Asymmetric Epoxidation of 1,4-Naphthoquinones Catalyzed by Guanidine-Urea Bifunctional Organocatalyst

Article abstract of DOI:10.1021/acs.orglett.8b00641

An enantioselective nucleophilic epoxidation of 2-substituted 1,4-naphthoquinones in the presence of a newly developed guanidine-bisurea bifunctional organocatalyst with tert-butyl hydroperoxide (TBHP) as an oxidant is presented. 1,4-Naphthoquinones bearing substituents at C6, C7, and C2 were available for the reaction, and the corresponding epoxides were obtained with 88:12-95:5 er in 71-98% yields. DFT calculations indicated that substituents at C2 and C6 in the terminal Ar group of the catalyst 9k play a key role in controlling the stereochemical outcome.

Full text of DOI:10.1021/acs.orglett.8b00641

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Epoxidation of 1,4-Naphthoquinones Catalyzed by
Guanidine−Urea Bifunctional Organocatalyst
Masaki Kawaguchi,†,§ Katsuhiro Nakano,‡,§ Keisuke Hosoya,† Tatsuya Orihara,† Masahiro Yamanaka,*,‡
Minami Odagi,*,† and Kazuo Nagasawa*,†
†Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei city,
184-8588, Tokyo, Japan
‡Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1, Nishi-Ikebukuro,
Toshima-ku, 171-8501, Tokyo, Japan
S
* Supporting Information
ABSTRACT: An enantioselective nucleophilic epoxidation of 2-substituted 1,4-naphthoquinones in the presence of a newly
developed guanidine−bisurea bifunctional organocatalyst with tert-butyl hydroperoxide (TBHP) as an oxidant is presented. 1,4-
Naphthoquinones bearing substituents at C6, C7, and C2 were available for the reaction, and the corresponding epoxides were
obtained with 88:12−95:5 er in 71−98% yields. DFT calculations indicated that substituents at C2 and C6 in the terminal Ar
group of the catalyst 9k play a key role in controlling the stereochemical outcome.
poxide is a valuable functional group in synthetic
1
Eintermediates due to its high reactivity.
In addition,
epoxy structures are seen in many biologically active natural
products, as well as pharmaceuticals.2 Thus, asymmetric
epoxidation has been widely explored. An important landmark
was the Katsuki−Sharpless asymmetric epoxidation for allylic
alcohols.3 In this reaction, a hydroxyl group in the allylic
alcohol serves as a directing group for the construction of the
asymmetric environment by complexation with chiral tartrate
and Ti(Oi-Pr)4.4 Among the various types of asymmetric
epoxidation reactions,5 epoxidation of electron-deficient enones
or enoates with nucleophilic chiral oxidants or oxidants in the
presence of a chiral catalyst has also been energetically
Figure 1. Structures of bioactive molecules containing a naphthoqui-
none epoxide motif.
