Thieme Chemistry Journals Awardees - Where Are They Now? Chiral Sulfinamide Ligands and Pd-Catalyzed Asymmetric Allylic Alkylations of Ethyl 2-Fluoroacetoacetate

Article abstract of DOI:10.1055/s-0036-1589033

New chiral sulfinamide ligands made from salicylic acids and chiral tert -butanesulfinamide was utilized in Pd-catalyzed asymmetric allylic substitutions of ethyl 2-fluoroacetoacetate, which afforded the fluorinated allyl products with up to 98% yield, 94% ee, and 2.2:1 dr. Both sulfoxide and hydroxyl group on the sulfanilamide ligands are crucial for enantiocontrol in the Pd-catalyzed allylic alkylations of ethyl 2-fluoroacetoacetate.

Full text of DOI:10.1055/s-0036-1589033

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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M. Zhao et al.
Letter
Synlett
Thieme Chemistry Journals Awardees – Where Are They Now?
Chiral Sulfinamide Ligands and Pd-Catalyzed Asymmetric Allylic
Alkylations of Ethyl 2-Fluoroacetoacetate
O
O
Mingzhu Zhaoa
Yawei Tiana
Xiaoming Zhao*a,b
O
O
S
[Pd(C3H5)Cl]2 (4 mol%)
(R)-L1 (8 mol%)
O
O
∗
OAc
R1
OEt
F
R1
N
+
OEt
R1
R1
∗
H
K3PO4, THF/dioxane, r.t.
10 examples
H
F
OH
52–98% yields
61–94% ee
1.5:1 to 2.2:1 dr
R1 = aryl
a Shanghai Key Lab of Chemical Assessment and Sustainabili-
ty, School of Chemical Science and Engineering, Tongji Uni-
versity, Shanghai 200092, P. R. of China
(R)-L1
xmzhao08@mail.tongji.edu.cn
b Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032, P. R. of China
Received: 16.03.2017
Accepted after revision: 18.04.2017
Published online: 08.05.2017
DOI: 10.1055/s-0036-1589033; Art ID: st-2017-w0191-l
Abstract New chiral sulfinamide ligands made from salicylic acids and
chiral tert-butanesulfinamide was utilized in Pd-catalyzed asymmetric
allylic substitutions of ethyl 2-fluoroacetoacetate, which afforded the
fluorinated allyl products with up to 98% yield, 94% ee, and 2.2:1 dr.
Both sulfoxide and hydroxyl group on the sulfanilamide ligands are
crucial for enantiocontrol in the Pd-catalyzed allylic alkylations of ethyl
2-fluoroacetoacetate.
Key words sulfinamide ligand, allylation, palladium, enantioselectivi-
ty, fluorinated allylproduct
Xiaoming Zhao obtained his Ph.D. from Daliang University of Technol-
ogy in 1995. He conducted his postdoctoral research at the University
of Florida (UF) and University of Southern California (USC) in the group
of Prof G. K. Prakash and Prof G. A. Olah. He is currently a professor in
Tongji University at Shanghai. His research group’s interests were rec-
ognized by the award of a Thieme Chemistry Journal Award in 2012 and
focus on reaction design, asymmetric synthesis, and fluorine chemistry.
Chiral fluorinated compounds are of great importance
with regard to pharmaceuticals and materials.1 For exam-
ple, drugs such as Clevudine,2 Clofarabine,3 Fluticasone Fu-
roate,4 and Difluprednate5 contain a chiral fluorinated car-
bon center. Accordingly, new methods for the synthesis of
chiral fluorinated compounds are highly desirable. A direct
way to build a chiral fluorinated carbon center is by transi-
tion-metal-catalyzed asymmetric allylic substitutions of
fluorinated methylene derivatives.6 Several fluorinated
methylene derivatives such as fluorobisphenylsulfonyl-
methane7 and 2-fluoromalonate8 have been applied in Pd9
or Ir10-catalyzed allylation reactions or one-pot tandem
substitution and Krapcho reaction,11 whereas other fluori-
nated nucleophiles are less exploited. Organocatalytic en-
antioselective reactions have also been applied for the syn-
thesis of chiral fluorinated compounds.12
was the first to develop a chiral ligand with a sulfoxide15
unit, which is suitable in asymmetric synthesis.16 Recently,
the sulfinamide-olefin hybrid ligands were independently
developed by Liao,17 Xu,18 Du,19 and Xia,20 and these ligands
show satisfactory catalytic performance. Chiral sulfin-
amide-pyridine ligands derived from either tert-butanesul-
finamide or o-aniline sulfoxides were also synthesized and
they are effective for Pd-catalyzed asymmetric allylic sub-
stitutions of dimethyl 2-fluoromalonate.21 The develop-
ment of chiral sulfinamide ligands for Pd-catalyzed allyla-
tion of fluorinated methylene derivatives is a less explored
area in asymmetric catalysis. In this paper, we describe the
synthesis of chiral sulfinamide ligands and the application
of these ligands in Pd-catalyzed asymmetric allylations of
ethyl 2-fluoroacetoacetate.
