-Carbidopa
Derivative D
O
OH
O
N
O
N
Figure 4. Relative orientation of the ligand and PLP cofactor for LꢀCarbidopa and a
fluorinated derivative from induced fit docking simulations.
Overall, eight fluorinated analogues of LꢀCarbidopa were tested (Figure 5) and results
highlighted that one aromatic hydroxyl group is fundamental to guarantee the correct orientation
of the ligand in the binding site of the receptor (for a full description of the results see the SI).
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Figure 5. The eight fluorinated analogues of LꢀCarbidopa tested as DDC ligands.
As reported in Figure 4a, the hydroxyl groups form strong hydrogen bonds (1.48 Å) with the
phosphate group of PLP. If at least one of the two hydroxyl groups is preserved, our simulations
show that the molecule enters the active site of DDC in a suitable orientation. If, conversely, the
ligand does not present a hydroxyl group, then these hydrogen bonds cannot be formed. In such
cases, molecules that are not forbidden to enter the binding pocket by sterical factors will
assume an "upside down" conformation (Figure 4b), in which the carboxyl group of the ligand
is involved in interaction with the phosphate. Thus, according to these calculations, a hydrogen
bond donor has to be maintained on the aromatic ring for the ligand to act as an inhibitor for
DDC.
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Figure 6. Positioning of fluorinated analogue F of LꢀCarbidopa in the active site of DDC,
with indication of an electrostatic interaction with a positively charged residue, LYS303.
Distance in Å.
Figure 6 reports the binding pose of derivative F in the active site of DDC. This molecule
presents a fluorine atom and a hydroxyl group on the aromatic ring. While the oxygen of the
hydroxyl group acts as hydrogen bond acceptor (distance 1.74 Å), maintaining the molecule in
the correct orientation in the site, the fluorine atom, which bears a negative partial charge, is
involved in an electrostatic interaction with a nearby positively charged lysine residue. This
suggests that fluorination may result in the formation of stabilizing interactions that further
concur to fixing the position of the ligand in the active site of DDC.
In this work we present the preparation of (S)ꢀfluorous precursors of LꢀCarbidopa through a
highly enantioselective αꢀamination key step of a series of acyclic βꢀketo esters possessing
different fluorous substituents at the arene ring or in the intercarbonilic position, with excellent
chemical yields (70ꢀ87%) and enantiomeric excesses (90ꢀ99%). We found that neither using
diphenylꢀpybox as chiral ligand nor working at low temperature is essential. The advantage of
this finding is that the simple commercially available phenylꢀpybox (both enantiomers are
commercial giving access to both (S) and (R)ꢀ5 enantiomers) can be used, and that reactions can
be performed at room temperature. They could be transformed to fluorous LꢀCarbidopa
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derivatives following previously known chemistry. Some of the fluorous LꢀCarbidopa
analogues were then studied to assess how fluorination tunes their affinity for the DDC target.
We conclude that the presence of at least one hydroxyl group on the arene moiety of Lꢀ
Carbidopa scaffold is crucial to maintain the molecule in the correct orientation for inhibition of
the DDC binding site. Additionally, fluorine atoms may be involved in electrostatic interactions
with positively charged residues of DDC, indicating that fluorination can concur in stabilizing
the inhibitorꢀreceptor complex. Further binding experiments with DDC should be performed to
confirm this hypothesis.
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Experimental Section
General Information. GLC chromatographies were performed on a capilar column (5%
biphenyl and 95 % dimethylpolysiloxane) of 15 m x 0.25 mm with stationary phase diameter of
0.25 ꢁm. Column chromatographies were performed on silica gel (230ꢀ400 mesh). IR spectra
were determined either by transmission or by Attenuated Total Reflectance mode (ATR).
Enantiomeric excesses were determined, unless otherwise stated, by HPLC using a chiral
column Chiracel DaicelꢀADꢀH. NMR spectra were recorded operating at 250MHz, 360MHz
and 400 MHz. Optical rotations are reported as follows: [α]Drt (c in g per 100 mL, solvent). 13Cꢀ
NMR spectra were registered at 62.5, 91 and 101 MHz,. Elemental analyses are the average of
two determinations. HRMS were recorded by a Bruker micrOTOFꢀQII Mass Spectrometer (flyꢀ
time analyzer) through positive electrospray ionization.
General procedure for the preparation of fluorous βꢀketo esters 2. In a 250 mL round
bottom flash 2 eq. of sodium hydride, 25 mL THF and 2 eq. of dimethyl carbonate (1.5 equiv.
when using methyl 1Hꢀimidazoleꢀ1ꢀcarboxylate) are disposed. The second step consists on
preparing a solution of the acetophenone derivative (1 eq.) in THF, that solution is added
dropwise to the first solution by using an addition funnel. Once the addition is finished, the
mixture is warmed to reflux until TLC analyses shows that starting material has been totally
consumed. When the reaction is finished, the reaction is neutralized with HCl 1M and the
solution is brought to pH acidic, then extractions with dichloromethane are carried out. The
organic fractions are dried with sodium sulfate and solvent is removed under vacuum. The
reaction crude is purified with silica gel column chromatography using hexane:AcOEt (4:1) as
eluent obtaining the desired methyl βꢀketo esters.
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Methyl 3ꢀ(3ꢀtrifluoromethylꢀ4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate, 2d. yellowish solid; Mp.
43ꢀ45ºC; 1H NMR (360 MHz, CDCl3) δ (ppm): keto (85%) ꢀ enol (15%) mixture, 3.72 (s, 3H),
3.77 (s, 0.13H), 3.95 (s, 5H), 5.58 (s, 0.7H), 7.01 (d, J = 9.1 Hz, 0.16H), 7.05 (d, J = 9.1 Hz,
1H), 7.88 (dd, J = 1.9 Hz, J = 9.1 Hz, 0.15H), 7.94 (s ap, 0.15H), 8.09 (dd, J = 2.0 Hz, J = 9.1
Hz, 1H), 8.14 (s ap, 1H), 12.54 (s, 0.14H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ63.2 (s,
0.5F), ꢀ63.4 (s, 3F); 13C NMR [1H] (CDCl3, 91 MHz) δ (ppm): 45.3, 51.4, 52.5, 56.1, 56.3, 86.3,
111.8, 111.9, 119.0 (q, J = 31.8 Hz), 122.9 (q, J = 273.9 Hz), 125.2, 128.1 (q, J = 20.1 Hz),
131.2, 134.4, 159.7, 161.5, 167.7, 169.8, 173.5, 190.1; IR (ATR) ν (cmꢀ1): 2976, 1728, 1684;
HRꢀMS (ESI) m/z: [M+H]+ Calcd for C12H12F3O4 277.0682; found 277.0679. Isolated yield:
240 mg (95%) from 200 mg of 1d.
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Methyl 3ꢀ((3ꢀtrifluoromethoxyꢀ4ꢀfluoro)phenyl)ꢀ3ꢀoxopropanoate, 2i. Oil; H NMR (400
MHz, CDCl3) δ (ppm): keto (75%) ꢀ enol (25%) mixture, 3.78 (s, 3H), 3.83 (s, 1H), 4.00 (s,
2H), 5.65 (s, 0.35H), 7.29 (t, J = 8.9 Hz, 1H), 7.35 (t, J = 8.9 Hz, 0.3H), 7.73 (m, 0.67H), 7.93
(m, 2H), 12.54 (s, 0.36H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ58.8 (m, 3.9F), ꢀ119.3 (q, J =
4.5 Hz, 1F), ꢀ123.9 (q, J = 4.5 Hz, 0.36F);13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 45.5,
51.6, 52.6, 87.8, 117.5 (d, J = 19.4 Hz), 117.8 (d, J = 19.4 Hz), 120.3 (q, J = 260.0 Hz), 121.8,
124.3, 126.1 (d, J = 7.8 Hz), 129.1 (d, J = 7.8 Hz), 132.9 (d, J = 3.3 Hz), 156.2 (d, J = 258.3
Hz), 157.9 (d, J = 258.3 Hz), 167.2, 168.6, 173.1, 188.5; IR (ATR) ν (cmꢀ1): 2968, 1735, 1685,;
HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C11H8F4O4Na 303.0251; found 303.0244; Isolated yield:
105 mg (38%) from 220 mg of 1i.
Methyl 3ꢀ((3ꢀtrifluoromethylꢀ4ꢀfluoro)phenyl)ꢀ3ꢀoxopropanoate, 2j. Oil; 1H NMR (360
MHz, CDCl3) δ (ppm): keto (70%) ꢀ enol (30%) mixture, 3.75 (s, 3H), 3.80 (s, 1.2H, OCH3),
4.01 (s, 2H), 5.65 (s, 0.75H), 7.25 (t, J = 9.3 Hz, 0.4H), 7.32 (t, J = 9.2 Hz, 1H), 7.90 – 7.97 (m,
0.4H), 8.01 (dd, J = 6.6 Hz, J = 1.8 Hz, 0.4H), 8.13 – 8.20 (m, 1H), 8.32 (dd, J = 6.6 Hz, J = 1.8
Hz, 1H), 12.54 (s, 0.4H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ62.2 (d, J = 12.6 Hz, 1.2F), ꢀ
62.3 (d, J = 12.6 Hz, 3F), ꢀ106.2 (q, J = 12.6 Hz, 1F), ꢀ110.7 (q, J = 12.6 Hz, 0.35F); 13C NMR
[1H] (CDCl3, 90 MHz) δ (ppm): 45.4, 51.6, 52.6, 87.9, 117.3 (d, J = 21.4 Hz), 117.6 (d, J = 21.4
Hz), 121.9 (q, J = 273.9 Hz), 122.1 (q, J = 273.9 Hz), 125.2 (m), 128.2 (m), 129.8 (d, J = 3.7
Hz), 131.6 (d, J = 9.1 Hz), 132.3 (d, J = 3.7), 134.60 (d, J = 9.5 Hz), 161.2 (d, J = 267.3 Hz),
162.8 (d, J = 267.3 Hz), 167.3, 168.5, 173.2, 189.8; IR (ATR) ν (cmꢀ1): 2958, 1739, 1681; HRꢀ
MS (ESI) m/z: [M+Na]+ Calcd for C11H8F4O3Na 287.0302; found 287.0299; Isolated yield: 307
mg (80%) from 300 mg of 1j.
