Organocatalytic Enantioselective Cycloetherifications Using a Cooperative Cation-Binding Catalyst

Article abstract of DOI:10.1021/acs.orglett.8b02240

A highly enantioselective cycloetherification strategy for the straightforward synthesis of enantioenriched tetrahydrofurans, tetrahydropyrans, and oxepanes using Song's cation-binding oligoEG catalyst and KF as the base is demonstrated. A wide range of ?

Full text of DOI:10.1021/acs.orglett.8b02240

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalytic Enantioselective Cycloetherifications Using a
Cooperative Cation-Binding Catalyst
Amol P. Jadhav,†,§ Jeong-A Oh,†,§ In-Soo Hwang,† Hailong Yan,‡ and Choong Eui Song*,†
†Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea
‡Innovative Drug Research Centre (IDRC), School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
S
* Supporting Information
ABSTRACT: A highly enantioselective cycloetherification strategy for the straightforward synthesis of enantioenriched
tetrahydrofurans, tetrahydropyrans, and oxepanes using Song’s cation-binding oligoEG catalyst and KF as the base is
demonstrated. A wide range of ε-, ζ-, and η-hydroxy-α,β-unsaturated ketones were cyclized to the corresponding five-, six-, and
seven-membered chiral oxacycles with high enantiopurity. This remarkably successful catalysis can be ascribed to systematic
cooperative cation-binding catalysis in a densely confined supramolecular chiral cage generated in situ from the chiral catalyst,
substrate, and KF.
THP rings.9 The catalytic asymmetric intramolecular haloether-
xacyclic frameworks are prominent scaffolds and have
Oattracted immense attention due to their widespread
ification strategy has been used to effectively access halogen-
containing chiral THF and THP rings.10 However, the synthesis
presence in natural products and bioactive compounds. Chiral
of chiral oxacycles through the direct cyclization of α,β-
unsaturated carbonyl substrates bearing a pendant nucleophilic
hydroxyl group (i.e., intramolecular oxa-Michael reactions) has
been rarely explored.11 For five- and six-membered cyclic ethers,
the rapid nature of a noncatalyzed intramolecular cyclization
event makes asymmetric oxycyclization reactions highly
challenging. For example, all attempts for the intramolecular
oxa-Michael reactions for the synthesis of chiral THFs with
chiral NHC catalysts have afforded almost racemic products (0−
11% ee) (Scheme 1, eq 1).11d Furthermore, the direct
construction of chiral large ring ethers such as seven- and
eight-membered cyclic ethers from acyclic precursors remains a
more challenging problem mainly because of the unfavorable
entropic factor. The probability of meeting both reactive sites for
the reaction would decrease as the chains get longer.12
tetrahydrofuran (THF) and tetrahydropyran (THP) subunits in
particular are abundant in several macrodiolides,1 acetogenins,2
C-glycosides,3 lignans4 and ionophores,5 macrolides,6 and
salinomycin and its derivatives.7 In addition, many polycyclic
marine natural products and terpenoids possess chiral seven-
membered oxepane moieties8 (Figure 1). Several methods have
been developed for the enantioselective synthesis of THF and
Given the importance of chiral oxacyclic compounds of
various ring sizes, developing a general and direct synthetic
method to access them is highly desirable. In order to effectively
transfer the chiral information from the catalyst during an
oxycyclization event, simultaneous activation of a pendant
hydroxyl group of terminal hydroxy-α,β-unsaturated ketones
(nucleophilic site) and their electrophilic β-carbon is an
essential condition. Thus, the use of catalysts capable of
Figure 1. Some natural and bioactive compounds containing chiral
five-, six-, and seven-membered oxacyclic frameworks.
Received: July 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
respectively. Excellent yields and enantioselectivity were
obtained with a variety of 2-substituted THFs and THPs.
Furthermore, this protocol was also successfully extended for
use in synthesizing more challenging highly enantioenriched 2-
substituted seven-membered oxacycles.
Scheme 1. Asymmetric Synthesis of Chiral Cyclic Ethers via
Catalytic Intramolecular Oxa-Michael Reactions
We initiated our investigation of the asymmetric cyclo-
etherification of (E)-6-hydroxy-1-phenylhex-2-en-1-one (2a)
with catalyst (R)-1a (15 mol %) in toluene at 0 °C to form the
chiral THF product 3a. In the absence of KF loading, the
reaction did not take place (Table 1, entry 1). However, in the
presence of KF (3 equiv), the desired intramolecular cyclization
proceeded smoothly, providing the desired product 3a in good
yield and good enantioselectivity (Table 1, entry 2). These
results strongly indicate that KF is necessary not only to promote
the cyclization of 2a but also to cooperate with Song’s chiral
oligoEG catalyst (R)-1 to generate a well-organized chiral
a
Table 1. Optimization of Reaction Conditions
cat.
