Efficient Enantioselective Synthesis of Oxahelicenes Using Redox/Acid Cooperative Catalysts

Article abstract of DOI:10.1021/jacs.6b07424

An efficient and enantioselective synthesis of oxa[9]helicenes has been established via vanadium(V)-catalyzed oxidative coupling/intramolecular cyclization of polycyclic phenols. A newly developed vanadium complex cooperatively functions as both a redox and Lewis acid catalyst to promote the present sequential reaction and afford oxa[9]helicenes in good yields with up to 94% ee.

Full text of DOI:10.1021/jacs.6b07424

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Communication
Efficient Enantioselective Synthesis of Oxahelicenes
Using Redox/Acid Cooperative Catalysts
Makoto Sako, Yoshiki Takeuchi, Tetsuya Tsujihara, Junpei
Kodera, Tomikazu Kawano, Shinobu Takizawa, and Hiroaki Sasai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07424 • Publication Date (Web): 30 Aug 2016
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Efficient Enantioselective Synthesis of Oxahelicenes Using
Redox/Acid Cooperative Catalysts
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Makoto Sako,† Yoshiki Takeuchi,† Tetsuya Tsujihara,‡ Junpei Kodera,† Tomikazu Kawano,‡ Shinobu
Takizawa,*,† and Hiroaki Sasai*,†
†The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibarakiꢀshi, Osaka 567ꢀ0047,
Japan
‡Department of Medicinal and Organic Chemistry, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028ꢀ3694,
Japan
Supporting Information Placeholder
including, for example, epoxidation,8f sulfoxidation,8g the
ABSTRACT: An efficient and enantioselective synthesis of
oxidative coupling of 2ꢀnaphthols,8hꢀi and the oxidation of αꢀ
oxa[9]helicenes has been established via vanadium(V)ꢀcatalyzed
hydroxy carbonyl compounds.8j In addition, the Lewis acidity of
oxidative coupling/intramolecular cyclization of polycyclic
vanadium complexes9 can be used to promote Diels–Alder
phenols. A newly developed vanadium complex cooperatively
reactions,9a cyanations,9b the ringꢀopening of mesoꢀepoxides,9c
functions as both a redox and Lewis acid catalyst to promote the
present sequential reaction and afford oxa[9]helicenes in good
and Friedel–Craftsꢀtype reactions.9d However, there are few
reports describing the cooperative effect of these two properties in
vanadiumꢀcatalyzed sequential reactions.10 The enantioselective
sequential reaction using a chiral vanadium complex with tertꢀ
butylhydroperoxide as the primary oxidant was first reported by
Toste10a in 2006 with further contributions by Liu10b and You.10b,c
These groups succeeded in the development of both epoxidation
reactions and ringꢀopening cascades. As part of our effort to
explore chiral vanadium catalysis,9d,11 we were interested in
designing novel vanadiumꢀmediated sequential reactions to access
important structural motifs. We assumed that if the chiral
vanadium complex functioned as both a redox and Lewis acid
catalyst for the coupling of 2ꢀhydroxybenzo[c]phenanthrenes (1),
oxa[9]helicenes (2) would be obtained in a single operation via
aerobic oxidative coupling and subsequent Lewis acidꢀmediated
yields with up to 94% ee.
Helicenes are polycyclic aromatic compounds with nonplanar
screwꢀshaped skeletons formed from orthoꢀfused benzene or other
aromatic rings. Optically active helicenes and other related helical
molecules have received considerable attention as a result of their
high potential1 as chiral ligands,1a auxiliaries,1b organocatalysts,1c
liquid crystals,1d,e and molecular motors.1f Helicene derivatives
have classically been synthesized via photocyclization of stilbene
units followed by dehydrogenation.1g,2 This method generally
affords trans/cis isomers and is difficult to apply to the
asymmetric synthesis of helicene derivatives. Since Starý and
Stará reported a synthesis of heliceneꢀlike molecules using the
transition metalꢀcatalyzed [2+2+2] cycloadditions of alkynes,3a
cycloaddition methodologies are principally utilized for the
construction of helicene and heliceneꢀlike molecules;3 however,
syntheses of heterohelicenes, which have at least one
heteroaromatic ring in the helical chain, and oxahelicenes based
on furan rings in particular, are still scarce. In 2005, Nozaki
reported the preparation of an optically active oxa[7]helicene via
the oxidative coupling of phenol derivatives catalyzed by an
achiral Cu complex followed by the optical resolution of the
coupling product and Pdꢀcatalyzed intramolecular cyclization.4
Recently, Karikomi5 and Bedekar6 independently reported that
oxa[9 or 11]helicene derivatives could be synthesized from πꢀ
expanded phenol derivatives in a few steps. Although the
construction of oxahelicenes via oxidative coupling has been
Scheme 1. Synthesis of oxahelicenes
intramolecular cyclization (Scheme 1).