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Methyl 3ꢀ(3,4,5ꢀtrifluorophenyl)ꢀ3ꢀoxopropanoate, 2k. Oil; H NMR (250 MHz, CDCl3) δ
(ppm): keto (60%) ꢀ enol (40%) mixture , 3.78 (s, 3H), 3.83 (s, 2.3Hl), 3.96 (s, 2H), 5.63 (s,
0.75H), 7.42 (dd, 1.42H, J = 7.7 Hz, J = 6.5 Hz, enol, 2H), 7.62 (dd, J = 7.7 Hz, J = 6.5 Hz,
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2H), 12.50 (s, 0.7H);19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ131.9 (d, , J = 20.1 Hz, 0.75F), ꢀ
133.4 (d, , J = 20.1 Hz, 2F), ꢀ151.2 (t, J = 20.1 Hz, 0.4F) ꢀ155.8 (t, J = 20.1 Hz, 1F); 13C NMR
[1H] (CDCl3, 64 MHz) δ (ppm): 45.4, 51.7, 52.8, 61.4, 88.3, 110.5 (dd, J = 6.7 Hz, J = 15.7 Hz),
112.2 (dd, J = 6.7 Hz, J = 15.7 Hz), 129.4 (t, J = 6.3 Hz), 141.1, 125.2, 128.1 (q, J = 20.1 Hz),
131.2, 134.4, 159.7, 154.5 (d, J = 252.8 Hz), 167.1, 167.8, 173.0, 188.9; HRꢀMS (ESI) m/z:
[M+Na]+ Calcd for C10H7F3O3Na 255.0239; found 255.0233; Isolated yield: 270 mg (84%) from
240 mg of 1k.
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General procedure for transesterification reactions. Preparation of compounds 3. In a 100
mL round bottom flash, 1.50 mmol of the methoxy βꢀketo ester were dissolved in 2 mL of
toluene. Then, 10 equivalents of 3ꢀpentanol and 25 mg (0.20 eq.) of ZnO were added. The
system was carried out to reflux temperature; a distillation system is required in order to isolate
the methanol formed during the reaction. Upon reaction completion the solution is filtered off
through Celite® and the solvent is removed under reduced pressure. The reaction crude is
purified with silica gel column chromatography using hexane:AcOEt (4:1) as eluent obtaining
the desired 3ꢀpentanyl βꢀketo esters.
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3ꢀPentanyl 3ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ3ꢀoxopropanoate, 3a. Oil; H NMR (250 MHz,
CDCl3) δ (ppm): keto (67%) ꢀ enol (33%) mixture, 0.85 (t, J = 7.5 Hz, 6H), 0.94 (t, J = 7.5 Hz,
3H), 1.47 – 1.61 (m, 4H), 1.61 – 1.70 (m, 2H), 3.83 (s, 2.3H), 4.03 (s, 2H), 4.83 (quint, J = 6.1
Hz, 1H), 4.93 (quint, J = 6.1 Hz, 0.5H), 5.74 (s, 0.5H), 7.67 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.2
Hz, 2H), 7.89 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 12.69 (s, 0.5H); 19F NMR (235
MHz, CDCl3) δ (ppm): ꢀ63.0 (s, 1.6F), ꢀ63.3 (s, 3F); 13C NMR [1H] (CDCl3, 64 MHz) δ (ppm):
9.4, 9.5, 26.2, 26.5, 46.4, 77.2, 78.5, 89.2, 123.5 (q, J = 272.8 Hz), 123.8 (q, J = 272.8 Hz),
125.4 (q, J = 3.8 Hz), 125.8 (q, J = 3.8 Hz), 126.3, 128.8, 132.6 (q, J = 32.7 Hz), 134.9 (q, J =
32.7 Hz), 136.9, 138.7, 166.8, 169.3, 172.9, 191.7; IR (ATR) ν (cmꢀ1): 1735, 1694; HRꢀMS
(ESI) m/z: [M+Na]+ Calcd for C15H17F3O3Na 325.1022; found 325.102; Isolated yield: 210 mg
(85%) from 200 mg of 2a.
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3ꢀPentanyl 3ꢀ(4ꢀ(trifluoromethoxy)phenyl)ꢀ3ꢀoxopropanoate, 3b. Oil; H NMR (250 MHz,
CDCl3) δ (ppm): keto (67%) ꢀ enol (33%) mixture, 0.85 (t, J = 7.5 Hz), 0.94 (t, J = 7.5 Hz, 3H),
1.47 – 1.61 (m, 4H), 1.61 – 1.70 (m, 2H), 3.83 (s, 2.3H), 4.03 (s, 2H), 4.83 (quint, J = 6.1 Hz,
1H), 4.93 (quint, J = 6.1 Hz, 0.5H), 5.74 (s, 0.5H), 7.67 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz,
2H), 7.89 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.2 Hz, 2H), 12.69 (s, 0.5H); 19F NMR (235 MHz,
CDCl3) δ (ppm): ꢀ63.0 (s, 1.6F), ꢀ63.3 (s, 3F); 13C NMR [1H] (CDCl3, 64 MHz) δ (ppm): 9.4,
9.5, 26.2, 26.5, 46.4, 77.2, 78.5, 89.2, 123.5 (q, J = 272.8 Hz), 123.8 (q, J = 272.8 Hz), 125.4 (q,
J = 3.8 Hz), 125.8 (q, J = 3.8 Hz), 126.3, 128.8, 132.6 (q, J = 32.7 Hz), 134.9 (q, J = 32.7 Hz),
136.9, 138.7, 166.8, 169.3, 172.9, 191.7; IR (ATR) ν (cmꢀ1): 2971, 1735, 1694; HRꢀMS (ESI)
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m/z: [M+Na]+ Calcd for C15H17F3O4Na 341.0971; found 341.0974; Isolated yield: 260 mg
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(85%) from 250 mg of 2b.
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3ꢀPentanyl 3ꢀ(3ꢀfluoroꢀ4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate, 3c. Oil; H NMR (360 MHz,
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CDCl3) δ (ppm): keto (89%) ꢀ enol (11%) mixture, 0.83 (t, J = 7.5 Hz), 0.91 (t, J = 7.5 Hz,
0.7H), 1.47 – 1.63 (m, 4.66 H), 3.92 (s, 2H), 3.94 (s, 3H), 4.80 (quint, J = 7.2 Hz), 4.88 (quint, J
= 7.2 Hz, 0.12H), 5.56 (s, 0.12H), 6.99 (t, J = 8.3 Hz, 0.16H), 7.06 (t, J = 8.3 Hz, 1H), 7.48 (dd,
J = 10.8 Hz, J = 3.6 Hz, 0.12H), 7.54 (dd, J = 10.8 Hz, J = 3.6 Hz, 0.12H), 7.68 (dd, J = 10.8
Hz, J = 3.6 Hz, 1H), 7.73 (s ap, 1H), 12.69 (s, 0.12H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ
133.8 (s, 1F), ꢀ63.5 (s, 0.1F); 13C NMR [1H] (CDCl3, 91 MHz) δ (ppm): 9.4, 9.4, 26.3, 26.5,
46.1, 56.2, 56.3, 86.8, 112.4 (d, J = 1.6 Hz), 112.8 (d, J = 1.6 Hz), 113.8 (d, J = 20.1 Hz), 116.0
(d, J = 20.1 Hz), 122.5 (d, J = 3.2 Hz), 126.1 (d, J = 3.2 Hz), 129.3 (d, J = 5.4 Hz), 152.0 (d, J =
249.3 Hz), 152.4 (d, J = 11.0 Hz), 167.8, 170.1, 173.5, 190.1; IR (ATR) ν (cmꢀ1): 2973, 1726,
1685; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C15H19FO4Na 305.1160; found 305.115; Isolated
yield: 280 mg (89%) from 250 mg of 2c.
