Dianionic Phase-Transfer Catalyst for Asymmetric Fluoro-cyclization

Article abstract of DOI:10.1021/jacs.7b13690

Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro-cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro-carbocation intermediate.

Full text of DOI:10.1021/jacs.7b13690

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Communication
Dianionic Phase-Transfer Catalyst for Asymmetric Fluorocyclization
Hiromichi Egami, Tomoki Niwa, Hitomi Sato, Ryo Hotta, Daiki Rouno, Yuji Kawato, and Yoshitaka Hamashima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13690 • Publication Date (Web): 09 Feb 2018
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Hiromichi Egami,† Tomoki Niwa,† Hitomi Sato,† Ryo Hotta,† Daiki Rouno,† Yuji Kawato,† and Yoshit-
aka Hamashima*†
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†School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Supporting Information Placeholder
ABSTRACT: Inspired by the dicationic nature of the
a. Asymmetric fluorolactonization
electrophilic fluorinating reagent, Selectfluor (1), we
rationally designed a series of di-carboxylic acid precat-
alysts (2), which, when deprotonated, act as anionic
phase-transfer catalysts for asymmetric fluorination of
alkenes. Among them, 2a having the shortest linker moi-
ety efficiently catalyzed unprecedented 6-endo-fluoro-
cyclization of various allylic amides, affording fluori-
nated dihydrooxazine compounds with high enantiose-
lectivity (up to 99% ee). In addition to cyclic substrates,
acyclic tri-substituted alkenes underwent the reaction
with good diastereoselectivity, whereas low diastereose-
lectivity was observed for linear di-substituted alkenes.
Results suggest that the reaction proceeds via a fluoro-
carbocation intermediate.
precatalyst
Selectfluor (1)
Na3PO4, Na2SO4
Ar
F
R2
OH
R2
R1
O
R1
cyclohexane, rt
Cl
CO2H
Ar
CO2H
O
N+
N+
–
2BF4
up to 94% ee
precatalyst
F
Selectfluor (1)
b. Active complex and the basic design of di-anion catalysts
O–
R
Ar
R
O
F
H
O
–O2C
O
O
–
CO2
N+
N+
–
CO2
F
R
N+
N+
Cl
Cl
Ar
Phase-transfer activity
R
Forming two ionic pairs between
the designed catalyst and Selectfluor
<
mono-anion
formal di-anion
c. This work: 6-endo fluorocyclization of allylic amides
R3
precatalyst 2
O
Fluorinated compounds have found extensive applica-
tions in pharmaceutical, agrochemical, and materials
sciences.1 Many methods for the introduction of fluorine
atoms into organic frameworks have been reported.2 In
particular, asymmetric fluorofunctionalization of alkenes
has attracted much attention, because it is a powerful
approach to obtain structurally diverse fluorinated com-
pounds.3 However, stereoselective fluorination of al-
kenes is still challenging, although cinchona alkaloid-
derived chiral fluorinating reagents4 and chiral hyperva-
lent iodine reagents5 have been studied.
Following Toste’s pioneering work,6,7 we became in-
terested in anionic phase-transfer catalysis for enantiose-
lective fluorination. We recently reported the first suc-
cessful example of enantioselective fluorolactonization
of ene-carboxylic acids with a carefully designed hy-
droxyl-carboxylic acid precatalyst (Figure 1a).8 Upon
deprotonation in-situ, the carboxylate ion of the active
catalyst acts as a phase-transfer unit to form an ion pair
with Selectfluor (1), whilst the hydroxyl group interacts
with the anionic substrate to define its position (Figure
1b, left).
Selectfluor (1)
O
N
base
N
R3
R1
up to 99% ee
H
R2
toluene
R1
R2
F
Ph
O
Ph
R1
O
R1
O
n
O
CO2H HO2C
CO2H HO2C
Ph Ph
R2 R2
2d: R1 = H, R2 = Ph
2e: R1 = H, R2 = H
2a: n = 1
2b: n = 2
2c: n = 3
Figure 1. Background and our design strategy for novel di-
carboxylate catalysts
Mechanistic studies of the fluorolactonization8 strong-
ly indicated that a binary complex between the catalyst
and the substrate anion is responsible for bringing 1 into
the organic phase (Figure 1b, left). This observation
prompted us to think that the cooperative action of two
carboxylate anions located at an appropriate separation
distance would achieve high reaction efficiency.9 Based
on this hypothesis, we designed dicarboxylic acid
precatalysts 2 (Figure 1c), which would form a series of
linked dicarboxylate catalysts (Figure 1b, right). Even
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though the designed catalysts are conformationally flex-
base depends on the nature of the substrate, since
Na2HPO4 gave slightly better results for 5a (entry 9).
