Enantioselective Synthesis of Trifluoromethyl α,β-Unsaturated δ-Lactones via Vinylogous Aldol-Lactonization Cascade

Article abstract of DOI:10.1021/acs.joc.8b01672

The novel vinylogous aldol-lactonization cascade of alkylidene oxindole with trifluoromethyl ketones is presented. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient application of the vinylogous reactivity of alkylidene oxindoles for the preparation of enantioenriched trifluoromethylated α,β-unsaturated δ-lactones.

Full text of DOI:10.1021/acs.joc.8b01672

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Article
Enantioselective Synthesis of Trifluoromethyl #,#-Unsaturated-
-lactones via Vinylogous Aldol-Lactonization Cascade
#
Simone Crotti, Nicola Di Iorio, Andrea Mazzanti, Paolo Righi, and Giorgio Bencivenni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01672 • Publication Date (Web): 13 Sep 2018
Downloaded from http://pubs.acs.org on September 13, 2018
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Enantioselective Synthesis of Trifluoromethyl α,β-Unsaturated-
δ-lactones via Vinylogous Aldol-Lactonization Cascade
Simone Croꢀ,† Nicola Di Iorio,† Andrea Mazzanꢁ, Paolo Righi, and Giorgio Bencivenni*
Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Viale del
Risorgimento 4, 40136, Bo-Italy.
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ABSTRACT
The novel vinylogous aldol-lactonization cascade of alkylidene oxindole with
trifluoromethylketones is presented. The reaction, catalyzed by a bifunctional tertiary amine,
provides an efficient application of the vinylogous reactivity of alkylidene oxindoles for the
preparation of enantioenriched trifluoromethylated α,β-unsaturated-δ-lactones.
INTRODUCTION
1
Alkylidene oxindoles are suitable substrates for vinylogous processes. They have been
2
successfully employed as nucleophiles in many reactions with different electrophilic partners.
Among these, the recent works by Han on the reaction of oxindoles with 2,3-indolinediones,
3
extended their vinylogous reactivity to cascade processes for the first time. The excellent yields
and the high stereoselectivity obtained, also with alkylidene oxindoles bearing prochiral site at the
γ-position, showed the potentiality of these reactions as promising tools for synthetic protocols.
Organofluorine compounds find many applications in agrochemical industry and in medicinal
4
chemistry. In particular, chiral compounds containing the trifluoromethyl group (CF
3
) bonded to a
5
stereogenic center, showed potent activity against various diseases (Figure 1).
Figure 1. Examples of biologically active trifluoromethyl compounds
The search of novel and always more efficient methodologies for the synthesis of fluorinated
compounds is an actual and challenging research field which has constantly seen the commitment
6
of many research groups to the development of innovative reactions. Recently, organocatalytic
7
Henry and cross-aldol reactions of trifluoromethyl aryl ketones, emerged as a valid alternative to
6
c-e
the classical Ruppert-Prakash reaction.
With the aim to pursue our studies on the vinylogous
reactions of oxindoles, we wondered if it was possible to realize the unprecedented vinylogous
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aldol-lactonization cascade using trifluoromethyl ketones (Scheme 1a).
This vinylogous aldol-
lactonization represents an alternative strategy to the methods reported by Chi and Connon based
on NHC/Lewis Acid and base catalyzed cycloadditions, for the synthesis of α,β-unsaturated-δ-
8
lactones bearing a CF
3
-group as part of a tetrasubstituted stereocenter (Scheme 1b-d). The α,β-
unsaturated-δ-lactone core is responsible for the activity of many natural and unnatural
compounds against cancer, HIV and artery diseases. Considering that the catalytic synthesis of
optically active 5,6-dihydropyran-2-ones is limited to few examples, new methods for their
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preparation are highly desirable.
Scheme 1. Access to enantioenriched CF -containing α,β-unsaturated-δ-lactone
3
1
0
We believe that for the realization of the cascade reaction, the use of a bifunctional catalyst is
fundamental to activate the two reagents and direct the reaction through the desired double
synthetic sequence (Scheme 2a). It is furthermore essential that the catalyst controls the
regiochemistry of the addition, that should occur mainly at the γ-site rather than the γ'-site of the
oxindole since the resulting (Z)-aldol adduct intermediate would cyclize easily onto the amidic
carbonyl group than the (E)-aldol adduct (Scheme 2b).
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Scheme 2. Vinylogous aldol/lactonization process
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RESULTS AND DISCUSSION
We started our investigation exploring the reactivity of diverse thiourea and squaramide
derivatives of Cinchona alkaloids organocatalysts (Table 1). This class of catalysts has been
2
a-c, h
successfully applied to vinylogous processes
and demonstrated to be effective for the
2d
generation of an s-cis enolate after selective deprotonation at the γ-site.
a
Table 1. Screening of reaction conditions
b
c
e
entry
cat
solvent
DCM
DCM
DCM
DCM
3aa/4aa
9:1
yield (%) 3aa
ee (%) 3aa
1
2
3
4
5
6
7
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9
I
II
III
IV
I
70
48
56
21
52
82
20
70
n.r.
>99
-99
97
-91
nd
nd
nd
nd
--
2:1
4:1
1:3
CHCl
3
3:1
I
Tol
6:1
I
THF
1:2
I
Et
2
O
7:1
I
MeOH
MeCN
--
d
96
1
0
I
>19:1
95
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d
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PhCF
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>19:1
96
99
a
The reactions were performed on a 0.1 mmol scale using a 1:1 ratio of 1a and 2a and 0.5 ml of
b
1
c
1
solvent. Determined via H-NMR on the crude mixture. Determined via H-NMR with 1,3,5-
d
e
trimethoxybenzene as internal standard. Isolated yield. Determined by HPLC on chiral stationary
phase.
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In general these catalysts were able to promote the formation of compound 3aa in moderate to
good yields and excellent enantioselectivity together with variable amounts of aldol adduct 4aa
(
entries 1-4). The first attempt using the thiourea derivatives of 9-NH
3aa in a 70% yield and >99% ee. Catalyst II, the pseudoenantiomer of catalyst I, gave 3aa in 48%
yield and 99% ee, whilst squaramide derivatives 9-NH -9-(epi)quinine III and quinidine IV furnished
worst results (entries 2-4). The solvents have a strong influence on the product selectivity since
variable ratios between 3aa and 4aa were observed (entries 5-12). Only using MeCN and CF Ph a
2
-9-(epi)dihydroquinine I gave
2
3
complete selectivity in favor of lactone 3aa was realized. In particular in this last case, 3aa was
isolated in 96% yield and 99% ee after 72 hours of reaction at 25 °C.
With the optimized condition the scope of the reaction was performed (Table 2).
a
Table 2. Scope of the reaction
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O
O
O
(R)
O
(R)
CF3
CF3
NH
NH
Boc
Boc
Cl
Br
b
c
b
c
3
ac: 92% yield , >99% ee
3ae: 84% yield , 96.5% ee
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a
b
The reactions were performed on a 0.2 mmol scale using a 1:1 ratio of 1 and 2 in 1.0 ml of PhCF
3
.
c
Isolated yield. Determined by HPLC on chiral stationary phase.
In general catalyst I gave high control on the stereochemistry with both electron-withdrawing and
releasing substituents at the C(5) and C(7) of the oxindole core (3ba-3ea). Excellent yields and ee’s
were also obtained with oxindoles having different aromatic substituents at the double bond (3fa-
3
ha). However with great surprise the reaction failed to give the desired lactons or even traces of
aldol adduct when 1-t-butoxycarbonyl-3-(pentan-3-ylidene)indolin- 2-one or 3-cyclohexylidene-1-
t-butoxycarbonylindolin-2-one were employed. Various aromatic trifluoromethylketones 2b-i were
then prepared and used for the vinylogous aldol-cascade process in combination with oxindole 1a.
In almost all cases the corresponding cyclic esters were the sole products obtained after 72 hours
in excellent yields and remarkable enantioselectivities (3ab-3ai). Moderate yields were however
obtained with 2-chloro-trifluoroacetophenone 2d and 4-methoxy trifluoroacetophenone 2f. In
these two cases the overall reaction rate is probably influenced negatively by steric and electron-
donating effects. It is furthermore important to underline that in the case of compound 3ah the
reaction was performed using the hydrate form of 2,2,2-trifluoro-1-(4-nitrophenyl)ethan-1-one 2h.
It should be outlined that the reaction failed to give any products when alkyl
trifluoromethylketones were employed. However, it is important to underline that these
trifluoromethylated lactones were isolated as mixture of conformers due to the slow rotation of
the C-C single bond between the aryl substituent and the α-carbon of the double bond. In the case
3
of compound 3aa the anti/syn ratio was 58:42 in CDCl and the energy barrier to rotation was
‡
determined to be ΔGꢀꢁꢂ= 19.0 ± 0.5 kcal/mol in CD
3
CN by means of 1D-EXSY experiments (Figure
2
).
Figure 2. Conformational equilibrium observed
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The absolute configuration of compound 3aa was determined to be R by means of TD-DFT
calculations of the electronic circular dichroism (ECD) spectra, as described in the Supporting
Information. The R absolute configuration is the result of a vinylogous addition of the oxindole to
the prochiral Si face of the trifluoromethyl ketone. In order to elucidate the reaction mechanism,
we decide to analyze the reaction in DCM at regular interval of time. After 24 hours, 3aa was
obtained in a 30% and >99% ee and compound 4aa was obtained in a 19% yield and 93% ee. After
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8 hours, compound 3aa was obtained as single enantiomer but in a 60% yield whilst 4aa was
recovered in a 11% yield and 88% ee. Finally after 72 hours of reaction 3aa and 4aa were obtained
in a 70% and 7.8% yield and >99% and 90% ee respectively. These results would suggest that the
present cascade proceeds by forming a stable aldol adduct which undergoes the ring-closing
lactonization in a stepwise fashion (Scheme 3).