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3ꢀPentanyl 3ꢀ(3ꢀtrifluoromethylꢀ4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate, 3d. Oil; 1H NMR (400
MHz, CDCl3) δ (ppm): keto (90%) ꢀ enol (10%) mixture, 0.86 (t, J = 7.5 Hz, 6H), 0.94 (t, J =
7.5 Hz, 0.80H), 1.55 – 1.72 (m, 4.5H), 3.97 (s, 0.4H), 3.98 (s, 3H), 4.00 (s, 0.3H), 4.83 (quint, J
= 6.2 Hz, 1H), 4.91 (quint, J = 6.2 Hz, 0.11H), 5.64 (s, 0.12H), 7.05 (d, J = 9.1 Hz, 0.09H), 7.09
(d, J = 9.1 Hz, 1H), 7.95 (dd, J = 1.9 Hz, J = 9.1 Hz, 0.13H), 8.00 (d, J = 2.0 Hz, 0.13H), 8.16
(dd, J = 2.0 Hz, J = 9.1 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 12.76 (s, 0.10H);19F NMR (376 MHz,
CDCl3) δ (ppm): ꢀ62.78 (s, 0.12F), ꢀ63.01 (s, 1F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm):
9.4, 9.5, 26.2, 26.5, 46.0, 56.1, 56.3, 78.3, 85.9, 111.7, 111.8, 119.0 (q, J = 31.2 Hz), 122.9 (q, J
= 272.6 Hz), 125.1, 125.5, 128.1 (q, J = 5.0 Hz), 131.2, 134.4, 161.4, 167.0, 169.6, 173.1,
190.2; IR (ATR) ν (cmꢀ1): 2976, 1728, 1610; Elemental analysis Calcd C16H19F3O4 C: 57.83%,
H: 5.76%. Found C: 58.20%, H: 5.91%; Isolated yield: 222 mg (92%) from 200 mg of 2d.
1
3ꢀPentanyl 3ꢀ(3ꢀtrifluoromethoxyꢀ4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate, 3f. Oil; H NMR
(250 MHz, CDCl3) δ (ppm): keto (70%) ꢀ enol (30%) mixture, 0.81 (t, J = 7.4 Hz, 6H), 0.89 (t, J
= 7.4 Hz, 2.5H), 1.48 – 1.62 (m, 5.7H), 3.97 (s, 5H), 4.77 (quint, J = 7.4 Hz), 4.87 (quint, J =
7.3 Hz, 0.5H), 5.63 (s, 0.34H), 6.98 (d, J = 8.6 Hz, 0.4H), 7.02 (d, J = 8.6 Hz, 1H), 7.62 (s,
0.4H), 7.67 (dd, J = 8.6 Hz, J = 2.1 Hz, 0.4H), 7.83 (s, 1H), 7.87 (dd, J = 8.6 Hz, J = 2.1 Hz,
1H) 12.72 (s, 0.4H);19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ58.9 (s, 1.3F), ꢀ59.0 (s, 3F);13C
NMR [1H] (CDCl3, 91 MHz) δ (ppm): 9.3, 9.5, 26.2, 26.5, 46.0, 56.0, 56.2, 76.9, 78.3, 86.9,
112.2 (d, J = 19.3 Hz), 112.5 (d, J = 19.3 Hz), 120.5 (q, J = 259.8 Hz), 120.7, 123.1, 125.9,
126.2, 129.1, 129.3, 137.8, 137.9, 154.3, 156.4, 167.1 169.5, 173.2, 190.1; IR (ATR) ν (cmꢀ1):
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2972, 1731, 1683; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C16H19F3O5Na 371.1077; found
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371.1079; Isolated yield: 262 mg (95%) from 220 mg of 2f.
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3ꢀPentanyl 3ꢀ(3,5ꢀdifluoroꢀ4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate, 3g. Oil; 1H NMR (400 MHz,
CDCl3) δ (ppm): keto (80%) ꢀ enol (20%) mixture, 0.86 (t, J = 7.5 Hz, 6H3), 0.93 (t, J = 7.5 Hz,
2.1H), 1.60 (m, 5H), 3.92 (s, 2H), 4.07 (t, J = 4.0 Hz), 4.12 (t, J = 4.0 Hz, 3H), 4.83 (quint, J =
6.7 Hz, 1H), 4.90 (quint, J = 6.7 Hz, 0.3H), 5.64 (s, 0.3H), 7.34 (d, J = 9.7 Hz, 0.3H), 7.53 (d, J
= 9.7 Hz, 2H), 12.64 (s, 0.3H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ126.9 (s, 2F), ꢀ127.8 (s,
0.5F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3, 9.4, 26.2, 26.4, 45.8, 61.5 (q, J = 4.0 Hz),
77.0, 78.4, 88.0, 110.0 (dd, J = 17.4 Hz, J = 7.5 Hz), 112.8 (dd, J = 17.4 Hz, J = 7.5 Hz), 127.9
(t, J = 6.3 Hz), 129.8 (t, J = 6.3 Hz), 138.6 (t, J = 13.2 Hz), 141.1 (t, J = 13.2 Hz), 156.7 (dd, J =
250.2 Hz, J = 5.9 Hz), 155.1 (dd, J = 250.2 Hz, J = 5.9 Hz), 166.7, 168.3, 172.8, 188.9 (t, J =
2.2 Hz); IR (ATR) ν (cmꢀ1): 2970, 1732, 1694; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for
C15H18F2O4Na 323.1063; found 323.1065; Isolated yield: 261 mg (85%) from 250 mg of 2g.
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3ꢀPentanyl 3ꢀ(3,4ꢀdifluorophenyl)ꢀ3ꢀoxopropanoate, 3h. Oil; H NMR (360 MHz, CDCl3) δ
(ppm): keto (70%) ꢀ enol (30%) mixture, 0.85 (t, J = 7.4 Hz, 6H), 0.93 (t, J = 7.4 Hz, 2.67H),
1.55 (m, 4H), 1.65 (m, 1.50H), 3.96 (s, 2H), 4.82 (quint, J = 7.4 Hz, 1H), 4.92 (quint, J = 7.4
Hz, 0.30H), 5.62 (s, 0.24H), 7.27 (m, 1H), 7.62 (m, 0.7H), 7.82 (m, 2H), 12.69 (s, 0.26H,); 19
F
NMR (235 MHz, CDCl3) δ (ppm): ꢀ129.0 (d, J = 20.9 Hz, 1F), ꢀ133.7 (d, J = 21.1 Hz, 0.3F,
enol), ꢀ137.0 (d, J = 20.9 Hz, 1F), ꢀ137.2 (d, J = 21.1 Hz, 0.3F); 13C NMR [1H] (CDCl3, 101
MHz) δ (ppm): 9.4, 9.6, 26.3, 26.5, 46.2, 78.6, 88.2, 115.8 (d, J = 19.3 Hz), 118.2 (m), 122.5
(dd, J = 7.6 Hz, J = 3.6 Hz), 126.07 (dd, J = 7.6 Hz, J = 3.6 Hz), 133.7 (dd, J = 7.6 Hz, J = 3.7
Hz), 150.9 (dd, J = 251.5 Hz, J = 18.4 Hz), 154.4 (dd, J = 253.5 Hz, J = 18.1 Hz), 166.2, 173.4,
190.5; IR (ATR) ν (cmꢀ1): 2973, 2943, 1737, 1695; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for
C14H16F2O3Na 293.0960; found 293.0955; Isolated yield: 201 mg (80%) from 200 mg of 2h.
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3ꢀPentanyl 3ꢀ(3ꢀtrifluoromethoxyꢀ4ꢀfluorophenyl)ꢀ3ꢀoxopropanoate, 3i. Oil; H NMR (360
MHz, CDCl3) δ (ppm): keto (67%) ꢀ enol (33%) mixture, 0.83 (t, J = 7.4 Hz, 6H), 0.92 (t, J =
7.4 Hz, 3H), 1.51 – 1.58 (m, 4H), 1.59 – 1.66 (m, 2H), 3.97 (s, 2H), 4.81 (quint, J = 7.4 Hz,
1H), 4.91 (quint, J = 7.3 Hz, 0.5H), 5.63 (s, 0.5H), 7.24 (t, J = 8.6 Hz, 0.5H), 7.31 (t, J = 8.6 Hz,
1H), 7.72 (m, 1H), 7.94 (m, 2H), 12.72 (s, 0.5H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ59.36
(d, J = 7.8 Hz, 1F), ꢀ59.42 (d, J = 6.5 Hz, 3F), ꢀ120.25 (q, J = 5.5 Hz, 1F), ꢀ124.83 (q, J = 5.5
Hz, 0.5F); 13C NMR [1H] (CDCl3, 91 MHz) δ (ppm): 9.3, 9.5, 26.2, 26.5, 46.2, 77.2, 78.6, 80.8,
117.4 (d, J = 19.3 Hz), 117.7 (d, J = 19.3 Hz), 121.8, 124.3, 126.1 (d, J = 8.5 Hz), 129.1 (d, J =
8.5 Hz), 130.8 (d, J = 3.8 Hz), 133.2 (d, J = 3.8 Hz), 136.5 (dq, J = 19.2 Hz, J = 2.8 Hz), 136.8
(dq, J = 19.2 Hz, J = 2.8 Hz), 156.1 (d, J = 258.4 Hz), 157.7 (d, J = 258.4 Hz), 166.7, 168.4,
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172.9, 189.9; IR (ATR) ν (cmꢀ1): 2991, 2960, 1739, 1681; HRꢀMS (ESI) m/z: [M+Na]+ Calcd
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for C15H16F4O4Na 359.0877; found 359.0884; Isolated yield: 275 mg (92%) from 230 mg of 2i.