explored. The carbonyl group in the electron-deficient olefin
usually serves as a directing group to control the
enantioselectivity of epoxidation. Nevertheless, quinones
1,4-naphthoquinones (4a) as substrates, and the conditions
with a stoichiometric amount of chiral hydroperoxide or
oxidants with a chiral organocatalyst have been reported.8−11
To date, the best enantioselectivity for 4a was reported by
Berkessel and co-workers using sodium hypochlorite as an
oxidant in the presence of quinuclidine-derived phase-transfer
remain challenging substrates for asymmetric epoxidation,
because of their highly symmetric and planar structures with
two carbonyl groups, so that it is difficult to differentiate the si-
and re-faces of the olefins with chiral oxidants or catalysts. In
particular, 1,4-naphthoquinone epoxides are important syn-
thetic intermediates for biologically active molecules, such as
A80915G (1),7c,h fluostatin C (2),7f,g and nanaomycin E (3)7a
(Figure 1).6,7 Currently, asymmetric epoxidation of 1,4-
naphthoquinones has been mainly explored with 2-methyl-
Received: February 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00641
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Letter
catalyst 6. They obtained epoxide 5a with 93:7 er in 73% yield
(Scheme 1a).11f
Table 1. Optimization of the Structure of Catalyst 9 for
Asymmetric Epoxidation of 4a
a
Scheme 1. (a) Enantioselective Epoxidation of 2-Methyl-1,4-
naphthoquinone (4a) Reported by Berkessel et al.; (b) Our
Previous Work on Enantioselective Epoxidation of Chalcone
(7) in the Presence of 9a
b
c
entry
9
R
Ar
yield (%)
er
1
9a
9b
9c
9d
9e
9f
Bn
Me
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
3,5-F2-C6H3
87
84
70
94
92
92
99
93
98
98
93
66:34
66:34
55:45
70:30
70:30
76:24
72:28
71:29
65:35
88:12
90:10
2
3
4
5
6
3,5-(OMe)2-C6H3
2-CF3-C6H4
7
9g
9h
9i
8
3-CF3-C6H4
9
4-CF3-C6H4
10
11
9j
2,4,6-Br3-C6H2
2,4,6-Cl3-C6H2
9k
a
Reaction conditions: 4a (0.1 mmol), TBHP (0.5 mmol), and NaOH
(0.05 mmol) in the presence of 9 (5 μmol) in toluene/H2O (1 mL/0.1
b
c
mL) at 0 °C. Yield of isolated product. Determined by HPLC
analysis using a chiral stationary phase.
and 11). Thus, we focused on the catalyst 9k for the reaction
and further investigated the reaction conditions.
Our group has reported a series of guanidine−bis(thio)urea
bifunctional organocatalysts.12 We previously applied catalyst
9a to the asymmetric nucleophilic epoxidation of chalcones and
obtained high enantioselectivity and high yield (Scheme 1b).13
Under the conditions used, the interactions of the guanidine
and urea groups with chalcones and hydrogen peroxide were
proposed to fix the transition state in an optimum three-
dimensional structure for the nucleophilic epoxidation reaction.
In the present work, we applied the guanidine−bisurea
bifunctional organocatalyst 9 for asymmetric epoxidation of 2-
substituted 1,4-naphthoquinones 4. The transition state of the
epoxidation reaction catalyzed by 9 was also investigated by
means of DFT calculations.
We initially attempted structural optimization of the catalyst
9 for asymmetric epoxidation of 4a in the presence of tert-butyl
hydroperoxide (TBHP) as an oxidant and sodium hydroxide as
a base under toluene−H2O biphasic conditions at 0 °C (Table
1).13 Under these conditions, the R and Ar groups in 9 were
varied. First, the influence of the R group was examined by
varying it from benzyl to methyl, isopropyl, and phenyl groups
(entries 1−4, respectively). We found that catalyst 9d with the
phenyl group was most effective, and 5a was obtained with
70:30 er in 94% yield. Next, the effect of the Ar group in the
catalyst 9d was investigated. The enantioselectivity was hardly
affected by changing the CF3 group to a F or electron-donating
OMe group. In addition, changing the substitution position of
the CF3 group among 2, 3, or 4 did not affect the
enantioselectivity (entries 7−9). On the other hand, tribromo
or trichloro substitution of the Ar group had a marked influence
on the enantioselectivity, and 5a with 88:12 and 90:10 er was
obtained, respectively, and without loss of reactivity (entries 10
We examined the base in the presence of catalyst 9k (Table
2, entries 1−6). Among the bases we investigated, none had a
significant influence on the enantioselectivity, with the
exception of DBU, which provided 5a with 75:25 er. Next,
the solvent was varied. Dichloromethane or chloroform did not
affect the enantioselectivity. On the other hand, ethers were
effective, and 95:5 and 94:6 er were observed with tert-butyl
methyl ether and cyclopentyl methyl ether (CPME),
respectively. These reactions proceeded in high yields under
biphasic solvent conditions with H2O (entries 9 and 11).14 To
demonstrate the practical synthetic utility, a 1 mmol scale
reaction was carried out (entry 12).