achieved, there is no report detailing
a catalytic and
We initially tested the reaction of 1a (R = H)12 with the chiral
dinuclear vanadium complex (Ra,S,S)ꢀ5, which efficiently
catalyzes the enantioselective oxidative coupling reaction of 2ꢀ
naphthols.11b Among the reaction conditions screened (solvent,
temperature, and coꢀoxidant; see Table S1, ESI), we found that
the desired oxa[9]helicene 2a was formed in 81% yield with 58%
ee at 60 °C in CCl4 under a molecular oxygen atmosphere (Table
enantioselective preparation of their derivatives to the best of our
knowledge.
Vanadium catalysis is intriguing from an environmental
viewpoint because of the abundant natural availability of
vanadium as well as the relatively low toxicity of this metal
compared with other heavy metals.7 The redox characteristics of
vanadium complexes have been utilized for asymmetric reactions8
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1, entry 1). Some starting material 1a remained after the reaction
sequential process. The reaction employing catalyst (S)ꢀ6, which
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period but no diol 3a and/or quinone 4a was detected. During
further investigation of suitable vanadium complexes, we found
that the mononuclear vanadium complex (S)ꢀ6 also promoted this
possesses a naphthyl skeleton, yielded 2a in 61% yield with 19%
ee (entry 2); catalysts (Ra,S)ꢀ7 and (Ra,S)ꢀ8, which both bear a
binaphthyl unit, resulted in an improved yield and ee of helicene
2a (entries 3 and 4). Catalyst (Ra,S)ꢀ9, which has a free hydroxy
group on the binaphthyl unit, increased the chemical yield of 2a
without a decrease in the ee (87% yield, 58% ee, entry 5). The
phenolic hydroxy group in the catalyst could cooperatively
activate of 1a with the vanadium metal to accelerate the present
sequential reaction.13 The diastereomeric complex (Sa,S)ꢀ9 was
found to be a mismatched catalyst, affording 2a with lower
enantioselectivity (entry 6). Catalyst (Ra,S)ꢀ10, having a benzyl
group instead of a tert-butyl group on the amino acid unit, did not
show any improvement (entry 7). Among the catalysts that were
screened, the presence of a substituent at the 3' position of the
binaphthyl unit proved effective for the improvement of
enantioselectivity. The phenylꢀsubstituted catalyst (Ra,S)ꢀ11
afforded 2a in 86% yield with 66% ee (entry 8). This result
prompted us to examine the effect of substituents at the 3' position
of the binaphthyl moiety. The 3,5ꢀdimethylphenylꢀsubstituted
catalyst (Ra,S)ꢀ12 increased the chemical yield and ee to 95% and
75%, respectively, (entry 9), while the 9ꢀanthrylꢀsubstituted
catalyst (Ra,S)ꢀ13 resulted in a decreased yield and ee, probably as
the result of steric hindrance between the substituents (entry 10).
When the 3,5ꢀdiphenylphenylꢀsubstituted catalyst (Ra,S)ꢀ14 was
employed, 2a was obtained in quantitative yield with 75% ee
(entry 11). Finally, 2a was obtained in 95% yield with 78% ee in
the reaction that employed 10 mol% of catalyst (Ra,S)ꢀ14 at 50 °C
(entry 12). Furthermore, optically pure 2a was readily accessible
by single recrystallization of the enantioenriched product from
CH2Cl2 and hexane. The optical rotation value of optically pure
2a showed a characteristic value, ꢀαꢁꢃꢂꢄ = −2647 (c 0.32, CHCl3).