1
2
3
4
5
6
7
8
ible, we envisaged that the two-point ionic pairing of the
catalyst with 1 would form a well-defined chiral envi-
ronment. Based on our halogenation project regarding
bromocyclization reactions of allylic amides,10 we se-
lected fluorocyclization of ene-amides as a model reac-
tion, since the amide has a hydrogen-bonding donor for
interaction with a catalyst carboxylate and asymmetric
6-endo-fluorocyclization is unprecedented in the litera-
ture.11 Herein, we disclose a highly enantioselective flu-
orocyclization of allylic amides using designed and nov-
el dianionic phase-transfer catalysts (Figure 1c).
Table 1. Catalyst Screeninga
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entry
precatalyst
yield (%)b
ee (%)c
93
1
2
87
75
76
84
37
48
44
84
95
2a
2b
2c
2d
2e
9
The precatalyst 2a was readily synthesized in 5 steps
from compound 3 (Scheme 1). Thus, monoprotection of
3,3’-dibromo-BINOL (3) and etherification with 1,3-
propanediol-ditosylate, followed by acidic hydrolysis,
provided linked-BINOL derivative 4 in 64% yield over 2
steps. After the introduction of phosphate groups, all
bromine atoms were replaced with phenyl groups. Final-
ly, reductive carboxylation with lithium-naphthalenide12
furnished the desired diacid 2a in 69% yield.
64
3
87
4
33
5
40
6
–17
–55
–68
95
7
10
11
2a
8
9d
Scheme 1. Preparation of 2a
10
11
58e
5g
6g
89 / 96f
–9 / - f
–20 / –40 f
2a
9
12
13
14h
10
11
2a
trace
76e
-
93 / 98 f
In order to identify the optimum catalyst, fluorination
reactions of chromene derivative 5a were carried out in
toluene using Na3PO4 as an insoluble base (Table 1). To
our delight, 2a promoted the desired reaction smoothly
to give 6a in 87% yield with 93% ee as a single dia-
stereomer (entry 1). The length of the methylene linker
affected the reaction efficiency, revealing that the C3
linker gave the best results (entries 2 and 3). Both the
chemical yield and the enantioselectivity decreased sig-
nificantly when 2d and 2e were used, revealing that full
substitution at the 3,3’-positions of the catalyst is essen-
tial for this reaction (entries 4 and 5). Interestingly, pre-
viously known precatalysts7,8 were less effective.
Binaphthyl dicarboxylic acid 9 provided the product
with only 17% ee (entry 6). Hydroxyl-carboxylic acid 10
and phosphoric acid 11 were also examined, and again,
lower enantioselectivities were observed (entries 7 and
8). These control experiments supported our working
hypothesis regarding the optimum ionic valency within
the catalyst as well as the distance between the ionic
parts. Further optimization13 revealed that the optimum
a
The reactions were carried out with precatalyst, 1,
Na3PO4 in toluene (1 mL) on a 0.1 mmol scale, unless oth-
b
1
erwise mentioned. Yields were determined by H NMR
analysis using 1,1,2,2,-tetrabromoethane as an internal
c
standard. Ee values were determined by chiral HPLC
d
e
analysis. Run with Na2HPO4 instead of Na3PO4. Dia-
stereomer ratio was 1:1. f Ee values of each diastereomers. g
Diastereomer ratio was 2:1. h Run with Na2SO4.
Notably, reactions of less reactive acyclic substrate 7a
clearly demonstrated that 2a is superior to other known
catalysts (entries 10-13). For example, phosphoric acid 11
was totally ineffective (entry 13). As found in our previous
study,8 the addition of Na2SO4 was effective for accelerat-
ing the fluorination of 7a (entry 14). Although the diastere-
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omer ratio was almost 1:1, the enantioselectivity was excel-
applicable, and high asymmetric induction was observed
(6k-6n). It should be noted that reactions generally gave
complex mixtures when carried out without catalyst and
in MeCN. This observation emphasizes the use of phase-
transfer conditions as crucial for this type of fluorination
reaction.
1
2
3
4
5
6
lent for both diastereomers (vide infra).
Table 2. Fluorination of Cyclic Allylic Amidesa
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8
Table 3. Fluorination of Acyclic Substratesa
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a
a
b
Condition A: The reaction was carried out with 2a, 1,
The conditions were the same as in Table 2. Deter-
c
Na2HPO4 at 15 °C in toluene for 72 h. Condition B: The
reaction was carried out with 2a, 1, Na3PO4 and Na2SO4 at
25 °C in toluene for 24 h. b Run with 20 mol % of 2a. c Run
for 5 d. d Run with 3 equiv. of Na2HPO4.
mined by NMR analysis of the crude mixture. Run at
15 °C. d Run for 4 d. e Run for 3 d. f Run for 2 d.