Under the optimal conditions (Table 2, entry 9), we next
examined the substrate scope (Scheme 2). The substrates with
a methoxy or chloro substituent at C6 gave the corresponding
5b and 5c with 92:8 and 94:6 er in 90% and 97% yields,
respectively. Both electron-donating and -withdrawing groups
at C7 were tolerated, and epoxides 5d−5f were obtained with
91:9−92:8 er in 71−93% yields. This asymmetric epoxidation
was applicable to compounds with n-propyl, i-butyl, i-propyl,
benzyl, 4-methylbenzyl, and 4-chlorobenzyl groups at C2,
affording the corresponding epoxides 5g−5l with 85:15−94:6
er in 76−96% yields.
To elucidate the origin of the high enantioselectivity in the
guanidine−bisurea-catalyzed asymmetric epoxidation reaction,
DFT calculations were conducted.15 The epoxidation of
electron-deficient olefins with peroxides under basic conditions
(Weitz−Scheffer epoxidation) is generally agreed to proceed
through a stepwise mechanism.16 In the guanidine−bisurea-
catalyzed asymmetric epoxidation of 4a using TBHP, the first
addition of the peroxide anion (TSadd) is energetically more
B
DOI: 10.1021/acs.orglett.8b00641
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
favored than the second cyclization step (elimination of the
alkoxide anion, TScy) (Scheme 3; details are shown in Figure
Table 2. Influences of Base and Solvent on the Asymmetric
Epoxidation of 4a in the Presence of 9k
a
Scheme 3. Proposed Reaction Mechanism, Based on DFT
Calculation
b
c
entry
base
solvent
time (h)
yield (%)
er
1
NaOH
LiOH
KOH
DBU
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
3.5
3
93
94
97
81
80
88
88
89
98
93
99
89
90:10
90:10
90:10
75:25
90:10
90:10
91:9
2
3
3
4
1.5
5
5
Et3N
6
K2CO3
KOH
KOH
KOH
KOH
KOH
KOH
2.5
7
7
8
7
91:9
9
t-BuOMe
i-Pr2O
0.5
1.5
0.5
4
95:5
10
11
92:8
CPME
94:6
d
12
t-BuOMe
94:6
a
Reaction conditions: 4a (0.1 mmol), TBHP (0.5 mmol), and base
(0.05 mmol) in the presence of 9k (5 μmol) in solvent/H2O (1 mL/
b
c
S1). An induced-fit-type structural change of the guanidine−
bisurea catalyst efficiently holds 4a and TBHP via hydrogen
bonding networks through the sequential addition/cyclization
process.17
0.1 mL) at 0 °C. Yield of isolated product. Determined by HPLC
analysis using a chiral stationary phase. Reaction was carried out on 1
d
mmol scale for 4a.