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3ꢀPentanyl 3ꢀ(3ꢀtrifluoromethylꢀ4ꢀfluorophenyl)ꢀ3ꢀoxopropanoate, 3j. Oil; H NMR (400
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MHz, CDCl3) δ (ppm): keto (71%) ꢀ enol (29%) mixture, 0.86 (t, J = 7.5 Hz, 6H), 0.94 (t, J =
7.5 Hz, 2.5H), 1.51 – 1.74 (m, 6.4H), 4.01 (s, 2H), 4.83 (quint, J = 6.2 Hz, 1H), 4.93 (quint, J =
6.2 Hz, 0.4H), 5.68 (s, 0.4H), 7.27 (t, J = 9.2 Hz, 0.4H), 7.34 (t, J = 9.1 Hz, 1H), 7.95 – 8.01 (m,
0.4H), 8.04 (d, J = 6.7 Hz, 0.4H), 8.18 – 8.22 (m, 1H), 8.26 (d, J = 6.7 Hz, 1H), 12.75 (s,
0.40H);19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ61.67 (d, 1.3F, J = 12.6 Hz), ꢀ61.82 (d, J = 12.5
Hz, 3F), ꢀ105.74 (q, J = 12.5 Hz, 1F), ꢀ110.45 (q, J = 12.6 Hz, 0.4F); 13C NMR [1H] (CDCl3,
101 MHz) δ (ppm): 9.3, 9.5, 26.2, 26.4, 46.1, 77.3, 78.6, 88.5, 117.2, 117.6, 119.1 (dd, J = 13.2
Hz, J = 33.6 Hz), 121.9 (q, J = 272.7 Hz), 122.1 (q, J = 272.7 Hz), 125.1, 130.0 (d, J = 3.8 Hz),
131.5 (d, J = 9.1 Hz), 132.4 (d, J = 3.7 Hz), 134.5 (d, J = 9.8 Hz), 161.1 (d, J = 262.2 Hz),
162.7 (d, J = 265.2 Hz), 166.6, 168.3, 172.8, 189.9; IR (ATR) ν (cmꢀ1): 2993, 2958, 1739, 1681;
Elemental analysis Calcd for C16H19F3O4 C: 57.83%, H: 5.76%. Found C: 58.20%, H: 5.91%;
Isolated yield: 215 mg (88%) from 200 mg of 2j.
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3ꢀPentanyl 3ꢀ(3,4,5ꢀtrifluorophenyl)ꢀ3ꢀoxopropanoate, 3k. Oil; H NMR (400 MHz, CDCl3)
δ (ppm): keto (67%) ꢀ enol (33%) mixture, 0.87 (t, J = 7.4 Hz, 6H), 0.94 (t, J = 7.4 Hz, 3H),
1.57 (m, 4H), 1.65 (m, 2H), 3.95 (s, 2H), 4.83 (m, 1H), 4.92 (m, 0.5H), 7.44 (m, 1H), 7.63 (m,
2H), 12.68 (s, 0.5H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ131.7 (d, J = 19.9 Hz, 2F), ꢀ133.2
(d, J = 19.9 Hz, 1F), ꢀ151.2 (t, J = 19.9 Hz) ꢀ155.7 (t, J = 19.9 Hz, 0.5F); 13C NMR [1H]
(CDCl3, 101 MHz) δ (ppm): 9.3, 9.5, 26.2, 26.4, 46.0, 77.4, 78.4, 88.9, 110.4 (dd, J = 16.6 Hz, J
= 6.4 Hz), 113.1 (dd, J = 16.6 Hz, J = 6.4 Hz), 129.6 (m, ArC), 131.6, 143.4, 151.2, 166.4,
167.5, 172.7, 189.0; IR (ATR) ν (cmꢀ1): 3018, 2962, 2921, 1755, 1628, 1517, 1450, 1217, 1174,
1043; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C14H15F3O3Na 311.0865; found 311.0866; Isolated
yield: 255 mg (82%) from 250 mg of 2k.
General procedure for the alkylation reactions. Preparation of compounds 4 and 10e. In a
10 ml roundꢀbottom flash provided with a reflux condenser 1.25 mmol of βꢀketoester is
dissolved in 3 ml of dry acetone. After solution of starting material 1.38 mmol of K2CO3 and
1.82 mmol of the corresponding iodide are added. The system is maintained at 40ºC with
stirring up to 24 hours. After reaction completion (TLC) the solution is filtered, the crude is
extracted with CH2Cl2 and washed with HCl 1M. Organic phase is dried with sodium sulphate
and purified with column chromatography using mixtures of hexane:AcOEt (7:3) as eluent.
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3ꢀPentanyl 3ꢀ(4ꢀtrifluoromethylphenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4a. Oil; H NMR (360
MHz, CDCl3) δ (ppm): 0.70 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H), 1.45 (m, 7H), 4.37 (q, J
= 7.0 Hz, 1H), 4.71 (quint, J = 6.2 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 8.10 (d, J = 8.3 Hz,
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2H);19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ63.1 (s, 3F); 13C NMR [1H] (CDCl3, 91 MHz) δ
(ppm): 9.1, 9.2, 13.4, 26.1, 49.0, 78.2, 123.4 (q, J = 272.7 Hz), 125.6 (q, J = 3.7 Hz), 128.8,
134.5 (q, J = 32.8 Hz), 138.8, 170.2, 194.7; IR (ATR) ν (cmꢀ1): 2973, 1736, 1697; HRꢀMS (ESI)
m/z: [M+Na]+ Calcd for C16H19F3O3Na 339.1179; found 339.1176; Isolated yield: 160 mg
(85%) from 180 mg of 3a.
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3ꢀPentanyl 3ꢀ(4ꢀtrifluoromethoxyphenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4b. Oil; 1H NMR (360
MHz, CDCl3) δ (ppm): 0.66 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H), 1.43 (m, 7H), 4.33 (q, J
= 7.0 Hz, 1H), 4.72 (quint, J = 6.2 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz,
2H);19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ58.1 (s, 3F);13C NMR [1H] (CDCl3, 91 MHz) δ
(ppm): 9.1, 9.3, 13.4, 26.2, 48.8, 78.1, 120.2 (q, J = 258.8 Hz), 120.4, 130.5, 134.3, 152.7 (q, J =
1.8 Hz), 170.5, 194.1. IR (ATR) ν (cmꢀ1): 2976, 1740, 1680; HRꢀMS (ESI) m/z: [M+Na]+ Calcd
for C16H19F3O4Na 355.1128; found 355.1124; Isolated yield: 143 mg (81%) from 160 mg of 3b.
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3ꢀPentanyl 3ꢀ((3ꢀfluoroꢀ4ꢀmethoxy)phenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4c. Oil; H NMR
(400 MHz, CDCl3) δ (ppm): 0.72 (t, J = 7.5 Hz, 3H), 0.79 (t, J = 7.5 Hz, 3H), 1.48 (m, 7H),
3.94 (s, 3H), 4.29 (q, J = 7.0 Hz, 1H), 4.73 (quint, 1H, J = 7.5 Hz), 7.00 (t, J = 8.3 Hz, 1H), 7.73
(dd, J = 2.2 Hz, J = 10.9 Hz, 1H), 7.78 (ddd, J = 1.0 Hz, J = 2.2 Hz, J = 10.9 Hz, 1H);19F NMR
(376 MHz, CDCl3) δ (ppm): ꢀ134.4 (s, 1F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.2, 9.3,
13.6, 26.1, 26.1, 48.4, 56.2, 77,9, 112.3 (d, J = 1.6 Hz), 116.1 (d, J = 20.1 Hz), 125.9 (d, J = 3.2
Hz), 129.2 (d, J = 5.4 Hz), 151.9 (d, J = 248.5 Hz), 152.1 (d, J = 11.0 Hz), 170.6, 193.3; IR
(ATR) ν (cmꢀ1): 2974, 2941, 1728, 1688; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C16H21FO4Na
319.1316; found 319.1303; Isolated yield: 185 mg (89%) from 200 mg of 3c.
3ꢀPentanyl 3ꢀ((3ꢀtrifluoromethylꢀ4ꢀmethoxy)phenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4d. Oil;
1H NMR (400 MHz, CDCl3) δ (ppm): 0.75 (t, J = 6.3 Hz, 3H), 0.79 (t, J = 6.3 Hz, 3H), 1.42 –
1.57 (m, 7H), 3.99 (s, 3H), 4.35 (q, J = 7.0 Hz, 1H), 4.83 (quint, J = 7.2 Hz, 1H), 7.08 (d, J =
8.8 Hz, 1H), 8.19 (dd, J = 2.0 Hz, J = 8.7 Hz, 1H), 8.25 (s, 1H); 19F NMR (376 MHz, CDCl3) δ
(ppm): ꢀ63.42 (s, 3F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3, 9.4, 13.6, 26.2, 48.4,
56.3, 78.2, 111.7, 119.0 (q, J = 31.0 Hz), 123.0 (q, J = 273.4 Hz), 128.2 (q, J = 5.1 Hz), 128.3,
134.3, 161.2, 170.5, 193.3; IR (ATR) ν (cmꢀ1): 2972, 2948, 1723, 1618; Elemental analysis
calculated for C16H19F3O4 C: 57.83%, H: 5.76%. Found C: 58.20%, H: 5.91%; Isolated yield:
187 mg (90%) from 200 mg of 3d.
