Enantioselective Cobalt-Catalyzed Sequential Nazarov Cyclization/Electrophilic Fluorination: Access to Chiral α-Fluorocyclopentenones

Article abstract of DOI:10.1021/acs.orglett.8b01597

A newly designed thiazoline iminopyridine ligand for enantioselective cobalt-catalyzed sequential Nazarov cyclization/electrophilic fluorination was developed. Various chiral α-fluorocyclopentenones were prepared with good yields and diastereo- and enantioselectivities. Further derivatizations could be easily carried out to provide chiral cyclopentenols with three contiguous stereocenters. Furthermore, a direct deesterification of fluorinated products could afford chiral α-single fluorine-substituted cyclopentenones.

Full text of DOI:10.1021/acs.orglett.8b01597

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Cobalt-Catalyzed Sequential Nazarov Cyclization/
Electrophilic Fluorination: Access to Chiral α‑Fluorocyclopentenones
Heyi Zhang, Biao Cheng, and Zhan Lu*
Department of Chemistry, Zhejiang University, Hangzhou 310058, China
S
* Supporting Information
ABSTRACT: A newly designed thiazoline iminopyridine
ligand for enantioselective cobalt-catalyzed sequential Nazarov
cyclization/electrophilic fluorination was developed. Various
chiral α-fluorocyclopentenones were prepared with good
yields and diastereo- and enantioselectivities. Further
derivatizations could be easily carried out to provide chiral
cyclopentenols with three contiguous stereocenters. Further-
more, a direct deesterification of fluorinated products could
afford chiral α-single fluorine-substituted cyclopentenones.
Chiral cyclopentenone derivatives are extensively present in
rganic fluorine compounds currently play an increasingly
Oimportant role in pharmaceuticals, agrochemicals, and many bioactive compounds and also used as key intermediates
in asymmetric synthesis.7 Asymmetric Nazarov cyclization is
one of the most efficient methods for the construction of chiral
cyclopentenones.8 A sequential Nazarov cyclization/electro-
philic fluorination, reported by Ma and co-workers9 in 2007,
has been demonstrated as an efficient strategy to construct α-
fluoroindanones as well as three chiral examples. Later, Itoh
and co-workers10 developed a racemic iron-catalyzed sequen-
tial Nazarov cyclization/electrophilic fluorination to afford α-
fluorocyclopentenones in moderate to good yields (Scheme
1b). Recently, a direct strategy for synthesis of α-
fluorocyclopentenones without a carbon−fluorine stereo-
center, via a fluorine-directed and activated Nazarov
cyclization, was reported by Ichikawa and co-workers.11
Based on previously reported works, the development of
asymmetric sequential Nazarov cyclization/electrophilic fluo-
rination for the synthesis of chiral α-fluorocyclopentenones is
still highly desirable. Herein, we report an efficient
enantioselective cobalt-catalyzed sequential Nazarov cycliza-
tion/electrophilic fluorination to deliver chiral α-fluorocyclo-
pentenones with adjacent carbon- and fluorine-substituted
quaternary and tertiary stereocenters (Scheme 1b).
materials science1 due to the unique properties of the carbon−
fluorine bond.2 The development of efficient methods for
synthesis of chiral fluorinated molecules has become
increasingly attractive in recent years.3 In particular, the
construction of chiral carbon−fluorine quaternary stereo-
centers is not only fascinating but also still challenging.4
Since the first example was reported by Togni and co-workers,5
enantioselective fluorination of β-ketoesters, as one of the most
efficient strategies for the construction of carbon−fluorine
quaternary stereocenters, has been successfully achieved in
both chiral metal catalysis and organocatalysis4,6 (Scheme 1a).
Although asymmetric fluorinations of indanone and cyclo-
pentanone derivatives were widely investigated, to the best of
our knowledge, asymmetric fluorination of cyclopentenone
derivatives has not been reported.
Scheme 1. Construction of Chiral Carbon−Fluorine
Quaternary Stereocenters through Fluorination of β-
Ketoesters
At the beginning of our investigation, we employed α-methyl
ester divinyl ketone 1a as a model substrate and NFSI as the
fluorinating agent for sequential Nazarov cyclization/electro-
philic fluorination in the presence of OIP·Ni(ClO4)2·3H2O
which was the best catalyst for our previous asymmetric
sequential Nazarov reaction.12 To our delight, the reaction
proceeded quantitatively to afford desired product 2a, albeit
with moderate enantioselectivity (72% ee) (Table 1, entry 1).
We envisioned that a more electron-rich ligand might display
unusual catalytic selectivities and thiazoline could be an
Received: May 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01597
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimizations
Scheme 3. Substrate Scope
b
b
c
entry
cat.
2a (%)
3a/4a/1 (%)
ee of 2a (%)
1
2
3
4
5
[OIP-Ni]
[TIP-Ni]
[TIP-Co]
[TIP-Co]
[TIP-Co]
[TIP-Co]
[TIP-Co]
>99
93
98
96
77
−/−/−
2/3/−
−/2/−
−/4/−
15/−/6
−/2/−
2/4/−
72
94
94
92
92
82
96
d
e
f
6
7
97
94(93)
g
a
Reaction conditions: 1a (0.2 mmol), NFSI (0.3 mmol), and cat. (10
mol %) were dissolved in solvent and stirred for 15 h at 80 °C.