Scheme 3. Proposed mechanism for the cascade sequence
Finally by treating compound 3ca with 2 equivalents of pyrrolidine in anhydrous THF the
tetrasubstituted alkene 5ca can be obtained in a 86% yield and with complete retention of the
configuration of the stereocenter (Scheme 4).
Scheme 4. Derivatization of the enantioenriched trifluoromethylated lactone 3ca
CONCLUSION
In conclusion we realized the enantioselective synthesis of novel trifluoromethyl-α,β-unsaturated-
1
1
δ-lactones through the first vinylogous aldol-lactonization cascade of 3-alkylidene oxindoles and
unsaturated trifluoromethyl ketones. The reaction proceeded with high enantiocontrol and
represents a valuable strategy to access fluorinated lactones, a moiety often present in important
biological active compounds. Experiments are ongoing to elucidate the reaction mechanism.
EXPERIMENTAL
All the NMR spectra were recorded on Inova 300 MHz, Gemini 400 MHz or Mercury 600 MHz
1
13
Varian spectrometers for H, 75 MHz, 100 MHz and 150 MHz for C and 282 MHz, 376 MHz, 564
19
1
19
13
MHz for F respectively. The chemical shifts (δ) for H, F and C are given in ppm relative to
internal standard TMS (0.0 ppm) or residual signals of CHCl (7.26 ppm). Coupling constants are
3
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given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet;
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t, triplet; q, quartet; m, multiplet; bs, broad signal. Concerning the C spectra of the products, we
were never able to see the signal (quartet) of the fluorinated carbon regardless of the delay and
the acquisition time we employed (not even a 5 days-acquisition with a 60 seconds delay at 150
MHz showed any signal). It is likely that, due to the splitting of the signal and the very high
relaxation time of this particular carbon, the corresponding signal is lost in the baseline.
Purification of reaction products was carried out by flash chromatography (FC) on silica gel (230-
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4
00 mesh). Organic solutions were concentrated under reduced pressure on a Büchi rotary
evaporator. High Resolution Mass spectra were obtained from the Mass Facility of the Department
of Chemistry and Drug Technology of the University of Rome on a Orbitrap Exactive, source: ESI
(+): capillary temp: 250°C, spray voltage: 4.0 (kV), capillary voltage: 65 V, tube lens: 125 V. Chiral
HPLC analysis was performed on an Agilent 1100-series instrumentation. HPLC traces for all
compounds were compared to racemic sample prepared using DABCO as catalyst except for
compound 3ea-3ai, 5ca where a quasi racemic samples was prepared by mixing the two product
antipodes obtained performing the reactions with catalyst I and the pseudo-enantiomer II
separately. Optical rotations are reported as follows: [α] ꢄꢃ ꢅ (c in g per 100 mL, CHCl
) and the
3
numerical values are relative to the products obtained from catalyst I. All reactions were carried
12
out in air. Chiral catalyst I, II, III, IV and V were prepared following literature procedures.
General procedure for the synthesis of N-Boc-alkylidene oxindoles
The appropriate isatin (15 mmol, 1 equiv) was placed in a 100 mL round flask and suspended in
MeOH (37.5 mL, 0.4 M) before adding hydrazine (30.15 mmol, 2.6 ml of 55% solution in water, 2
equiv). The solution was left refluxing (2 to 3 hours) under magnetic stirring until the formation of
a precipitate is observed, then cooled to room temperature. The precipitate was filtered on a
2
gooch funnel, washed with water, cold MeOH and cold Et O to afford the pure hydrazone that was
added to a freshly prepared solution of EtONa in EtOH (3.7 equiv of metallic Na dissolved in EtOH
so that the hydrazone is 0.4 M). This new solution was heated to reflux until the reagent
disappeared (TLC monitoring), then it was cooled and quenched with 10% HCl. The crude was now
extracted with DCM, made anhydrous over MgSO
4
and purified by either flash column
chromatography or crystallization to obtain the pure oxindole. The oxindole was then dissolved in
a mixture of EtOH:Acetone 1:1 (0.5 M) before adding piperidine (4.0 equiv). After one night of
reflux the temperature was allowed to go down and the crude was flushed through a plug of silica
(50 mL of DCM:EtOAc 1:1 as eluent) to remove piperidine and the Knoevenagel adduct was
purified by precipitation from Et
2
O. The nitrogen protection was carried out dissolving the
O (1.2 equiv) and a
alkylidene oxindole in DCM (0.5 M) freshly filtered on basic alumina with Boc
2
catalytic amount of DMAP (5% molar). The reaction was monitored via TLC and, when over, the
crude was concentrated and the final product was purified by flash column chromatography. NMR
1
3
14
13
14
14
spectra of oxindoles 1a, 1b, 1d, 1e, 1f, were consistent with those previously reported.
tert-Butyl 7-fluoro-2-oxo-3-(propan-2-ylidene)indoline-1-carboxylate (1c)
The title compound was synthesized following the literature procedure on a 2 mmol scale. The
product was purified by flash column chromatography (hexane:EtOAc = 95:5 and then 90:10) with
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an overall yield of 77% (91% for the Knoevenagel reaction and 85% for the protection) and a total
of 450 mg of 1c that presented itself as an amorphous solid. HRMS-ESI-ORBITRAP (+): calculated
+
+ 1
for [C16
H
18FNNaO
3
] 314.1163, found 314.1159 [M+Na] . H-NMR (400 MHz, CDCl
3
) δ 7.36 (d, J =
.7 Hz, 1H), 7.15 – 6.97 (m, 2H), 2.62 (s, 3H), 2.40 (s, 3H), 1.61 (s, 8H). F-NMR (376 MHz, CDCl ) δ
) δ 165.4, 158.8, 149.8, 148.1, 147.3, 127.0 (d, J = 2.9 Hz), 124.3
d, J = 7.1 Hz), 121.6 (d, J = 2.9 Hz), 119.1 (d, J = 3.7 Hz), 115.7 (d, J = 20.0 Hz), 84.5, 27.7, 25.8,
4.0.
1
9
7
3
1
3
-
(
121.52. C-NMR (150 MHz, CDCl
3
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tert-Butyl (E)-3-(1-(4-fluorophenyl)ethylidene)-2-oxoindoline-1-carboxylate (1g)
The title compound was synthesized following the literature procedure on a 5 mmol scale. The
product was purified by flash column chromatography (hexane:EtOAc = 90:10) with an overall
yield of 73% (85% for the Knoevenagel reaction and 86% for the protection) and a total of 1.29 g of
1
g that presented itself as an amorphous solid. HRMS-ESI-ORBITRAP (+): calculated for
+
+ 1
3 3
[C21H20FNNaO ] 376.1319, found 376.1322 [M+Na] . H-NMR (400 MHz, CDCl ) δ 7.82 (ddd, J =
8
3
.3, 1.1, 0.6 Hz, 1H), 7.31 – 7.09 (m, 5H), 6.76 (ddd, J = 7.7, 1.1 Hz, 1H), 6.28 – 6.19 (m, 1H), 2.76 (s,
1
9
13
3 3
H), 1.68 (s, 9H). F-NMR (376 MHz, CDCl ) δ -121.54. C-NMR (150 MHz, CDCl ) δ 166.0, 164.0,
161.5, 155.1, 149.5, 138.8 (d, J = 3.8 Hz), 138.3, 128.5, 128.4 (d, J = 8.1 Hz), 123.3, 122.9 (d, J = 3.6
Hz), 122.5, 116.5 (d, J = 21.9 Hz), 114.5, 84.1, 28.2, 23.8.
tert-Butyl (E)-2-oxo-3-(1-(4-(piperidin-1-yl)phenyl)ethylidene)indoline-1-carboxylate (1h)
The title compound was synthesized following the literature procedure on a 1 mmol scale. The
product was purified by flash column chromatography (hexane:EtOAc = 85:15) with an overall
yield of 56% (75% for the Knoevenagel reaction and 75% for the protection) and a total of 210 mg
of 1h that presented itself as an amorphous solid. HRMS-ESI-ORBITRAP (+): calculated for
+
+ 1
[
C
26
H
30
N
2
NaO
3 3
] 441.2149, found 441.2143 [M+Na] . H-NMR (400 MHz, CDCl ) δ 7.80 (d, J = 8.7
Hz, 2H), 7.26 – 7.07 (m, 3H), 6.97 (d, J = 8.7 Hz, 2H), 6.77 (ddd, J = 7.7, 1.1 Hz, 1H), 6.69 – 6.58 (m,
1
3
1H), 3.32 – 3.24 (m, 4H), 2.76 (s, 3H), 1.67 (m, 15H). C-NMR (150 MHz, CDCl
3
) δ 166.3, 157.6,
52.2, 149.6, 137.8, 132.1, 128.3, 127.7, 123.6, 123.0, 122.3, 121.4, 115.6, 114.2, 83.7, 49.6, 28.1,
5.6, 24.2, 23.8.