3ꢀPentanyl 3ꢀ((3ꢀtrifluoromethoxyꢀ4ꢀmethoxy)phenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4f. Oil;
1H NMR (360 MHz, CDCl3) δ (ppm): 0.70 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), 1.47 (m,
7H), 3.95 (s, 3H), 4.29 (q, J = 7.0 Hz, 1H), 4.73 (quint, J = 7.3 Hz, 1H), 7.04 (d, J = 8.6 Hz,
1H), 7.90 (s, 1H), 7.95 (dd, J = 8.6 Hz, J = 2.1 Hz, 1H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ
58.82 (s, 3F); 13C NMR [1H] (CDCl3, 91 MHz) δ (ppm): 9.2, 9.3, 16.6, 26.2, 26.2, 48.5, 56.3,
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78.1, 112.1, 120.5 (q, J = 260.5 Hz), 123.4, 129.1 (d, J = 8.5 Hz), 129.2, 137.9 (d, J = 2 Hz),
156.2, 170.6, 193.1; IR (ATR) ν (cmꢀ1): 2978, 2932, 1736, 1688; HRꢀMS (ESI) m/z: [M+Na]+
Calcd for C17H21F3O5Na 385.1239; found 385.1232; Isolated yield: 150 mg (81%) from 180 mg
of 3f.
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3ꢀPentanyl 3ꢀ((3,5ꢀdifluoroꢀ4ꢀmethoxy)phenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4g. Oil; 1H
NMR (360 MHz, CDCl3) δ (ppm): 0.75 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H), 1.51 (m,
7H), 3.95 (s, 3H), 4.11 (q, J = 4.0 Hz, 1H), 4.76 (quint, J = 6.7 Hz, 1H), 7.56 (d, J = 9.5 Hz,
2H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ127.1 (s, 2F); 13C NMR [1H] (CDCl3, 91 MHz) δ
(ppm): 9.3, 9.4, 13.6, 26.2, 48.5, 61.6, 78.3, 112.9 (dd, J = 16.4 Hz, J = 7.9 Hz), 129.9 (t, J = 6.7
Hz), 140.9 (t, J = 13.3 Hz), 154.8 (dd, J = 250.0 Hz, J = 5.7 Hz), 170.3, 192.5 (t, J = 2.0 Hz); IR
(ATR) ν (cmꢀ1): 2970, 1732, 1694; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C16H20F2O4Na
337.1222; found 337.122; Isolated yield: 140 mg (89%) from 150 mg of 3g.
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3ꢀPentanyl 3ꢀ(3,4ꢀdifluorophenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4h. Oil; H NMR (360 MHz,
CDCl3) δ (ppm): 0.72 (t, J = 7.4 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H), 1.49 (m, 7H), 4.29 (q, J = 7.0
Hz, 1H), 4.75 (quint, J = 7.4 Hz, 1H), 7.26 (dd, J = 21.0 Hz, J = 8.6 Hz, 1H), 7.82 (m, 2H); 19
NMR (235 MHz, CDCl3) δ (ppm): ꢀ129.5 (d, J = 21.0 Hz, 1F), ꢀ136.1 (d, J = 21.0 Hz, 1F); 13
F
C
NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3, 9.4, 13.5, 26.1, 26.2, 48.8, 78.3, 117.6 (d, J = 117.6
Hz), 117.9 (dd, J = 18.1 Hz, J = 1.4 Hz), 125.6 (dd, J = 7.4 Hz, J = 4.0 Hz), 133.2 (t, J = 4.0
Hz), 150.5 (dd, J = 251.3 Hz, J = 13.0 Hz), 153.8 (dd, J = 251.3 Hz, J = 13.0 Hz), 170.3, 193.1;
IR (ATR) ν (cmꢀ1): 2973, 1735, 1693; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C15H18F2O3Na
307.1116; found 307.1114; Isolated yield: 183 mg (92%) from 190 mg of 3h.
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3ꢀPentanyl 3ꢀ((3ꢀtrifluoromethoxyꢀ4ꢀfluoro)phenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4i. Oil; H
NMR (250 MHz, CDCl3) δ (ppm): 0.72 (t, J = 7.5 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H), 1.49 (m,
7H), 4.31 (q, J = 7.0 Hz, 1H), 4.76 (quint, J = 6.2 Hz, 1H), 7.34 (t, J = 9.1 Hz, 1H), 7.98 (m,
2H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ59.3 (d, J = 4.8 Hz, 3F), ꢀ120.6 (q, J = 4.8 Hz, 1F);
13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.1, 9.3, 13.4, 26.1, 26.1, 48.8, 78.3, 117.6 (d, J =
19.4 Hz), 120.3 (q, J = 263.4 Hz), 124.4, 128.9 (d, J = 8.4 Hz), 133.1 (d, J = 3.6 Hz), 136.7 (dq,
J = 12.9 J = 2.2 Hz), 157.6 (d, J = 261.8 Hz), 170.1, 192.8; IR (ATR) ν (cmꢀ1): 2999, 2985,
1745, 1686; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C16H18F4O4Na 373.1033; found 373.1041;
Isolated yield: 135 mg (86%) from 150 mg of 3i.
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3ꢀPentanyl 3ꢀ((3ꢀtrifluoromethylꢀ4ꢀfluoro)phenyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate, 4j. Oil; H
NMR (400 MHz, CDCl3) δ (ppm): 0.75 (t, J = 7.5 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H), 1.51 (m,
7H), 4.36 (q, J = 7.0 Hz, 1H), 4.77 (quint, 7.2 Hz, 1H), 7.33 (t, J = 9.2 Hz), 8.24 (ddd, J = 9.2
Hz, J = 6.7 Hz, J = 2.3 Hz, 1H), 8.30 (dd, J = 6.7 Hz, J = 2.3 Hz, 1H); 19F NMR (376 MHz,
CDCl3) δ (ppm): ꢀ61.8 (d, J = 12.6 Hz, 3F), ꢀ106.3 (q, J = 12.6 Hz, 1F); 13C NMR [1H] (CDCl3,
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101 MHz) δ (ppm): 9.1, 9.3, 13.4, 26.1, 26.1, 48.8, 78.3, 117.5 (d, J = 19.4 Hz), 120.3 (q, J =
260.0 Hz), 124.4, 128.9 (d, J = 8.4 Hz), 133.1 (d, J = 3.7 Hz), 136.7, 157.6 (d, J = 261.8 Hz),
170.1, 192.8; IR (ATR) ν (cmꢀ1): 2993, 2958, 1739, 1681; HRꢀMS (ESI) m/z: [M+Na]+ Calcd
for C16H18F4O3Na 357.1090 found 357.1091; Isolated yield: 180 mg (88%) from 200 mg of 3j.
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MHz, CDCl3) δ (ppm): 0.74 (t, J = 7.5 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H), 1.44 – 1.50 (m, 7H),
4.25 (q, J = 7.0 Hz, 1H), 5.75 (quint, 7.2 Hz, 1H), 7.66 (dd, J = 7.7 Hz, J = 6.7 Hz, 2H); 19F
NMR (235 MHz, CDCl3) δ (ppm): ꢀ132.3 (d, J = 20.1 Hz, 2F), ꢀ152.0 (t, J = 20.1 Hz, 1F); 13C
NMR [1H] (CDCl3, 63 MHz) δ (ppm): 9.2, 9.3, 13.4, 26.2, 48.7, 78.4, 113.1, 131.7 (d, J = 4.4
Hz), 143.3 (dt, J = 260.7 Hz, J = 15.5 Hz), 151.2 (ddd, J = 253.1 Hz, J = 10.3 Hz, J = 3.3 Hz),
170.0, 192.1; IR (ATR) ν (cmꢀ1): 2994, 2962, 1751, 1621; HRꢀMS (ESI) m/z: [M+Na]+ Calcd
for C15H17F3O3Na 325.1022; found 325.1019; Isolated yield: 176 mg (89%) from 190 mg of 3k.
3ꢀPentanyl 3ꢀ(3,4ꢀdimethoxybenzoyl)ꢀ6,6,6ꢀtrifluorohexanoate, 10e. Oil; 1H NMR (360
MHz, CDCl3) δ (ppm): 0.68 (t, J = 7.4 Hz, 3H), 0.74 (t, J = 7.4 Hz, 3H), 1.43 (m, 4H), 1.59
(quint J = 7.4 Hz, 2H), 2.08 (m, 4H, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 4.24 (t, J = 7.1 Hz, 1H),
4.70 (quint, J = 6.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H); 19
F
NMR (235 MHz, CDCl3) δ (ppm): ꢀ66.9 (s, 3F); 13C NMR [1H] (CDCl3, 91 MHz) δ (ppm): 9.3,
9.3, 20.1 (q, J = 2.9 Hz), 26.1, 26.2, 27.9, 33.6 (q, J = 28.7 Hz), 53.9, 55.9, 56.0, 78.1, 110.0,
110.5, 123.3, 126.9 (q, J = 276.4 Hz), 129.3, 149.1, 153.7, 169.6, 192.7; IR (ATR) ν (cmꢀ1):
2970, 1965, 1730, 1675, 1585, 1514, 1418, 1257, 1134, 1023; HRꢀMS (ESI) m/z: [M+Na]+
Calcd for C20H27F3O5Na 427.1703; found 427.1702; Isolated yield: 422 mg (96%) from 320 mg
of 3k.