Compound 2a was obtained with excellent diastereoselectivity (>20/
b
1
1). Determined by H NMR analysis using TMSPh as an internal
c
standard. Isolated yield in the parentheses. Determined by chiral
HPLC analysis. Toluene. CH2Cl2 at 60 °C. 1,2-DCE. 7.5 mol %
cat. and 1.1 equiv of NFSI with 0.5 mmol scale.
d
e
f
g
alternative of oxazoline to form a more electron-rich thiazoline
iminopyridine (TIP) ligand. The TIP ligand could be
conveniently synthesized using a one-step reaction of OIP
ligand with P2S5 (Scheme 2).13 In addition, the corresponding
a
Standard conditions: 1 (0.50 mmol), NFSI (0.55 mmol), and [TIP-
Co] (7.5 mol %) were dissolved in PhCl and heated to 80 °C for 15
h; products 2 were obtained with excellent diastereoselectivity (>20/
1); isolated yields after column chromatography; ee was determined
Scheme 2. Synthesis and Structure Analysis of Thiazoline
Iminopyridine Complexes
b
by chiral HPLC analysis. 1 (0.55 mmol) and NFSI (0.50 mmol)
were used. 24 h. After recrystallization.
c
d
substituents on the R3 position were well tolerated regardless
of the position of the substituents (ortho, meta, or para) and
their electronic properties to furnish the corresponding
products 2b−j in 91−96% yields and 81−97% ee. Notably,
electron-withdrawing groups on aryl groups, such as amide,
nitro, and cyano, delivered 2k−m with slightly lower ee values.
Next, the substituents on R2 were explored and the results
demonstrated that an aryl ring with an electron-donating group
(2o) was more suitable for this asymmetric transformation
than one with an electron-withdrawing group (2n). When
compared with 2a, other alkyl esters substituted substrates had
no effect on yield. However, a deleterious effect on the
enantioselectivity was observed (2p−r) especially with the
more bulky isopropyl ester (2q). In the case of phenyl
substitution on the R1 position, both yield and enantiose-
lectivity were reduced (2s). Interestingly, 2s with 94% ee could
be obtained after recrystallization from petroleum ether and
dichloromethane. In addition, polycycle and heterocycles, such
as 2-naphthyl, 2-thienyl, and 3-pyridyl groups, were also well
tolerated (2t−w). It is worth noting that substrates bearing
cyclohexyl and ethyl groups could afford 2x and 2y in
moderate yields with 73% ee and 44% ee, respectively. The
absolute configuration of the fluorinated products was
determined by the X-ray diffraction analysis of 2f (CCDC
1832033).
metal perchlorate complexes were prepared easily and
determined by X-ray diffraction analysis (TIP·M(ClO4)2·
3H2O: CCDC 1812597 for [Ni] and CCDC 1817973 for
[Co]) (Scheme 2). When using the TIP·Ni(ClO4)2·3H2O
instead of OIP-nickel complex, fortunately, the reaction
afforded 2a in 93% yield with 94% ee (Table 1, entry 2).
The cobalt catalyst displayed higher reactivity than the nickel
catalyst (entry 3). Further screening of other solvents gave no
better results (entries 4−6). It is noteworthy that the
fluorinated product 2a could be obtained in 93% isolated
yield with 96% ee using a 7.5% loading of catalyst and 1.1
equiv of NFSI when scaled up to 0.5 mmol (entry 7).
Under the optimal reaction conditions, we evaluated divinyl
ketones with various substituents (Scheme 3). Various aryl
B
DOI: 10.1021/acs.orglett.8b01597
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To demonstrate the synthetic potential of this asymmetric
sequential reaction, gram scale reaction of 1a was carried out to
afford 2a in 95% yield with 93% ee (Scheme 4). The more
deliver chiral α-single fluorine substituted cyclopentenones.
Further studies on newly designed ligands for asymmetric
sequential reactions are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Gram Scale Reaction and Further Derivatizations
of 2a
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01597.
Experimental details, characterization data of all
1
compounds, and copies of H and 13C NMR spectra
(PDF)
Accession Codes
CCDC 1812597, 1817973, and 1832033 contain 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.
enantioenriched (>99% ee) 2a can be obtained after
recrystallization. Next, the chiral fluorinated product 2a
could undergo direct reduction of the β-ketone ester group
and nucleophilic addition of a carbonyl group to construct
chiral cyclopentenols 5−7a with three contiguous stereo-
centers (Scheme 4). Although a direct highly enantioselective
α-fluorination of cyclic ketones has been achieved by
MacMillan and co-workers,14 the highly enantioselective α-
fluorination of cyclopentanone (88% ee) is still a challenge.
Under reflux in a solution of sulfuric acid, α-fluorocyclopente-
nones 8a and 9a were obtained from 2a in two separable
diastereoisomers with excellent enantioselectivity (Scheme 4).
To elucidate the stereochemical course of this sequential
process, the reaction of 1a without NFSI under the standard
reaction conditions was first conducted (eq 1). Compound 3a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luzhan@zju.edu.cn.
ORCID
Zhan Lu: 0000-0002-3069-079X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(21772171, 21472162).
■
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DOI: 10.1021/acs.orglett.8b01597
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