KF
time
(h)
yield
b
ee
c
multipoint interactions in the reaction transition state via
hydrogen bonding and steric interactions would help ensure the
high enantioselectivity of resultant oxacycles. In this context,
Asano and Matsubara have reported the successful use of
bifunctional cinchona-derived thiourea catalysts for the syn-
thesis of five- and six-membered chiral cyclic ethers (THFs and
THPs) from ε- and ζ-hydroxy-α,β-unsaturated ketones,
respectively (Scheme 1, eq 2).13a,b Soon after, Zou and Zhao
also reported the successful intramolecular oxa-Michael
reactions to chiral THFs and THPs catalyzed by chiral
primary-secondary diamines (Scheme 1, eq 2).13c
Less than a decade ago, we developed easily accessible and
efficient multifunctional 1,1′-bi-2-naphthol (BINOL)-based
organocatalysts (Song’s oligoEGs 1, Scheme 1, eq 3)14,15
bearing polyether-tethered free phenol groups for asymmetric
cation-binding catalysis. Metal ions such as K+ coordinate with
the Lewis basic ether oxygen sites to generate a soluble chiral
anion in a confined chiral space. Moreover, terminal phenol
groups are capable of simultaneously activating the electrophile
by hydrogen bonding interaction, resulting in a well-organized
transition state. Several challenging catalytic asymmetric
reactions have been successfully accomplished using Song’s
chiral oligoEGs as an evolved cation-binding catalytic system
based on the above-described ambiphilic activation mecha-
nism.15 The ease of modulation and vast application potential of
this systematic cooperative hydrogen-bonding catalytic system
led us to explore challenging intramolecular cycloetherification
reactions using Song’s oligoEGs for the synthesis of
enantioenriched 2-substituted oxacycles.
entry
1
(mol %)
solvent
toluene
(equiv)
(%)
(%)
(R)-1a
(15)
(R)-1a
(15)
(R)-1b
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(15)
(R)-1a
(10)
(R)-1a (5) CH2Cl2
(R)-1a (1) CH2Cl2
−
24
24
15
24
24
20
20
168
72
16
20
24
28
25
n.r.
91
96
96
95
97
96
96
96
96
96
97
96
95
−
2
toluene
toluene
o-xylene
m-xylene
anisole
MTBE
THF
3
80
55
78
80
90
80
91
90
91
96
97
96
97
3
3
4
3
5
3
6
3
7
3
8
3
9
2-methyl
THF
3
10
11
12
13
14
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
1.2
0.5
0.3
0.5
15
16
0.5
0.5
26
100
98
96
97
95
a
The reactions were performed on a 0.2 mmol scale of 2a at 0 °C.
Isolated yield. Enantiomeric excess (ee) was determined through
HPLC analysis (see the Supporting Information). Anisole: methox-
ybenzene. MTBE: methyl-tert-butylether. THF: tetrahydrofuran. 2-
Methyl THF: 2-methyl-tetrahydrofuran. n.r.: no reaction.
b
c
Herein, we describe a Song chiral oligoEG catalyzed highly
enantioselective cycloetherification method for the synthesis of
chiral 2-substituted tetrahydrofurans and tetrahydropyrans from
the corresponding ε- and ζ-hydroxy-α,β-unsaturated ketones,
B
DOI: 10.1021/acs.orglett.8b02240
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
pocket for stereoinduction. Under the same conditions as those
of entry 2, the CF3-substituted catalyst (R)-1b provided only
moderate enantioselectivity (Table 1, entry 3). In further
experiments, different solvents were examined with catalyst (R)-
1a (15 mol %) and KF (3 equiv) (Table 1, entries 4−10). In
nonpolar solvents such as o-xylene and m-xylene, although we
observed almost quantitative formation of the cyclized product
3a, the enantioselectivity obtained was still unsatisfactory (Table
1, entries 4 and 5). Comparatively higher enantioselectivity (ee =
90%) for 3a was observed when anisole was used as a solvent
(Table 1, entry 6). Using ethereal solvents such as THF and 2-
methyl THF for the cyclization of 2a also resulted in high
enantioselectivity (ee = up to 91%), but the reactions proceeded
too slowly (72−168 h, Table 1, entries 8−9). Dichloromethane
proved to be the optimal choice in terms of reaction time (16 h)
and enantioselectivity (ee = 91%) (Table 1, entry 10). Thus, for
the further optimization of reaction conditions on KF loading,
CH2Cl2 was used as a solvent (Table 1, entries 11−13). It was
evident that a substoichiometric amount of KF was sufficient to
achieve both excellent conversion and enantioselectivity for the
cyclization of 2a (Table 1, entries 11−13). Enantioselectivity
was significantly increased up to 97% ee when reducing the KF
loading. Furthermore, we were also able to reduce the catalyst
loading of (R)-1a up to 5 mol % without compromising the
reaction time, yield, or enantioselectivity (Table 1, entry 15).