General procedure for αꢀfluorination with Selectfluor®. In a 25 mL round bottom flask with
a magnetic stirrer 3.15 mmol of Selectfluor® are dissolved in 10 mL of acetonitrile. Then, 2.1
mmol of the desired βꢀketo ester are disposed into the system. The reaction is warmed up to
50ºC during 24 hours. The reaction completion is followed by TLC. Once there are no
evidences of the presence of the starting material, the crude is poured into 25 mL of methyl tertꢀ
buthyl ether. After filtration, the organics are removed in a vacuum system and the crude
residue is purified by flash silica gel chromatography using mixture of hexane:AcOEt (4:1)
obtaining the desired αꢀfluoro βꢀketo ester.
Methyl 3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀfluoroꢀ3ꢀoxopropanoate, 6e. White solid; Mp. 59ꢀ60ºC;
1H NMR (400 MHz, CDCl3) δ (ppm): keto (95%) ꢀ enol (5%) mixture, 3.75 (s, 0.15H), 3.83 (s,
3H), 3.90 (s, 0.15H), 3.93 (s, 3H), 3.96 (s, 3H), 5.85 (d, J = 49.5 Hz, 1H), 6.92 (d, J = 8.6 Hz,
1H), 7.57 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 2.1 Hz, J = 8.6 Hz, 1H); 19F NMR (235 MHz,
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CDCl3) δ (ppm): ꢀ188.8 (d, J = 49.5 Hz, 1F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 53.3,
56.1, 56.3, 90.1 (d, J = 197.3 Hz), 110.3, 111.2 (d, J = 2.3 Hz), 125.1 (d, J = 5.4 Hz), 126.4 (d, J
= 2.3), 149.4, 154.7, 165.4 (d, J = 23.2 Hz), 187.7 (d, J = 20.1 Hz); IR (ATR) ν (cmꢀ1): 2965,
1742, 1681; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C12H13FO5Na 279.0639; found 279.0631;
Isolated yield: 504 mg (95%) from 500 mg of 2e.
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3ꢀPentanyl 3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀfluoroꢀ3ꢀoxopropanoate, 7e. Oil; 1H NMR (400 MHz,
CDCl3) δ (ppm): keto (92%) ꢀ enol (8%) mixture, 0.70 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.1 Hz,
3H), 1.62 (abs. compl., 4H), 3.93 (s, 3H), 3.96 (s, 3H), 4.89 (quint, J = 6.2 Hz, 1H), 5.82 (d, J =
48.9 Hz, 1H), 6.91 (d, J = 8,6 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 1.9 Hz, J = 8.6Hz,
1H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ188.3 (d, J = 48.8 Hz, 1F); 13C NMR [1H] (CDCl3,
101 MHz) δ (ppm): 9.4, 9.6, 26.4, 26.5, 56.2, 56.3, 80.1, 89.7 (d, J = 200.3 Hz), 110.3, 111.2 (d,
J = 2.1 Hz), 125.0 (d, J = 4.6 Hz), 126.6 (d, J = 2.1), 149.4, 154.6 165.4 (d, J = 23.2 Hz), 188.1
(d, J = 20.1 Hz); IR (ATR) ν (cmꢀ1): 2969, 1749, 1679; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for
C16H21FO5Na 335.1265; found 335.1267; Isolated yield: 510 mg (95%) from 500 mg of 3e.
General procedure for the introduction of the trifluoromethylthio group in the αꢀposition.
A dry and nitrogenꢀflushedꢀ10mL tube equipped with a magnetic stirrer and a septum is charged
with the desired βꢀketo ester (0.38 mmol) and TsNMeSCF3 (1.2 equiv.). The tube was
evacuated and refilled with nitrogen three times, and then dry 0.5 mL of THF is added. Under a
gentle argon atmosphere, the reaction mixture was cooled to 0°C, and LDA 2M (0.2equiv.)
solution (in THF/heptanes/ethylbenzene) was added dropwise via a syringe. The conversion was
checked by TLC until the starting material disappeared. The reaction is quenched with distilled
water after completion. Reaction is warmed at room temperature and 5 mL of Et
The organic layer is washed with aqueous HCl 0.5M solution, NaHCO saturated solution, NaCl
1M solution, and then the organics are dried over NaSO . After filtration, the solvent was
2
O were added.
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removed and the crude was purified by flash chromatography with hexane:AcOEt (7:3) to give
the desired product.
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Methyl 3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀtrifluoromethylthioꢀ3ꢀoxopropanoate, 8e. Oil; H NMR
(CDCl3, 400 MHz) δ (ppm): keto (57%) ꢀ enol (43%) mixture, 3.70 (s, 3H), 3.82 (s, 0.7H), 3.83
(s, 0.7H), 3.84 (s, 3H), 3.88 (s, 3H), 5.61, 6.84 (d, J = 8.5 Hz, 0.3H), 6.87 (d, J = 8.5 Hz, 0.3H),
7.19 (d, J = 1.9 Hz, 0.3H), 7.27 (dd, J = 1.9 Hz, J = 8.5Hz, 0.3H), 7.46 (d, J = 1.9 Hz, 1H), 7.61
(dd, J = 2.1 Hz, J = 8.6Hz, 1H), 14.49 (s, 0.23H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ40.8
(s, 3F), ꢀ45.4 (s, 0.9F); 13C NMR (CDCl3, 101 MHz) δ (ppm): 52.8, 53.7, 54.5, 55.7, 55.7, 55.8,
55.9, 110.0, 110.2, 110.7, 112.2, 123.1, 124.2, 127.6, 129.1 (q, J = 312.1 Hz, SCF3), 130.0 (q, J
= 312.1 Hz), 148.0, 149.3, 151.5, 154.7, 166.6, 173.7, 183.5, 186.53; IR (ATR): 2970, 1735,
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1675; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C13H13F3O5SNa 361.0333; found 361.0335;
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Isolated yield: 180 mg (65%) from 200 mg of 2e.
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3ꢀPentanyl 3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀtrifluoromethylthioꢀ3ꢀoxopropanoate, 9e. Oil; 1H
NMR (CDCl3, 360 MHz) δ (ppm): keto (57%) ꢀ enol (43%) mixture, 0.69 (t, J = 7.5 Hz, 3H),
0.80 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 1.5H), 1.51 (m, 4H), 1.69 (m, 1H), 3.90 (s, 0.6H),
3.92 (s, 3H), 3.96 (s, 3H), 4.77 (quint, J = 6.2 Hz, 1H), 4.97 (quint, J = 6.2 Hz, 0.2H), 5.59 (s,
1H), 6.89 (d, J = 8.5 Hz, 0.3H), 6.91 (d, J = 8.5 Hz, 0.3H), 7.26 (d, J = 1.9 Hz, 0.2H), 7.34 (dd,
J = 1.9 Hz, J = 8.5Hz, 0.3H), 7.53 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 2.1 Hz, J = 8.5Hz, 1H),
14.81 (s, 0.2H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ40.6 (s, 3F), ꢀ44.8 (s, 0.6F); 13C NMR
(CDCl3, 91 MHz) δ (ppm): 9.1, 9.2, 9.4, 26.0, 26.1, 26.2, 55.4, 55.8, 56.0, 56.2, 79.6, 80.4,
110.0, 110.2, 110.8, 112.3 , 123.1, 124.3, 127.6, 129.3 (q, J = 312.1 Hz,), 130.0 (q, J = 312.1
Hz), 148.1, 149.4, 151.3, 154.7, 166.1, 173.3, 183.5, 186.9; IR (ATR): 2970, 2939, 1675, 1585;
HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C17H21F3O5SNa 417.0957; found 417.0965; Isolated
yield: 132 mg (66%) from 150 mg of 3e.
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General procedure for the enantioselective αꢀamination reactions. A solution of Eu(OTf)3
(0.017 mmol) and Phꢀpybox (0.023 mmol) in dry acetonitrile (1.5 mL) was stirred overnight in
the presence of 4Å molecular sieves under argon atmosphere at room temperature. Then, the βꢀ
ketoester (0.184 mmol) and the electrophile (0.298 mmol) were sequentially added. The mixture
was stirred for the time indicated in the tables (TLC monitoring), and the product was
chromatographed through a silica gel column with hexane:AcOEt (4:1) as eluent.
(S)ꢀdiꢀtertꢀbutylꢀ(2ꢀmethylꢀ1,3ꢀdioxoꢀ1ꢀ(pentanꢀ3ꢀyloxy)ꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)
propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5a. White solid, Mp. 42ꢀ44ºC; 1H NMR (400 MHz,
CDCl3) δ (ppm): 0.91 – 1.82 (complex abs., 31H), 4.92 (broad s, 1H,), 6.20 (s, 1H), 7.31 (broad
s, 2H), 8.60 (broad s, 2H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ63.1 (s, 3F); 13C NMR [1H]
(CDCl3, 101 MHz) δ (ppm): 9.4, 9.5, 26.2, 26.3 – 28.1, 79.6, 81.6, 116.5, 119.0, 119.8, 121.6,
124.1, 131.3, 1542.1, 155.6, 169.2, 189.4, 190.2; IR (ATR) ν (cmꢀ1): 3284, 2980, 2915, 1746,
1710, 1685, 1670, 1602; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C26H37F3N2O7Na 569.2445;
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found 569.2453; [α]D = 91.4 (c = 0.009, CH3CN), 98% ee (absolute configuration S); HPLC
separation: Daicel ADꢀH, a racemic mixture shows two peaks, tr(S) = 15.81 min and tr(R) =
19.12 min with hexane:isopropanol (98:2); Isolated yield: 133 mg (77%) from 100 mg of 4a.