Chiral ligands are crucial for enantiocontrol in transi-
tion-metal-catalyzed allylic substitutions.13 The design and
synthesis of novel chiral ligands have therefore drawn con-
siderable attention. Chiral dienes, alkene, and P- and/or N-
hybrid ligands have been extensively investigated.14 Dorta
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
M. Zhao et al.
Letter
Synlett
To develop chiral sulfinamide ligands for asymmetric al-
lylic substitutions of fluorinated methylene derivatives un-
der Pd catalysis, we focused on the preparation of sulfin-
amide ligands derived from salicylic acid and (R)-tert-
butanesulfinamide according to the synthetic sequence
shown in Scheme 1. For example, sulfinamide ligand (R)-L1
was synthesized in 62% yield by an amidation reaction be-
tween an active amide, which was initially converted by a
reaction of salicylic acid with N,N′-carbonyldiimidazole
(CDI) in THF at 50 °C, with potassium (R)-tert-butanesulfin-
amide, made from treatment of (R)-tert-butanesulfinamide
with potassium hydride (KH) in THF.22 The molecular struc-
ture of (R)-L1 was established by its X-ray diffraction analy-
sis (Figure 1).23 A range of the sulfinamide ligands L2–L6
was also synthesized by using a similar procedure (Figure
2).22
O
O
S
O
O
S
O
O
S
N
H
N
N
H
H
OH
OH
OH
(R)-L3
(R)-L1
(R)-L2
O
O
S
O
O
S
O
O
S
N
N
H
N
H
H
MeO
OH
(R)-L4
OMe
(R)-L5
(R)-L6
O
O
NH
HN
PPh2
PPh2
Ph2P
PPh2
PPh2
Ph2P
(S,S)-Chiralphos
(S,S)-DACH-naphthyl Trost
(R)-BINAP
With the chiral sulfinamide ligands L1–L6 in hand, we
then evaluated their catalytic performance. Thus, we chose
a Pd-catalyzed allylic alkylation reaction between (E)-1,3-
bis(3-chlorophenyl)allyl acetate (1a) and ethyl 2-fluoroace-
toacetate (2a) as a model reaction. To our delight, the allylic
products 3a were obtained in 95% yield with 45–56% ee and
1.5:1 dr with the assistance of the Pd complex formed from
4 mol% [Pd(C3H5)Cl]2 and 8 mol% (R)-L1 in THF at room
temperature (Table 1, entry 1). Encouraged by these results,
we then examined the use of various solvents. The solvent
survey indicated that the use of dioxane resulted in the al-
lylic products 3a in 62% yield with 73–76% ee and 1.6:1 dr
Figure 2 Chiral ligands L used in this reaction
(entry 2); CH2Cl2 gave 51% yield, and toluene was almost
completely ineffective for this reaction (entries 3 and 4).
Unexpectedly, when a mixture of THF and dioxane (1:1)
was used, the allylic products 3a were afforded in 98% yield
with 78–80% ee and 1.6:1 dr (entry 5). We next investigated
the influence of the base on the efficiency, enantioselectivi-
ty, and diastereoselectivity of this allylation (entries 6–11).
A range of bases such as K3PO4, t-BuOK, K2CO3, Cs2CO3,
Na3PO4, CsF, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
were tested. We found that K3PO4 was suitable, and t-BuOK,
K2CO3 and Cs2CO3 resulted in good results (entries 6–8), but
both Na3PO4 and CsF were unsuitable for this allylation re-
action (entries 9 and 10). When DBU was used, the allylic
products 3a were obtained with 97% yield but in racemic
form (entry 11). Ligands play a significant role in Pd-cata-
lyzed asymmetrical allyic alkylations.13 Therefore, the set of
chiral ligands L2–L4 was further explored. For instance, we
modified the phenyl ring of L1 as a naphthyl group to give
L2 and L3. The use of L2 resulted in similar outcomes to that
of L1, whereas the use of L3 gave slight worse results than
L2 (entry 5 vs. entry 12 vs. entry 13).