Next, we turned our attention to acyclic alkene sub-
strates. First, di-substituted allylic amides were subject-
ed to the reaction conditions (Table 3a). While the elec-
tronic nature of the substituents did not significantly
affect the diastereoselectivity, the ee values of these re-
actions were generally excellent (8a-8e).14 To probe the
stereochemistry of the products, Mosher’s ester method
was applied after hydrolysis of the dihydrooxazine ring
of 8a.13 This revealed that the diastereomers are derived
from the stereoisomer at the benzylic position, while the
facial selectivity of the fluorination step is well regulat-
ed. Coupled with findings in the literature,15 these results
suggest that the fluorocyclization proceeds via the for-
mation of a benzylic carbocation intermediate, which
undergoes less stereoselective intramolecular C–O bond
formation.
Having optimized the reaction conditions, we exam-
ined the generality for cyclic substrates (Table 2). Alt-
hough minor tuning of the reaction conditions (condi-
tions A or B) was needed depending on the substrate, the
desired reaction occurred to give the corresponding
fluorinated tricyclic compound as a single diastereomer.
In these reactions, various functional groups including
ester, ether, benzylic methyl group, and halogens were
tolerated. Substituents on the chromene framework did
not impact largely on the enantioselectivity (6b-6d). The
dimethyl groups of the chromene core were not essential
as a stereocontrolling element. Thus, sterically less hin-
dered chromene and dihydronaphthalene substrates also
underwent the fluorination reaction with excellent enan-
tioselectivity (6e-6i). In addition to six-membered ring
substrates, a five-membered indene derivative was also a
good substrate, affording 6j in 63% yield with 93% ee.
Furthermore, substituted aryl amide groups were also
Based on the above consideration, we expected the ste-
reoselectivity of the cyclization step to be improved if
the conformation of the carbocation intermediate was
restricted sterically by additional substituents.16 Thus,
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Wiley-Blackwell: Oxford, 2009. (c) Gouverneur, V.; Müller, K. Fluo-
we examined the fluorocyclization of acyclic tri-
substituted allylic amides (Table 3b). Gratifyingly, the
reactions proceeded with high diastereoselectivity, af-
fording products 8f-8h with a fluorinated quaternary
carbon center in up to 99% ee. The reaction was appli-
cable to heteroaromatic compounds (8i-8k). Reduced
diastereoselectivity observed for indole and benzofurane
derivatives 8i and 8j is attributed to higher stability of
the carbocation intermediate. In contrast, thiophene de-
rivative was converted to the cyclized compound 8k
with high diastereo- and almost perfect enantioselectivi-
ty (dr = 1:8.4, 99% ee).
rine in Pharmaceutical and Medicinal Chemistry: From Biophysical
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In summary, we have developed a new dianionic
phase-transfer catalyst for highly enantioselective 6-
endo fluorocyclization of allylic amides with Selectfluor.
The catalyst was able to control the fluorine-delivery
step with high enantioselectivity in all the examples re-
ported herein, indicating that the designed catalyst
would be applicable to other types of fluoro-
functionalization. Since the obtained compounds are
highly functionalized, this method would be useful in
synthesizing a variety of fluorinated compounds. Further
investigations to expand the scope of the reaction and to
elucidate the reaction mechanism are underway in our
laboratory.
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!33/#)!4%$ #/.4%.4
Supporting Information. Experimental procedures and
spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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(13) See Supporting Information.
(14) The ee values between the diastereomers are generally differ-
ent, probably because a kinetic resolution of the fluorocarbenium ion
intermediate occurs during the cyclization step.
(15) (a) Stavber, S.; Sotler-Pecan, T.; Zupan, M. Bull. Chem. Soc. J.
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hamashima@u-shizuoka-ken.ac.jp
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The authors declare no competing financial interest.
!#+./7,%$'-%.4
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 16H05077) from JSPS, Basis for Sup-
porting Innovative Drug Discovering and Life Science Re-
search (BINDS) from AMED, the Naito Foundation (Ja-
pan), The Research Foundation for Pharmaceutical Scienc-
es, and The FUGAKU Trust for Medicinal Research. We
thank Prof. Kenji Watanabe and Dr. Yuta Tsunematsu of
University of Shizuoka for their kind help for mass spec-
trometry analysis.
2%&%2%.#%3
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Re-
activity, Applications, 2nd ed.; Wiley-VCH: Weinheim, 2013. (b)
Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology;
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