Xꢀray crystallographic analysis of 2a unambiguously
demonstrated its helical structure, and the absolute configuration
Table 1. Screening of chiral vanadium complexesa
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entry
1d
2
Catalyst
(Ra,S,S)ꢀ5
(S)ꢀ6
yield (%)b
ee (%)c
58
81
61
71
72
87
91
90
86
95
52
99
95
19
3
(Ra,S)ꢀ7
(Ra,S)ꢀ8
(Ra,S)ꢀ9
(Sa,S)ꢀ9
60
4
58
5
58
6
41
7
(Ra,S)ꢀ10
(Ra,S)ꢀ11
(Ra,S)ꢀ12
(Ra,S)ꢀ13
(Ra,S)ꢀ14
(Ra,S)ꢀ14
41
8
66
9
75
10
11
12e
42
75
78 (99)f
aThe reaction of 1a (0.04 mmol) with 10 mol% of
vanadium complex (0.004 mmol) was carried out in CCl4
(0.2 mL) at 60 °C under O2 (1 atm). bYields were
determined by 1H NMR spectroscopy using 1,3,5ꢀ
trimethoxybenzene as an internal standard. cees were
determined using HPLC (DAICEL CHIRALPAK ADꢀH). d5
mol% of (Ra,S,S)ꢀ5 (0.002 mmol) for 72 h. eAt 50 °C. fAfter
a single recrystallization.
Figure 1. Xꢀray structure of (M)ꢀoxa[9]helicene (2a) with
thermal ellipsoids at the 50% probability level. Hydrogen
atoms are omitted for clarity. Only one of the two independent
molecules present in the unit cell is shown.
of 2a was definitely determined to be M based on the Flack
parameter (Figure 1).
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Table 2. Substrate scope and limitationsa
Scheme 3. Plausible catalytic cycle
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Scheme 4. Oxidative heteroꢀcoupling of 1a with 1ga
aThe reaction of 1 (0.04 mmol) with 10 mol% of catalyst
(Ra,S)ꢀ14 (0.004 mmol) was carried out in CCl4 (0.2 mL) at
50 °C under O2 (1 atm) for 48 h. bYield of isolated product. ees
were determined by HPLC (DAICEL CHIRALPAK ADꢀH).
d
e
f
cFor 72 h. 94% NMR yield. At 60 °C for 72 h. 61% NMR
yield. gAt 60 °C with 10 mol% of TMSCl.
With the optimal conditions in hand, the substrate scope and
aThe reaction of 1a (0.02 mmol) and 1g (0.02 mmol) with
catalyst (Ra,S)ꢀ14 (0.004 mmol) was carried out in CCl4 (0.2
mL) at 50 °C under O2 (1 atm) for 72 h.
limitations of the reaction were investigated using analogs of 1
containing various substituents (Table 2). Phenylꢀ, pꢀtolylꢀ, and pꢀ
fluorophenylꢀsubstituted substrates (1b, 1c, and 1d, respectively)
were converted to the corresponding products 2b, 2c, and 2d in
good yields with ca. 50% ee. Alkylꢀsubstituted substrates, such as
those with methyl or hexyl groups at the 6 position, afforded
coupling products 2e and 2f in moderate yields with 88% and
76% ee, respectively. In the coupling reaction of the bromoꢀ
substituted substrate 1g at 60 °C for 72 h, the desired
dibrominated helicene 2g was obtained in 56% yield with 94% ee.
We next examined the effect of a substitution at the 9 to 12
positions on the terminal aromatic ring. The reaction of 1h
smoothly proceeded to provide 2h in 68% yield with 80% ee. In
contrast, substrate 1i showed low reactivity, affording 2i in only
32% yield with 30% ee. When 10 mol % of TMSCl8i was added
to the reaction of 1i at 60 °C, an improvement in both the yield
with a methyl group at the 12 position, did not form the desired
product probably as a result of steric hindrance during the
coupling.
To further demonstrate the introduction of substituents on
oxa[9]helicenes 2, several transformations were carried out
(Scheme 2). Oxa[9]helicene (2a) could be further modified by
regioselective bromination; bromination was conducted using
1.05 or 2.1 equivalents of pyridinium tribromide (PyHBr3) to
yield monoꢀ and dibrominated oxa[9]helicene 2k and 2l,
respectively, in good yields (Scheme 2a). Pdꢀcatalyzed Suzukiꢀ
Miyaura coupling of dibrominated oxa[9]helicene 2g with
phenylboronic acid (PhB(OH)2) smoothly proceeded to give 2b in
81% yield with a retention of the enantiomeric excess (Scheme
2b).