(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(2ꢀmethylꢀ1,3ꢀdioxoꢀ1ꢀ(pentanꢀ3ꢀyloxy)ꢀ3ꢀ(4ꢀ(trifluoromethoxy)phenyl)
propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5b. White solid, Mp. 60ꢀ62ºC; 1H NMR (400 MHz,
CDCl3) δ (ppm): 0.91 – 1.82 (complex abs., 31H), 4.92 (broad s, 1H), 6.20 (s, 1H), 7.29 (broad
s, 2H), 8.60 (broad s, 2H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ57.6 (s, 3F); 13C NMR [1H]
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(CDCl3, 101 MHz) δ (ppm): 9.4, 9.5, 26.2, 26.3 – 28.1, 79.6, 81.6, 116.5, 119.0, 119.8, 121.6,
124.1, 131.3, 1542.1, 155.6, 169.2, 189.4, 190.2.IR (ATR) ν (cmꢀ1): 3284, 2980, 2915, 1746,
1710, 1685, 1670, 1602; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C26H37F3N2O8Na 585.2394;
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found 585.2394; [α]D = 105.7 (c = 0.013, CH3CN), 96% ee (absolute configuration S); HPLC
separation: Daicel ADꢀH, a racemic mixture shows two peaks, tr(S) = 9.41 min and tr(R) = 16.75
min with hexane:isopropanol (99.5:0.5); Isolated yield: 101 mg (76%) from 80 mg of 4b.
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(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(3ꢀfluoroꢀ4ꢀmethoxyphenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentanꢀ3ꢀyloxy)
propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5c. White solid, Mp. 44ꢀ45ºC; 1H NMR (400 MHz,
55ºC, CDCl3) δ (ppm): 0.93 (t, 3H, J = 7.5 Hz), 1.00 (t, 3H, J = 7.5 Hz), 1.27 – 1.55 (complex,
abs., 18H), 1.67 (m, 4H), 1.81 (s, 3H), 3.94 (s, 3H), 4.89 (broad s, 1H), 6.15 (s, 1H), 7.00 (d,
1H, J = 7.3 Hz), 8.17 (s, 1H), 8.43 (s, 1H); 19F NMR (376 MHz, 55ºC, CDCl3) δ (ppm): ꢀ135.5
(s, 1F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3, 26.2, 26.3, 27.5, 28.1, 56.1, 79.4, 81.5,
112.4, 117.2, 126.8, 128.1, 151.3, 155.5, 156.1, 169.3, 190.1.IR (ATR) ν (cmꢀ1): 3234, 2974,
2936, 1737, 1704, 1696, 1686, 1611; Elemental analysis Calcd for C26H39FN2O8: C: 59.30%, H:
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7.46%, N: 5.32%. Experimental: C: 59.47%, H: 7.54%, N: 5.16%; [α]D = 115.4 (c = 0.013,
CH3CN), 92% ee (absolute configuration S); HPLC separation: Daicel ADꢀH, a racemic mixture
shows two peaks, tr(S) = 13.80 min and tr(R) = 21.04 min with hexane:isopropanol (95:5);
Isolated yield: 111 mg (74%) from 85 mg of 4c.
(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(4ꢀmethoxyꢀ3ꢀ(trifluoromethyl)phenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentan
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ꢀ3ꢀyloxy)propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5d White solid, Mp. 33ꢀ35ºC; H NMR
(400 MHz, 55ºC, CDCl3) δ (ppm): 0.96 (complex abs., 6 H), 1.29 – 1.54 (complex abs., 18H),
1.68 (m, 4H), 1.82 (s, 3H) 3.97 (s, 3H), 4.89 (broad s, 1H), 6.21 (s, 1H), 7.06 (d, J = 8.7 Hz,
1H), 8.56 (s, 1H), 8.93 (s, 1H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ62.5 (s, 3F); 13C NMR
[1H] (CDCl3, 101 MHz) δ (ppm): 9.4, 9.6, 20.2, 26.1, 26.2, 27.4 – 28.0, 56.1, 79.5, 81.6 – 85.3,
111.2, 118.8, 123.2, 129.2, 134.9, 135.9, 155.8, 156.6, 160.4, 160.2, 169.4, 189.0, 190.0; IR
(ATR) ν (cmꢀ1): 3297, 2980, 2938, 1739, 1716, 1689, 1610, 1607; HRꢀMS (ESI) m/z: [M+H]+
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Calcd for C27H40F3N2O8 577.2731; found 577.2739; [α]D = 94.3 (c = 0.010, CH3CN), 94% ee
(absolute configuration S); HPLC separation: Daicel ADꢀH, a racemic mixture shows two
peaks, tr(S) = 16.89 min and tr(R) = 22.92 min with hexane:isopropanol (98:2); Isolated yield:
115 mg (87%) from 80 mg of 4d.
(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(4ꢀmethoxyꢀ3ꢀ(trifluoromethoxy)phenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ
1
(pentanꢀ3ꢀyloxy)propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5f. White solid, Mp. 63ꢀ64ºC; H
NMR (400 MHz, 55ºC, CDCl3) δ (ppm): 0.97 (complex abs., 6 H), 1.26 – 1.71 (complex abs.,
18H), 1.68 (m, 4H), 1.83 (s, 3H) 3.96 (s, 3H), 4.91 (broad s, 1H), 6.19 (s, 1H), 7.06 (d, J = 8.7
Hz, 1H), 8.37 (s, 1H), 8.73 (s, 1H); 19F NMR (376 MHz, CDCl3) δ (ppm): ꢀ58.4 (s, 3F); 13C
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NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3, 20.7, 26.2, 26.3, 27.5 – 28.1, 56.0, 79.5, 81.4,
111.9, 119.34, 121.9, 124.6, 127.9, 130.2, 137.8, 155.4, 155.5, 156.13, 169.2, 160.2, 169.4,
189.3. IR (ATR) ν (cmꢀ1): 3294, 2981, 2922, 1715, 1709, 1679, 1622, 1615; HRꢀMS (ESI) m/z:
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[M+H]+ Calcd for C27H40F3N2O9 593.2680; found 593.2682; [α]D = 81.4 (c = 0.010, CH3CN),
90% ee (absolute configuration S). HPLC separation: Daicel ADꢀH, a racemic mixture shows
two peaks, tr(S) = 14.00 min and tr(R) = 21.40 min with hexane:isopropanol (98:2); Isolated
yield: 103 mg (75%) from 85 mg of 4f.
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(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(3,5ꢀdifluoroꢀ4ꢀmethoxyphenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentanꢀ3ꢀ
yloxy)propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5g. White solid, Mp. 42ꢀ43ºC; 1H NMR (400
MHz, 55ºC, CDCl3) δ (ppm): 0.96 (complex abs., 6 H), 1.32 – 1.56 (complex abs., 18H), 1.66
(m, 4H), 1.80 (s, 3H) 4.09 (s, 3H), 4.89 (broad s, 1H), 6.16 (s, 1H), 8.16 (s, 2H); 19F NMR (376
MHz, 55ºC, CDCl3) δ (ppm): ꢀ127.8 (s, 3F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3,
9.4, 20.4, 26.2, 26.3, 27.6 – 28.1, 61.3, 79.6, 81.7, 113.7, 128.9, 140.1, 153.3, 153.3, 153.4,
155.6, 155.7, 155.8, 159.2, 169.0, 188.3.IR (ATR) ν (cmꢀ1): 3291, 2981, 2922, 1745, 1725,
1682, 1664, 1621; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C26H38F2N2O8Na 567.2488; found
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567.2493; [α]D = 101.1 (c = 0.011, CH3CN), 92% ee (absolute configuration S); HPLC
separation: Daicel ADꢀH, a racemic mixture shows two peaks, tr(S) = 10.03 min and tr(R) =
15.45 min with hexane:isopropanol (98:2); Isolated yield: 132 mg (76%) from 100 mg of 4g.
(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(3,4ꢀdifluorophenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentanꢀ3ꢀyloxy)propanꢀ2ꢀ
yl)hydrazineꢀ1,2ꢀdicarboxylate, 5h. White solid, Mp. 35ꢀ37ºC; 1H NMR (360 MHz, CDCl3) δ
(ppm): 0.91 – 1.98 (abs. complex, 32 H), 4.89 (bs, 1H), 6.23 (s, 1H), 7.23 (bs, 1H), 8.13 – 8.62
(complex abs., 2H); 19F NMR (235 MHz, CDCl3) δ (ppm): ꢀ131.3 (d, J = 297.6 Hz, 1F), ꢀ137.17
(d, J = 150.7 Hz, 1F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.6, 20.5, 26.2, 26.3, 27.4 –
28.2, 78.3, 81.6 – 85.3, 117.6, 117.0, 118.8, 131.8, 148.6, 155.7, 169.2, 188.6, 188.9, 189.7. IR
(ATR) ν (cmꢀ1): 3286, 2988, 2925, 1745, 1715, 1700, 1682, 1669, 1618; HRꢀMS (ESI) m/z:
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[M+Na]+ Calcd for C25H36F2N2O7Na 537.2383; found 537.2389; [α]D = 91.7 (c = 0.009,
CH3CN), >99% ee (absolute configuration S); HPLC separation: Daicel ADꢀH, a racemic
mixture shows two peaks, tr(S) = 16.05 min and tr(R) = 20.67 min with hexane:isopropanol
(95:5); Isolated yield: 88 mg (82%) from 60 mg of 4h.