1
2
General procedure for the synthesis of trifluoromethylketones
CO is added at room temperature to a DMSO (15 mL) solution of the appropriate aromatic
K
2
3
aldehyde (5 mmol, 1.0 equiv.) and trifluoromethyl trimethylsilane (6.5 mmol, 1.3 equiv.). The
reaction is completed, (check by TLC) the mixture is poured to ice/water mixture and extracted
with ethyl acetate (3 x 30 ml). The collected organic phases are washed with water (2 x 50 ml) then
threated with MgSO and filtered. The crude alcohol is purified by column chromatography using
4
1
0-15% of acetone or ethyl acetate in hexane as eluent mixture and directly added to a suspension
of IBX in ethyl acetate. The resulting suspension is refluxed overnight. The crude mixture is filtered
and trifluoroketone was purified by column chromatography using 5-10% of Et O in hexane as the
eluent mixture. All trifluoromethylketones prepared were consistent with those previously
2
15
15
16
17
reported: 2c, 2f, 2g, 2h. Trifluoroketones 2a, 2b, 2e, 2d and 2i were commercially available
and used as is.
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General procedure for the vinylogous aldol reaction
In an ordinary vial equipped with a teflon-coated magnetic stir bar, catalyst I (12 mg, 0.02 mmol,
.1 equiv), oxindole (0.2 mmol, 1 equiv) and trifluoromethylketone (0.2 mmol, 1 equiv) were
dissolved in 1 mL of PhCF . After 72 hours of stirring at 25 °C, the reaction was flushed through a
0
3
short silica plug with a 1:1 mixture of DCM:EtOAc to remove the catalyst and the crude product
1
1
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1
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2
2
2
2
2
2
2
2
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4
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5
5
5
5
5
5
5
6
0
1
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9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was concentrated to perform a H-NMR analysis to measure the yield (1,3,5-trimethoxybenzene
was used as internal standard) and determine the ratio between aldol and cascade product. At this
point the product was purified with flash column chromatography and the ee% was determined
through HPLC on a chiral stationary phase. Yield after chromatography are all cases identical to
those determined via NMR analysis.
tert-Butyl
(R)-(2-(4-methyl-2-oxo-6-phenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3aa)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 80:20) and the title compound was obtained as a
yellowish oil in a 0.72/1.00 mixture of conformers in 96% yield (85.8 mg) and 99% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
PrOH 95:5, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 8.5 min, τII = 11.9 min. [α] ꢄꢃ ꢅ -37.5 (c 1.0,
+
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C H F NNaO ] 470.1550, found 470.1544
3
24 24 3
4
+
1
[
3
M+Na] . H-NMR (400 MHz, CDCl ) δ 7.82 (m, 1.10 H), 7.64 – 7.40 (m, 5.14 H), 7.34 – 7.22 (m, 1.00
H), 7.17 – 7.03 (m, 0.84 H), 6.89 (td, J = 7.5, 1.2 Hz, 0.58 H), 6.53 (s, 0.56 H), 6.18 (dd, J = 7.6, 1.6
Hz, 0.57 H), 5.20 (s, 0.43 H), 3.44 (m, 1.00 H), 3.19 (m, 1.00H), 1.80 (s, 1.27 H), 1.74 (s, 1.73 H), 1.50
19
13
(
s, 5.05 H), 1.43 (s, 3.70 H). F-NMR (376 MHz, CDCl
3 3
) δ -79.32, -79.54. C-NMR (150 MHz, CDCl )
δ 161.7, 160.9, 153.2, 152.8, 151.8, 151.7, 136.6, 135.9, 134.0, 133.9, 131.0, 130.1, 129.9, 129.8,
1
8
29.4, 129.3, 129.2, 128.9, 126.5, 126.3, 126.1, 125.9, 125.0, 124.1, 123.7, 123.4, 123.3, 122.2,
1.9 (q, J = 30.9 Hz), 81.4 (q, J = 30.9 Hz), 80.5, 80.4, 34.0, 33.6, 28.4, 28.3, 22.1, 22.0.
tert-Butyl (R)-(4-chloro-2-(4-methyl-2-oxo-6-phenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ba)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 85:15) and the title compound was obtained as a
yellowish oil in a 0.76/1.00 mixture of conformers in 97% yield (93.5 mg) and 95% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
ꢄꢅ
PrOH 95:5, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C24
M+Na] . H-NMR (400 MHz, CDCl
H), 7.11 (d, J = 2.5 Hz, 0.40 H), 6.46 (s, 0.56 H), 6.17 (d, J = 2.5 Hz, 0.54 H), 5.16 (s, 0.42 H), 3.44 (m,
I
= 5.8 min, τII = 7.9 min. [α] -24.3 (c 1.0,
ꢃ
+
3
H
23ClF
3
NNaO
4
] 504.1160, found 504.1154
+
1
[
3
) δ 7.81 (m, 1.09 H), 7.66 – 7.41 (m, 5.22 H), 7.30 – 7.20 (m, 1.20
19
1
.00 H), 3.20 (m, 1.00 H), 1.82 (s, 1.28 H), 1.77 (s, 1.70 H), 1.49 (s, 5.00 H), 1.42 (s, 4.00 H). F-NMR
1
3
(
376 MHz, CDCl
152.6, 135.5, 134.7, 133.8, 133.6, 130.7, 130.2, 130.0, 129.6, 129.4, 129.3, 129.2, 129.1, 128.5,
28.4, 126.2, 126.0, 125.3, 124.7, 124.1, 124.0, 122.2, 122.1, 82.0 (q, J = 30.8 Hz), 81.5 (q, J = 30.6
Hz), 80.9, 80.8, 34.0, 33.7, 28.3, 28.2, 22.1, 22.0.
3 3
) δ -79.31, -79.55. C-NMR (150 MHz, CDCl ) δ 161.3, 160.5, 153.0, 152.8, 152.7,
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tert-Butyl
(R)-(2-fluoro-6-(4-methyl-2-oxo-6-phenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ca)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 80:20) and the title compound was obtained as a
yellowish oil in a 0.60/1.00 mixture of conformers in 96% yield (80.0 mg) and 94% enantiomeric
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
ꢄꢅ
PrOH 95:5, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 5.9 min, τII = 7.1 min. [α] -198.6 (c 1.0,
ꢃ
+
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C H F NNaO ] 488.1455, found 488.1449
3
24 23 4
4
+
1
[M+Na] . H-NMR (400 MHz, CDCl
3
) δ 7.69 – 7.35 (m, 5.21 H), 7.22 (td, J = 8.0, 5.2 Hz, 0.43 H), 7.15
–
6.99 (m, 1.68 H), 6.99 – 6.91 (m, 0.40 H), 6.20 – 5.97 (m, 1.26 H), 4.85 (s, 0.40 H), 3.48 – 3.30 (m,
1
9
1
H), 3.17 (m, 1.00 H), 1.83 (s, 1.08 H), 1.77 (s, 1.97 H), 1.45 (s, 5.79 H), 1.37 (s, 3.58 H). F-NMR
1
3
3 3
(376 MHz, CDCl ) δ -79.41, -79.56. C-NMR (150 MHz, CDCl ) δ 161.3, 161.0, 159.4, 159.1, 157.7,
1
57.5, 153.5, 153.0, 151.5 (double), 134.2, 133.9, 133.4, 132.0, 130.0, 129.8, 129.2, 128.9, 127.5
d, J = 27.7 Hz), 127.4 (d, J = 27.7 Hz), 126.3, 126.1, 125.3 (d, J = 3.7 Hz), 124.8 (d, J = 3.7 Hz), 124.6
(bs), 124.5 (bs), 124.2, 123.2 (q, J = 284.0 Hz), 123.1 (q, J = 284.0 Hz), 116.5, 116.4 (d, J = 11.0 Hz),
(
1
2
16.3 (d, J = 11.0 Hz), 81.9 (q, J = 31.0 Hz), 81.5 (q, J = 30.0 Hz), 80.4 (double), 34.1, 33.5, 28.1,
8.0, 22.1, 22.0.
tert-Butyl
(R)-(2-(4-methyl-2-oxo-6-phenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-yl)-4-
nitrophenyl)carbamate (3da)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 9:1) and the title compound was obtained as a
yellowish oil in a 0.79:1.00 mixture of conformers in 92% yield (90.7 mg) and 95% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
PrOH 90:10, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C24
I
= 7.6 min, τII = 11.9 min. [α] ꢄꢃ ꢅ -98.5 (c 1.0,
+
3
H
23
3
F N
2
6
NaO ] 515.1400, found 515.1393
+
1
[
M+Na] . H-NMR (300 MHz, CDCl ) δ 8.27 (m, 2.36 H), 8.19 – 8.12 (m, 2H), 8.01 (d, J = 2.6 Hz,
3
1.00H), 7.66 – 7.45 (m, 12.33 H), 7.11 (d, J = 2.6 Hz, 1.22 H), 6.80 (bs, 1.24 H), 5.53 (bs, 0.97 H),
3
3
.54 (dd, J = 7.0, 1.2 Hz, 0.98 H), 3.48 (dd, J = 7.1, 1.2 Hz, 1.40 H), 3.30-3.24 (m, 2.37 H), 1.86 (s,
1
9
.29 H), 1.81 (s, 4.04 H), 1.52 (s, 11.90 H), 1.45 (s, 9.45 H). F-NMR (282 MHz, CDCl
3
) δ -79.12, -
) δ 161.1, 160.2, 154.4, 154.3, 152.0, 151.7, 143.1, 142.4, 142.3,
42.3, 133.6, 133.6, 130.4, 130.3, 129.5, 129.2, 127.0, 126.2, 126.1, 125.9, 125.2, 124.9, 124.4,
23.3, 123.1, 122.2, 119.8, 119.7, 82.2, 82.1 (q, J = 30.8 Hz), 81.6 (q, J=30.8 Hz) , 34.0, 31.6, 28.3,
1
3
79.62. C-NMR (75 MHz, CDCl
3
1
1
28.2, 25.4, 22.7, 22.2, 14.1.