O
O
O
S
H2N
CDI (1.0 equiv)
OH
N
N
THF, r.t. to 50 °C
KH (2.0 equiv)
THF, r.t.
OH
OH
active amide
salicylic acid
O
O
S
N
H
OH
(R)-L1
62% yield
The use of L4, with an electron-donating group (p-MeO)
on the phenyl ring, led to somewhat worse results than
those obtained with L1 (Table 1, entry 5 vs. entry 14). Li-
gand L5, in which the hydroxyl group was protected by a
methyl group, gave a trace amount of product (entry 15).
Ligand L6, without a hydroxyl group on the phenyl ring, af-
forded 3a in racemic form with only 62% yield (entry 16).
These results indicated that the stereochemistry of the al-
lylation reaction is predominantly governed by the sulfin-
amide fragment and the hydroxyl group. In contrast, well-
known ligands such as (R)-BINAP,24 (S,S)-Josiphos,25 and
(S,S)-DACH-naphthyl Trost ligand26 were respectively tested
and they gave good yields but poor stereoselectivities (en-
Scheme 1 Synthesis of chiral sulfinamide ligand (R)-L1
Figure 1 The X-ray structure of (R)-L1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
M. Zhao et al.
Letter
Synlett
O
O
[Pd(C3H5)Cl]2
(R)-L1
O
O
∗
∗
OAc
OEt
F
R1
+
OEt
R1
R1
R1
K3PO4, THF/dioxane, r.t.
H
F
1
3
2a
O
O
F
O
O
O
O
F
O
O
∗
∗
∗
∗
OEt
OEt
OEt
OEt
F
F
Br
F
Br
Cl
Cl F
∗
∗
∗
∗
Cl
Cl
3a
3b
3c
3d
98% yield, dr 1.6:1
85% yield, dr 1.5:1
94% yield, dr 1.8:1
97% yield, dr 2.0:1
80% and 78% ee
77% and 70% ee
90% and 94% ee
63% and 70% ee
O
O
F
O
O
O
O
O
O
F
∗
∗
∗
∗
∗
∗
OEt
OEt
OEt
OEt
F
F
Me
∗
∗
F
F Br
O
Br
3e
3f
3g
3h
65% yield, dr 2.0:1
68% and 67% ee
98% yield, dr 1.8:1
67% and 62% ee
62% yield, dr 2.2:1
52% yield, dr 1.6:1
76% and 83% ee
77% and 70% ee
O
O
O
F
O
O
∗
∗
∗
∗
OEt
Cl
OEt
OEt
F
Cl
∗
∗
Me
3i
3j
3a'
0% yield
91% yield, dr 1.8:1
0% yield
61% and 67% ee
Scheme 2 Scope of the reaction with allylic acetates 1 and ethyl 2-fluoroacetoacetate 2a. Reaction conditions: [Pd(C3H5)Cl]2 (4 mol%), (R)-L1 (8 mol%)
1 (0.1 mmol), 2 (0.3 mmol) and K3PO4 (0.3 mmol) in THF/dioxane (2 mL, 1:1) at room temperature under argon for about 12–24 h. Isolated yields are
given. The diastereomeric ratio was determined by 1H NMR spectroscopic analysis. The ee was determined by chiral HPLC analysis.
tries 17–19). Lowering the temperature from 25 °C to zero
slightly improved the enantioselectivity, but had a negative
effect on this reaction yield (entry 20).
weak electron-donating group at the 3-position (e.g., 3-Me)
on the phenyl ring, resulted in the allylic products 3h in
52% yield with 70–77% ee and 1.6:1 dr. 2-Naphthyl-substi-
tuted allylic acetate 1i produced 3i in 91% with 61–67% ee
and 1.8:1 dr. The reaction with (E)-1,3-ditolyl allylacetate 1j
failed to proceed. These results imply that 2a is a weak nuc-
leophile in this alllylation process and that the reaction de-
pends strongly upon the nature of the substituent and the
substitution pattern on the allylic substrate. Ethyl 2-fluoro-
3-oxo-3-phenylpropanoate (2b) was also tested in the al-
lylation reaction of 1a, but the corresponding product 3k
was not obtained. More significantly, ethyl 3-oxobutanoate
2a′ was examined under the optimized conditions and it
did not give the corresponding products 3a′, in contrast to
its analogue 2a containing a fluorine atom (Table 1 and
Scheme 2).