Focusing on the rate- and stereodetermining cyclization step,
we also obtained deep insight into the stereocontrol mechanism
for the asymmetric induction by comparing four diastereomeric
TSs corresponding to regioselectivity (TS-a, TS-b) and facial
selectivity (Si-face, TS-1; Re-face, TS-2) for Ar = 2,4,6-Cl3C6H2
and Ph (Figure 2, Figure S2). The TS-a tends to be more stable
than TS-b due to the steric repulsion between the methyl group
in 4a and the urea side chain of the catalyst. In the case of Ar =
2,4,6-Cl3C6H2, TS-a1 is more stable than TS-a2. Exchange of
2,4,6-Cl3C6H2 with Ph (as a model for 4- or 3,5-substituted Ar
group) considerably decreased the energy difference between
the diastereomeric TSs (TS-a1* and TS-a2*). These computa-
tional results are qualitatively consistent with the experimen-
tally observed enantiomer ratio values. To clarify the energy
difference between TS-a1 and TS-a2, structural and energetic
features of these TS models were investigated in detail. In both
TS-a1 and TS-a2, the S-shaped catalyst constructs similar
hydrogen-bonding networks with 4a and the peroxide anion
(a−f in Figure 2a). Whereas three NH residues of the
guanidinium/urea groups coordinate with one carbonyl group
of 4a (a−c), two NH residues of the other urea group hold the
peroxo moiety in place via multiple hydrogen bonds (d−f). An
intramolecular hydrogen bond (i in TS-a1) between the
noncoordinated NH residue of the guanidinium group and a Cl
atom of the 2,4,6-Cl3C6H2 group is seen only in TS-a1. The
aromatic ring moiety of 4a induces significant conformational
changes of the catalyst through a relay of sterically repulsive
interactions along the Ph (colored in orange, Figure 2a) and
2,4,6-Cl3C6H2 groups in TS-a2. The terminal 2,4,6-Cl3C6H2
group is kicked out by the conformationally changed Ph group
to a position far from the NH residue of the guanidinium group
in TS-a2. Consequently, the intramolecular NH···Cl hydrogen
Scheme 2. Substrate Scope for the Asymmetric Epoxidation
of 4 under the Optimized Conditions
a
Reaction was carried out at −10 °C with 10 mol % of 9k.
C
DOI: 10.1021/acs.orglett.8b00641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. 3D models and relative energies (kcal/mol) of (a) TS-a1 and TS-a2 (Ar = 2,4,6-Cl3C6H2, catalyst moieties are highlighted in green) and
(b) TS-a1* and TS-a2* (Ar = Ph). The relative electronic energies at the B3LYP/6-31G* and B3LYP-D3/6-31+G** (italics) levels and the relative
Gibbs free energies (underlined) at the B3LYP/6-31G* level are shown in parentheses. Bond lengths are in Å.
ORCID
bond is completely lacking in TS-a1* and TS-a2*, albeit with
no change in the gross structure or the hydrogen-bonding
network between 4a and the catalyst (Figure 2b). Therefore,
the arrangement of the terminal 2,4,6-Cl3C6H2 group plays a
key role in determining the stability of the TS. The TS-a1 is
mainly stabilized by the intramolecular NH···Cl hydrogen bond
in the catalyst (see also the distortion/interaction analysis in
Figure S3).
In conclusion, we have developed an enantioselective
nucleophilic epoxidation of 2-substituted 1,4-naphthoquinones
with TBHP in the presence of our newly developed guanidine−
bisurea bifunctional organocatalyst. Various substituents at C6
and C7, as well as C2, are tolerated, and the corresponding
epoxides were obtained with 85:15−95:5 er in 71−98% yields.
DFT calculations revealed that substituents at C2 and C6 in the
terminal Ar group of the catalyst 9k are key players in
controlling the stereochemical outcome.
Masahiro Yamanaka: 0000-0001-7978-620X
Kazuo Nagasawa: 0000-0002-0437-948X
Author Contributions
§M.K. and K.N. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.N. thanks the Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” (No. 23105013) and “Middle Molecular
Strategy” (No. JP16H01134) from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT), KAKENHI
Grant Number JP26282214, and the A3-foresight program.
M.O. thanks the Japan Society for the Promotion of Science
(JSPS), KAKENHI Grant Number 16K17897, JSPS for a
fellowship (No. 201506486) and The Japan Science Society for
a Sasakawa Scientific Research Grant. M.Y. thanks MEXT,
KAKENHI Grant Number 17KT0011.
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.8b00641.
REFERENCES
■
Experimental procedures and detail of the optimization
reaction conditions; characterization data for all new
compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: myamanaka@rikkyo.ac.jp.
*E-mail: odagi@cc.tuat.ac.jp.
*E-mail: knaga@cc.tuat.ac.jp.
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