(S)ꢀdiꢀtertꢀbutylꢀ1ꢀ(1ꢀ(4ꢀfluoroꢀ3ꢀ(trifluoromethoxy)phenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentanꢀ
1
3ꢀyloxy)propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5i. White solid, Mp. 51ꢀ54ºC; H NMR
(400 MHz, 55ºC, CDCl3) δ (ppm): 0.96 (complex abs., 6 H), 1.30 – 1.56 (complex abs., 18H),
1.68 (m, 4H), 1.83 (s, 3H), 4.91 (bs, 1H), 6.21 (s, 1H), 7.29 (s, 1H), 8.56 (complex abs., 2H);19F
NMR (376 MHz, 55ºC, CDCl3) δ (ppm): ꢀ58.8 (complex abs., 3F), ꢀ121.7 (complex abs., 1F);
13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.3, 26.2, 26.3, 27.5 – 28.0, 79.7, 80.7, 81.7, 116.7,
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121.7, 125.7, 135.9, 136.3, 155.5, 159.5, 161.7, 168.9, 183.7; IR (ATR) ν (cmꢀ1): 3286, 2988,
2925, 1745, 1725, 1702, 1690, 1679, 1615; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for
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C26H36F4N2O8Na 603.2320; found 603.2300; [α]D = 79.4 (c = 0.010, CH3CN), 94% ee
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7
8
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(absolute configuration S); HPLC separation: Daicel ADꢀH, a racemic mixture shows two
peaks, tr(S) = 17.85 min and tr(R) = 22.94 min with hexane:isopropanol (99:1); Isolated yield:
85 mg (70%) from 70 mg of 4i.
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(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(4ꢀfluoroꢀ3ꢀ(trifluoromethyl)phenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentanꢀ3ꢀ
yloxy)propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5j. White solid, Mp. 39ꢀ41ºC; 1H NMR (400
MHz, 55ºC, CDCl3) δ (ppm): 0.93 ꢀ 1.80 (complex abs., 31H), 4.92 (bs, 1H), 6.25 (s, 1H), 7.37
(s, 1H), 8.97 (complex abs., 2H); 19F NMR (376 MHz, 55ºC, CDCl3) δ (ppm): ꢀ61.4 (complex
abs., 3F), ꢀ108.6 (complex abs., 1F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm): 9.4, 9.6, 19.9,
26.1, 26.3, 27.5 – 29.6, 79.7, 81.7, 83.4, 116.7, 118.7, 120.8, 123.6, 129.2, 131.2, 135.3, 155.8,
156.7, 160.6, 163.2, 169.0, 188.4, 189.6.IR (ATR) ν (cmꢀ1): 3295, 2980, 2915, 1749, 1724,
1702, 1690, 1679, 1615; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C26H36F4N2O7Na 587.2351;
found 587.2365; [α]D20 = 107.7 (c = 0.010, CH3CN ), 93% ee (absolute configuration S); HPLC
separation: Daicel ADꢀH, a racemic mixture shows two peaks, tr(S) = 16.51 min and tr(R) =
20.65 min with hexane:isopropanol (99:1); Isolated yield: 110 mg (75%) from 90 mg of 4j.
(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(3,4,5ꢀtrifluorophenyl)ꢀ2ꢀmethylꢀ1,3ꢀdioxoꢀ3ꢀ(pentanꢀ3ꢀyloxy)
propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 5k. White solid, Mp. 37ꢀ39ºC; 1H NMR (400 MHz,
55ºC, CDCl3) δ (ppm): 0.98 (complex abs., 6 H), 1.40 – 1.78 (complex abs., 25H), 4.91 (broad
s, 1H), 6.24 (s, 1H), 7.98 – 8.50 (complex abs., 2H); 19F NMR (376 MHz, 55ºC, CDCl3) δ
(ppm): ꢀ133.0 (complex abs., 2F), ꢀ153.7 (complex abs., 1F); 13C NMR [1H] (CDCl3, 91 MHz) δ
(ppm): 9.3, 9.6, 20.0, 20.9, 26.1, 27.6 – 28.1, 79.8, 81.8, 83.6, 113.8, 114.0, 114.6, 126.7, 130.3,
141.1, 144.0, 144.2, 149.4, 149,5, 152.3, 155.5, 187.5, 188.8. IR (ATR) ν (cmꢀ1): 3286, 2988,
2925, 1745, 1715, 1700, 1682, 1669, 1618; HRꢀMS (ESI) m/z: [M+Na]+ Calcd for
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C25H35F3N2O7Na 555.2289; found 555.2298. [α]D = 126.7 (c = 0.009, CH3CN), 90% ee
(absolute configuration S); HPLC separation: Daicel ADꢀH, a racemic mixture shows two
peaks, tr(S) = 15.21 min and tr(R) = 19.65 min with hexane:isopropanol (98:2); Isolated yield:
110 mg (74%) from 80 mg of 4k.
(R)ꢀdiꢀtertꢀButylꢀ1ꢀ(1ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀfluoroꢀ1,3ꢀdioxoꢀ3ꢀ(3ꢀpentanylꢀ3ꢀoxyl)
1
propanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 11e. White solid, Mp. 37ꢀ39ºC; H NMR (CDCl3,
400 MHz) δ (ppm): 0.79 (abs. compl., 6H), 1.30ꢀ1.46 (abs. compl., 22H), 3.34 (s, 3H), 3.80 (s,
3H), 4.77 (abs. compl., 1H), 6.38 (s, 1H), 6.55 (d, J = 8.6 Hz, 1H), 8.08 (s, 1H), 8.26 (s, 1H);19F
NMR (DMSO, 100.6 MHz) δ (ppm): ꢀ122.1 (s, 1F); 13C NMR (DMSO, 100.6 MHz) δ (ppm):
8.3, 8.6, 25.0, 25.2, 26.9ꢀ27.7, 55.5, 55.7, 78.5, 78.8, 79.8, 110.8, 125.0, 126.2, 148.1, 153.5,
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154.6, 155.2, 159.6, 186.1; IR (ATR) ν (cmꢀ1): 3313, 2975, 2937, 2882, 1736, 1691, 1594, 1584;
20
HRꢀMS (ESI) m/z: [M+Na]+ Calcd for C26H39FN2O9Na 565.2532; found 565.2528; [α]D
=
99.3 (c = 0.012, CH3CN), 94% ee (absolute configuration R); HPLC separation: Daicel ADꢀH, a
racemic mixture shows two peaks, tr(S) = 19.03 min and tr(R) = 37.29 min with
hexane:isopropanol (95:5); Isolated yield: 132 mg (78%) from 100 mg of 7e.
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(S)ꢀdiꢀtertꢀButylꢀ1ꢀ(2ꢀ(3,4ꢀdimethoxybenzoyl)ꢀ6,6,6ꢀtrifluoroꢀ1ꢀoxoꢀ1ꢀ(pentanꢀ3ꢀyloxy)
hexanꢀ2ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate, 12e. White solid, Mp. 78ꢀ80ºC; 1H NMR (400 MHz,
CDCl3) δ (ppm): 0.93 – 1.70 (complex abs., 31H), 1.94 (m, 4H), 2.30 (m, 2H), 3.94 (bs, 6H),
4.91 (bs, 1H), 6.15 (s, 1H), 6.91 (bs, 1H), 7.99ꢀ8.38 (complex abs., 2H, ArH);19F NMR (376
MHz, CDCl3) δ (ppm): ꢀ61.4 (complex abs., 3F); 13C NMR [1H] (CDCl3, 101 MHz) δ (ppm):
9.3, 9.5, 9.6, 17.6, 26.0, 26.1, 26.2, 26.3 – 29.6, 33.6, 33.9, 34.2,55.9, 56.1, 78.3, 79.5, 81.5,
81.7, 84.9, 110.1, 111.1, 111.4, 122.9, 123.8, 125.3, 128.1, 148.6, 152.9, 155.6, 155.8, 169.4,
188.8, 189.7; IR (ATR) ν (cmꢀ1): 3300, 2982, 2925, 1744, 1715, 1701, 1690, 1679, 1600. HRꢀ
MS (ESI) m/z: [M+H]+ Calcd for C30H46F3N2O9 635.3150; found 635.3164; [α]D = 99.3 (c =
20
0.008, CH3CN), 99% ee (absolute configuration S); HPLC separation: Daicel ADꢀH, a racemic
mixture shows two peaks, tr(S) = 10.40 min and tr(R) = 18.95 min with hexane:isopropanol
(95:5); Isolated yield: 98 mg (78%) from 80 mg of 10e.
Acknowledgements
We are thankful for financial support form Spain’s MICINN (CTQ2014ꢀ53662ꢀP, CTQ2014ꢀ
59544ꢀP) and MEC (CTQ2014ꢀ51912ꢀREDC, CTQ2016ꢀ81797ꢀREDC) and DURSIꢀGeneralitat
de Catalunya (2014SGRꢀ1105, 2014SGRꢀ482).
Supporting Information
Copies of the 1H, 13C and 19F NMR are reported. IR, HRMS spectra, the HPLC chromatograms
and the details of experiment procedures are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
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