Excellent enantioselectivity (ee = 95%) was also obtained even
with a 1 mol % catalyst loading (Table 1, entry 16).
Scheme 2. Substrate Scope
With the optimized reaction conditions in hand (0.5 equiv of
KF and 5 mol % catalyst (R)-1a in CH2Cl2 at 0 °C), the
generality of our catalytic protocol was evaluated through
enantioselective cyclization of a range of enones (2, 4, and 6),
and these results are summarized in Scheme 2. Regardless of the
electronic and steric nature of the substituents on the aromatic
ring, the ε-hydroxy-α,β-unsaturated ketones 2b−2i were
smoothly cyclized to the corresponding 2-substituted THF
products 3b−3i with high yields and excellent ee’s (ee = up to
97%). An enone substituted by an alkyl group 2j was also
cyclized with excellent yield, but the enantioselectivity obtained
was moderate.16 Although the reactions were comparatively
slower, ζ-hydroxy-α,β-unsaturated ketones 4a−4c of varied
electronic nature also underwent the cycloetherification
reaction, producing the corresponding 2-substituted THPs
5a−5c with excellent yield and high enantioselectivity (ee = 87−
93%).16 To our delight, with increased catalytic loading of (R)-
1a (20 mol %) and by carrying out the reaction at room
temperature, the scope of the present protocol was successfully
extended to the synthesis of highly challenging seven-membered
2-substituted oxepanes 7a−7c with moderate yields and
moderate to good enantioselectivities from η-hydroxy-α,β-
unsaturated ketones 6a−6c.16 To the best of our knowledge,
this is the first successful preparation of chiral oxepane
derivatives via direct catalytic cyclization from the acyclic
precursors 6.17 However, an intramolecular oxa-Michael
reaction for the synthesis of eight-membered chiral cyclic ethers
did not occur. Perhaps, the high degree of ring strain and
unfavorable entropic factor precluded the formation of the ring.
Based on our previous reports regarding cation-binding
catalysis,15 a plausible reaction mechanism is illustrated in
Figure 2. First, the binding of catalyst (R)-1a to KF generates a
soluble chiral fluoride anion, which enhances the nucleophilicity
of terminal alcohols, 2, 4, and 6 through H---F hydrogen
bonding. Simultaneously, the acidic phenol moiety of the
BINOL backbone of (R)-1a activates the carbonyl group of α,β-
a
b
The reactions were carried out on a 0.25 mmol scale. The reaction
c
was carried out at 1 mmol scale. 20 mol % loading of catalyst (R)-1a
and reactions were run at 25 °C.
Figure 2. Plausible catalytic cycle.
unsaturated ketones. Subsequently, intramolecular oxa-Michael
addition proceeds with high enantioselectivity in the confined
chiral cage generated in situ through the coordination of KF with
the catalyst.
In conclusion, we have successfully developed an efficient
catalytic asymmetric method for the direct cycloetherification of
C
DOI: 10.1021/acs.orglett.8b02240
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Organic Letters
Letter
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ε-, ζ-, and η-hydroxy-α,β-unsaturated ketones using Song’s
chiral oligoEG as a cation-binding catalyst and KF as a base.
Highly useful cyclic ether skeletons such as 2-substituted THFs,
THPs, and oxepanes were obtained with excellent yields and
enantioselectivities via asymmetric intramolecular oxa-Michael
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02240.
■
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Experimental details and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s1673@skku.edu.
ORCID
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Hailong Yan: 0000-0003-3378-0237
Choong Eui Song: 0000-0001-9221-6789
Author Contributions
§A.P.J. and J.-A.O. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Korean Research Foundation
(Grant No: NRF-2017R1A2A1A05001214 and NRF-2016R1-
A4A1011451).
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DOI: 10.1021/acs.orglett.8b02240
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