These results strongly suggest that the fluorine atom on
2a interacts with the Pd complex, which may promote the
Pd-catalyzed allylation process. The nature of this interac-
tion is unclear and further studies are being undertaken to
address this question.
The synthesis of α-fluorinated β-lactone has been at-
tracting great attention over the last decade because of the
importance of the β-lactone moiety in biological sciences
and medicinal chemistry.28 As an illustration of the applica-
Having established the optimal reaction conditions (Ta-
ble 1, entry 5), the generality and scope of the reaction be-
tween the various allylic substrates 1 and ethyl 2-fluoroac-
etoacetate (2a) was examined.27 As shown in Scheme 2, the
substituent pattern on the phenyl ring of the allylic acetates
1 had a significant influence on the yield, enantioselectivi-
ty, and diastereoselectivity. Allylic substrates 1a–c having
an electron-withdrawing group at the 3-position (e.g., 3-Cl,
3-F, and 3-Br) on the phenyl ring led to the corresponding
allylic products 3a–c in high yields with good to high enan-
tioselectivity but reduced diastereoselectivities. Notably,
(E)-1,3-di(3-bromophenyl)allyl acetate (1c) afforded the
corresponding products 3c in 94% yield with 90–94% ee and
1.8:1 dr. The chirality induced in this reaction was strongly
facilitated by both L1 and the allylic substrate. Allylic ace-
tates 1d–f, with an electron-withdrawing group at the 4-
position (e.g., 4-Cl, 4-F, and 4-Br) on the phenyl ring, pro-
vided allylic products 3d and 3f in high yields with 62–70%
ee and dr ranging from 1.8:1 to 2.0:1; however, the yield of
3e was significantly lower than those of 3d and 3f (Scheme
2). (E)-1,3-Diphenylallyl acetate (1g) gave rise to 3g in 62%
yield with 76–83% ee and 2.2:1 dr. Allylic acetate 1h, with a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
M. Zhao et al.
Letter
Synlett
tion of this methodology, the reduction of the allylic prod-
ucts 3c with NaBH4 in EtOH gave 4 in 74% yields with 84%
ee and 10:7:6:1 dr (Scheme 3). The hydrolysis of 4 with
NaOH following by an esterification in the presence of N,N-
dicyclohexylcarbodiimide (DCC) and 4-(N,N-dimethylami-
no)pyridine (DMAP) in CH2Cl2 provided α-fluoro-β-lactone
5 in 52% yield with 17:1.6:1 dr. The ee value of 5 was not
determined because of its low stability in the chiral HPLC
system used.
OH
O
F
O
O
F
∗
∗
∗
∗
OEt
Br
OEt
NaBH4
EtOH
Br
Br
Br
∗
4
3c
74% yield
84%, 84% ee (major product)
90%, 94% ee
dr 1.8:1
dr 10:7:6:1
O
O
∗
∗
F
1) NaOH then HCl
Br
Br
∗
2) DCC, DMAP
CH2Cl2
5
Table 1 Optimizing Conditions for Pd-Catalyzed Allylic Substitution of 2a
52% yield
ee n.d.
dr 17:1.6:1
O
O
R
∗
∗
Scheme 3 Preparation of the α-fluoro-β-lactone
OAc
OEt
Cl
O
O
[Pd(C3H5)Cl]2
L
+
OEt
base
solvent
r.t.
H
R
In summary, we have developed chiral sulfinamide li-
gands made from salicylic acid and (R)-tert-butanesulfin-
amide in a single step. The ligands are effective for Pd-cata-
lyzed asymmetric allyllic alkylations of ethyl 2-fluoroaceto-
acetate. This method furnished the monofluorinated allyl
products in high yields with moderate to high enantioselec-
tivities but lower diastereoselectivities. This is the first ex-
ample of a ligand endowed with a hydroxyl group on the
phenyl ring in the mono-sulfinamide for enhancing catalyt-
ic activity and stereocontrol in Pd-catalyzed asymmetric al-
lylations.