Scheme 2. Synthetic transformations
To gain an insight into the reaction mechanism, the reaction
order with respect to the vanadium catalyst was investigated by
calculating the initial rate of the reaction using 5, 10, or 15 mol%
catalyst loading; the reaction was found to be that of the first
order in catalyst (Ra,S)ꢀ14 (see ESI). This result rules out a dual
activation mechanism involving radical–radical coupling
mediated by two molecules of the vanadium complex.11,14 The
present oxidative coupling likely occurred through a radical–anion
coupling with one molecule of the vanadium complex.15
A
plausible catalytic cycle for the sequential synthesis of
oxa[9]helicenes is shown in Scheme 3. The reaction of the
mononuclear vanadium(V) complex (Ra,S)ꢀ14 with substrate 1a
generates an intermediate A. A then undergoes an intermolecular
coupling with another molecule of 1a after a single electron
and ee of 2i was observed (84% yield, 60% ee). The reaction of 1j,
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(1) Selected reports, see: (a) ligand: Aillard, P.; Voituriez, A.; Dova, D.;
transfer to a vanadium(V) species. This is followed by oxidation
of vanadium(IV) by O2 to form an intermediate B. Finally,
intramolecular cyclization assisted by the Lewis acidity of
vanadium(V) affords the desired product 2a and the intermediate
A is regenerated. It is likely that the hydroxy group on the
binaphthyl ligand in the vanadium complex increased the Lewis
acidity of vanadium metal through an intramolecular hydrogen
bond in intermediates A and B. When a racemic quinone
derivative 4a5a was treated with 10 mol% of catalyst (Ra,S)ꢀ14, 2a
was produced in racemic form with 71% conversion; the
remaining 4a was also racemic (Scheme 3). Kinetic resolution
was not observed in the reaction of 4a to yield 2a, which implies
that the enantioꢀdetermining step is the oxidative coupling step of
intermediate A to intermediate B. The quinone 4a might be
outside of the catalytic cycle and in an equilibrium with the
intermediate B. The radicalꢀanion coupling mechanism is also
supported by the fact that the treatment of both of electronꢀrich 1a
(0.02 mmol) and ꢀpoor 1g (0.02 mmol) by (Ra,S)ꢀ14 (0.004 mmol)
afforded a mixture of the oxa[9]helicenes (Scheme 4); heteroꢀ
coupling product 2ag (30% yield, 84% ee) and the homoꢀcoupling
products 2a (28% yield, 69% ee) and 2g (13% yield, 94% ee)
(Scheme 4) though the radical–radical coupling would
preferentially form homoꢀcoupling product 2a.14ꢀ16
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In conclusion, we have developed an efficient and
enantioselective sequential synthesis of oxa[9]helicenes catalyzed
by a newly developed chiral vanadium complex. In this process,
the vanadium complex works as both a redox and a Lewis acid
catalyst, allowing the sequential reaction via an oxidative
coupling/intramolecular cyclization sequence. Additional
investigations into the reaction mechanism and the substrate
generality in other heteroꢀcouplings are now in progress.
Furthermore, synthetic studies on other heterohelicenes containing
nitrogen, silicon, and/or sulfur are in process in our laboratory.
ASSOCIATED CONTENT
Supporting Information
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Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental procedures, spectroscopic data
Xꢀray crystallographic data for (M)ꢀ2a (CCDC
1493624)
AUTHOR INFORMATION
Corresponding Author
sasai@sanken.osakaꢀu.ac.jp
taki@sanken.osakaꢀu.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Numbers
JP16H01152 in Middle Molecular Strategy, The Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan Society for the Promotion of Science (JSPS), the CREST
project of the Japan Science and Technology Corporation (JST),
and JST Advance Catalytic Transformation Program for Carbon
Utilization (ACTꢀC). We acknowledge the technical staff of the
Comprehensive Analysis Center of ISIR, Osaka University
(Japan).
(9) Selected examples (pioneer work), see: (a) DielsꢀAlder reaction:
Togni, A. Organometallics, 1990, 9, 3106. (b) cyanation of
aldehydes: Belokon, Y. N.; North, M.; Parsons, T. Org. Lett. 2000,
2, 1617. (c) ringꢀopening of mesoꢀepoxides: Sun, J.; Dai, Z.; Yang,
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reaction: Takizawa, S.; Arteaga, F. A.; Yoshida, Y.; Kodera, J.;
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(16) Cyclic voltammetry was performed in CH2Cl2/MeCN (10 : 1, v/v) in
the presence of Bu4NPF6. ν = 100 mVsꢀ1, versus Fc/Fc+. E1a(ox)
1.04 V. E1g(ox) = 0.84 V.
=
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Table of Contents artwork
4
tBu
5
6
7
R
N
O
V
Single operation
R
O
O
Vnadium cat. (10 mol %)
OH
O
HO
8
9
1) Oxidative coupling
2) Intramolecular cyclization
Ph
O
OH
(Ra,S)-Vnadium cat.
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R
Ph
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