tert-Butyl (R)-(4-methoxy-2-(4-methyl-2-oxo-6-phenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-
3
-yl)phenyl)carbamate (3ea)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 19:1) and the title compound was obtained as a
yellowish oil in a 0.70:1.00 mixture of conformers in 84% yield (80.3 mg) and 92% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
ꢄꢅ
PrOH 95:5, flow rate 0.8 mL/min, 50 °C, λ = 254 nm: τ = 9.9 min, τII = 11.8 min. [α] -113.7 (c 1.0,
ꢃ
I
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+
CHCl
3 26 3 5
). HRMS-ESI-ORBITRAP (+): calculated for [C25H F NNaO ] 500.1655, found 500.1647
+
1
[
M+Na] . H-NMR (400 MHz, CDCl ) δ 7.67 – 7.38 (m, 10.48 H), 6.85-6.82 (dd, J = 8.9, 3.0 Hz, 1.78
3
H), 6.67 (d, J = 3.0 Hz, 0.71 H), 6.33 (bs, 0.98 H), 5.73 (d, J = 2.9 Hz, 1.00 H), 5.02 (bs, 0.60 H), 3.76
(
s, 2.04 H), 3.61 (s, 3.13 H), 3.47 – 3.36 (m, 1.79 H), 3.17 (m, 1.87 H), 1.81 (d, J = 0.9 Hz, 2.12 H),
1
9
1
7
1
1
2
.76 (d, J = 0.9 Hz, 3.17 H), 1.47 (s, 8.98 H), 1.41 (s, 6.11 H). F-NMR (376 MHz, CDCl
3
) δ -79.38, -
13
9.51. C-NMR (100 MHz, CDCl
3
) δ 161.6, 160.9, 156.1, 155.8, 153.9, 153.4, 151.8, 151.7, 134.1,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
33.9, 130.1, 129.8, 129.6, 129.3, 129.0, 128.9, 126.5, 126.4, 126.1, 125.1, 116.1, 115.6, 114.7,
14.0, 82.5, 82.0 (q, J=30.8 Hz), 81.5 (q, J=30.5 Hz), 80.2, 80.2, 55.5, 55.3, 34.0, 33.6, 31.6, 28.4,
8.3, 22.7, 22.1, 22.1, 14.1.
tert-Butyl
(R)-(2-(2-oxo-4,6-diphenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3fa)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 85:15) and the title compound was obtained as a
yellowish oil in a 0.42/1.00 mixture of conformers in 83% yield (84.8 mg) and >99% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
ꢄꢅ
PrOH 85:15, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 4.4 min, τII = 7.9 min. [α] -187.9 (c 1.0,
ꢃ
+
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C29
3
H
26
F
3
NNaO
4
] 532.1706, found 532.1700
+
1
[
M+Na] . H-NMR (300 MHz, CDCl ) δ 7.79 – 7.38 (m, 8.56 H), 7.25 – 7.09 (m, 5.76 H), 7.04 (dd, J =
3
7.8, 1.7 Hz, 0.63 H), 7.00 – 6.85 (m, 3.57 H), 6.78 – 6.58 (m, 1.63 H), 6.02 (dd, J = 7.7, 1.6 Hz, 0.77
H), 5.27 (s, 0.54 H), 3.80 (d, J = 8.5 Hz, 0.42 H), 3.74 (d, J = 8.6 Hz, 0.98 H), 3.65 (d, J = 6.3 Hz,
1
9
1
.00H), 3.59 (d, J = 6.3 Hz, 0.42 H), 1.49 (s, 7.50 H), 1.39 (s, 5.66 H). F-NMR (282 MHz, CDCl
3
) δ -
) δ 162.8, 161.8, 153.2, 152.5, 151.3, 151.0, 137.1, 136.9,
36.7, 135.9, 133.7 (double), 131.9, 130.5, 130.2, 129.9, 129.7 (double), 129.4, 129.1, 129.0,
13
79.01, -79.22. C-NMR (75 MHz, CDCl
3
1
1
1
28.5, 127.6, 127.5, 126.9, 126.5, 126.3, 125.4, 125.1 (double), 124.1 (bs), 123.8, 123.4, 123.1 (bs),
22.3, 121.3, 82.3 (q, J = 30.9 Hz), 81.9 (q, J = 30.5 Hz), 80.4, 80.2, 34.3, 34.0, 28.4, 28.3.
tert-Butyl (R)-(2-(4-(4-fluorophenyl)-2-oxo-6-phenyl-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ga)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 19:1) and the title compound was obtained as a
yellowish oil in a 0.70:1.00 mixture of conformers in 99% yield (105 mg) and >99% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
PrOH 95:5, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C29
[M+Na] . H-NMR (300 MHz, CDCl
I
= 6.8 min, τII = 9.8 min. [α] ꢄꢃ ꢅ -218.0 (c 1.0,
+
3
H
25
F
4
NNaO
4
] 550.1612, found 550.1603
+
1
3
) δ 7.71 – 7.44 (m, 10.52 H), 7.18 (qd, J = 8.5, 1.7 Hz, 1.84 H),
.07 – 6.80 (m, 8.42 H), 6.71 (td, J = 7.5, 1.2 Hz, 1.88 H), 5.99 (dd, J = 7.7, 1.6 Hz, 0.94 H), 5.27 (bs,
.63 H), 3.81 – 3.68 (m, 1.74 H), 3.61 (d, J = 7.4 Hz, 1-16 H), 3.55 (d, J = 7.3 Hz, 0.54 H), 1.49 (s, 9.04
7
0
19
13
3 3
H), 1.39 (s, 6.54 H). F-NMR (282 MHz, CDCl ) δ -79.03, -79.22. C-NMR (75 MHz, CDCl ) δ 164.8,
1
1
62.7, 161.7, 161.4, 153.3, 152.5, 150.0, 149.7, 137.1, 135.9, 133.7, 133.7, 132.9, 132.9, 132.7,
32.7, 131.8, 130.5, 130.2, 130.0, 129.9, 129.8, 129.8, 129.7, 129.5, 129.3, 129.1, 127.1, 126.4,
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5
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126.3, 125.6, 124.1, 123.7, 115.9, 115.6, 82.2 (q, J = 34.5 Hz), 81.8 (q, J = 30.6 Hz), 80.5, 80.4, 34.2,
3
4.0, 28.4, 28.3, 25.4.
tert-Butyl (R)-(2-(2-oxo-6-phenyl-4-(4-(piperidin-1-yl)phenyl)-6-(trifluoromethyl)-5,6-dihydro-2H-
pyran-3-yl)phenyl)carbamate (3ha)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 82:18) and the title compound was obtained as a
yellowish oil in a 0.66:1.00 mixture of conformers in 82% yield (97 mg) and 99% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
PrOH 90:10, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
0.2, CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C34
I
= 11.0 min, τII = 12.0 min. [α] ꢃꢄ ꢅ -281.0 (c
+
3
1
H
35
3
F N
2
4
NaO ] 615.2432, found 615.2430
+
[
M+Na] . H-NMR (400 MHz, CDCl ) δ 7.85 – 7.54 (m, 3.10 H), 7.53 – 7.39 (m, 3.07 H), 7.18 (dddd, J
3
=
9.9, 8.6, 7.4, 1.6 Hz, 1.01 H), 7.10 (dd, J = 7.8, 1.6 Hz, 0.39 H), 7.02 – 6.85 (m, 2.48 H), 6.80 (s,
0.59 H), 6.71 (dd, J = 7.5, 1.2 Hz, 0.82 H), 6.62 (s, 1.80 H), 6.00 (dd, J = 7.7, 1.6 Hz, 0.62 H), 5.31 (s,
0
1
.44 H), 3.75 – 3.56 (m, 2.00 H), 3.17 (d, J = 5.5 Hz, 3.94 H), 1.76 – 1.51 (m, 6.65 H), 1.47 (s, 5.31 H),
1
9
13
3 3
.37 (s, 3.68 H). F-NMR (376 MHz, CDCl ) δ -79.05, -79.32. C-NMR (100 MHz, CDCl ) δ 163.4,
162.3, 153.3, 152.6, 152.2, 150.5, 150.1, 137.3, 136.0, 133.9, 131.9, 130.6, 129.9, 129.7 (double),
29.6, 129.3, 128.9, 128.8, 128.7, 126.5, 126.3, 124.7, 123.9, 123.4, 121.9, 113.9, 81.9 (q, J = 30.3
1
Hz), 81.5 (q, J = 30.3 Hz), 80.2, 80.0, 48.6, 33.3, 32.8, 28.4, 28.3, 25.3, 24.2.