1a
2a R = F
2a' R = H
3a R = F
3a' R = H
Cl
Cl
Cl
Entry
L
Base
Solvent
Yield (%)b dr (%)c ee (%)d
1
2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
95
1.5:1 56, 45
1.6:1 76, 73
dioxane
CH2Cl2
toluene
62
3
51
–
–
–
–
4
trace
5
THF/dioxane 98
1.6:1 80, 78
1.3:1 73, 74
1.4:1 79, 79
1.3:1 75, 70
6
t-BuOK THF/dioxane 85
K2CO3 THF/dioxane 92
7
8
Cs2CO3 THF/dioxane 97
Na3PO4 THF/dioxane 48
Funding Information
9
–
–
–
National Science Foundation of China 21272175
Shanghai Science and Technology Commission 14DZ2261100
10
11
12
13
14
15
16
17
19
19
20e
20f
CsF
THF/dioxane 35
THF/dioxane 97
THF/dioxane 95
THF/dioxane 82
THF/dioxane 95
THF/dioxane trace
THF/dioxane 62
THF/dioxane 93
THF/dioxane 95
THF/dioxane 82
THF/dioxane 85
THF/dioxane n.r.
–
DBU
1:1
rac
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
1.6:1 80, 78
1.5:1 78, 77
1.3:1 72, 72
Supporting Information
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589033.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
–
–
1:1
1:1
1:1
1:1
rac
References and Notes
BINAP
24, 22
25, 16
6, 11
(1) For selected papers, reviews, and books, see: (a) Bégué, J. P.;
Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluo-
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2008, 51, 4359. (d) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
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Chiralphos K3PO4
Trost
L1
K3PO4
K3PO4
K3PO4
1.6:1 81, 79
L1
–
–
a Reaction conditions: [Pd(C3H5)Cl]2 (4 mol%), L (8 mol%), 1a (0.1 mmol), 2
(0.3 mmol) and base (0.3 mmol) in solvent (2 mL) at room temperature
under argon for 12 h.
b Isolated yield.
c The diastereomeric ratio was determined by 1H NMR spectroscopic analy-
sis.
d Determined by chiral HPLC analysis, the ee of the major diastereomer is
given first.
e The reaction was conducted at 0 °C.
f 2a′ instead of 2a was used.
(3) Montgomery, J. A.; Shortnacy-Fowler, A. T.; Clayton, S. D.;
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(22) Typical Procedure for the Synthesis of (R)-L1
To a solution of salicylic acid (1.0 mmol) in THF (2.0 mL) was
added 1,1′-carbonyldiimidazole (CDI; 1.0 mmol, 1.0 equiv)
slowly at room temperature, then the reaction mixture was
heated to 50 °C for 1.0 h. The solution was cooled to room tem-
perature and concentrated to give the active amide. To a sus-
pension of KH (30% in oil, 2.0 mmol, 2.0 equiv) in THF (5.0 mL)
was added (R)-tert-butanesulfinamide (1.0 mmol) under argon
at room temperature and the mixture was stirred for 0.5 h. The
active amide was added and the mixture was stirred at 50 °C for
1.0 h. The reaction mixture was cooled to room temperature
and acidified with aqueous HCl to pH >7, then the mixture was
diluted with EtOAc (10 mL), washed with H2O (3 × 10 mL) and
brine (10 mL), dried over anhydrous Na2SO4, filtered, and con-
centrated under vacuum. The residue was purified by column
chromatography on silica gel (EtOAc) to give the desired
product (R)-L1 (149.4 mg, 62% yield) as a white solid; mp
144.6–145.9 °C; [α]D25 –73.8 (c = 1.0, MeOH). 1H NMR (400 MHz,
CDCl3): δ = 7.78 (d, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.01
(d, J = 8.1 Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 1.36 (s, 9 H). 13C NMR
(100 MHz, CDCl3): δ = 168.94, 159.16, 135.22, 129.55, 119.79,
118.01, 115.40, 57.05, 22.26. IR (KBr): 3259, 2963, 2930, 2854,
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258. (j) Dieguez, M.; Pamies, O. Acc. Chem. Res. 2010, 43, 312.
(k) He, H.; Ye, K. Y.; Wu, Q. F.; Dai, L. X.; You, S. L. Adv. Synth.
Catal. 2012, 354, 1084. (l) Liu, W. B.; Xia, J. B.; You, S. L. Top.
Organomet. Chem. 2012, 38, 155.
