Development of Planar Chiral Iodoarenes Based on [2.2]Paracyclophane and Their Application in Catalytic Enantioselective Fluorination of β-Ketoesters

Article abstract of DOI:10.1021/acs.orglett.8b00711

The design and synthesis of novel planar chiral iodoarenes based on [2.2]paracyclophane is reported. A process of highly enantioselective oxidative fluorination of a β-ketoester with 3HF-Et₃N as a nucleophilic fluoride source mediated by these new hypervalent iodine catalysts has been developed. This represents the first highly enantioselective reaction catalyzed by planar chiral hypervalent iodine.

Full text of DOI:10.1021/acs.orglett.8b00711

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Development of Planar Chiral Iodoarenes Based on
[2.2]Paracyclophane and Their Application in Catalytic
Enantioselective Fluorination of β‑Ketoesters
Yang Wang,†,§ Hang Yuan,‡,§ Hongfei Lu,*,‡ and Wen-Hua Zheng*,†
†State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, Jiangsu, China
‡School of Environment and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, Jiangsu, China
S
* Supporting Information
ABSTRACT: The design and synthesis of novel planar chiral
iodoarenes based on [2.2]paracyclophane is reported. A
process of highly enantioselective oxidative fluorination of a
β-ketoester with 3HF−Et3N as a nucleophilic fluoride source
mediated by these new hypervalent iodine catalysts has been
developed. This represents the first highly enantioselective
reaction catalyzed by planar chiral hypervalent iodine.
stereocenter ortho to the iodine atom on the aromatic ring
n recent decades, hypervalent iodine(III) reagents have been
Iused in a wide range of synthetically important trans- developed by Wirth and co-workers, a variety of iodobenzenes
formations,1 even in a catalytic version.2 Hypervalent iodine-
with a chiral stereocenter on the side chain have been
synthesized and then been applied in enantioselective oxidative
reactions.5 Notable among these seminal contributions are the
development of conformationally flexible C2-symmetric iodoar-
ene catalysts by Ishihara’s group,6 which have been shown to be
efficient in different kinds of reactions with high enantiose-
lectivity. In addition, axially chiral or chiral spiro iodoarenes
have been designed and synthesized.7 Particularly, Kita8 and co-
workers discovered chiral iodides based on a spirobiindane
backbone and applied it in asymmetric dearomatization of
naphtholic substrates, affording the corresponding chiral
products with excellent enantioselectivity. Despite these
advances, the hypervalent iodine catalysts are still limited to
containing chiral stereocenters or axially/spiro chiral elements.
Therefore, it is still highly desirable to design a new hypervalent
iodine catalyst based on a novel scaffold.
catalyzed asymmetric organic transformations have received
enormous attention in the past several years, and considerable
efforts have been directed toward developing new asymmetric
reactions.3 Despite the significant progress made in this area,
interest in developing new scaffold iodoarenes as catalyst is
growing.
Early examples of chiral hypervalent iodine compounds are
those bearing a chiral leaving group connected to iodine
directly, but usually show low enantiocontrol in asymmetric
catalysis (Figure 1).4 Benchmarked by iodoarene with a chiral
Planar chiral [2.2]paracyclophane9 provides a unique frame-
work with a conformationally stable chiral environment and has
been widely used as chiral ligands in asymmetric catalysis and
optical materials development. In this regard, we envisioned
that planar chiral iodoarene-based [2.2]paracyclophane could
potentially be an excellent catalyst in hypervalent iodine
catalysis (Figure 1). Although iodoarene-based [2,2]-
paracyclophanes are frequently used as intermediates in the
synthesis of [2,2]paracyclophane derivatives, studies on hyper-
valent iodine bearing this framework are extremely limited.10a
Moreover, to the best of our knowledge, only one study
involving a chiral hypervalent iodine based on [2,2]-
Figure 1. Chiral iodoarenes in enantioselective hypervalent iodine
catalysis.
Received: March 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00711
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
paracyclophane catalysis has been reported in the literature but
afforded almost no enantioselectivity.10b Herein, we design and
synthesize a new type of planar chiral iodoarene based on
[2.2]paracyclophane.
available. In this regard, Jacobsen15 and others have developed
excellent processes in asymmetric difluorination/oxyfluorina-
tion reactions of alkenes with high enantioselectivity in the
presence of chiral hypervalent iodine catalysts. In contrast,
development of a highly enantioselective nucleophilic fluorina-
tion of α-carbonyl compounds catalyzed by hypervalent iodine
remains a challenging task. Although the highly enantioselective
electrophilic fluorination of α-carbonyl substrates is realized by
transition-metal catalysts and organocatalysts,13 the asymmetric
nucleophilic α-fluorination of carbonyl compounds is less
studied (Scheme 2). Very recently, Rueping and co-workers
Scheme 1 shows the syntheses of the target planar chiral
iodoarenes we designed.11 Starting from known racemic
Scheme 1. Preparation of Catalysts
Scheme 2. Enantioselective Fluorination of β-Ketoester
reported the C2 symmetric iodoarene catalyzed nucleophilic
fluorination of β-ketoester with high enantioselectivity.16
Herein, we report a highly enantioselective fluorination of a
β-ketoester with a nucleophilic fluoride source in the presence
of a new planar chiral iodoarene, as described above.
To test our hypothesis, we began with identification of the
best catalyst using β-ketoester 6a as a model substrate,
hydrofluoride triethylamine as a nucleophilic fluoride source,
and m-CPBA as the oxidant in the presence of a catalytic planar
chiral iodoarene. As shown in Table 1, the transformation