tert-butyl (R)-(2-(4-methyl-6-(naphthalen-2-yl)-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-
3-yl)phenyl)carbamate (3ab)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 19:1) and the title compound was obtained as a
yellowish oil in a 0.66:1.00 mixture of conformers in 99% yield (98.6 mg) and 95% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralcel OD-H column: hexane/i-
PrOH 90:10, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C28
I
= 5.5 min, τII = 6.1 min. [α] ꢄꢃ ꢅ -42.0 (c 1.0,
+
3
H
26
F
3
NNaO
4
] 520.1706, found 520.1692
+
1
[
M+Na] . H-NMR (400 MHz, CDCl
3
) δ 8.13 (d, J = 2.0 Hz, 0.62 H), 8.06 – 8.05 (m, 1.05 H), 7.97 –
7
.95 (m, 1.04 H), 7.94 – 7.93 (m, 0.62 H), 7.90 – 7.86 (m, 4.09 H), 7.77 (d, J = 8.3 Hz, 0.63H), 7.66
(
dd, J = 8.7, 2.0 Hz, 0.1.3 H), 7.61 – 7.55 (m, 4.15 H), 7.28 (ddd, J = 8.6, 7.3, 1.7 Hz, 0.63 H), 7.25 –
.23 (m, 0.83 H), 7.16 – 7.15 (m, 0.59 H), 7.14 – 7.11 (m, 0.69 H), 6.80 (td, J = 7.5, 1.2 Hz, 1.0 H),
6.52 (bs, 1.02 H), 6.14 (dd, J = 7.6, 1.6 Hz, 1.08 H), 5.33 (bs, 0.69 H), 3.55 – 3.50 (m, 1.60 H), 3,38-
7
3
4
,35 (m, 0.62 H), 3.32 – 3.29 (m, 1.04 H), 1.84 (s, 1.61 H), 1.76 (s, 2.81 H), 1.50 (s, 8.18 H), 1.18 (s,
1
9
13
3 3
.51 H). F-NMR (282 MHz, CDCl ) δ -78.99, -79.09. C-NMR (150 MHz, CDCl ) δ 160.7, 160.0,
152.3, 151.7, 150.7, 150.7, 135.6, 135.0, 132.5, 132.5, 131.8, 131.7, 130.3, 130.2, 129.9, 129.0,
1
1
28.3, 128.3, 128.3, 127.9, 127.7, 127.6, 126.7, 126.6, 126.5, 126.5, 126.1, 126.1, 125.6, 125.5,
25.4, 123.9, 122.7, 122.5, 121.9, 121.4, 81.2, 81.0 (q, J = 30.6 Hz) 80.6 (q, J = 30.4 Hz), 80.4, 79.5,
79.2, 33.2, 32.8, 30.6, 27.3, 27.0, 21.6, 21.1, 21.0.
tert-Butyl (R)-(2-(6-(4-chlorophenyl)-4-methyl-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ac).
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The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 19:1) and the title compound was obtained as a
yellowish oil in a 0.75:1.00 mixture of conformers in 92% yield (88.7 mg) and >99% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak IC column: hexane/i-PrOH
9
0:10, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 7.9 min, τII = 9.5 min. [α] ꢄꢃ ꢅ -87.6 (c 1.0, CHCl
3
).
+
+ 1
HRMS-ESI-ORBITRAP (+): calculated for [C H ClF NNaO ] 504.1160, found 504.1156 [M+Na] . H-
2
4
23
3
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
NMR (600 MHz, CDCl ) δ 7.89 – 7.77 (m, 1.97 H), 7.56 (d, J = 8.6 Hz, 1.63 H), 7.51 – 7.43 (m, 5.62
H), 7.34 – 7.28 (m, 1.96 H), 7.14 – 7.06 (m, 1.69 H), 6.97 – 6.93 (m, 1.33 H), 6.48 (bs, 1.13 H), 6.29
(
dd, J = 7.6, 1.4 Hz, 1.24 H), 5.32 (bs, 0.79 H), 3.50 – 3.39 (m, 1.98 H), 3.21 – 3.07 (m, 2.11 H), 1.83
19
(
s, 2.27 H), 1.76 (s, 3.00 H), 1.50 (s, 9.01 H), 1.45 (s, 6.25 H). F-NMR (282 MHz, CDCl
3
) δ -79.38, -
13
7
1
1
9.58. C-NMR (150 MHz, CDCl ) δ 161.3, 160.7, 153.3, 152.8, 151.7, 151.6, 136.6, 136.3, 136.2,
3
36.0, 132.7, 132.6, 131.0, 130.0, 129.6, 129.5, 129.4, 129.3, 127.8, 127.6, 126.5, 125.1, 124.8,
24.0, 123.9, 123.6, 122.2, 122.1, 81.5 (q, J = 30.8 Hz), 81.1 (q, J = 30.8 Hz), 80.7, 80.6, 33.9, 33.6,
28.3, 22.2, 22.2.
tert-Butyl (R)-(2-(6-(2-chlorophenyl)-4-methyl-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ad)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 85:15) and the title compound was obtained as a
yellowish oil in a 0.72:1.00 mixture of conformers in 60% yield (57.8 mg) and 96% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
ꢄꢅ
PrOH 90:10, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 8.8 min, τII = 12.7 min. [α] -45.9 (c 1.0,
ꢃ
+
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C H ClF NNaO ] 504.1160, found 504.1153
3
24 23
3
4
+
1
[
(
M+Na] . H-NMR (300 MHz, CDCl
3
) δ 7.91 – 7.74 (m, 3.34 H), 7.55 – 7.47 (m, 1.65 H), 7.44 – 7.27
m, 5.07 H), 7.18 – 7.07 (m, 1.57 H), 6.92 (td, J = 7.5, 1.2 Hz, 1.00 H), 6.50 (bs, 0.87 H), 6.25 (dd, J =
7.6, 1.5 Hz, 0.97 H), 5.36 (bs, 0.60 H), 4.18 (d, J = 11.4 Hz, 0.79 H), 4.11 (d, J = 11.8 Hz, 0.96 H), 3.49
(
dd, J = 10.2, 1.1 Hz, 0.93 H), 3.43 (dd, J = 10.6, 1.1 Hz, 0.79 H), 1.87 (s, 2.21 H), 1.84 (s, 3.08 H),
19
13
1
.50 (s, 8.87 H), 1.47 (s, 7.10 H). F-NMR (282 MHz, CDCl
3
) δ -77.34, -77.36. C-NMR (75 MHz,
CDCl
3
) δ 161.6, 160.9, 153.2, 153.0, 152.9, 136.7, 135.9, 133.2, 132.8, 132.2, 132.1, 131.4, 131.2,
1
1
2
31.2, 130.9, 130.8, 130.4, 130.0, 129.4, 129.3, 127.7, 127.5, 125.9, 124.5, 124.4, 123.8, 123.7,
23.7, 122.5, 122.5, 83.4, 82.7 (q, J =31.5 Hz), 82.3 (q, J = 31.1 Hz), 80.6, 80.5, 33.1, 32.8, 28.4,
8.3, 21.5.
tert-Butyl (R)-(2-(6-(4-bromophenyl)-4-methyl-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-
3-yl)phenyl)carbamate (3ae)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 80:20) and the title compound was obtained as a
yellowish oil in a 0.66:1.00 mixture of conformers in 84% yield (88.2 mg) and 96.5% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
PrOH 80:20, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C24
I
= 8.6 min, τII = 5.9 min. [α] ꢄꢃ ꢅ -54.6 (c 1.0,
+
3
H
23BrF
3
NNaO
4
] 548.0655, found 548.0649
+
1
[M+Na] . H-NMR (300 MHz, CDCl ) δ 7.82 (dd, J = 11.0, 8.3 Hz, 0.94 H), 7.67 – 7.54 (m, 2.07 H),
3
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2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7.45 (m, 2.16 H), 7.36 – 7.26 (m, 1.07 H), 7.14 – 7.06 (m, 0.79 H), 6.94 (td, J = 7.5, 1.2 Hz, 0.61 H),
6
.46 (s, 0.56 H), 6.29 (dd, J = 7.6, 1.6 Hz, 0.59 H), 5.33 (s, 0.36 H), 3.50 – 3.40 (m, 1.00 H), 3.13 (m,
19
1
.00 H), 1.82 (s, 1.16 H), 1.75 (s, 1.78 H), 1.48 (s, 5.51 H), 1.45 (s, 3.85 H). F-NMR (282 MHz,
13
3 3
CDCl ) δ -79.36, -79.54. C-NMR (75 MHz, CDCl ) δ 161.3, 160.6, 153.2, 152.8, 151.6, 151.5, 136.6,
1
1
3
35.9, 133.2, 133.1, 132.5, 132.2, 131.0, 129.9, 129.5, 129.4, 128.0, 127.8, 126.4, 125.1, 124.8,
24.6, 124.4, 123.9, 123.6, 123.4, 122.8, 122.3, 81.55 (double, q, J = 31.0 Hz), 80.7, 80.5, 33.8,
3.5, 28.3 (double), 22.2 (double).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-butyl
(R)-(2-(6-(4-methoxyphenyl)-4-methyl-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-
pyran-3-yl)phenyl)carbamate (3af)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 80:20) and the title compound was obtained as a
yellowish oil in a 0.61:1.00 mixture of conformers in 66% yield (63.0 mg) and 98% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
PrOH 75:25, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C25
[M+Na] . H-NMR (300 MHz, CDCl
I
= 7.2 min, τII = 4.9 min. [α] ꢄꢃ ꢅ -123.2 (c 1.0,
+
3
H
26
F
3
NNaO
5
] 500.1655, found 500.1649
+
1
3
) δ 7.83 (m, 0.96 H), 7.48 (m, 2.16 H), 7.35 – 7.23 (m, 1.80 H),
.17 – 7.04 (m, 0.86 H), 7.03 – 6.86 (m, 2.77 H), 6.53 (s, 0.50 H), 6.27 (dd, J = 7.6, 1.6 Hz, 0.55H),
.30 (s, 0.32 H), 3.85 (s, 1.58), 3.83 (s, 1.21 H), 3.41 (m, 1.00 H), 3.15 (m, 1.00 H), 1.81 (s, 1.28 H),
7
5
1
9
13
1.75 (s, 1.87 H), 1.50 (s, 5.78 H), 1.43 (s, 4.11 H). F-NMR (282 MHz, CDCl
NMR (75 MHz, CDCl ) δ 161.8, 161.0, 160.5, 153.3, 152.9, 151.8, 136.6, 135.9, 131.1, 130.0, 129.4,
29.2, 127.8, 127.5, 126.4, 125.5, 125.0, 124.9, 123.7, 123.4, 123.3, 121.9, 114.7, 114.2, 81.8 (q, J
= 30.6 Hz), 81.3 (q, J = 30.5 Hz), 80.7 (double), 55.4, 55.2, 33.9, 33.5, 38.3, 28.2, 22.2, 22.1.