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Chem. Int. Ed. 2004, 43, 3364. (b) Defieber, C.; Grützmacher, H.;
Carreira, E. M. Angew. Chem. Int. Ed. 2008, 47, 4482. (c) Hayashi,
T. Aldrichimica Acta 2009, 42, 31. (d) Feng, C. G.; Xu, M. H.; Lin,
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1677, 1605, 1464, 1408, 1393, 1304, 1232, 1107, 1032 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H16NO3S: 242.0845;
found: 242.0841
(23) CCDC-1499293, (R)-L1, contains the supplementary crystallo-
graphic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures
(24) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Noyori, R. J. Org. Chem. 1986, 51, 629.
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759.
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(27) Typical Procedure for Pd-Catalyzed Allylic Alkylation Reac-
tion
[Pd(C3H5)Cl]2 (0.004 mmol, 4 mol%), (R)-L1 (0.008 mmol, 8
mol%), and (E)-1,3-disubstituted allyl acetate 1 (0.1 mmol) were
dissolved in THF/dioxane (2.0 mL, 1:1) in a dry Schlenk tube
filled with argon. The reaction mixture was stirred for 30 min at
room temperature, then ethyl 2-fluoroacetoacetate (2a; 0.3
mmol, 3.0 equiv) and K3PO4 (0.3 mmol, 3.0 equiv) were added.
The reaction mixture was stirred at room temperature and the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
M. Zhao et al.
Letter
Synlett
progress of the reaction was monitored by TLC. Upon comple-
tion, the mixture was filtered through Celite and the solvent
was evaporated under vacuum. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate) to give the desired products 3a–i.
201.32 (d, J = 29.8 Hz), 201.14 (d, J = 29.9 Hz), 164.66 (d, J =
25.7 Hz), 164.26 (d, J = 25.9 Hz), 139.01, 138.42, 138.10, 138.03,
134.60, 134.46, 133.61, 133.30, 130.04, 130.02, 129.85, 129.52
(d, J = 2.5 Hz), 129.19 (d, J = 2.6 Hz), 128.11, 128.06, 128.05,
128.00, 127.70 (d, J = 2.2 Hz), 127.12 (d, J = 2.6 Hz), 126.38,
126.33, 125.79, 125.75, 125.60, 125.55, 124.89, 124.80, 102.68
(d, J = 206.1 Hz), 102.52 (d, J = 207.9 Hz), 63.09, 62.84, 52.88 (d, J
= 18.1 Hz), 52.82 (d, J = 18.2 Hz), 26.85, 26.84, 14.18, 13.77. 19F
NMR (376 MHz, CDCl3, stereoisomeric mixture): δ = –174.49, –
175.05. IR (KBr): 3064, 2982, 2932, 2854, 1754, 1734, 1594,
(E)-Ethyl 2-Acetyl-3,5-bis(3-chlorophenyl)-2-fluoropent-4-
enoate (3a): Colorless oil (39.8 mg, 98% yield). The diastereo-
meric ratio was 1.6:1 determined by 1H NMR spectroscopic
analysis. The ee value of the major diastereomer was 80%, the
minor diastereomer was 78%, determined by chiral HPLC [Daicel
CHIRALCEL OJ-H (0.46 cm × 25 cm); hexane/i-PrOH = 98:2; flow
rate = 1.0 mL/min; detection wavelength = 254 nm; tR (major) =
16.984, 19.423 min; tR (minor) = 21.968, 25.166 min]. 1H NMR
(400 MHz, CDCl3, stereoisomeric mixture): δ = 7.42–7.17 (m,
13 H), 6.61–6.21 (m, 3.3 H), 4.52 (dd, J = 32.6, 8.8 Hz, 1.6 H),
4.37–4.16 (m, 2 H), 4.06 (m, 1.3 H), 2.32 (d, J = 5.7 Hz, 1.9 H),
2.01 (d, J = 5.6 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.06 (t, J = 7.1 Hz,
1.9 H). 13C NMR (100 MHz, CDCl3, stereoisomeric mixture): δ =
1570, 1476, 1431, 1356, 1246, 1205, 967, 913, 781, 742 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd. for C21H19Cl2FNaO3:
431.0587; found: 431.0592
(28) For the biological activity and synthesis of β-lactones, see:
(a) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem. 1993, 58,
7768. (b) Liu, D. Z.; Wang, F.; Liao, T. G.; Tang, J. G.; Steglich, W.;
Zhu, H. J.; Liu, J. K. Org. Lett. 2006, 8, 5749. (c) Groll, M.; Huber,
R.; Potts, B. C. J. Am. Chem. Soc. 2006, 128, 5136.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F