indeed took place, and the desired product 7a was obtained in
low yield and poor enantioselectivity with 4a. It is worth
mentioning that the major side product is α-hydroxyl β-
ketoester, coming from oxidation of the substrate with m-CPBA
[2.2]paracyclophane 1, followed by protection with MOMCl,
ortho-lithiation/quenched with I2, and deprotection under
acidic condition, iodo[2.2]paracyclophane 4 was obtained in
high yield. Then optical resolution of rac-4 was carried out on
preparative HPLC using a chiral stationary phase column (see
Supporting Information (SI)) to give both planar chiral
iodoarenes (Sp)-4 and (Rp)-4. With planar chiral (Sp)-4 and
(Rp)-4 in hand, we next carried out an alkylation or acylation to
obtain a series of planar chiral iodoarenes 5 with different
functional groups on the hydroxyl group ortho to the iodine
atom. The structure of (Rp)-5i was unambiguously determined
by single crystal X-ray crystallography, as shown in Figure 2.
a
Table 1. Reaction Optimization
b
c
entry
catalyst
yield (%)
er
1
4a
5a
5b
5c
5d
5e
5f
19
24
37
24
35
37
38
31
41
39
42
45
54:46
2
61:39
3
78:22
4
59.5:40.5
76.5:23.5
78:22
5
6
7
79:21
Figure 2. Ball-and-stick drawing of the single crystal X-ray of structure
(Rp)-5i.
8
5g
5h
5i
85:15
9
86:14
10
11
89.5:10.5
94:6
With these catalysts in hand, we next studied the catalytic
ability. Enantioselective incorporation of fluoride into organic
molecules is highly valuable in modern medicinal chemistry and
material science.12 Development of asymmetric fluorination
involving electrophilic fluorinated13 reagents has witnessed
encouraging progress. However, enantioselective nucleophilic
fluorination14 is still in its infancy because of the low reactivity
of the fluoride atom and few asymmetric inductive protocols
5j
d
12
5j
94.5:5.5
a
Unless otherwise indicated, the reaction was carried out at the 6a 0.1
mmol scale and catalyzed by 15 mol % (Rp)-5 in DCM (1 mL) at rt
for 24 h. The molar ratio of 6a/mCPBA/Et3N-3HF was 1:1.3:5.
b
c
d
Isolated yield. The er value was determined by HPLC. DCM (2
mL).
B
DOI: 10.1021/acs.orglett.8b00711
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Organic Letters
Letter
directly. After extensive screening of iodoarenes with different
functional groups (Table 1, entries 2−7), benzoylated
iodoarene was identified as the optimal catalyst, based on
yield and er (38% yield and 79:21 er). Next, we examined
iodoarenes 5g−5i with different electronic effects on the phenyl
ring. Although the enantioselectivity of 7a with nitro-
substituted 5g is comparable to that with methoxyl-substituted
5h (85:15 er to 86:14 er), the reaction activity of 5g is much
lower. In the search for additional improvement of the activity
and enantioselectivity, we synthesized iodoarenes 5i17 (CCDC
1816180) and 5j with more methoxyl groups on the phenyl
ring. We were pleased that the er value of the product was
further improved to 94:6 with 5j, and a higher enantiose-
lectivity was obtained at lower concentration (entry 12).
Further attempts to improve the yield of the reaction by
changing oxidants, solvents, and temperature proved to be
unfruitful. The absolute configuration of 7a was determined to
be S by comparison of the sign of its optical rotation with that
of the literature data.
Scheme 4. Plausible Catalytic Cycle
step. Finally, reductive elimination of 10 occurred to regenerate
the catalyst and deliver the desired product 7a.
Under the optimized conditions, a series of substrates were
explored to prove the generality of this process. As shown in
Scheme 3, β-ketoesters with a range of electron-withdrawing
In summary, we have designed and synthesized a novel
planar chiral iodoarene based on [2,2]paracyclophane. A
process of highly enantioselective oxidative fluorination with a
nucleophilic fluoride source mediated by hypervalent iodine has
been developed. To the best of our knowledge, it represents the
first hypervalent iodine catalysis with a planar chiral iodoarene.
Detailed mechanism studies and further application of those
chiral catalysts are underway in our laboratory.
Scheme 3. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00711.
General Information, procedures of catalysts syntheses,
spectral data and HPLC (PDF)
Accession Codes
CCDC 1816180 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
and -donating groups were tolerated, affording corresponding
products (7a−7i) with high enantioselectivity. The size of the
ester group has an enormous impact on the enantioselectivity.
For instance, 7j with methyl ester was obtained with 21:79 er,
lower than that of 7a. In addition, 7k with an ester, with a
similar size to that of 7a, was obtained with high
enantioselectivity. Notably, β-ketoamide proceeded well under
the above conditions, affording the product 7l with excellent
enantioselectivity. Further efforts toward extension to acyclic
substrates proved to be unsuccessful.
Although the detailed mechanism for this transformation is
unkown, a possible catalytic cycle is proposed based on
literature.17 As shown in Scheme 4, the catalytic cycle started
with oxidation of iodoarene with m-CPBA and HF, affording
fluoro-substituted tricoordinated intermediate 8.17a Then,
ligand exchange took place with the substrate β-ketoester 6a
to form O-bonded hypervalent iodine species 9,17b which
underwent 1,3-migration to afford intermediate 10.16,17b This
step is presumably the rate-determining and enantioselective
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wzheng@nju.edu.cn.
*E-mail: zjluhf1979@just.edu.cn.
ORCID
Wen-Hua Zheng: 0000-0002-0299-3953
Author Contributions
§Y.W. and H.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (21772086), the Fundamental Research
Funds for the Central Universities (020514380118), and
Nanjing University is gratefully acknowledged (W.-H.Z.).
C
DOI: 10.1021/acs.orglett.8b00711
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Letter
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DOI: 10.1021/acs.orglett.8b00711
Org. Lett. XXXX, XXX, XXX−XXX