3
) δ -79.70, -79.90. C-
3
1
tert-Butyl
(R)-(2-(6-(3-methoxyphenyl)-4-methyl-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-
pyran-3-yl)phenyl)carbamate (3ag).
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 80:20) and the title compound was obtained as a
yellowish oil in a 0.66:1.00 mixture of conformers in 88% yield (84 mg) and 94% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
ꢄꢅ
PrOH 75:25, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ = 9.3 min, τ = 4.6 min. [α] -211.4 (c 1.0,
I
II
+
ꢃ
CHCl
3
). HRMS-ESI-ORBITRAP (+): calculated for [C25
H
26
F
3
NNaO
) δ 7.83 (m, 0.96 H), 7.48 (m, 2.16 H), 7.35 – 7.23 (m, 1.80 H),
.17 – 7.04 (m, 0.86 H), 7.03 – 6.86 (m, 2.77 H), 6.53 (s, 0.50 H), 6.27 (dd, J = 7.6, 1.6 Hz, 0.55H),
.30 (s, 0.32 H), 3.85 (s, 1.58), 3.83 (s, 1.21 H), 3.41 (m, 1.00 H), 3.15 (m, 1.00 H), 1.81 (s, 1.28 H),
5
] 500.1655, found 500.1650
+
1
[M+Na] . H-NMR (400 MHz, CDCl
3
7
5
1
9
13
1.75 (s, 1.87 H), 1.50 (s, 5.78 H), 1.43 (s, 4.11 H). F-NMR (376 MHz, CDCl
NMR (150 MHz, CDCl ) δ 161.7, 160.9, 160.1, 159.9, 153.2, 152.8, 151.9, 151.8, 136.6, 136.0,
35.6, 135.4, 131.0, 130.3, 130.0, 129.9, 129.4, 129.2, 126.4, 125.9, 124.9, 124.1, 124.0, 123.7,
123.4, 123.2, 122.2, 122.1, 121.9, 118.5, 118.0, 115.7, 115.0, 112.7, 112.2, 81.8 (q, J = 30.8 Hz),
1.3 (q, J = 30.8 Hz), 80.5, 80.4, 55.4, 55.3, 34.0, 33.7, 28.3 (double), 22.1, 22.0.
3
) δ -79.20, -79.40. C-
3
1
8
tert-Butyl (R)-(2-(4-methyl-6-(4-nitrophenyl)-2-oxo-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ah)
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The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 80:20) and the title compound was obtained as a
yellowish oil in a 0.63:1.00 mixture of conformers in 86% yield (84.8 mg) and 90% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
PrOH 70:30, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 6.6 min, τII = 10.4 min. [α] ꢄꢃ ꢅ -97.2 (c 1.0,
+
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C H F N NaO ] 515.1400, found 515.1391
3
24 23 3
2
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
[
M+Na] . H-NMR (600 MHz, CDCl
3
) δ 8.39 – 8.33 (m, 3.42 H), 7.85 (d, J = 8.6 Hz, 1.83 H), 7.79 (d, J
8.7 Hz, 2.02 H), 7.39 – 7.29 (m, 2.56 H), 7.16 – 7.07 (m, 1.41H), 6.96 (td, J = 7.5, 1.2 Hz, 1.02 H),
.42 (bs, 0.96 H), 6.29 (dd, J = 7.5, 1.5 Hz, 1.00 H), 5.36 (bs, 0.77 H), 3.52 (m, 1.65 H), 3.22 (m, 1.64
=
6
1
9
H), 1.86 (s, 1.74 H), 1.81 (s, 2.77 H), 1.50 (s, 8.50 H), 1.40 (s, 5.25 H). F-NMR (282 MHz, CDCl
3
) δ -
1
3
7
1
1
8.80, -78.82. C-NMR (75 MHz, CDCl ) δ 161.1, 160.2, 154.4, 154.3, 152.0, 151.7, 143.1, 142.4,
3
42.3, 142.3, 133.6, 133.6, 130.4, 130.3, 129.5, 129.2, 127.0, 126.2, 126.1, 125.9, 125.2, 124.9,
24.4, 123.3, 123.1, 122.2, 119.8, 119.7, 82.2, 82.1 (q, J = 30.8 Hz), 81.6 (q, J = 30.8 Hz) , 34.0, 31.6,
28.3, 28.2, 25.4, 22.7, 22.2, 14.1.
tert-Butyl (S)-(2-(4-methyl-2-oxo-6-(thiophen-2-yl)-6-(trifluoromethyl)-5,6-dihydro-2H-pyran-3-
yl)phenyl)carbamate (3ai)
The reaction was carried out following the general procedure. The crude mixture was purified by
flash column chromatography (hexane:EtOAc = 85:15) and the title compound was obtained as a
yellowish oil in a 0.99:1.00 mixture of conformers in 89% yield (87.7 mg) and 87% enantiomeric
excess. The ee was determined by HPLC analysis on a Daicel Chiralpak AD-H column: hexane/i-
PrOH 90:10, flow rate 1.0 mL/min, 50 °C, λ = 254 nm: τ
I
= 8.3 min, τII = 14.6 min. [α] ꢄꢃ ꢅ -43.3 (c 1.0,
+
CHCl ). HRMS-ESI-ORBITRAP (+): calculated for [C H F NNaO S] 476.1114, found 476.1108
3
22 22 3
4
+
1
[
M+Na] . H-NMR (600 MHz, CDCl
.36 – 7.27 (m, 4.51 H), 7.13 – 7.07 (m, 4.32 H), 6.95 (td, J = 7.5, 1.0 Hz, 1.22 H), 6.49 (bs, 1.18 H)
6.34 (dd, J = 7.6, 1.4 Hz, 1.18 H), 5.31 (bs, 0.87 H), 3.45 (m, 2.28 H), 3.09 (m, 2.32 H), 1.86 (s, 3.00
3
) δ 7.84 (d, J = 8.1 Hz, 1.43 H), 7.44 (td, J = 5.0, 1.2 Hz, 2.16 H),
7
1
9
H), 1.81 (s, 3.03 H), 1.50 (s, 8.93 H), 1.48 (s, 9.56 H). F-NMR (282 MHz, CDCl
3
) δ -80.17, -80.49.
) δ 161.1, 160.2, 153.3, 152.8, 151.8, 151.6, 137.0, 136.9, 136.7, 136.0,
131.0, 130.0, 129.4, 129.3, 128.5, 128.4, 128.1, 127.7, 127.6, 127.4, 126.3, 124.9, 123.8, 123.5,
13
C-NMR (150 MHz, CDCl
3
1
3
23.5, 123.4, 122.9, 121.6, 121.6, 80.8 (q, J = 31.8 Hz), 80.5, 80.3 (q, J = 31.9 Hz), 77.2, 77.0, 76.8,
5.3, 35.0, 31.6, 28.4, 28.3, 22.6, 22.1, 22.0.
tert-Butyl
(R,Z)-(2-fluoro-6-(6,6,6-trifluoro-5-hydroxy-3-methyl-1-oxo-5-phenyl-1-(pyrrolidin-1-
yl)hex-2-en-2-yl)phenyl)carbamate (5ca)
Product 3ca (40.5 mg, 0.09 mmol, 1 equiv) was dissolved in 225 µL of anhydrous THF before
addition of pirrolidine (15 µL, 0.18 mmol, 2 equiv) and the solution was allowed to stir at room
temperature for 24 hours. After this time a control TLC (hexane:EtOAc 70:30) showed the reaction
was complete so the crude mixture was purified directly by flash column chromatography
(hexane:EtOAc = 70:30) and the title compound was obtained with an isolated yield of 86% (41.5
+
32 4 2 4
mg of white amorphous solid). HRMS-ESI-ORBITRAP (+): calculated for [C28H F N NaO ]
+
1
5
7
3
59.2190, found 559.2193 [M+Na] . H-NMR (300 MHz, CDCl ) δ 7.72 (d, J = 7.4 Hz, 2H), 7.42 –
.28 (m, 3H), 7.18 – 7.00 (m, 2H), 6.91 (d, J = 7.5 Hz, 1H), 6.55 (s, 1H), 3.65 – 3.37 (m, 2H), 3.37 –
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3.13 (m, 2H), 3.02 – 2.74 (m, 2H), 2.03 – 1.63 (m, 4H), 1.52 (s, 9H), 1.04 (s, 3H). F-NMR (286 MHz,
13
CDCl ) δ -79.93, -116.6. C-NMR (75 MHz, CDCl ) δ 169.1, 156.2, 153.0, 138.9, 138.4, 134.5, 133.1,
3
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4
28.2, 128.1, 126.5, 126.3, 126.2, 126.1, 124.8, 124.7, 116.1, 115.8, 80.6, 74.7 (q, J = 28.0 Hz),
7.6, 46.67, 41.3, 28.2, 26.2, 23.9, 20.1.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website. NMR
spectra, HPLC chromatograms, computational details and thermodynamic data.
AUTHOR INFORMATION
Corresponding Author
*
†
Email: giorgio.bencivenni2@unibo.it
These authors contributed equally to this work.
ORCID
Simone Crotti: 0000-0003-3659-0551
Nicola Di Iorio: 0000-0002-4431-4007
Andrea Mazzanti: 0000-0003-1819-8863
Paolo Righi: 0000-0003-1419-2560
Giorgio Bencivenni: 0000-0002-0855-1232
ACKNOWLEDGMENT
We are grateful to the University of Bologna for the financial support. We are grateful to Prof.
Alessia Ciogli of the University of Rome “La Sapienza” for the HRMS analyses.
REFERENCES
1
. For representative reviews about vinylogy see: (a) Battistini, L.; Curti, C.; Rassu, G.; Sartori,
A.; Zanardi, F. Enolizable Alkylidene Heterocyclic and Carbocyclic Carbonyl Systems-:
Valuable Vinylogous Donor Substrates in Synthesis. Synthesis 2017, 49, 2297. (c) Jurberg, I.
D.; Chatterjee, I.; Tannert, R.; Melchiorre, P. When Asymmetric Aminocatalysis Meets the
Vinylogy Principle. Chem. Commun. 2013, 49, 4869. (d) Casiraghi, G.; Battistini, L.; Curti, C.;
Rassu, G.; Zanardi, F. The Vinylogous Aldol and Related Addition Reactions: Ten Years of
Progress. Chem. Rev. 2011, 111, 3076. (e)Hepburn, H. B., Dell’ Amico, L.; Melchiorre, P.
Enantioselective Vinylogous Organocascade Reactions. Chem. Rec. 2016, 16, 1787. (f)
Denmark, S. E.; Heemstra, J. R. Jr.; Beutner, G. L. Catalytic, Enantioselective, Vinylogous
Aldol Reactions. Angew. Chem., Int. Ed. 2005, 44, 4682. For representative examples of
vinylogous reactions: (g) Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli, G.; Melchiorre,
P. Direct Asymmetric Vinylogous Michael Addition of Cyclic Enones to Nitroalkenes via
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Dienamine Catalysis. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20642. (h) Tian, X.; Hofmann
N.; Melchiorre, P. Asymmetric vinylogous Diels-Alder Reactions Catalyzed by a Chiral
Phosphoric Acid. Angew. Chem. Int. Ed., 2014, 53, 2997. (i) Dell’ Amico, L.; Albrecht, Ł.;
Naicker, T.; Poulsen, P. H.; Jørgensen, K. A. Beyond Classical Reactivity Patterns: Shifting
from 1,4- to 1,6-Additions in Regio- and Enantioselective Organocatalyzed Vinylogous
Reactions of Olefinic Lactones with Enals and 2,4-Dienals. J. Am. Chem. Soc. 2013, 135,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
063. (j) Stiller, J.; Poulsen, P. H.; Cruz Cruz, D.; Dourado, J.; Davis, R. L.; Jørgensen, K. A.
Organocatalytic [4+2] Addition Reactions via Tetraenamine Intermediate. Chem. Sci. 2014,
, 2052. (k)Di Iorio, N.; Righi, P.; Mazzanti, A.; Mancinelli, M.; Ciogli, A.; Bencivenni, G.
5
Remote Control of Axial Chirality Aminocatalytic Desymmetrization of N-Arylmaleimides via
Vinylogous Michael Addition. J. Am. Chem. Soc. 2014, 136, 10250. (l) Xiong, X.-F.; Zhou, Q.;
Gu, J.; Dong, L.; Liu, T.-Y.; Chen, Y.- C. Trienamine Catalysis with 2,4-Dienones:
Development and Application in Asymmetric Diels–Alder Reaction. Angew. Chem., Int. Ed.
2012, 51, 4401.
2
. (a) Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.; Battistini, L.; Zanardi,
F.; Casiraghi, G. Bifunctional Cinchona Alkaloid/Thiourea Catalyzes Direct and
Enantioselective Vinylogous Michael Addition of 3-Alkylidene Oxindoles to Nitroolefins.
Angew. Chem Int. Ed. 2012, 51, 6200. (b) Chen, Q.; Wang, G.; Jiang, X.; Xu, Z.; Lin, L.; Wang,
R. Highly Enantioselective Organocatalyzed Vinylogous Michael-Type Reaction for the
Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters. Org. Lett. 2014,
1
6, 1394. (c) Zhong, Y.; Ma, S., Xu, Z.; Changa, M.; Wang, R. Organocatalytic Asymmetric
Vinylogous Michael Addition of 3-Alkylidene Oxindoles to α-Substituted β-Nitroacrylates:
Facile Construction of a Chiral all-Carbon Quaternary Center. RSC Adv. 2014, 4, 49930. (d)
Di Iorio, N.; Righi, P.; Ranieri, S.; Mazzanti, A.; Margutta, R. G.; Bencivenni, G. Vinylogous
Reactivity of Oxindoles Bearing Nonsymmetric 3-Alkylidene Groups. J. Org. Chem. 2015, 80,
7158. (e) Xiao, X.; Mei, H.; Chen, Q.; Zhao, L.; Lin, X.; Liu, X.; Feng, X. Direct Asymmetric
Vinylogous Michael Addition of 3-Alkylidene Oxindoles to Chalcones Catalyzed by a chiral
N,N′-Dioxide Ytterbium(III) Complex. Chem Commun. 2015, 51, 580. (f) Feng, J.; Li, X.;
Cheng, J.-P. Enantioselective Organocatalyzed Vinylogous Michael Reactions of 3-
Alkylidene Oxindoles with Enals. J. Org. Chem. 2017, 82, 1412. (g) Jadhav, A. P.; Ali, A.;
Singh, R. P. Vinylogous Nucleophilic Substitution of the Hydroxy Group in Diarylmethanols
with 3-Propenyl-2-silyloxyindoles: Towards the Synthesis of α-Alkylidene-δ-diaryl-2-
oxindoles. Adv. Synth. Catal. 2017, 359, 1508. (h) Kumar, K.; Jaiswal, M. K.; Singh, R. P.
Asymmetric Vinylogous Aldol Reaction of α-ketoesters with 3-alkylidene oxindoles. Adv.
Synth. Catal. 2017, 359, 4136.
3. (a) Han, J.-L.; Chang, C.-H. An Asymmetric Assembly of Spirooxindole Dihydropyranones
Through a Direct Enantioselective Organocatalytic Vinylogous Aldol-cyclization Cascade
Reaction of 3-Alkylidene Oxindoles with Isatins. Chem. Commun. 2016, 52, 2322. (b) Han,
J.-L.; Tsai, Y.-D.; Chang, C.-H. Asymmetric Synthesis of Spirooxindole δ-Lactones with Vicinal
Tertiary and Quaternary Stereocenters via Regio-, Diastereo-, and Enantioselective
Organocatalytic Vinylogous Aldol-cyclization Cascade Reaction. Adv. Synth. Catal. 2017,
359, 4043.
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1
2
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4. (a) Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications; Petrov, V.
A.; John Wiley & Sons: Hoboken, NJ, 2009; pp 397. (b) O’Hagan, D. Fluorine in Health Care:
Organofluorine Containing Blockbuster Drugs. J. Fluorine Chem. 2010, 131, 1071.
5
. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry.
Chem. Soc. Rev. 2008, 37, 320. (b) Wang, J.; Sánchez-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. Chem.
Rev. 2014, 114, 2432. (c) Ma, J.-A.; Cahard, D. Asymmetric Fluorination,
Trifluoromethylation, and Perfluoroalkylation Reactions. Chem. Rev. 2008, 108, PR1-PR43.
. (a) Ma, J.-A.; Cahard, D. Strategies for Nucleophilic, Electrophilic, and Radical
Trifluoromethylations. J. Fluorine Chem. 2007, 128, 975 (b) Nagib, D. A.; Scott, M. E.;
MacMillan, D. W. C. Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox
Organocatalysis. J. Am. Chem. Soc. 2009, 131, 10875. (c) Ruppert, I.; Schlich, K.; Volbach,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
W. Die Ersten CF -substituierten Organyl(chlor)silane. Tetrahedron Lett. 1984, 25, 2195. (d)
3
Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. Fluoride-induced Trifluoromethylation of
Carbonyl Compounds with Trifluoromethyltrimethylsilane (TMS-CF3). A Trifluoromethide
Equivalent. J. Am. Chem. Soc. 1989, 111, 393. (e) Prakash, G. K. S.; Yudin, A. K.
Perfluoroalkylation with Organosilicon Reagents. Chem. Rev. 1997, 97, 757. (f) Kieltsch, I.;
Eisenberger, P.; Togni, A. Mild Electrophilic Trifluoromethylation of Carbon- and Sulfur-
Centered Nucleophiles by a Hypervalent iodine(III)-CF
3
reagent. Angew. Chem., Int. Ed.
2
007, 46, 754. (g) Ventre, S.; Filip R. Petronijevic, F. R.; MacMillan D. W. C. Decarboxylative
Fluorination of Aliphatic Carboxylic Acids via Photoredox Catalysis. J. Am. Chem. Soc. 2015,
137, 5654. (h) Braun M.-G.; Doyle A. G. Palladium-catalyzed Allylic C-H Fluorination. J. Am.
Chem. Soc. 2013, 135, 12990. (i) Bloom, S.; Pitts, C. R.; Miller, D. C.; Haselton, N.; Holl, M.
G.; Urheim, E.; Lectka, T. A Polycomponent Metal-catalyzed Aliphatic, Allylic, and Benzylic
Fluorination. Angew. Chem., Int. Ed. 2012, 51, 10580.
7
. For aldol reactions: (a) Duangdee, N.; Harnying, W.; Rulli, G.; Neudörfl, J.-M.; Gröger, H.;
Berkessel, A. Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol Synthesis - A
Caveat on Reaction Times and Product Isolation. J. Am. Chem. Soc. 2012, 134, 11196. (b)
Hara, N.; Tamura, R.; Funahashi, Y.; Nakamura S. N-(heteroarenesulfonyl)prolinamides-
catalyzed Aldol Reaction Between Acetone and Aryl Trihalomethyl Ketones. Org. Lett.
2
011, 13, 1662. (c) Kokotos C. G. Construction of Tertiary Alcohols Bearing Perfluoroalkyl
Chains Catalyzed by Prolinamide-Thioureas. J. Org. Chem. 2012, 77, 1131. (d) Wang, X.-J.;
Zhao, Y.; Liu, J.-T. Regiospecific Organocatalytic Asymmetric Aldol Reaction of Methyl
Ketones and α,β-Unsaturated Trifluoromethyl Ketones. Org. Lett. 2007, 9, 1343. (e) Wang,
P.; Li, H.-F.; Zhao, J.-Z.; Du, Z.-H.; Da, C.-S. Organocatalytic Enantioselective Cross-Aldol
Reaction of o-Hydroxyarylketones and Trifluoromethyl Ketones. Org. Lett. 2017, 19, 2634.
For nitro-aldol: (f) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Enantioselective
Organocatalyzed Henry Reaction with Fluoromethyl Ketones. Chem. Commun. 2008, 4360.
(
g) Palacio, C., Connon, S. J. A New Class of Urea-Substituted Cinchona Alkaloids Promote
Highly Enantioselective Nitroaldol reactions of Trifluoromethylketones. Org. Lett. 2011, 13,
1298.
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8. (a) Mo, J.; Chen, X.; Chi, Y. R. Oxidative γ-Addition of Enals to Trifluoromethyl Ketones:
Enantioselectivity Control via Lewis Acid/N-Heterocyclic Carbene Cooperative Catalysis. J.
Am. Chem. Soc. 2012, 134, 8810. (b) Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R.
3
Functionalization of Benzylic C(sp )-H Bonds of Heteroaryl Aldehydes through N-
Heterocyclic Carbene Organocatalysis. Angew. Chem. Int. Ed. 2013, 52, 11134. (c)
Cornaggia, C.; Gundala, S.; Manoni, F.; Gopalasetty, N.; Connon, S. J. Catalytic Formal
Cycloadditions Between Anhydrides and Aetones: Excellent Enantio and Diastereocontrol,
Controllable Decarboxylation and the Formation of Adjacent Quaternary Stereocentres.
Org. Biomol. Chem. 2016, 14, 3040. For further examples of organocatalytic vinylogous
aldol reactions see: d) Cassani, C.; Melchiorre, P. Direct Catalytic Enantioselective
Vinylogous Aldol Reaction of α-Branched Enals with Isatins. Org. Lett. 2012, 14, 5590. e)
Bastida, D.; Liu; Y.; Tian, X.; Escudero-Adán, E.; Melchiorre, P. Asymmetric Vinylogous Aldol
Reaction via H-Bond-Directing Dienamine Catalysis. Org. Lett. 2013, 15, 220.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9. (a) Chiu, P.; Leung, L. T.; Ko, B. C. B. Pseudolaric Acids: Isolation, Bioactivity and Synthetic
Studies. Nat. Prod. Rep. 2010, 27, 1066. (b) Florence, G. J.; Gardner, N. M.; Paterson, I.
Development of Practical Syntheses of The Marine Anticancer Agents Discodermolide and
Dictyostatin. Nat. Prod. Rep. 2008, 25, 342. (c) Shaw, S. J.; Sundermann, K. F.; Burlingame,
M. A.; Myles, D. C.; Freeze, B. S.; Xian, M.; Brouard, I.; Smith III, A. B. Toward Understanding
How the Lactone Moiety of Discodermolide Affects Activity. J. Am. Chem. Soc. 2005, 127,
6532. For a review on the sysnthesis of unsaturated γ-lactones see: (d) Boucard, V.;
Broustal, G.; Campagne, J.-M.; Synthetic Approaches to α,β-Unsaturated δ-Lactones and
Lactols. Eur. J. Org. Chem. 2007, 225. For selected examples: (e) Moreau, X.; Bazán-Tejeda,
B.; Campagne, J.-M. Catalytic and Asymmetric Vinylogous Mukaiyama Reactions on
Aliphatic Ketones:ꢂ Formal Asymmetric Synthesis of Taurospongin A. J. Am. Chem. Soc.
2
005, 127, 7288. (f) Shen, L.-T.; Shao, P.-L.; Ye, S. N-Heterocyclic Carbene-Catalyzed
Cyclization of Unsaturated Acyl Chlorides and Ketones. Adv. Synth. Catal. 2011, 353, 1943.
g) Tiseni, P. S.; Peters, R. Catalytic Asymmetric Formation of δ -Lactones by [4+2]
(
Cycloaddition of Zwitterionic Dienolates Generated from α,β-Unsaturated Acid Chlorides.
Angew. Chem. Int, Ed. 2007, 46, , 5325. (h) Tiseni, P. S.; Peters, R. Lewis Acid−Lewis Base
Catalyzed Enantioselective Hetero-Diels−Alder Reacꢁon for Direct Access to δ-Lactones.
Org. Lett. 2008, 10, 2019.
1
1
0. (a) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen. K. A. Squaramides: Bridging from Molecular
Recognition to Bifunctional Organocatalysis. Chem. Eur. J. 2011, 17, 6890. (b) Song, C.E. In
Cinchona Alkaloids in Synthesis and Catalysis; Wiley-VCH: Weinheim, 2009. (c) Connon, S. J.
Chem. Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea
organocatalysts. Commun. 2008, 2499. (d) Doyle, A. G.; Jacobsen, E. N.; Small-Molecule H-
Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713.
1. Recently, reactions based on an alkylation-lactonization sequence have been reported by
Zhao and Hu in the reaction of naphthols and hydroxyindoles with trifluoroethylidene
oxindoles: (a) Zhao, Y. L.; Lou, Q.-X.; Wang, L.-S.; Hu, W.-H.; Zhao, J.-L. Organocatalytic
Friedel-Crafts Alkylation/Lactonization Reaction of Naphthols with 3-Trifluoroethylidene
Oxindoles: The Asymmetric Synthesis of Dihydrocoumarins. Angew. Chem. Int, Ed. 2017,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
56, 338. (b) Xiao, M.; Xu, D.; Liang, W.; Wu, W.; Chan, A. S. C.; Zhao, J. Organocatalytic
Enantioselective Friedel–Crafts Alkylation/Lactonization Reaction of Hydroxyindoles with
Methyleneoxindoles. Adv. Synth. Catal. 2018, 360, 917.
1
2. (a) Cassani, C.; Martín-Rapún, R.; Arceo, E.; Bravo, F.; Melchiorre, P. Synthesis of 9-
Amino(9-deoxy)epi cinchona alkaloids, General Chiral Organocatalysts for the
Stereoselective Functionalization of Carbonyl Compounds. Nature Protocols 2013, 8, 325.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
b) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide Derivatives are Excellent
Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130, 14416. (c) Vakulya, B.; Varga,
S.; Csámpai, A.; Soós, T. Highly Enantioselective Conjugate Addition of Nitromethane to
Chalcones Using Bifunctional Cinchona Organocatalysts. Org. Lett. 2005, 7, 1967.
13. Rassu, G.; Zambrano, V.; Tanca, R.; Sartori, A.; Battistini, L.; Zanardi, F.; Curti, C.; Casiraghi,
G. 3-Alkenyl-2-silyloxyindoles: An Enabling, Yet Understated Progeny of Vinylogous Carbon
Nucleophiles. Eur. J. Org. Chem., 2012, 466.
14. Liu, Y.; Yang, Y.; Huang, Y.; Xu, X.-H.; Qing, F.-L.; Regio- and Diastereoselective Vinylogous
Mannich Addition of 3-Alkenyl-2-oxindoles to α-Fluoroalkyl Aldimines. Synlett, 2015, 26,
6
7.
15. Wu, W.; Qinli, T.; Taotao, C.; Zhiqiang, W. Copper-Mediated Trifluoroacetylation of
Arenediazonium Salts with Ethyl Trifluoropyruvate. Chem, Eur. J. 2016, 22, 16455.
1
1
6. Schenck, H. A.; Lenkowski, P. W.; Choudhury-Mukherjee, I.; Ko, S.-H.; Stables, J. P.; Patel,
M. K.; Brown, M. L. Design, Synthesis and Evaluation of Novel Hydroxyamides as Orally
Available Anticonvulsants. Bioorg. Med. Chem. 2004, 12, 979.
7. Emer, E.; Twilton, J.; Tredwell, M.; Calderwood, S.; Collier, T. L.; Liegault, B.; Taillefer, M.;
Gouverneur, V. Diversity-Oriented Approach to CF
CF (SCF )CH-Substituted Arenes from 1-(Diazo-2,2,2-trifluoroethyl)arenes Org. Lett. 2014,
6, 6004.
3 3 3 2 3 2
CHF-, CF CFBr-, CF CF -, (CF ) CH-, and
3
3
1
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